Phase 1 Trial to Determine the Recommended Phase 2 Dose (RP2D) of M6620 (VX-970, Berzosertib) When Combined With Whole Brain Radiotherapy (WBRT) in Patients With Brain Metastases From Lung Cancer
Phase: PHASE1
Conditions: Metastatic Lung Neuroendocrine Neoplasm, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Lung Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

NCI Protocol #: 9952 
Local Protocol #: HP-00068292 
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i 
 
 
To: 
CTEP Protocol and Information Office 
From: 
Pranshu Mohindra, M.D., M.B.B.S., D.A.B.R  
Date: 
June 21, 2021 
Re: 
Amendment in response to Dr. Wu’s April 22, 2021 notice to investigators using 
M6620 (VX-970, berzosertib). 
 
SUMMARY OF CHANGES – Protocol 
 
I. In response to the Notice to Investigators dated 04/22/2021: 
# 
Section 
Comments 
1. 
5.3,      
8.1.1,  
Appendix C,  
ICD 
The purpose of the notice is to alert investigators of the change to the drug 
monograph and the Patient Drug Interactions Handout and Wallet Card for 
M6620 (VX-970, berzosertib). The following sections of the protocol should 
be amended to include the updated information or replaced in its entirety:  
• Potential Drug Interactions section under the Pharmaceutical Agent 
Information section of the protocol.  
• The Patient Selection and the General Concomitant Medication and 
Supportive Care Guidelines sections of the protocol.  
• The Patient Drug Interactions Handout and Wallet Card appendix in the 
protocol.  
• The agent name should be updated throughout the protocol and consent. 
PI Response: The relevant sections of the protocol have been updated 
and the agent name revised throughout. 
 
II. Changes requested by the PI: 
 
# 
Section 
Comments 
2. 
Header, 
Title Page 
Updated protocol version date. 
 
 
SUMMARY OF CHANGES – Consent Forms (Groups 1 and 2) 
 
# 
Section 
Comments 
3. 
Header 
Updated protocol version date. 
4. 
All 
Updated agent name throughout the consent as specified in change #1. 

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Phase 1 Trial to Determine the Recommended Phase 2 Dose (RP2D) of M6620 (VX‐970, 
berzosertib) When Combined with Whole Brain Radiotherapy (WBRT) in 
Patients with Brain Metastases from Lung Cancer  
 
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center LAO 
 
Principal Investigator: 
Pranshu Mohindra, M.D., M.B.B.S., D.A.B.R. ® 
Associate Professor, Department Of Radiation Oncology,  
University of Maryland School of Medicine, Baltimore 
22 South Greene Street, Room GGJ 35 
Baltimore, MD 21201 
Telephone: (410) 328-9155 
Telefax: (410) 328-5279 
Email: pmohindra@som.umaryland.edu  
 
 
Participating Organizations  
 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey 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-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
 
 

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Resubmission / Version 4 / May 23, 2016 
Resubmission / Amendment 1 / October 7, 2016 
Resubmission / Amendment 2 / November 23, 2016 
Resubmission / Amendment 3 / July 26, 2017 
Resubmission / Amendment 4 / July 2, 2018 
Amendment 5 / Version 1 / January 31, 2020 
Amendment 6 / Version 1 / July 7, 2020 
Amendment 7 / Version 1 / June 6, 2021 
 
 
 

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PROTOCOL SYNOPSIS 
Title: 
 Phase 1 Trial to Determine the Recommended Phase 2 Dose (RP2D) of  
M6620 (VX‐970) when Combined with Whole Brain Radiotherapy (WBRT)  
in Patients with Brain Metastases from Lung Cancer  
Study 
Objectives: 
Primary Objective: To determine the RP2D of twice weekly intravenous (i.v.) 
M6620 (VX-970, berzosertib) administered concurrent with conventionally 
fractionated whole brain radiotherapy (WBRT), with M6620 (VX-970, 
berzosertib) starting 18-30 hours after the first dose of radiation (but prior to the 
second fraction of radiation).   
 
Dose-limiting toxicities (DLTs) will be defined as any grade 3 or more non-
hematological toxicity requiring more than 5-day interruption in therapy or any 
grade 4 or higher hematological toxicity that is attributable to the M6620 (VX-
970, berzosertib) and/or whole brain radiotherapy. 
 
DLTs will be assessed from the day of the start of WBRT until 3 weeks post 
completion of WBRT. 
 
Secondary Objectives: 
• To estimate the incidence of ≥ Grade 3 delayed neurological toxicity at 2, 
4 and 6-months post-completion of WBRT (for patients without 
intracranial progression).  This will include testing for delayed-recall 
through Hopkins Verbal Learning Test-Revised (HVLT-R) and 
Functional Assessment of Cancer Therapy-Brain (FACT-BR) 
assessments. 
 
• To observe and record anti-tumor activity.   
 
o To estimate the radiological response rates (RR) at 6 months 
including bi-directional and volumetric measurements of lesion 
size.  All patient accrued in group 1 (except the first three dose-
levels) will be included in the imaging objective. 
 
o To estimate the intracranial 6-month progression-free survival 
(PFS). 
 
Exploratory/ Hypothesis generating objectives: 
• Group 1 (patients accrued beyond dose-level 3): Magnetic resonance 
imaging (MRI): Changes in dynamic susceptibility contrast enhancement 
(DSC-MRI) perfusion and mean apparent diffusion coefficient (ADC) 
measurements in diffusion-weighted magnetic resonance imaging (DWI) 
 
 

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• Group 2: Restricted to the University of Maryland only 
In an exploratory study involving a small cohort of 6 patients who are 
scheduled to undergo a craniotomy, a single dose of M6620 (VX-970, 
berzosertib) at the above-identified RP2D will be administered 2 to 4 
hours prior to the planned craniotomy.  The objective of this cohort is to 
measure plasma and CSF M6620 (VX-970, berzosertib) levels, tumor 
M6620 (VX-970, berzosertib) levels and pATR T1989, pCHK1 S345 and 
RAD51 multiplex foci. 
 
For patients with identifiable target lesion (other than the resected lesion): 
Changes in DSC-MRI perfusion and mean ADC measurements in DWI 
 
A parallel study at the PI’s institution would be conducted wherein fresh 
tumor biopsies from 12 matched control patients who are scheduled to 
undergo a craniotomy but not accrued to the proposed study will be 
collected as a separate IRB approved study for assessments of pATR 
T1989, pCHK1 S345 and RAD51 multiplex foci.  Expression of these 
markers will be compared with the data from 6 patients in the group 2 of 
the proposed study. 
 
Study 
Design: 
 
 
 
 
 

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Treatment 
Interventions 
M6620 (VX-970, berzosertib)  
Group 1: 
 
Dose Escalation Schedule 1 
Dose Level 
Dose of M6620 (VX-970, berzosertib) (mg) 
2 
Level 1 
50 mg twice weekly 
Level 2 
 100  mg twice weekly 
Level n 
Estimated using the EWOC algorithm,  
≤ 2 times the dose level (n-1)3  
Highest level 
800 mg twice weekly 4 
1.   Once enrollment at level one has been completed, the subsequent 
dose escalation will be based on the Bayesian adaptive design, 
Escalation With Overdose Control (EWOC) algorithm, with all 
DLT data from all tested dose levels being part of the data set for 
defining dose levels for new trial participants.  
2.   See Section 13.2.2 for special early stoppage and slow 
convergence scenarios  
3.   In case of no toxicities at prior levels the EWOC may escalate the 
dose quite rapidly.  As an added precaution, dose level n will not 
exceed the dose at level n-1 by more than a factor of 2, see 
section 13.2.2 for further details. 
4.   Highest dose-level may be increased if the MTD in the single 
agent 002 study turns out to be higher before the commencement 
of our phase I trial. 
 
WBRT will be allowed to start on any day from Monday through Thursday, with 

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• Intracranial  6-month PFS. 
 
 
Exploratory:  
• Group 1 (Patients accrued beyond dose level 3): Changes in DSC-MRI 
perfusion, mean ADC measurements in DWI 
 
• Group 2: Restricted to the University of Maryland only 
 
• Pharmacokinetic measurements: Intra-operative blood and CSF 
M6620 (VX-970, berzosertib) levels  and  craniotomy tumor 
specimen M6620 (VX-970, berzosertib) concentration  
• Biomarker (Pharmacodynamic) end-point: Percentage pATR T1989, 
pCHK1 S345and RAD51 multiplex in post-M6620 (VX-970, 
berzosertib) administration intra-cranial tumor tissue specimen   
• MRI end-points (For patients with identifiable target lesion, other 
than the resected lesion): Changes in DSC-MRI perfusion,  mean 
ADC measurements in DWI 
Sponsor: 
DCTD, NCI. 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS.................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................10 
1. 
OBJECTIVES ....................................................................................................................13 
1.1 
Primary Objectives .................................................................................................13 
1.2 
Secondary Objectives .............................................................................................13 
1.3 
Exploratory/ Hypothesis Generating Objectives ...................................................14 
2. 
BACKGROUND ...............................................................................................................14 
2.1 
Brain Metastases from Non‐Small Cell Lung Cancer (NSCLC) ...........................14 
2.2 
ATR and DNA Damage response ..........................................................................16 
2.3 
M6620 (VX-970, berzosertib) ............................... Error! Bookmark not defined. 
2.4 
Rationale ................................................................................................................24 
2.5 
Hypotheses .............................................................................................................25 
2.6 
Correlative Studies Background ............................................................................27 
2.7 
Role of Magnetic Resonance Imaging for Response Assessment in Brain 
Metastases ..............................................................................................................28 
2.8 
Relevance of Neurocognitive Testing for Whole Brain Radiotherapy 
Clinical Trials .........................................................................................................30 
3. 
PATIENT SELECTION ....................................................................................................31 
3.1 
Eligibility Criteria ..................................................................................................31 
3.2 
Exclusion Criteria ..................................................................................................33 
3.3 
Inclusion of Women and Minorities ......................................................................34 
4. 
REGISTRATION PROCEDURES ...................................................................................34 
4.1 
Investigator and Research Associate Registration with CTEP ..............................35 
4.2 
Site Registration .....................................................................................................36 
4.3 
Patient Registration ................................................................................................38 
4.4 
General Guidelines .................................................................................................40 
5. 
TREATMENT PLAN ........................................................................................................40 
5.1 
Agent Administration .............................................................................................42 
5.2 
Definition of Dose-Limiting Toxicity ....................................................................51 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................52 
5.4 
Duration of Therapy ...............................................................................................54 
5.5 
Duration of Follow Up ...........................................................................................55 
5.6 
Criteria for Removal from Study ...........................................................................55 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................55 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................56 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............57 

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7.2 
Adverse Event Characteristics ...............................................................................59 
7.3 
Expedited Adverse Event Reporting ......................................................................59 
7.4 
Routine Adverse Event Reporting .........................................................................63 
7.5 
Secondary Malignancy ...........................................................................................64 
7.6 
Second Malignancy ................................................................................................64 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................64 
8.1 
CTEP IND Agent(s) ...............................................................................................64 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................68 
9.1 
Exploratory Biomarker Studies - Performed for Group 2 at the University 
of Maryland Only ...................................................................................................68 
10. 
STUDY CALENDAR .......................................................................................................74 
10.1  Neurocognitive Evaluation ....................................................................................80 
10.2 
Functional Assessment of Cancer Therapy with Brain Subscale (FACT-
BR) for Quality of Life (QOL) ..............................................................................81 
11. 
MEASUREMENT OF EFFECT........................................................................................82 
11.1 
Antitumor Effect – Intracranial Metastases ...........................................................82 
11.2 
Other Response Parameters ...................................................................................86 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS .............................................................................................................87 
12.1 
Study Oversight .....................................................................................................87 
12.2 
Data Reporting .......................................................................................................88 
12.3 
CTEP Multicenter Guidelines ................................ Error! Bookmark not defined. 
12.4 
Collaborative Agreements Language .....................................................................90 
13. 
STATISTICAL CONSIDERATIONS...............................................................................92 
13.1 
Study Design/Endpoints.........................................................................................92 
13.2 
Sample Size/Accrual Rate ......................................................................................93 
13.3 
Stratification Factors ..............................................................................................97 
13.4 
Analysis of Secondary and Exploratory Endpoints ...............................................97 
REFERENCES 
....................................................................................................................98 
APPENDIX A: PERFORMANCE STATUS CRITERIA ...........................................................104 
APPENDIX B: GRADED PROGNOSTIC ASSESSMENT (GPA) SCORE FOR BRAIN 
METASTASES FON NON-SMALL CELL LUNG CANCER (NSCLC) .....................105 
APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD ......106 
APPENDIX D: PATIENT DEXAMETHASONE DIARY .........................................................108 

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APPENDIX E: MRI Protocol ......................................................................................................110 

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1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To conduct a phase 1 dose escalation trial in patients with brain metastases from non-
small cell lung cancer (NSCLC) to determine the recommended phase 2 dose (RP2D) of 
twice weekly intravenous (i.v.) M6620 (VX-970, berzosertib) administered concurrent 
with conventionally fractionated whole brain radiotherapy (WBRT), with M6620 (VX-
970, berzosertib) starting 18-30 hours after the first dose of radiation (but prior to the 
second fraction of radiation).   
 
Dose-limiting toxicities (DLTs) will be defined as any grade 3 or more non-
hematological toxicity requiring more than 5-day interruption in therapy or any grade 4 
or higher hematological toxicity that is attributable to the M6620 (VX-970, berzosertib) 
and/or whole brain radiotherapy. 
 
DLTs will be assessed from the day of the start of WBRT until 3 weeks post completion 
of WBRT. 
 
1.2 
Secondary Objectives 
 
In patients with brain metastases from NSCLC undergoing therapy with a combination of 
twice weekly intravenous (i.v.) M6620 (VX-970, berzosertib) administered concurrent 
with conventionally fractionated whole brain radiotherapy (WBRT), with M6620 (VX-
970, berzosertib) starting 18-30 hours after the first dose of radiation: 
 
• To estimate the incidence of ≥ Grade 3 delayed neurological toxicity at 2, 4 and 6-
months post-completion of whole-brain radiotherapy (for patients without 
intracranial progression).  This will include testing for delayed-recall through 
Hopkins Verbal Learning Test-Revised (HVLT-R) and Functional Assessment of 
Cancer Therapy-Brain (FACT-BR) assessments. 
 
• To observe and record anti-tumor activity.  Although the clinical benefit of 
M6620 (VX-970, berzosertib) has not yet been established, the intent of offering 
this treatment is to provide a possible therapeutic benefit, and thus the patient will 
be carefully monitored for tumor response and symptom relief in addition to 
safety and tolerability.  The objectives will be: 
 
• To estimate the radiological response rates (RR) at 6 months including bi-
directional and volumetric measurements of lesion size.  All patients 
accrued in group 1 (except the first three dose-levels) will be included in 
the imaging objective. 
 
• To estimate the intracranial  6-month progression-free survival (PFS). 

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1.3 
Exploratory/ Hypothesis Generating Objectives 
 
As exploratory, hypothesis generating objectives, we will collect observational data as 
below: 
 
Group 1: For patients accrued beyond dose-level 3 only 
Magnetic resonance imaging (MRI): Changes in dynamic susceptibility contrast 
enhancement (DSC-MRI) perfusion and mean apparent diffusion coefficient (ADC) 
measurements in diffusion-weighted magnetic resonance imaging (DWI)  
 
Group 2: Restricted to the University of Maryland only 
• In an exploratory study involving a small cohort of 6 patients who are scheduled 
to undergo a craniotomy, a single dose of M6620 (VX-970, berzosertib) at the 
above-identified RP2D will be administered 2-4 hours prior to the planned 
craniotomy.  The objective of this cohort is to measure CSF M6620 (VX-970, 
berzosertib) levels, tumor M6620 (VX-970, berzosertib) levels, and pATR T1989, 
pCHK1 S345 and RAD51 multiplex foci. 
 
• For patients with identifiable target lesion (other than the resected lesion): 
Changes in DSC-MRI perfusion and mean ADC measurements in DWI 
 
 
2. 
BACKGROUND 
 
2.1 
Brain Metastases from Non‐Small Cell Lung Cancer (NSCLC) 
 
Brain metastases continue to be a major health problem for cancer patients.  While the 
exact incidence is not known, a range of 8.3-14.3 per 100,000 populations has been 
reported [1-3].  The incidence in cancer population has been described from 9% to 17%. 
Increased used of high resolution diagnostic imaging such as magnetic resonance 
imaging (MRI) combined with increasing systemic therapy options may explain the 
rising trends in the diagnoses of brain metastases.  The treatment options range from 
surgical resection, stereotactic radiosurgery (SRS) and WBRT or steroids with best 
supportive care alone.  The diagnosis of brain metastases carries a poor prognosis.  In the 
two landmark studies for patients with single brain metastases by Patchell et al., nearly 
50% of the patients had a local recurrence with either surgery alone or WBRT alone, 
while the combination of two modalities resulted in a local recurrence of 10-20% [4, 5].  
The median survival with WBRT alone was 15 weeks, while with surgery ± WBRT 
ranged from 40-48 weeks.  In addition to the mortality risks, occurrence of brain 
metastases is associated with a significant impact on quality of life.  In a phase III trial, 
the baseline Spitzer Quality of Life Index (SQLI) score was nearly 30-40% reduced in 
patients diagnosed to have brain metastases [6].  In addition, more than 90% patients may 
have changes in one or more neurocognitive domains, with up to 40% patients having 

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changes in more than three domains [7].  
 
With nearly 80% of patients with brain metastases presenting with multiple identifiable 
lesions in the brain, WBRT continues to be the backbone of therapy with surgery and 
radiosurgery reserved for patients with limited metastatic disease [8].  The use of 
adjuvant WBRT in these patients continues to be an area of debate.  In a randomized 
European study, while no overall survival (OS) difference was noted with the addition of 
WBRT to surgery or SRS in patients with one to three cerebral metastases, WBRT did 
result in a reduction of 2-year recurrences at the sites of initial disease and at distant sites, 
reducing the need for salvage treatments.  In this study, 28% of the patients in WBRT 
arm had death due to intracranial progression as against 44% in patients who did not 
receive adjuvant WBRT.  More recently, in a cooperative group trial from the U.S. 
intracranial tumor control at 12 months was better with the addition of WBRT (85% vs 
51%, p < 0.001) though this did not translate into any benefit in OS (median 7.5 m vs 
10.7 m, p = 0.93).  These results were presented at the 2015 annual meeting of American 
Society of Clinical Oncology (ASCO) [9].  The detailed results from the study are 
awaited to further understand the reasons for an apparent, non-significant, reduction in 
OS with WBRT.  In routine clinical practice, deaths from toxicity of WBRT are unusual 
and the likely difference in OS may be reflective of disparities in patient population 
between the two cohorts.  Further, intracranial control has been shown to impact 
neurocognitive function and survival [10].  As such, WBRT continues to play a central 
role in the palliative therapy of brain metastases with selective use of surgical or SRS 
approaches for patients with good performance status, limited extra cranial disease and 
young age [8].  The parameters defining the choice between WBRT and SRS are practice 
dependent.  The intent of this protocol is to not define the parameters that define this 
choice, but to evaluate use of concurrent systemic therapy in patient whom WBRT is 
clinically indicated. 
 
Approximately 50-60% of patients with NSCLC develop brain metastases with a poor 
survival post-development of brain metastases (1-year survival < 20%, median survival 
of 4-6 months) [11].  In a retrospective multi-institutional database from 11 institutions 
that lead to the identification of disease-specific graded prognostic assessment index (DS-
GPA), the median survival for the entire cohort of nearly 1900 NSCLC patients was 7 
months (95% CI 6.5-7.5).  Even for patients with > 3 metastases, if the DS-GPA index 
was 3 or 1.5-2.5, the median survival was 11.3 and 6.5 months respectively [12].  
However, unlike non-metastatic but loco-regionally advanced presentations where 
concurrent chemoradiotherapy has shown survival benefit, role of concurrent 
chemotherapy with WBRT is limited by toxicity and restricted penetration through the 
blood-brain-barrier.  At this point, there are no approved drugs to be delivered 
concurrently with WBRT for the management of brain metastases in NSCLC.  In a 
recently published meta-analysis of 6 trials evaluating use of concurrent systemic therapy 
with WBRT for patients with brain metastases from NSCLC, improvement in response 
rate was noted with the addition of chemotherapy [13].  The agents evaluated in these 
trials included motexafin gadolinium, temozolomide, carboplatin and multi agent CCNU 
based chemotherapy.  No differences in survival or time to neurological progression were 

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seen, yet, there was an increase in the incidence of ≥ Grade 3 adverse events.  Hence, the 
choice of appropriate concurrent radio sensitizer with WBRT that improves outcome 
without adding to toxicity continues to be an area of unmet need with immense clinical 
significance. In view of these concerns, ongoing clinical studies are looking at targeted 
therapy options for brain metastases from NSCLC.  Erlotinib was evaluated in a phase 3 
trial assessing its combination with WBRT [14].  No significant differences were seen in 
the neurological PFS with the addition of erlotinib to WBRT.  In a phase 1/2 study for 
patients with crizotinib resistant ALK-rearranged NSCLC, alectinib, a novel, highly 
selective and potent ALK inhibitor, was well tolerated by patients with active brain 
metastases and with 55% objective radiological responses [15].  Additional studies are 
needed to look at newer targeted therapies which could be safely combined with WBRT 
for the management of patients with brain metastases. 
 
With this background, the Cancer Therapy Evaluation Program (CTEP) led a Project 
Team to help direct the development of M6620 (VX-970, berzosertib), a potent inhibitor 
of ataxia telangiectasia mutated and Rad3-related (ATR) kinase, as an anticancer agent in 
collaboration with Vertex Pharmaceuticals Incorporated (Vertex), Boston, MA.  The 
details of the agent M6620 (VX-970, berzosertib) are described below.  Between the 
months of December 2014 and February 2015, a series of weekly teleconferences with 
multiple additional correspondences were completed between the Project Team members 
to guide the development of a clinical plan for M6620 (VX-970, berzosertib).  One of the 
recommended ideas was to test the combination of M6620 (VX-970, berzosertib) and 
WBRT in the management of brain metastases.  A preliminary outline of the protocol 
concept was presented at the IDSC meeting on February 13, 2015 followed by a detailed 
review of the Letter of Intent (LOI) leading to the development of this clinical trial 
proposal. 
 
2.2 
ATR and DNA Damage response 
 
The DNA-damage response (DDR) is a multi-complex network of signaling pathways 
involved in surveillance and repair of DNA damage and transient cell cycle arrest to 
ensure genomic stability and cell viability [16-18].  Deficiencies in DDR mechanisms 
have been shown to contribute to tumor development.  The primary sensors of DNA 
damage and regulators of DDR are ataxia telangiectasia mutated (ATM) and ATR protein 
kinases.  They both contribute to maintaining genome integrity in response to various 
exogenous and endogenous genotoxic insults, e.g., cytotoxic chemotherapy, ultraviolet 
light, ionizing radiation (IR), or hypoxia [16, 19, 20].  Although ATR and ATM have 
broadly overlapping substrate specificities, they have non-redundant functions, which are 
well coordinated during DDR.  ATR appears to be primarily activated by single-strand 
DNA (ssDNA) breaks (SSB) during replicative stress while ATM is a main sensor of 
double-strand DNA (dsDNA) breaks (DSB).  The key outcomes of ATR activation are 
inhibition of cell-cycle progression and suppression of late replicating origin firing [18].  
ATR not only helps to stabilize but also restarts stalled replication forks, and suppresses 
recombination.  ATR is recruited to the sites of SSB at stalled replication forks resulting 
from replication stress [16, 19].  ATR phosphorylates/activates checkpoint kinase 1 

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(CHK1) at serine 345 (CHK1pS345), which stabilizes stalled replication forks until 
replication stress is resolved and DNA damage is repaired.  Activated CHK1 
phosphorylates and inhibits the cell division cycle 25A (CDC25A) phosphatase, which 
ultimately results in cell cycle arrest in intra-S-phase and/or G2-phase and blocks cells 
from entering mitosis until DNA is repaired and completely replicated [19,21].  The ATR 
function is not entirely restricted to CHK1 activation as it has been shown to be 
independently involved in replication of DNA and regulation of a DNA-damage protein 
network [16].  Upon detecting DSBs, ATM activates CHK2, which controls p53-
dependent G1-phase arrest.  Unlike normal cells, cancer cells are often deficient in ATM 
signaling.  It has been hypothesized that loss of the G1 checkpoint renders tumor cells 
more reliant on the ATR-controlled S/G2 checkpoints for repairing DNA damage and 
survival [16, 22].  Therefore, in tumor cells with defective ATM signaling, ATR 
inhibition may exacerbate replication stress leading to accumulation of DSBs, collapse of 
stalled replication forks, and eventually to lethal mitotic catastrophe.  In contrast, normal 
cells which exhibit a low level of replicative stress and have functional ATM are 
expected to tolerate ATR inhibition.  Indeed, preclinical studies have shown that 
disruption of the ATR pathway can exacerbate replication stress in oncogene-driven 
tumors and promotes cell killing.  In addition, tumor cells, which proliferate rapidly, are 
more susceptible to the cytotoxic effects of chemotherapy and radiation than slowly 
proliferating normal cells [16, 17].  However, the effectiveness of such DNA damage-
inducing therapies in cancer treatment is attenuated by cells developing drug resistance, 
leading to tumor recurrence.  Acquired resistance to cytotoxic therapies in tumors has 
been linked to the activation of DDR.  There is accumulating preclinical evidence that 
ATR inhibition can sensitize tumor cells to the effects of radiation or chemotherapy.   
 
2.3 
M6620 (VX-970, berzosertib)  
 
2.3.1 Mechanism of Action 
 
M6620 (VX-970, berzosertib) (former names VET-0768079 or VE-822) is a highly 
potent and selective ATP-competitive inhibitor of ATR, with an inhibition constant (Ki) 
< 0.2 nmol/L (nM) [23].  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 > 1mcM), and PI3K-gamma (Ki = 0.22 mcM) (Fokas et al., 2012).  Overall, 
among 291 kinases tested, M6620 (VX-970, berzosertib)’s Ki values were > 500-fold 
higher for 278 kinases (Ki > 200 nM), > 50-fold higher for 12 kinases (Ki >15 nM), and 
> 25-fold higher for FLT4 (Ki = 8 nM) than its Ki for ATR.  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) [23]. 
 
Effect of M6620 (VX-970, berzosertib) on DDR Signaling and DNA Damage 
 
Concurrent treatment of cancer cell lines with M6620 (VX-970, berzosertib) and various 

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DNA-damaging agents led to sustained M6620 (VX-970, berzosertib)-dose-dependent 
decreases in levels of chemotherapy-induced CHK1pS345, a major substrate of ATR [23, 
24].  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.) [25]. 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 damage [26].  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 alone [24].  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).  However, over time, 
phospho-CHK1 reappeared despite continued exposure to M6620 (VX-970, berzosertib).  
The rebound of phospho-CHK1 has been attributed to non-specific phosphorylation by an 
undefined kinase.  However, despite the transient inhibition of phospho-CHK1, the 
sustained accumulation of γH2AX and KAP1pS824 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.  Failure to repair chemotherapy-induced DNA damage in the 
presence of M6620 (VX-970, berzosertib) has been hypothesized to drive enhanced 
cytotoxicity in cancer cells.  These data support using γH2AX and KAP1pS824 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 repair [23].  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.   
 
2.3.2 Nonclinical Studies 
 
In vitro Antitumor Activity 
 
In the absence of exogenous DNA-damaging agents, M6620 (VX-970, berzosertib) 
demonstrated stronger antiproliferative effects against three cancer cell lines tested 
(HCT116, HT29, and NCI-H23 with IC50s of 35, 48, and 170 nM, respectively) compared 
to noncancerous fibroblast and epithelial cells (IC50 = 110-200 nM).  However, among the 

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three cancer cell lines, potent cytotoxicity by single-agent M6620 (VX-970, berzosertib) 
was seen only in a colorectal cancer [CRC] cell line HCT116: a 50% effect (death in 50% 
of cells ) was observed at a concentration of 61 nM M6620 (VX-970, berzosertib) (EC50).  
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).  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 impact of M6620 (VX-970, berzosertib) 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 
lines.  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 IC50 of the cytotoxic agent 
alone [24].  Enhanced sensitivity was also observed with etoposide (53% of cell lines), 
irinotecan (49% of cell lines) and oxaliplatin (39% of cell lines).  About 40% of cell lines 
were hypersensitized (>10-fold reduction in IC50 observed) to cisplatin by M6620 (VX-
970, berzosertib).  Marked synergy between the two agents was also seen against four of 
seven human NSCLC primary tumors tested in vitro [24].  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. 
 
In addition, significant radio sensitization 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 lines 
[23].  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 [24].  
Loss of p53 promoted sensitivity to ATR inhibition in combination with all five cytotoxic 
agents in contrast with the effects in wild-type A549.  M6620 (VX-970, berzosertib) also 
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but no cytotoxicity was observed against wild-type fibroblasts.  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) + chemotherapy [24].  
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 hung cancer cell lines and primary human tumor 
cells [24].  M6620 (VX-970, berzosertib) potentiated antitumor effects of cisplatin, 
gemcitabine, irinotecan, and IR in a dose-dependent as well as dosing 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) 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 
chemoradiation [23].  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 dosing-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 two 
human pancreatic cancer and NSCLC xenograft mouse models.  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.   
 
Therapeutic human dose 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 

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cisplatin) in mice.  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 non-clinical species (the mouse, rat, dog, and monkey), M6620 (VX-970, 
berzosertib) exhibited a high volume of distribution (Vd); tissue exposure, including 
tumor, was high.  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 (Investigator’s 
Brochure, 2015).  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 responsible.  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 in-house manual patch-clamp human ether-a-go-go-related gene (hERG) assay 
demonstrated moderate inhibition of the hERG channel.  However, a telemetry dog study 
did not demonstrate any cardiovascular (CV) effects at exposures greatly exceeding the 
target human exposure.   
 
Nonclinical Toxicology 
 
M6620 (VX-970, berzosertib) was administered PO or IV for up to 28 days in rats and 
dogs.  The oral studies used an aggressive dosing regimen (every 2 days) to define the 
toxicity profile, while IV studies (dosed twice per week) were more representative of the 
planned clinical dosing schedule (Investigator’s Brochure, 2015).  In the rat, the severely 
toxic dose in 10% of animals (STD10) was 30 mg/kg/day IV.  The highest non-severely 
toxic dose (HNSTD) in dogs was 20 mg/kg/day IV.  The target organs for M6620 (VX-
970, berzosertib) toxicity in rats included testes and peripheral blood cell populations (red 
cell mass, eosinophils, and platelets).  Target organs in the dog included the liver, testes, 
and peripheral blood cell populations (red cell mass and eosinophils); changes in these 
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both rats and dogs. 
 
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) does absorb 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 studies.  However, VX 970 inhibits DNA-damage repair and will be 
administered in conjunction with cytotoxic chemotherapy, thus the potential for 
teratogenicity should be considered high.   
 
2.3.3 Clinical Studies 
 
The suggested starting dose of M6620 (VX-970, berzosertib) in humans, 18 mg/m2 IV, 
was equivalent to 1/10 of the rat STD10 (30 mg/kg or 180 mg/m2).  This dose represents a 
more conservative estimate than 37 mg/m2 IV which would an estimate corresponding to 
the 1/6 of the dog HNSTD (20 mg/kg or 222 mg/m2).  
 
Vertex Pharmaceuticals, Inc. has sponsored the first-in-human M6620 (VX-970, 
berzosertib) phase 1 study withM6620 (VX-970, berzosertib) being administered in 
combination with DNA-damaging agents to patients with advanced solid malignancies 
(Study 001); the study is ongoing.  This study evaluates M6620 (VX-970, berzosertib) in 
combination with either gemcitabine +/- cisplatin or cisplatin +/- etoposide.  M6620 (VX-
970, berzosertib) is dose-escalated (18, 36, 60 or 72 mg/m2 IV) following the standard 
3+3 design.  To allow for the single-agent M6620 (VX-970, berzosertib) PK, a 7-day 
lead-in treatment period of M6620 (VX-970, berzosertib) before cycle 1 has been 
included.  Combinations of M6620 (VX-970, berzosertib) with gemcitabine or cisplatin 
are administered on a weekly schedule, with M6620 (VX-970, berzosertib) being dosed 
24 h after a DNA-damaging agent. 
 
Clinical Pharmacokinetics   
 
Clinical PK have been evaluated both in whole blood and plasma (Investigator’s 
Brochure, 2015).  Preliminary clinical PK data are available from the lead-in period for 
the first two cohorts (M6620 (VX-970, berzosertib) 18 mg/m2 and 36 mg/m2).  Mean 
exposure (AUC) profiles were similar in whole blood and plasma.  The terminal 
elimination t1/2 was approximately 16 h across all doses.  Overall, the Cmax was 1.36 times 
greater and AUC0-∞ 1.43 times greater in whole blood than in plasma.  The results 
suggest that plasma is an appropriate matrix to characterize the M6620 (VX-970, 
berzosertib) PK.  M6620 (VX-970, berzosertib) exposures were similar for the agent 
administered alone and in combination with gemcitabine, suggesting no apparent drug-
drug interactions.  In the M6620 (VX-970, berzosertib) single dose studies, the plasma 
Cmax and AUC0-∞ increase in linear fashion with dose up to 480 mg/m2. 

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Clinical Efficacy 
 
Preliminary efficacy data (cut off February 27, 2015) are available for 38 patients treated 
with M6620 (VX-970, berzosertib) in combination with gemcitabine or cisplatin (study 
001) and for 11 patients treated with single-agent M6620 (VX-970, berzosertib) (study 
002).  Of 29 evaluable patients (receiving M6620 (VX-970, berzosertib) + gemcitabine, 
16 patients had stable disease (SD) (5/6, 4/9, and 7/13 patients with NSCLC, CRC, or 
other cancers, respectively) and 1 patient with EBV+ nasopharyngeal cancer 
demonstrated a 51% tumor reduction corresponding to a partial response (PR).  Four of 
seven evaluable patients receiving M6620 (VX-970, berzosertib) + cisplatin 
demonstrated SD.  Among 10 evaluable patients treated with M6620 (VX-970, 
berzosertib) monotherapy, there were 3 SD and 1 PR.  The CRC patient who achieved a 
PR (80% reduction of the lesion) on monotherapy continues on treatment after 
completing 11 cycles.  
 
Clinical Safety 
 
Preliminary safety data for 38 patients receiving M6620 (VX-970, berzosertib) in 
combination with gemcitabine or cisplatin (Study 001) and 11 patients receiving M6620 
(VX-970, berzosertib) alone (Study 002) can be found in Investigator’s Brochure (2015).  
No dose-limiting toxicities (DLTs) were observed during either 7-14-day or 21-days 
lead-in period of M6620 (VX-970, berzosertib) monotherapy in Study 001.  There were 
no deaths attributable to treatment with M6620 (VX-970, berzosertib) alone.  There were 
no grade 3+ AEs; serious AEs (SAEs) were experienced by 2 patients (palpitation, 
pyrexia, and dyspnea).  In the combination phase evaluating M6620 (VX-970, 
berzosertib) + gemcitabine, M6620 (VX-970, berzosertib) was administered at 18-140 
mg/m2 IV and gemcitabine at 500-875 mg/m2 IV.  Of 27 patients included in the DLT 
analysis, 4 patients (14.8%) experienced 7 DLTs (2 alanine aminotransferase [ALT], 2 
aspartate aminotransferase [AST], 1 alkaline phosphatase, 1 thrombocytopenia, 1 
fatigue). A total of 16 patients (2 during the M6620 (VX-970, berzosertib) lead-in phase 
and 14 during the combination treatment) experienced serious SAEs; 9 of them were 
assessed as related to treatment.  The most common AEs regardless causality were nausea 
(65%), vomiting (55%), and fatigue (48%).  In the sub-study evaluating M6620 (VX-970, 
berzosertib) + cisplatin, six patients received M6620 (VX-970, berzosertib) (90-140 
mg/m2) with cisplatin 40 mg/m2.  There were no DLTs and two SAEs (1 patient with 
metastases to CNS treated during the lead-in period and 1 patient with dyspnea), none of 
which were related to treatment.  The most common AEs, regardless of causality, were 
nausea and fatigue, both observed in 4/6 patients (67%).  
 
In the single-agent M6620 (VX-970, berzosertib) study (Study 002), M6620 (VX-970, 
berzosertib) was administered IV at doses ranging from 60-480 mg/m2.  There were no 
DLTs among 11 patients evaluated for toxicities (cut-off February 10, 2015).  One SAE 
of grade 3 fatigue was classified as possibly related to M6620 (VX-970, berzosertib).  
The most common AE was fatigue (5/11 patients [46%]); nausea, urinary infection, 

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headache, and flushing were observed in 3 patients (28%).   
 
As of April 17, 2015, acute hypersensitivity, reported in 2/66 patients (3%) during 
administering M6620 (VX-970, berzosertib), has been identified as an adverse drug 
reaction for VX 970. 
 
Safety Summary and Guidance for Investigators (Investigator’s Brochure, 2015) 
 
• 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.  
The intravenous infusion site should be monitored closely for the development of 
erythema, induration, purulence, tenderness, or warmth. 
 
• Because the drug-interaction profile of M6620 (VX-970, berzosertib) has not 
been fully characterized, caution should be used when co-administering 
medications with VX 970.  Because M6620 (VX-970, berzosertib) is primarily 
metabolized by CYP3A4, concomitant administration with strong inhibitors or 
inducers of CYP3A4 should be avoided. 
 
• Preclinical studies suggested that M6620 (VX-970, berzosertib) causes testicular 
changes with signs of reversibility after the drug discontinuation.  Developmental 
and reproductive toxicity studies have not been conducted yet.  Therefore, 
patients should take stringent measures to avoid fathering or bearing children 
while on study drug and for 6 months after discontinuation of M6620 (VX-970, 
berzosertib).   
 
2.4 
Rationale 
 
Tumor type:  By virtue of the mechanism of action of the M6620 (VX-970, berzosertib), 
the histology spectrum which may manifest response to treatment may be broad.  
Nevertheless, the ultimate outcome of brain metastases is highly dependent on the 
histology of primary tumor.  Prior experiences have shown that brain metastases from 
NSCLC and from breast cancer need independent studies due to the inherent differences 
in the biology [11, 14, 27].  NSCLC continues to be one of the most common causes of 
brain metastases accounting for 25-45% of all brain metastases [3].  Further, 30-40% of 
patients with NSCLC may develop brain metastases as the only site of metastatic disease, 
justifying the need to develop therapeutic approaches targeting brain metastases from 
NSCLC.  Hence, to initially test the agent, M6620 (VX-970, berzosertib), we have 
elected to restrict the trial to patients with NSCLC primary.  There is extensive published 
phase III data on outcomes with this histology, and the results obtained from the current 

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phase1 trial with a modern adaptive trial design, would provide initial data on outcomes 
which can then be used to power the future phase 2/3 study.   
 
Justification for a phase 1 trial:  There is no clinical data regarding the efficacy of M6620 
(VX-970, berzosertib) in combination with radiation.  Pre-clinical data has demonstrated 
enhanced efficacy of M6620 (VX-970, berzosertib) + radiation, justifying its evaluation 
in clinic.  However, in absence of any safety data of the combination with radiation in 
humans, and due to concerns that there may be some overlap between the downstream 
effects of ATR inhibition and ATM pathways, which is a known factor, predisposing to 
extreme radiosensitivity, an initial phase 1 trial is imperative before embarking on a large 
scale randomized phase 2 design.  Further, patients with NSCLC are more likely to have 
pre-existing smoking history with resulting microvascular changes that put them at higher 
risk of delayed toxicity. Hence, the NSCLC-specific clinical trial platform provides a 
higher bar of safety which can then be used to guide trials in other histologies like breast 
cancer with brain metastases, where the survival is expected to be longer and hence, 
delayed toxicities may have high clinical relevance. Finally, while the initial phase 1 
studies with M6620 (VX-970, berzosertib) monotherapy in extra-cranial malignancies 
have demonstrated the relative tolerance of this drug, the data regarding penetration of 
M6620 (VX-970, berzosertib) across the blood-brain barrier and blood-CSF barrier in 
humans is unavailable. Hence, a formal dose-escalation trial is necessary to define the 
optimal dose with maximal therapeutic ratio. This proposal was extensively discussed in 
the preliminary teleconferences by the M6620 (VX-970, berzosertib) project team 
members and received full support. Further, due to the relative commonness of brain 
metastases in NSCLC, we don’t expect any hurdles in accrual, especially with support 
from the participating UM1 sites. 
 
With regards to timing of administration of M6620 (VX-970, berzosertib) and WBRT, in 
vitro cell culture experiments and animal models have shown that maximal cytotoxicity 
was noted when VX‐970 was given 24 hours after administration of a DNA‐damaging 
agent.  Radiation being the DNA-damaging agent in this trial, M6620 (VX-970, 
berzosertib) will be administered starting 18-30 hours after the first fraction of WBRT 
since.  A broad range of 18-30 hours will allow for the logistics of delivering treatments 
in two different departments (radiation and medical oncology) and due to the inherent 
variability in timing of radiation on a given day as per the clinic schedule.  This will be 
especially important in a multi-institutional setting where there may be a wide variation 
in clinic schedules.   
 
 
2.5 
Hypotheses   
 
2.5.1 Primary Objective 
 
The combination of concurrent M6620 (VX-970, berzosertib) administered as twice 
weekly infusion at the identified RP2D can be safely administered with whole brain 
radiotherapy in patients with brain metastases from NSCLC.  The recommended phase 2 

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dose (RP2D) using this dosing schedule will be established as the primary objective. 
 
2.5.2 Secondary Objective 
 
When compared to whole brain radiotherapy alone, the combination of concurrent 
M6620 (VX-970, berzosertib) administered as twice weekly infusion at the identified 
RP2D along with whole brain radiotherapy in patients with brain metastases from 
NSCLC will result in: 
  
• ≤ 10% incidence of Grade 3 or higher, 6-month neurological toxicity in absence 
of intracranial progression.  In the RTOG 9508 trial, the incidence of Grade 1/2 or 
Grade 3/4 late toxicities (> 90-days after treatment) were approximately 20% and 
< 5% respectively [28].  The corresponding incidences with the addition of SRS 
were comparable with only a marginal increase in Grade 3/4 toxicities (6%).  
When specifically evaluating cognitive function, in the WBRT-alone arm of the 
PCI-P-120-9801 clinical trial (motexafin gadolinium), the mean relative loss in 
HVLT-R delayed recall score at 4 months was 30% [11].   
 
• ≥ 50% radiological response rates (complete response/CR + partial response/PR).  
In recent phase-III trials looking at WBRT ± radio sensitizers, the rates of 
radiological responses (CR + PR) range from approximately 25-65% [29].  In the 
RTOG 9508 study, the response rates were 35-40% in WBRT ± SRS [28]. 
 
• ≥ 70% intra-cranial PFS at 6-months.  In the NSCLC sub-set, 6-month 
neurological PFS (clinical or radiological progression) has ranged from 15% in 
the recently reported phase-III trial evaluating WBRT ± erlotinib to 70% 
proportion of progression free (non-neurological deaths censored) in the WBRT ± 
Motexafin trial [11,14].  The corresponding median neurological PFS in the 
former trial was 1.6 months, while the median time to neurological progression in 
the latter trial was 10 months. 
 
2.5.3 Impact and Future Directions 
 
The current proposed study with a first-in-class ATR inhibitor is a novel and untested 
combination with WBRT for brain metastases.  Data from this study will lay the platform 
for testing of this drug using a phase 2 randomized design of WBRT ± M6620 (VX-970, 
berzosertib) for brain metastases from NSCLC.  Due to relative histology non-specific 
mechanism of action at the DNA repair level, responses seen in this study can be 
extrapolated to other tumor histologies.  Hence, if a positive response is seen, the concept 
could be extended to selected patient population with brain metastases from breast 
primary.  Further, if an intracranial response is seen, we would recommend proceeding 
with evaluation of M6620 (VX-970, berzosertib) in combination with standard 
chemoradiotherapy for loco-regionally advanced NSCLC through the platform of a phase 
1 study.  ATR mediated DNA damage repair pathways have also been reported to 
mediate resistance of glioblastoma and melanoma cells to temozolomide suggesting that 

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the drug may merit evaluation in setting of high-grade gliomas [30].  Data from this trial, 
including the translational cohort exploring evidence of CSF and tumor penetration, can 
help guide future efforts towards glioma management.  
 
2.6 
Correlative Studies Background 
   
Please refer to section 3.2 for information on DNA damage response and ATR pathway 
and section 3.3.1 for a detailed description of the relevant pre-clinical data and the 
description of mechanism of action of M6620 (VX-970, berzosertib) which lays the 
pretext for the following correlative studies.  
 
Based on the extensive discussions during the preliminary teleconferences of the experts 
within the M6620 (VX-970, berzosertib) Project Team, induction of γH2AX was 
proposed as an integrated marker to assess increased double-strand DNA damage with 
the combination of M6620 (VX-970, berzosertib) with another DNA damaging agent.  
This requires assessment of baseline and post-treatment tumor samples. However, in the 
current phase 1 clinical trial, intra-cranial location of the tumor sample precludes 
obtaining multiple/ serial pre- and post-treatment biopsies, which limits the utility of 
γH2AX as a biomarker of response.  Some patients with active extra-cranial disease may 
provide tumor tissue amenable to serial sampling.  However, use of WBRT alone without 
any planned radiation targeting the extra-cranial tissue, the effect of increased DNA 
damage with M6620 (VX-970, berzosertib) + radiation combination cannot be tested in 
these extra-cranial samples.   While some genomic alterations might correlate with 
sensitivity to an ATR inhibitor (cyclin E or ATR amplification, ATM mutation, p53 
mutation), this is a phase 1 study with most of the patients on dose escalation cohorts of 
M6620 (VX-970, berzosertib) the scope of pharmacodynamic/correlative biomarkers is 
limited.  Further, the effect of the genomic alterations on response or survival would be 
difficult to assess in a small study due to the effects of the systemic NSCLC disease on 
survival, which is not impacted by the M6620 (VX-970, berzosertib) + WBRT 
combination.  Also discussed during initial Project Team discussions was use of markers 
such as pATR, pCHK1 and pDNA-PK.  However, measurement of these labile markers 
in archived specimens, which would be the only available specimens in the group 1 
patients, is subject to limited test sensitivities and confounding effects.  As such, no PD 
biomarker testing will be done in group 1 patients. 
 
2.6.1 Intra-Operative Blood, CSF and Tumor Specimen Collection 
 
Based on animal pharmacokinetic studies, while excellent distribution into tissues was 
seen the peak brain tissue to plasma ratio was 0.71.  This suggests limited penetration of 
the blood-brain barrier.  However, in the setting of parenchymal metastases causing 
damaged blood-brain-barrier, the degree of drug-tumor penetration is expected to be 
higher.  Innovation:  To get a better estimate of the tumor drug penetration in setting of 
clinical brain metastases in human, the current study proposal includes Group 2, a novel 
design with a translational cohort of 6 patients in whom M6620 (VX-970, berzosertib) 
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and tumor specimen collection.  This will provide a direct estimation of intra-cranial and 
intra-lesional drug penetration in humans, which may be used to establish a PD-PK 
relationship.  A signal of drug effect will be measured through measurement of pATR-
Thr1989, pCHK1 S345 and RAD51 multiplex levels in the intra-cranial tumor specimen.  
Rad51, which plays a key role in the homologous recombination repair pathway and 
pATR-Thr1989, which is an autophosphorylation site critical for ATR function will be 
assessed through the multiplex assay.  Depending on the evolving understanding of drug 
effects in combination with other chemotherapy agents or radiation, additional 
biomarkers may be added in future, pending approval and funding.  Even if a definite 
PD-PK relationship is difficult to discern due to small patient number and the challenges 
as noted above, the mere observation of CSF and tumor penetration could also help direct 
efforts in other intra-cranial histologies including high-grade gliomas.  By virtue of the 
design, this data will be obtained without any added risks to the patient who will be 
scheduled to undergo a craniotomy to surgical de-bulk an intracranial mass per clinical 
indications.  
 
As noted above, due to the extreme and unjustifiable risk of obtaining intra-cranial tumor 
biopsy prior to M6620 (VX-970, berzosertib) administration, a definite PD relationship 
through the measurement of pATR and RAD51 foci is difficult to establish.  As an 
alternate, a parallel study at the PI’s institution would be conducted wherein fresh tumor 
biopsies from 12 matched control patients who are scheduled to undergo a craniotomy 
but not accrued to the proposed study will be collected as a separate IRB approved study 
for assessments of pATR T1989, pCHK1 S345 and RAD51 multiplex foci. Expression of 
these markers will be compared with the data from 6 patients in the group 2 of the 
proposed study.  The samples will be forwarded to the same central laboratories that will 
be performing study on the current protocol. 
 
 
2.7 
Role of Magnetic Resonance Imaging for Response Assessment in Brain Metastases 
 
Response assessment of brain metastasis after radiotherapy may be performed by a 
combination of morphologic and functional MR methods. 
 
2.7.1 Morphological Assessment  
 
Manual measurements of metastatic foci on contrast enhanced MR imaging remains the 
standard for assessment of treatment response.  Although a number of guidelines for such 
measurement exist, a standard approach is to obtain a maximal dimension on an axial 
image and a second dimension orthogonal to this (bidirectional assessment).  However, 
concerns about the reliability and reproducibility of such measurements are addressed in 
a recent reevaluation of the RANO-BM criteria (which propose obtaining such 
measurements on axial 5 mm thick non-overlapping MR slices and restrict such 
measurements to lesions that are greater than or equal to 10 mm in maximal dimension) 
[31-33].  Although such measurements will be obtained as a part of the study, the 
addition of a widely available standard volumetric T1 weighted contrast enhanced 

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sequence will permit both manual and automated measurements of smaller (less than 5 
mm) lesions.  It must however be acknowledged that the utility of routine volumetric 
assessment and the threshold of volume reduction necessary for treatment response have 
yet to be established.  For specific details of a standard volumetric T1 weighted post-
contrast MR imaging protocol please refer to Appendix E. 
 
 
2.7.2 Perfusion MRI  
 
A vast body of the literature exists describing the use of MR perfusion imaging in the 
diagnosis and grading of primary and secondary brain neoplasms and in monitoring their 
response to treatment [34].  MR perfusion imaging allows qualitative and quantitative 
estimation of cerebral perfusion parameters using intravenously administered gadolinium 
based contrast agents (GBCA).  Measurement of alterations in magnetic susceptibility 
(T2-Dynamic Susceptibility Contrast Enhanced MRI, DSC-MRI) or T1 relaxation 
(Dynamic Contrast-Enhanced MRI, DCE-MRI) provide information about the perfusion 
and vascular permeability characteristics of the tumoral micro-environment (indirectly 
related to intra-tumoral interstitial pressure), which is known to influence response and 
outcome to radiation therapy [35].  DSC-MRI involves monitoring of the first pass of 
intravenously administered GBCA through the brain using a rapidly acquired dynamic T2 
sequences.  The most robust and widely used parameter derived from DSC-MRI is rCBV 
(relative Cerebral Blood Volume).  Although the bulk of the perfusion MRI literature is 
focused on the evaluation of primary glial neoplasms, recent studies have demonstrated 
the use of this technique in patients with metastatic brain disease undergoing 
radiotherapy, both in the assessment of response to treatment and in the differentiation of 
recurrent metastatic tumor from radiation induced changes [36-40].  A decrease of the 
regional CBV value has been demonstrated to help predict response in radiosurgically 
treated metastatic disease with a sensitivity of greater than 80% [41]. The same group has 
also shown utility of non-tumor perfusion changes as a function of radiation dose, which 
may have role to play in assessment of toxicity from WBRT [42].  DSC-MRI is a part of 
routine brain tumor MR imaging protocols in many institutions.  For specific details of a 
standard protocol DSC-MRI lease refer to Appendix E.  
 
2.7.3 Diffusion MRI 
 
Measurement of the Apparent Diffusion Coefficient (ADC) of water molecules provides 
information about tumor characteristics such as cellularity, which may not be readily 
estimated by conventional MR imaging methods [43, 44].  Variations in ADC values 
based on histology have also been described with a value of 1.17 ± 0.49 for NSCLC [45]. 
Diffusion-weighted magnetic resonance imaging (DWI) of metastatic brain tumors has 
been employed to assess response to radiation and chemotherapy [46-48].  Most studies 
describe increased ADC values with treatment response, perhaps reflecting decreased 
tumor cellularity and increased necrosis. Increased ADC may be a marker, even at earlier 
time points, as a predictor of response to radiotherapy.  Specific details of a standard 
diffusion weighted imaging protocol may be found in Appendix E. 

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Response assessment criteria on DWI and DSC-MRI are still unclear with no published 
consensus recommendations.  Even the choice of fitting model to obtain an ADC value 
may impact the measurement though the definition of region of interest may not be that 
significant [49].  There is also suggestion that the changes in ADC values at the junction 
of tumor and peri-tumoral brain tissue may have prognostic significance [50].  Based on 
limited available literature, we anticipate treatment response to correspond to a decrease 
in rCBV (perhaps of the order of 25- 33%) and an increase in ADC value [51, 52]. 
Further, the precise degree of change in rCBV and ADC on DSC-MRI and DWI 
respectively cannot be predicted for the study drug due to lack of efficacy data.  As such, 
these end-points will be exploratory.  Information from the proposed phase-I study will 
provide data to help design the end-point in the future phase-II/III study. 
 
2.8 
Relevance of Neurocognitive Testing for Whole Brain Radiotherapy Clinical Trials 
 
Historically, patients with brain metastases had very limited survival [4, 5].  However, 
subgroups of patients exist in which prolonged survival is possible.  Based on graded 
prognostic assessment (GPA), the median survival of patients with brain metastases 
ranges from 3.1-13.5 months based on the risk score [53].  Specifically in patients with 
NSCLC, the factors favoring longer survival include age < 50 years, Karnofsky 
Performance Status (KPS) of 90-100, absent extra-cranial disease and solitary brain 
metastases.  Because of advances in the diagnosis and management of this condition, 
most patients receive effective palliation and many do not die from the metastases, which 
increases the relevance of delayed toxicity from WBRT. 
 
Neurocognitive impairment has received significant importance in recent clinical trials 
evaluating WBRT, though the occurrence of this toxicity was noted even in older series. 
In a retrospective review of 70 patients treated with WBRT in daily fractions of 3-6 Gy 
treated to a dose of 25-39 Gy, 11 percent showed evidence of progressive, debilitating 
dementia within 5 to 36 months of treatment [54].  RTOG 0018, a cooperative group 
Phase 2 trial, evaluated feasibility of cognitive testing of brain metastasis patients 
receiving WBRT.  With > 90% pre-WBRT and > 84% post-WBT compliance, this study 
established the feasibility of using multi-pronged and comprehensive neurocognitive 
testing in a multi-institution cooperative group setting, while also establishing the 
certification process to conduct these studies [55].  The first, large, international phase 3 
randomized study to evaluate cognitive function for patients with brain metastasis using a 
battery of cognitive tests showed that the majority of patients experienced cognitive 
decline after WBRT, with 59% experiencing a greater than 2 SD decline in their 
performance in one or more tests at 6 months [7].  In a phase 3 trial of SRS plus WBRT 
compared to radiosurgery alone, Chang and colleagues demonstrated a higher rate of 4-
month decline in list-learning recall, assessed using the Hopkins Verbal Learning Test-
Revised (HVLT-R), with the addition of upfront WBRT [56].  Similar findings were 
reported by Welzel et al., who observed a decline in verbal memory function, as assessed 
by the Auditory Verbal Learning Test (AVLT) 6 to 8 weeks after the completion of 
WBRT for brain metastases [57].  Results from a recent U.S. cooperative group trial 

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presented at the 2015 annual meeting of ASCO, the rates of cognitive decline ( > 1 
standard deviation decline from  baseline in any of the 6 cognitive tests at 3 months) were 
higher in the patients randomized to WBRT + SRS arm (88%) vs SRS alone arm (61.9%) 
[9]. These and many other institutional series provide the rationale for close monitoring 
of neuro-cognitive toxicity in this phase-I clinical trial.  
 
We will use Hopkins Verbal Learning Test-Revised for delayed recall (HVLT-R DR) and 
Functional Assessment of Cancer Therapy- Brain subscale (FACT-BR) to assess 
neurocognitive toxicity and impact on quality of life as was performed in the RTOG 0933 
evaluating the feasibility of hippocampal avoidance WBRT techniques [58].  
Participating institutions were all credentialed for these tests, which would allow 
standardized collection of data in the current protocol. 
  
3. 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients with a histologically confirmed diagnosis of non-small cell lung cancer 
(NSCLC), including neuroendocrine tumors or small cell lung cancer (SCLC) who are 
being evaluated for palliative WBRT (with or without neurosurgical resection or SRS) for 
radiologically or histologically diagnosed brain metastases presumed to be from the lung 
cancer are eligible for this Phase I study.   Group 2 will only include NSCLC patients. 
 
3.1.2 Life expectance of greater than two months to allow completion of study treatment and 
assessment of dose-limiting toxicity. 
 
3.1.3 Group 2 patients should have archived or fresh tumor tissue available from the non-
craniotomy site and will have fresh tumor tissue available from the planned craniotomy. 
 
3.1.4 Age ≥ 18 years.   
Because no dosing or adverse event data are currently available on the use of M6620 
(VX-970, berzosertib) in patients < 18 years of age, children are excluded from this 
study, but will be eligible for future pediatric trials. 
 
3.1.5 ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A). Note:  though 
patients with ECOG performance status of 3 due to neurological deficits who are 
otherwise fit to receive systemic therapy per clinician assessments will be allowed. 
 
3.1.6 Patients must have normal organ and marrow function as defined below: 
• Leukocytes 
≥ 3,000/mcL 
• Absolute Neutrophil Count (ANC)  ≥ 1,500/mcL 
• Platelets 
≥ 100,000/mcL 
 
• Total bilirubin, AST (SGOT) and ALT (SGPT): 

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 If no known liver metastases: 
 Total bilirubin < 1.5 x institutional upper limit of normal (ULN), AST/SGOT 
or ALT/SGPT < 2 x ULN.  
 
If known liver metastases, then: 
Total bilirubin < 2.5 x ULN, AST/SGOT or ALT/SGPT < 5 x ULN. 
 
• Creatinine within normal institutional limits for age 
OR 
Calculated creatinine clearance ≥ 45 mL/min/1.73 m2 for patients with creatinine 
levels above ULN. 
 
3.1.7 Negative serum or urine pregnancy test result for females of child bearing potential 
 
Note: The effects of M6620 (VX-970, berzosertib) on the developing human fetus are 
unknown.  For this reason and because radiation therapy is known to have teratogenic 
potential, women of child-bearing potential and 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 she or her partner is participating in this study, she should 
inform her treating physician immediately.  Men treated or enrolled on this protocol must 
also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 6 months after completion of M6620 (VX-970, berzosertib) 
administration. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
 

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3.2 
Exclusion Criteria 
 
3.2.1 Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, with stable systemic 
disease and ECOG score of 0-2, who would otherwise be eligible for SRS/SRT alone 
should not be enrolled into this study unless WBRT is recommended due to any medical 
reasons or logistic limitations as determined by the treating physician.  Patients who 
develop recurrence post-SRS/SRT or surgery alone and are recommended WBRT will be 
eligible for the protocol. 
 
3.2.2 Greater than 1 cm mid-line shift, severe uncal herniation or significant 
hemorrhage/hydrocephalous (intra-lesional hemorrhage is acceptable).  Patients with 
seizure at presentation who have been started on Levetiracetam and have been stable for 
48 hours prior to study registration are eligible at the discretion of treating physician. 
 
3.2.3 Patients who have received systemic cytotoxic chemotherapy and/or, immunotherapy or 
other intraveneous standard therapy for 2 weeks before initiation of planned WBRT, for 
oral targeted agents 3-7 days per clinician discretion or patients who have not recovered 
to CTCAE grade 2 or less from serious (CTCAE grade 3 or more) adverse events form 
the previously received agents.  For any other investigational agents, at least 4 half-lives 
of the agent (6 weeks for nitrosoureas or mitomycin C) should have elapsed prior to 
starting study treatment.  
 
3.2.4 Patients must not have received prior WBRT (previous SRS/SRT done at least 2 weeks 
from the planned start of WBRT is acceptable).  Patients planned upfront to undergo 
SRS/SRT/fractionated boosts or neurosurgery after WBRT are not eligible; however, 
these treatments/procedures can be performed once the DLT assessment has been 
completed, if felt clinically necessary. 
 
3.2.5 Pregnant women are excluded from this study because M6620 (VX-970, berzosertib) as a 
DNA-damage response (DDR) inhibitor may have the potential for teratogenic or 
abortifacient effects. Further, radiation therapy is known to have the potential for 
teratogenic or abortifacient effects.  Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with M6620 (VX-
970, berzosertib), breastfeeding should be discontinued if the mother is treated with 
M6620 (VX-970, berzosertib).   
 
3.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M6620 (VX-970, berzosertib). 
 

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3.2.7 M6620 (VX-970, berzosertib) is primarily metabolized by CYP3A4; therefore, 
concomitant administration with strong inhibitors or inducers of CYP3A4 should be 
avoided.  Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference for a list of drugs to avoid or 
minimize use of.  Appendix C (Patient Drug Information Handout and Wallet Card) 
should be provided to patients.  As part of the enrollment/informed consent procedures, 
the patient will be counseled on the risk of interactions with other agents, and what to do 
if new medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product. Ongoing phenytoin should be either discontinued if 
clinically safe or transitioned to non-enzyme-inducing antiepileptics like Levetiracetam 
with a 8-day washout period (half-life 18-22 hours, time to steady-state 4-8 days) prior to 
first dose of M6620 (VX-970, berzosertib) (7-days prior to WBRT). 
 
3.2.8 Patients needing more than 8 mg dexamethasone per day at the time of start of WBRT 
will not be eligible to participate in the study.  However, patients will be allowed entry 
into the study if it is medically safe to reduce the daily dose of dexamethasone to 8 mg or 
less from the day of the start of WBRT.  The dexamethasone dose for such patients may 
be increased beyond 8 mg per day during the course of treatment if medically necessary.  
This increased need for dose should be communicated to the study’s Principal 
Investigator, Dr Mohindra, at the University of Maryland. 
 
3.2.9 Uncontrolled intercurrent illness that would increase the risk of toxicity or limit 
compliance with study requirements.  This includes but is not limited to, ongoing 
uncontrolled serious infection requiring i.v. antibiotics at the time of registration, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.10 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with M6620 (VX-970, berzosertib) and the 
uncertainties of any impact thereof on the radiation toxicities.  In addition, these patients 
are at increased risk of lethal infections when treated with marrow-suppressive therapy.  
Appropriate studies will be undertaken in patients receiving combination antiretroviral 
therapy when indicated. 
 
3.2.11 Patients with known diagnoses that are associated with germline DDR defects such as Li 
Fraumeni syndrome and ataxia telangiectasia are excluded from the study as M6620 
(VX-970, berzosertib) is a DDR inhibitor. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. 
REGISTRATION PROCEDURES 
 

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• Act as the site-protocol Principal Investigator (PI) on the IRB approval, and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators act as the Site-Protocol PI, consenting/treating/drug shipment, or as 
the CI on the DTL must be rostered at the enrolling site with a participating organization (i.e., 
Alliance).  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval   
 
Sites participating with the NCI Central Institutional Review Board (NCI CIRB) must submit the 
Study Specific Worksheet for Local Context (SSW) to the CIRB using IRBManager to indicate 
their intent to open the study locally.  The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network.  Site preferences can be set at the network 
or protocol level.  Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
For trials that will include sites using their local IRB or REB as well as for a trial with non-U.S.-
based NCTN and NCORP sites, include the following paragraph and the three associated bullet 
points:  
 
Sites using their local IRB or REB must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website.  
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation, 
• IRB-signed CTSU IRB Certification Form, and/or 
• Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
 
In addition, the Site-Protocol PI (i.e., the investigator on the IRB/REB approval) must meet the 
following five criteria to complete processing of the IRB/REB approval record: 
• Holds an Active CTEP status, 
• Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) and 
on at least one participating roster, 

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• If using NCI CIRB, rostered on the NCI CIRB Signatory record, 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile, and 
• Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
 
Additional requirements to obtain an approved site registration status include: 
• An active Federalwide Assurance (FWA) number, 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization, and 
• 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.   
 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP 
IAM username and password. 
• Click on Protocols in the upper left of your screen.  
o Enter the protocol # 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-MN026 
and protocol # 9952. 
• Click on Documents, select Site Registration, and download and complete the 
forms provided.  (Note: For sites under the CIRB initiative, IRB data will load to 
RSS as described above.) 
 
4.2.2 Protocol Specific Requirements for 9952 Site Registration 
 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must be 
aligned to an RTI provider.  To manage provider associations or to add or remove associated 
providers, access the Provider Association page from the Regulatory section on the CTSU 
members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation.  Sites must be linked 
to at least one Imaging and Radiation Oncology Core (IROC) provider to participate on trials 
with an RTI component.  Enrolling sites are responsible for ensuring that the appropriate 
agreements and IRB approvals are in place with their RTI provider.  A primary role on any roster 
is required to update provider associations, though all individuals at a site may view provider 
associations.  To find who holds primary roles at your site, please view the Person Roster 
Browser under the RUMS link on the CTSU website. 
 

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• Site Initiation Teleconference (SIV TC with lead site) 
• Credentials showing proficiency in neurocognitive testing from a prior NRG or 
Alliance study 
 
 
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 → 
Regulatory → 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.  
 
• Log on to the CTSU members’ website 
• Click on Regulatory at the top of your screen 
• Click on Site Registration  
• 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. 
 
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:   

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• A valid CTEP-IAM account. 
• 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. 
• If a DTL is required for the study, the registrar(s) must hold the OPEN Registrar task on 
the DTL for the site. 
• 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: 
 
• Patient has met all eligibility criteria within the protocol stated timeframes, and  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website.  
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN.  Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on 
the protocol is available to the patient.  Once a slot reservation confirmation is obtained, site staff 
may then proceed to enroll the patient to this study.  
 
Prior to receiving ability to enroll a patient to this study, Registrar will have to have completed 
neurocognitive certification protocol-specific requirement. 
 
 
 
4.3.3 OPEN/IWRS Questions? 
 

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Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.orgor at https://open.ctsu.org.  For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
   
Theradex has developed a Slot Reservations and Cohort Management User Guide, which 
is available on the Theradex website:  
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. This 
link to the Theradex website is also on the CTSU website OPEN tab. For questions about 
the use of IWRS for slot reservations, contact the Theradex Helpdesk at 609-619-7862 or 
Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 14 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 
 
The current proposed study will be completed through the accrual of two sequential 
groups as below: 
 
Group 1: The study design is a dose-finding phase 1 trial in the relevant patient 
population with the aim of characterizing the safety profile and deriving the 
Recommended Phase 2 Dose (RP2D) of M6620 (VX-970, berzosertib) combined with 
WBRT for treatment of brain metastases.  This will include patients that are not being 
considered for an immediate SRS or craniotomy.  Patients may have already undergone 
craniotomy or SRS prior to being screened for the study.  This group of patients will be 
allowed to accrue into the dose-escalation phase 1 study with increasing doses of M6620 
(VX-970, berzosertib) combined with fixed dose radiotherapy.  The data from this group 
will be used in achieving the primary and the secondary objectives of the phase 1 study.  
 
It is noted that the ideal schedule and sequence of M6620 (VX-970, berzosertib) and 
radiation has not been determined with in vivo studies, which is being currently planned 
and coordinated through NCI.  Since the current study is a safety study to rule out 
toxicity, we will proceed with the current protocol guided by the studies described in the 
Investigator’s Brochure (IB), wherein it is noted through in vitro cell culture experiments 
and animal models that maximal cytotoxicity is noted when VX‐970 is given 24 hours 
after administration of a DNA‐damaging agent.  Radiation being the DNA-damaging 
agent in this trial, M6620 (VX-970, berzosertib) will be administered starting 18-30 hours 
after the first fraction of WBRT since (but prior to the second fraction of WBRT).  A 
broad range of 18-30 hours will allow for the logistics of delivering treatments in two 
different departments (radiation and medical oncology) and due to the inherent variability 

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in timing of radiation on a given day as per the clinic schedule.  This will be especially 
important in a multi-institutional setting where there may be a wide variation in clinic 
schedules.  It will be recommended to keep as close to 24 hours gap as possible between 
the first fraction of radiation and the first dose of M6620 (VX-970, berzosertib).  The 
timing of radiation and M6620 (VX-970, berzosertib) will be strictly recorded and 
monitored by the data monitoring committee.  Once new data regarding sequencing of 
M6620 (VX-970, berzosertib) and irradiation is available from the currently planned in 
vivo studies, we will appropriately modify the sequencing in the current protocol.     
 
 
 
 
Group 2: Restricted to the University of Maryland only  
This will include patients that are being considered for craniotomy prior to the initiation 
of WBRT.  If found eligible and study registration is completed after an informed 
consent, patients will receive a single dose of M6620 (VX-970, berzosertib) at the RP2D 
derived from the group 1.  This dose will be administered 2 to 4 hours prior to the 
planned craniotomy. Subsequent to craniotomy, patients will initiate WBRT preferably 
10-20 days post-operatively or as clinically appropriate. WBRT (37.5 Gy in 15 fractions 
or 30 Gy in 10 fractions) will be delivered concurrently with M6620 (VX-970, 
berzosertib) administered at the Group 1 identified RP2D.  As such, this group of patients 
will be enrolled after the identification of RP2D from group 1.  The scheduling of M6620 

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(VX-970, berzosertib) during WBRT will be identical to the group 1 patients, as detailed 
in section 5.1.1 below. 
 
 
 
 
5.1 
Agent Administration 
 
5.1.1 M6620 (VX-970, berzosertib) 
 
Group 1: Treatment will be administered on an outpatient basis.  The drug will be 
administered on a twice weekly schedule M6620 (VX-970, berzosertib) will be 
administered starting 18-30 hours after the first fraction of WBRT but prior to the second 
fraction of WBRT.  It will be recommended to keep as close to 24 hours gap as possible 
between the first fraction of radiation and the first dose of M6620 (VX-970, berzosertib).  
The timing of radiation and M6620 (VX-970, berzosertib) will be strictly recorded and 
monitored by the data monitoring committee.   
Since in routine clinical practice WBRT may start any day of the week and not 
necessarily on Mondays (like most curative intent chemo-radiations), for the protocol 
purpose the study protocol will allow a Monday through Thursday start of WBRT, with 
M6620 (VX-970, berzosertib) administered as follows: 
• Monday or Thursday WBRT start: M6620 (VX-970, berzosertib) administered 
Tuesday and Friday 
• Tuesday WBRT start: M6620 (VX-970, berzosertib) administered Wednesday 
and Friday in week 1 followed by Tuesday and Friday from week 2 onwards  
• Wednesday WBRT start: M6620 (VX-970, berzosertib) administered Thursday in 
week 1 and then Monday and Thursday from week 2 onwards.  
 
This will allow all patients to get 6 doses of M6620 (VX-970, berzosertib) over 3 weeks 

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course of WBRT (37.5 Gy in 15 fractions) or 4 doses of M6620 (VX-970, berzosertib) 
over 2 weeks course of WBRT (30 Gy in 10 fractions). 
 
For the protocol purpose and due to the logistic difficulties of M6620 (VX-970, 
berzosertib) administration on Saturdays, the study calendar will include a comment to 
avoid a Friday start of WBRT, when clinically appropriate. 
 
Patients can receive WBRT at a community site/satellite location within the health 
system where the study is approved as long as the study agent is received at the site 
approved to dispense/administer the study drug, and patient can be monitored closely for 
toxicities and undergo necessary HVLT-R and FACT-BR testing. 
 
For the second and subsequent doses of M6620 (VX-970, berzosertib), the drug will be 
administered after the day’s administration of radiation treatment.  This schedule will 
allow maximum overlap of drug during the active days of radiation treatment. 
 
M6620 (VX-970, berzosertib) Administration 
Premedication/ 
Precautions 
Dose* 
Route 
Schedule 
Duration 
Premedicate 
with 
dexamethasone 
as per 
institutional 
guidelines 
 
  
 
  
   
 
 
  
 
 
  
 
 
IV over 60 
minutes 
Twice 
weekly 
Three 
weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Group 2: Restricted to the University of Maryland only 
Patients will first receive a single dose of M6620 (VX-970, berzosertib) (per above 
administration guidelines) at the RP2D derived from the group 1.  This dose will be 
administered 2 to 4 hours prior to the planned craniotomy.   The time of M6620 (VX-970, 
berzosertib) administration and time of blood, CSF and tissue collection will be recorded. 
 
M6620 (VX-970, berzosertib) will also be administered concurrently with WBRT at the 
RP2D derived from group 1.  The scheduling of M6620 (VX-970, berzosertib) during 

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WBRT will be identical to the group 1 patients, as detailed above. 
 
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or 
therapies other than those described below may be administered with the intent to treat 
the patient's malignancy. 
 
5.1.1.1 Group 1 Dose Escalation  
 
Several statistical designs have been studied for dose-finding phase 1 trials.  We will 
employ a Bayesian adaptive design, Escalation With Overdose Control (EWOC), 
originally proposed by Babb, Rogatko and Zacks [59].  EWOC is coherent and utilizes 
all the toxicity data available at the time of each dose assignment and controls the 
probability of overdosing patients at each stage.  Compared to alternative, non-
parametric designs, EWOC treats fewer patients at either sub-therapeutic or severely 
toxic dose levels, treats more patients at optimal dose levels and estimates the 
maximum tolerated dose with smaller average bias and mean squared error.  Toxicities 
are treated as binary (yes-no) in the EWOC modeling.  Note, that with this type of 
design a discrete set of dose levels is not defined a priori.  The algorithm will estimate 
the next dose level where the expected incidence of toxicity is equal to the pre-defined 
target for maximum acceptable toxicity.  
 
EWOC requires definition of a range of doses to be studied.  Per the algorithm, the first 
dose level chosen will be the presumed “very-safe” dose based on available clinical 
data.  In the ongoing phase 1 clinical study (002) using M6620 (VX-970, berzosertib) 
as monotherapy, the currently open dose level is at 480 mg/m2.  No dose-limiting 
toxicity was seen at lower dose levels.  Note, however, that there are mechanistic 
reasons to expect interactions between M6620 (VX-970, berzosertib) and ionizing 
radiation and that the level of grade 3+ toxicity after WBRT alone is about 10%.  Since 
the drug was administered on a weekly schedule, while the current proposal is at a 
twice weekly schedule, a weekly dose of 60 mg/m2 (1/8th of the current dose level on 
the 002 study) was felt to be a “very-safe” dose at which the likelihood of toxicity is 
very low.  Assuming a BSA of 1.7, this translates into an absolute dose of 100 mg per 
week (50 mg twice weekly dose) approximately.  As a safeguard against putting 
patient’s safety at risk due to too rapid dose escalation in the EWOC design in case of 
no toxicities at the initial dose level(s), we will cap the dose at level n to be no more 
than a factor of two larger than the dose at level n-1. At each step, the next dose level 
will be guided by the EWOC algorithm, with all DLT data from the run-in being part of 
the data set for defining dose levels for new trial participants, but applying the cap on 
dose escalation if required. 
 
The maximum single dose is chosen to be 480 mg/m2 (800 mg), although this may be 
increased if the MTD in the single agent 002 study turns out to be higher before the 
commencement of our phase 1 trial. 
 

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Dose Escalation Schedule 1 
Dose Level 
Dose of M6620 (VX-970, berzosertib) (mg)  
Level 1 
50 mg twice weekly 
Level 2 
100 mg twice weekly 
Level n 
estimated using the EWOC algorithm, 
≤ 2 times the dose level (n-1) 3 
Highest level 
800 mg twice weekly 4 
1.   Once enrollment at level one has been completed, the subsequent 
dose escalation will be based on the Bayesian adaptive design, 
Escalation With Overdose Control (EWOC) algorithm, with all 
DLT data from all tested dose levels being part of the data set for 
defining dose levels for new trial participants.  
2.   See Section 13.2.2 for special early stoppage and slow 
convergence scenarios.  
3.   In case of no toxicities at prior levels the EWOC may escalate the 
dose quite rapidly.  As an added precaution, dose level n will not 
exceed the dose at level n-1 by more than a factor of 2, see 
section 13.2.2 for further details. 
4.  Highest dose-level may be increased if the MTD in the single 
agent 002 study turns out to be higher before the commencement 
of our phase I trial. 
 
 
Three patients will be accrued into an open dose-level to allow accrual at more than one 
participating site, without significant delay in accrual.  After accrual of the three 
patients to an open dose level, the next cohort will be opened once DLT assessment has 
been completed for all the three patients.  The next dose level will be computed by the 
statisticians, see statistics section below.  The dose level computation will rely on a 
real-time maintained log of DLT for the accrued patients.  If three patients have been 
accrued at the current dose level but one or more of these have not been followed for 
the planned duration required to evaluate DLTs (three weeks of WBRT and 3 weeks 
after the completion of WBRT), we will allow accrual of up to 3 patients to the next 
lower dose level that has been tested before the current dose level.  By virtue of the 
statistical approach, these additional 3 patients will contribute to the EWOC modeling 
and provide robustness in estimation of the ultimate RP2D.  If with newer patients in 
the lower dose, the estimated toxicity at the current dose is above the target 25%, the 
enrollment will be suspended immediately until the current dose level is evaluable for 
the DLT rate.  Accrual will open once the next dose level is estimate per the EWOC 
algorithm.  Further, based on the EWOC modeling, since the model allows dose 
escalation to the likely RP2D fairly quickly, most patients are expected to be treated at 
a dose very close to the final RP2D, thereby limiting use of sub-therapeutic treatment 
exposure. As soon as the cases enrolled at the current dose level have complete follow-
up for DLT assessments, we will revert to the standard EWOC algorithm.  

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Accrual will open once the next dose level is estimated as per the EWOC algorithm.  
  
Figure 3 shows a single simulated trial, starting at a dose level of 50 mg twice weekly 
and with a maximum dose of 800 mg twice weekly.  Three patients were enrolled at 
each dose level. The simulation was performed with a logistic dose response model 
with 10% toxicity at the minimum dose and 25% toxicity at a dose of 250 mg.  The 
simulated responses are shown for each patient, with 1/0 indicating that the patient did 
or did not experience a DLT, respectively.  Level 2 is capped at 100 mg and level 3 at 
200 mg as no toxicities have occurred at levels 1 and 2 in this particular simulated trial. 
As toxicities start to occur, the rate of dose escalation/de-escalation is reduced.  In this 
particular case only 20% of the 40 patients overall experienced a DLT and 85% were 
treated at doses within  15% of the (in this case known) MTD of 250 mg.  The final 
estimated MTD is 260 mg with the 90% highest posterior density credible interval 
estimate from 157 mg to 634 mg. 
 
 
Sample simulation of dose-escalation using a Bayesian adaptive design, Escalation 
With Overdose Control (EWOC)  
 
 
When a patient at any site is undergoing the study treatment, the PI of the study (or 
representative) will meet (in person, by teleconference or by email) with the 
participating site’s study team member(s) regularly to review any updates regarding 
potential adverse events being experienced by the study subject.  If necessary, clinical 
inputs from the treating physician and the participating site PI will be obtained to assist 
in the decision regarding the adverse event being labeled as a DLT. 
 
Unexpected severe late radiation toxicity will be recorded as a secondary end-point. 
These events will be reviewed by the study PI, CTEP and CIRB who will be charged 
with considering cessation of the trial if the long term/delayed (at 6 months) ≥ grade 3 
symptomatic neurotoxicity is > 20%.  Use of other therapies post-DLT assessments 
which might impact neurological functioning (including, but not limited to, 
immunotherapy, for which safety data of immune-related neurological adverse events 
after WBRT is relatively limited) will be considered for this decision.   
 
We will use the IWRS web-based registration system,   the CTSU website and all 
appropriate web-based electronic portals to provide information regarding the open 
dose level and availability of slot for accrual (section 4.3). 

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5.1.1.2 Determination of Recommended Phase 2Dose (RP2D) 
 
The stopping rule for the dose-escalation trial will be pre-defined and guided by the 
accepted level of ≥ Grade 3 acute dose limiting toxicity seen with the combination of 
M6620 (VX-970, berzosertib) with WBRT.  In the phase 3 randomized trial of WBRT 
plus motexafin gadolinium for patients with brain metastases from non-small cell lung 
cancer or with WBRT + efaproxiral for breast cancer, the incidence of ≥ Grade 3 
toxicity with WBRT alone was approximately 10%, while with WBRT + drug 
combination was approximately 25-30%.  Hence, for the purpose of this trial, an 
incidence of 25% ≥ Grade 3 toxicity from the combination therapy will be considered 
an acceptable upper limit.  In addition to the acute toxicity, severe late radiation toxicity 
will be recorded as a secondary end-point.  The RP2D will be defined as the dose level 
estimated to be associated with an incidence of dose-limiting toxicity (DLT) of 25%, 
see statistics section below. 
 
 
5.1.2 Whole Brain Radiotherapy (WBRT) 
 
5.1.2.1 Dose Specifications 
 
Protocol whole brain radiotherapy (WBRT) must begin within 14 days following 
registration; if day fourteen falls on a holiday or weekend, it is acceptable to begin 
treatment the next business day. Two dose fractions for WBRT are allowed: One 
treatment of 2.5 Gy will be given daily for not more than 5 days per week (15 
fractions), once daily fractionation,  without any planned interruptions for a total of 
37.5 Gy over three weeks or One treatment of 3 Gy will be given daily for not more 
than 5 days per week (10 fractions), once daily fractionation,  without any planned 
interruptions for a total of 30 Gy over two weeks.  All portals shall be planned to be 
treated during each treatment session.  Doses are specified as the target dose which 
shall be the dose on the central ray at mid-separation for two opposed coaxial equally 
weighted beams (or as mean dose to a specified target volume, in this case, whole 
brain).  “Compensating beams” that block hot spots (these hot spots are typically 
present along the midline due to less tissue present in these regions compared to mid-
brain) are allowed to achieve better dose homogeneity. 
 
5.1.2.2 Technical Factors  
 
Treatment shall be delivered with megavoltage machines of energy ranging from 4MV 
to 6 MV photons.  Patients will be planned and treated using three-dimensional 
conformal radiation technique (3D-CRT).  Intensity Modulated Radiotherapy (IMRT) 
with or without hippocampal avoidance (Fixed-gantry IMRT, helical tomotherapy or 
VMAT) will be allowed per institutional protocols.  Partial brain cone down, 
stereotactic, electron, particle or implant boost are not permissible during the course of 

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the study treatment and until the DLT assessments are complete.  However, patients 
will be eligible to undergo SRS/SRT/fractionated boosts or neurosurgery, once the DLT 
assessment has been completed, if felt clinically necessary. 
 
5.1.2.3 Localization, Simulation, and Immobilization 
 
The patient shall be treated in the supine or other appropriate position to allow 
planning and delivery of WBRT.  A head-holding device must ensure adequate 
immobilization during therapy and ensure reproducibility.  A non-contrast treatment-
planning CT scan of the entire head region extending into neck should be obtained. 
When using hippocampal avoidance WBRT, it is recommended he axial slice 
thickness should match the MRI axial slice thickness as much as possible (preferred 
1.5 mm). The treatment-planning CT scan must be acquired with the patient in the 
same position and immobilization device as for treatment. For 3D-CRT, the target 
volume shall include the entire cranial contents, with flashing beyond skin and 
adequate margin on the skull base as visualized on the simulator or portal films to 
account for beam penumbra and day-to-day set-up variation.  Treatments must be 
delivered through parallel opposed fields.  The lenses and the anterior globe will be 
excluded from the beam either by field arrangement or shielding.  ‘Helmet’ portals 
with customized immobilization and shielding are permitted.  
 
5.1.2.4 Critical Structures 
 
Care should be taken to minimize the dose to the lens. For patients post-cataract 
surgery, a surrogate lens structure should be created. 
 
 

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5.1.2.5 
Hippocampal avoidance WBRT:  
 
Hippocampal avoidance WBRT should be planned in accordance with the ongoing 
(or most recently completed, if no ongoing study) cooperative group protocol. The 
target volume will include the entire cranial contents to the foramen magnum (labeled 
as CTV). Care should be taken to delineate cribriform plate in the CTV. The PTV is 
equal to CTV without the hippocampal avoidance region.  
 
When prescribing 37.5 Gy in 15 fractions, the IMRT plan should be normalized such 
that 95% of the PTV volume receives prescription dose of 37.5 Gy (V37.5 Gy ≥ 
95%), D2% (Dose to hottest 2% of PTV) is ≤ 40 Gy, D98% (Dose to 2% of PTV) is ≥ 
32.5 Gy. Variation Acceptable include, V37.5 Gy ≥ 90%, D2% is ≤ 43 Gy and D98% 
is ≥ 30 Gy.  
 
When prescribing 30 Gy in 10 fractions, the IMRT plan should be normalized such 
that 95% of the PTV volume receives prescription dose of 30 Gy (V30 Gy ≥ 95%), 
D2% (Dose to hottest 2% of PTV) is ≤ 37.5 Gy, D98% (Dose to 2% of PTV) is ≥ 25 
Gy. Variation Acceptable include, V30 Gy ≥ 90%, D2% is ≤ 40 Gy and D98% is ≥ 
22.5 Gy.  
 
QA for the physician-approved plan should be performed per institutional policies.  
 
For hippocampal avoidance WBRT, bilateral hippocampal contours (Hippocampi) 
will be manually generated on the fused planning MRI/CT image set by the treating 
physician according to contouring instructions specified on 
http://www.rtog.org//corelab/contouringatlases/hippocampalsparing.aspx . 
Hippocampal avoidance region (Hippocampi_05) will be generated by three-
dimensionally expanding the hippocampal contours by 5 mm. Bilateral hippocampal 
contours will be subdivided into Left (Hippo_L) and Right (Hippo_R) hippocampi. 
Due to variance in eye position between the CT and MRI, if possible, the left 
(OpticNerve_L) and right (OpticNerve_R) optic nerve should be contoured using the 
CT dataset only. Located above the pituitary fossa, the optic chiasm (OpticChiasm) 
includes both anterior and posterior limbs. It is best visualized on SPGR/MPR/TFE 
T1 MRI sequence, but should be confirmed on CT dataset due to potential variation 
in CT/MRI fusion.  
 
OAR constraints for hippocampal avoidance WBRT (37.5 Gy in 15 fractions) are 
shown below: 
 
Name of 
Structure  
Dosimetric 
parameter  
Per Protocol  
Variation 
Acceptable  
Notes  
 
D100%(Gy)  
≤ 11  
11 to 13  
Dose to 100% of 
Hippocampus  
 
Dmax(Gy)  
≤ 16  
16 to 20  
Dose to hottest 0.03 
cc volume of 

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Hippocampus  
OpticNerve_L  
Dmax(Gy)  
≤ 39 
39 to 42 Gy 
Dose to hottest 0.03 
cc volume of 
OpticNerve_L  
OpticNerve_R  
Dmax(Gy)  
≤ 39  
39 to 42 Gy 
Dose to hottest 0.03 
cc volume of 
OpticNerve_R  
OpticChiasm  
Dmax(Gy)  
≤ 39  
39 to 42 Gy 
Dose to hottest 0.03 
cc volume of 
OpticChiasm  
  
OAR constraints for hippocampal avoidance WBRT (30 Gy in 10 fractions) are 
shown below: 
 
Name of 
Structure  
Dosimetric 
parameter  
Per Protocol  
Variation 
Acceptable  
Notes  
 
D100%(Gy)  
≤ 9  
9-10 Gy 
Dose to 100% of 
Hippocampus  
 
Dmax(Gy)  
≤ 16  
16 to 17 Gy 
Dose to hottest 0.03 
cc volume of 
Hippocampus  
OpticNerve_L  
Dmax(Gy)  
≤ 33 
33 to 37.5 Gy 
Dose to hottest 0.03 
cc volume of 
OpticNerve_L  
OpticNerve_R  
Dmax(Gy)  
≤ 33  
33 to 37.5 Gy 
Dose to hottest 0.03 
cc volume of 
OpticNerve R  
OpticChiasm  
Dmax(Gy)  
≤ 33  
33 to 37.5 Gy 
Dose to hottest 0.03 
cc volume of 
OpticChiasm  
  
 
In optimizing planning, the following treatment-planning priorities should be 
followed: 
1. OpticChiasm 
2. OpticNerve_L or OpticNerve_R 
3. Hippocampus 
4. PTV_3000 
5. Lens_L or Lens_R 
In the event that an OAR with higher priority than PTV cannot be constrained within 
Unacceptable Deviation limits, then D98% and/or V30Gy for PTV should be lowered 
to Variation Acceptable range to ensure that the OAR with higher priority does not 
exceed Unacceptable Deviation limits. Please contact the study PI (or representative) 
if there are challenges meeting above. 

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5.1.2.6    Documentation Requirements 
 
The following documents should be submitted to the PI at the University of Maryland 
• Radiation Total Dose  
• Radiation Dose per Fraction 
• Radiation Number of fractions 
• Radiation Technique: 3D-CRT or IMRT/VMAT/Tomotherapy 
• Use of Hippocampal avoidance: Yes or No 
• Radiation Start Date 
• Radiation Completion Date 
• Treatment Interruptions/Delays 
• Acute on-treatment toxicity with grades 
• RT plan report with dose to organs at risk, if applicable. 
• Dexamethasone pill diary during WBRT and for three weeks post-WBRT (DLT 
assessment period) 
 
5.1.2.7 Compliance Criteria 
 
The planned protocol treatment should be completed without any unplanned breaks/ 
interruptions.  Dose delay/modification table has been noted in section 7.  
 
5.1.2.8 Radiation Adverse Events 
 
Acute (≤ 90 days from treatment start): Expected adverse events include hair loss, 
erythema of the scalp, headache, nausea and vomiting, eye/ear irritation, mucositis, 
taste/salivary changes, loss of appetite, fatigue, lethargy, and transient worsening of 
neurological deficits.   
 
Late (> 90 days from treatment start): Possible adverse events include radiation 
necrosis, cognitive dysfunction, visual difficulties, accelerated atherosclerosis, and 
radiation-induced neoplasms.  
 
5.1.2.9 Radiation Adverse Event Reporting  
See Section 8 for Adverse Event Reporting  
 
 
5.2 
Definition of Dose-Limiting Toxicity 
 
Dose-limiting toxicity will be defined as any grade 3 or more non-hematological toxicity 
requiring more than 5-day interruption in therapy or any grade 4 or higher hematological 
toxicity that is attributable to the M6620 (VX-970, berzosertib) and/or whole brain 
radiotherapy. 
 
DLTs will be assessed from the day of the start of WBRT until 3 weeks post completion 

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of WBRT. 
 
Management and dose modifications associated with the above adverse events are outlined 
in Section 6. 
 
 
5.3 
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.  Concomitant 
administration with strong inhibitors or inducers of CYP3A4 should be avoided. 
Sensitive substrates of CYP3A4 should be used with caution. Because of the potential for 
drug interactions through CYP3A4, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with 
the potential for drug interactions.  The study team should check a frequently-updated 
medical reference for a list of drugs to avoid or minimize use of.  Appendix C (Patient 
Drug Information Handout and Wallet Card) should be provided to patients. 
 
M6620 (VX-970, berzosertib) is a moderate inhibitor of P-gp and BCRP.  It is a P-gp 
substrate but not BCRP.  Based on in vitro data, there is low risk of drug-drug interaction 
with OATP1B3 and BCRP. Use caution when administered with sensitive substrates of 
OATP1B3 and BCRP transporters. 
 
Ongoing phenytoin should be either discontinued if clinically safe or transitioned to non-
enzyme-inducing-antiepileptics like Levetiracetam with a 8-day washout period (half-life 
18-22 hours, time to steady-state 4-8 days) prior to first dose of M6620 (VX-970, 
berzosertib) (7-days prior to WBRT). 
 
VX 970 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.  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). 
 
Standard measures (e.g. antihistamines and/or steroids) may be used to manage infusion 
reactions that may include pruritis, flushing, chills/rigors, urticaria/rash, headache, 
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recurrence of these symptoms in subsequent administrations, appropriate desensitizing 
measures prior to the administration of the study drug may be employed (e.g., 
premedication with 200 mg hydrocortisone approximately 60 minutes before infusion and 
4 mg of chlorphenamine approximately 30 minutes before infusion; alternative anti-
histamine and steroid combinations may be considered).  If standard procedures to limit 
symptoms of an infusion reaction are insufficient, then the infusion time may be extended 
beyond 60 minutes but no more than 90 minutes.   
 
Serious acute hypersensitivity reactions can occur within minutes of re-exposure of 
M6620 (VX-970, berzosertib).  This may include hypotension and mental status changes.  
These require immediate discontinuation of the inciting infusion and administration of IV 
corticosteroid and anti-histamine with IV fluids and oxygen as needed. 
 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) and documented on each site’s source 
documents as concomitant medication.  
 
Patients with symptoms, neurologic signs or imaging evidence of edema or mass effect 
should be placed on dexamethasone at the time of brain metastasis diagnosis.  The 
recommended starting dose should be 8-16 mg per day of dexamethasone in four divided 
doses or equivalent doses of other types of glucocorticoids.   For this patient population, 
variations in the amount and frequency of steroid usage are anticipated.  Per standard of 
care, the least amount of steroid necessary is used.  Hence, it is not appropriate to define a 
uniform stable dose of steroid for all patients accrued to the clinical study.  It is also 
noted that M6620 (VX-970, berzosertib) pre-medication is with dexamethasone.   
Patients will record the use of steroid medications using the steroid medication diary in 
Appendix D from time of consent through the DLT assessment period (week 6 for Group 
1 patients, week 8 for Group 2 patients). 
 
Nevertheless, to reduce/limit any potential PK impact of the concurrent use of 
dexamethasone, the maximum dose of dexamethasone for the patients at the time of the 
start of WBRT will be restricted to 8 mg per day or lower (2 mg qid,  4 mg bid or 8 mg 
once a day).  Patients needing more than 8 mg dexamethasone on the day of the start of 
WBRT will not be eligible to participate in the study.  Patients already accrued in the 
study at a dose of 8 mg or less who subsequently need more than 8 mg of dexamethasone 
per day while undergoing study treatment should be reported to the study PI.  This will be 
recorded as an AE.  Steroids will be continued without taper until the whole brain 
radiation therapy is completed.   
 
At the completion of WBRT, a steroid taper should be initiated provide that the patient 
does not have persistent symptoms related to edema or mass effect from brain metastases.  
Every four days, the dose should be lowered as follows: 
 

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8 mg starting dose* 
Duration 
2 mg  
four times a day  
4 mg  
two times a day  
Throughout the course of WBRT 
2 mg  
twice daily 
2 mg  
twice daily 
4 days 
1 mg 
 twice daily 
1 mg  
twice daily 
4 days 
1 mg  
once daily 
1 mg  
once daily 
4 days 
 1 mg  
every other day 
1 mg  
every other day 
4 days 
Discontinue 
 
 
*If the daily dose is < 8 mg per day, then maintain the same dose during WBRT and 
thereafter reduce the dose by half every 4 days until 1 mg every other day times 4 days 
and then stop. 
 
In patients who cannot tolerate taper and/or cessation of steroids, the steroid dose will be 
maintained at the lowest dose consistent with good medical practice.  Patients on steroids 
are recommended to receive gastritis prophylaxis and monitoring/treatment for 
oropharyngeal candidiasis. 
 
Anticonvulsant usage and dosage should be noted at the time of study entry, at each 
follow-up evaluation and at any changes in medication use.   Please refer to section 6.4 
for choice of anticonvulsant therapy. 
 
Patients will be allowed to initiate systemic therapy per clinician preference 3 weeks after 
the last fraction of WBRT. 
 
 
5.4 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment (WBRT + M6620 
(VX-970, berzosertib)) will be planned for 2-3 weeks followed by 2 weeks for observation 
of acute toxicity and 6-months from the completion of WBRT for delayed toxicity or until 
one of the following criteria apply: 
 
• 
Inter-current illness that prevents further administration of treatment, 
 
• 
Unacceptable adverse event(s) 
 
• 
Patient decides to withdraw from the study, or 
 

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• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
• 
Patients already accrued in the study at a daily dose of 8 mg or less of 
dexamethasone who subsequently need more than 8 mg of dexamethasone per 
day while undergoing study treatment should be reported to the study PI.  This 
will be recorded as an AE. 
5.5 
Duration of Follow Up 
 
Patients will be followed for up to two years from the study registration or until death, 
whichever occurs first.  From the date of completion of WBRT, follow-ups would be 
done through clinic visits every 2 months (± 1 week) for the first 6 months, every 3-4 
months (± 2 weeks) for the next 6 months and every 6 months (± 3 weeks) for the next 
one year.  After the first DLT assessment visit (the primary endpoint), the clinic visits can 
be performed at an outside institution if appropriate clinical staff is available to complete 
adverse event, neurocognitive testing and QOL assessments. Neurocognitive testing may 
also be performed by the study team through videoconferencing, if feasible. , After 6 
months, the clinic visits may be replaced by phone calls or videoconference or visits at an 
outside institution.   Follow up notes or documentation of phone calls must be included in 
the study chart.  Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
Follow-up MRI at 6 months (± 2 weeks) from the completion of WBRT is required to 
assess intracranial treatment response and disease control.  As guided by institutional 
practices, MRIs performed are also recommended during follow-up visits every 2 months 
(± 1 week) for the first 6 months and every 3-4 months (± 2 weeks) for the next 6 months 
from the completion of WBRT.  If progressive disease is found in the brain by MRI, then 
subsequent MRI scans of the brain will be done off study as per clinical standard of care. 
 
5.6 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  
The reason for study removal and the date the patient was removed must be documented 
in the Case Report Form. 
 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose de-escalation will be pursued if patients develop a significant related AE as below. 
 
No intra-patient dose-escalation will be performed 
 
Dose delays (for M6620 (VX-970, berzosertib) with or without WBRT) are allowed for a 
maximum of two weeks if patient develops any grade 3 or higher toxicity. 
 

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Any Adverse Event 
Management/ 
Next Dose for M6620 (VX-970, 
berzosertib) 
Management/ 
Next Dose for WBRT 
≤ Grade 1 
(any toxicity) 
No change in dose 
No change in dose 
Grade 2 
(any toxicity) 
No change in dose 
No change in dose 
Grade 3 
(hematological 
toxicity) 
Hold* until Grade 2 or less 
hematological toxicity. 
Resume at a previous dose level 
that is a lower dose than the current 
level, if indicated. **‡ 
 No change in dose 
Grade 3 
(non-hematological 
toxicity) 
Hold* until Grade 2 or less 
non-hematological toxicity. 
Resume at a previous dose level 
that is a lower dose than the current 
level, if indicated. **‡ 
Hold* until Grade 2 or less.  
Resume treatment  
as originally planned 
Grade 4 
(any toxicity) 
Off protocol therapy 
Off protocol therapy. Once grade 2 
or less, then may consider re-start 
of whole brain radiation alone at 
the discretion of treating physician. 
*Patients requiring a delay of > 2 weeks should go off M6620 (VX-970, berzosertib). 
**Patients requiring > two dose reductions should go off M6620 (VX-970, berzosertib). 
‡ See Section 13.2.2 regarding the situation if Grade ≥ 3 DLT occurs at dose level 1. 
Adverse events to be managed per standard of care clinical recommendations. 
Please contact the PI and Study Statistician by email or phone to get information on the 
previous dose level that is a lower dose than the current level. The study team will also 
regularly update information on the accrued dose level on the cancer.gov website (and/or 
institutional web portal, information on which will be provided to each participating 
institution). 
 
 
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 7.1) and the characteristics of an observed AE 
(Sections 7.2 and 7.3) will determine whether the event requires expedited reporting 
via the CTEP Adverse Event Reporting System (CTEP-AERS) in addition to 
routine reporting. 
 

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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 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 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. 
 
• 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. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 

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7.3.1 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 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 

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7.3.4 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 
CTCAE Grade 
at which the 
event will not 
require 
expedited 
reporting1 
Gastrointestinal 
disorders 
Abdominal pain or diarrhea 
or gastroesophageal reflux 
disease or dry mouth 
Grade 1 or 2 
General Disorders 
and administration 
site conditions 
Fatigue  
Grade 1 or 2 
General Disorders 
and administration 
site conditions 
Flu-like symptoms 
Grade 1 
Investigations 
Weight loss 
Grade 1 or 2 
Metabolism and 
Nutrition Disorders 
Anorexia 
Grade 1 or 2 
Musculoskeletal and 
connective tissue 
disorders 
Arthralgia 
Grade 1 or 2 
Injury, Poisoning  
and Procedural 
Complications 
Radiation Dermatitis 
Grade 1 or 2 
Skin and 
Subcutaneous 
Connective Tissue 
Disorder 
Scalp Alopecia or dry skin 
Grade 1 or 2 
Skin and 
Subcutaneous 
Connective Tissue 
Disorder 
Hyperhidrosis 
Grade 1 

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Respiratory, Thoracic 
and Mediastinal 
Disorders 
Pharyngeal mucositis 
Grade 1 or 2 
Ear and Labyrinth 
Disorder 
External or middle ear 
inflammation 
Grade 1 or 2 
Hearing Loss 
Grade 1 
Tinnitus 
Eye Disorder 
Conjunctivitis 
Grade 1 or 2 
Blurred vision 
Grade 1 
Nervous System 
Disorder 
Dysgeusia or Headache or 
Lethargy 
Grade 1 or 2 
Nervous System 
Disorder 
Dizziness 
Grade 1 
Vascular disorders 
Hypotension 
Grade 1 or 2 
 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
• Hospitalizations for respite care 
• Planned hospitalizations required by the protocol 
• Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration) 
• Hospitalization for elective procedures unrelated to the current disease and/or treatment on 
this trial 
• Hospitalization for administration of study drug or insertion of access for administration of 
study drug 
• Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in 
place before study entry 
• Hospitalization, or other serious outcomes, for signs and symptoms of progression of the 
cancer. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 

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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. 
 
7.5 
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:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6 
Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine AE reporting unless otherwise specified. 
 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 M6620 (VX-970, berzosertib) (NSC 780162) 
 
Other Names: VRT-0768079, MSC2527093A, VX-970 
 
Chemical Name:  5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4-
((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine 

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Classification: ATR inhibitor  
 
 
CAS Registry Number:  1232416-25-9 
 
Molecular Formula: C24H25N5O3S 
 
M.W.: 463.55 Da 
 
Mode of Action: Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is an apical 
regulator of checkpoint pathways triggered by DNA damage.  The DNA damage response (DDR) is 
regulated by ATR kinase and ataxia telangiectasia mutated (ATM) kinase, which are recruited to 
distinct DNA damage structures.  M6620 (VX-970, berzosertib) disrupts ATR-mediated DNA 
damage response signaling and leads to sustained accumulation of DNA damage in cancer cells co-
treated with DNA-damaging agents. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
 
 
  
PMBAfterHours@mail.nih.gov 
 
  
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
  
 
  
 
  
 
 
  
 
Route of Administration: Intravenous (IV) infusion. 
 

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Method of Administration: Prior to administration the solution should be given one hour at 
ambient temperature to warm up if stored refrigerated following preparation. Infuse over 60 minutes 
using an infusion set containing low-sorption or non-PVC, DEHP-free tubing and an in-line 0.2 
micron filter. 5% dextrose in water solution must be used for IV line priming and flushing. M6620 
(VX-970, berzosertib) should not come in contact with 0.9% Sodium Chloride due to 
incompatibility. The infusion time may be extended beyond 60 minutes (as tolerated) but no 
more than 90 minutes if standard procedures to limit symptoms of an infusion reaction are 
insufficient or if the total volume of the infusion exceeds 600 mL.  To minimize the possibility of 
phlebitis, M6620 (VX-970, berzosertib) should be administered through a large bore catheter 
into a large caliber peripheral vein or central venous access.  
 
Patient Care Implications: Monitor for infusion site reactions, irritation, and phlebitis. M6620 
(VX-970, berzosertib) absorbs in the UV-visible radiation spectrum and is widely distributed 
including skin, so patients receiving M6620 (VX-970, berzosertib) should take protective 
measures to minimize sun exposure. 
 
Women of childbearing potential and men should use appropriate contraception while on study 
drug and for 6 months after discontinuation of M6620 (VX-970, berzosertib). 
 
Potential Drug Interactions: M6620 (VX-970, berzosertib) is primarily metabolized by 
CYP3A4.  M6620 (VX-970, berzosertib) has a low potential to inhibit CYP1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, and 3A4, and a moderate potential to reversibly inhibit CYP2E1.  The potential for 
M6620 (VX-970, berzosertib) to induce CYP450 enzymes CYP1A2, 2B6, and 3A4 at 
concentrations up to 6 µM is low.  Concomitant administration with strong inhibitors or inducers 
of CYP3A4 should be avoided. Sensitive substrates of CYP3A4 should be used with caution. 
 
M6620 (VX-970, berzosertib) is a weak/moderate inhibitor of UGT1A1, UGT1A14, UGT1A9, 
UGT2B15, and UGT2B17.  UGT2B7, UGT1A3, and UGT1A6 were weakly or not inhibited.  
M6620 (VX-970, berzosertib) is predicted to not inhibit significantly the metabolic clearance of 
SN-38 (active metabolite of irinotecan) at therapeutic exposures.   
 
M6620 (VX-970, berzosertib) is a moderate inhibitor of P-gp and BCRP.  It is a P-gp substrate 
but not BCRP.  Based on in vitro data, there is low risk of drug-drug interaction with OATP1B3 
and BCRP. Use caution when administered with sensitive substrates of OATP1B3 and BCRP 
transporters. 
 
Availability 
 
M6620 (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 
 

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8.1.2.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents.  The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-
supplied investigational agents for the study should be ordered under the name of one 
lead investigator at that institution. 
 
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.   
8.1.2.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
oral agents received from DCTD using the NCI Drug Accountability Record Form 
(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 
 
8.1.2.3 
Investigator Brochure Availability  
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB Online Agent Order Processing (OAOP) 
application.  Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status,a “current” password, and active person registration status.  Questions about IB 
access may be directed to the PMB IB coordinator via email. 
 
8.1.2.4 
Useful links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application:  
https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account:  
https://eapps-ctep.nci.nih.gov/iam/ 
• CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov  

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• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Exploratory Biomarker Studies - Performed for Group 2 at the University of 
Maryland Only  
 
9.1.1 Plasma Pharmacokinetics 
The PK of M6620 (VX-970, berzosertib) administered as a single agent or in 
combination with other chemotherapeutic agents has been tested and described in the 
Study 001 and 002.  Exposure (Cmax and AUC) tended to be approximately linear across 
the studied doses with no accumulation noted during the once weekly scheduling.  Mean 
whole blood AUC were similar with low to moderate inter-subject variability in each 
dose group.   
 
We do not anticipate any changes in PK with the addition of WBRT.  Hence, extensive 
blood PK studies are not needed in Group 1.  
 
Per the Investigator Brochure 2013, due to minimal inhibition or induction of cytochrome 
(CYP) 450 isozymes by M6620 (VX-970, berzosertib) a low potential for drug-drug 
interactions was predicted. However, since strong inducers or inhibitors of CYP3A4 may 
alter M6620 (VX-970, berzosertib) kinetics and blood levels, all patients on phenytoin 
based anti-seizure medications will be transitioned to non-enzyme-inducing-antiepileptics 
like Keppra (Levetiracetam) with a 8-day washout period (half -life 18-22 hours, time to 
steady-state 4-8 days) prior to first dose of M6620 (VX-970, berzosertib) (7-days prior to 
WBRT). 
 
Please see section 5.3 pertaining to the use of dexamethasone for patients accrued into the 
study. 
 
Group 2, on the other hand, is a novel translational cohort, where patients will undergo 
craniotomy 2-4 hours after M6620 (VX-970, berzosertib) administration.  This provides a 
unique opportunity to test the drug PK/PD effects intracranially. Additionally, for this 
small cohort, limited PK testing will be performed in week 1 of WBRT + M6620 (VX-
970, berzosertib).  
 
 
9.1.1.1 
Hypothesis and Rationale: 
 
Hypothesis:  The ratio of CSF: plasma M6620 (VX-970, berzosertib) levels and 
craniotomy tumor tissue: plasma M6620 (VX-970, berzosertib) levels will be 

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correlated with the radiological response and intracranial disease control. 
 
Rationale: This cohort was specifically designed to test intra-cranial tumor and CSF 
penetration in setting of known brain metastases, which may impair the blood-brain 
barrier.  In this cohort, intra-operative plasma, CSF and tumor tissue samples will be 
tested for drug concentration.  This will provide a direct estimation of intra-cranial 
and intra-lesional drug penetration in humans, which may be used to establish a PD-
PK relationship and also guide the appropriate choice of systemic dose.  The CSF and 
tumor penetration data will be obtained without any added risk to the patient since the 
patients will be scheduled to undergo a craniotomy to surgical de-bulk an intracranial 
mass per clinical indications. 
 
Even if a definite PD-PK relationship is difficult to discern due to small patient 
number and the challenges as noted above, the mere observation of CSF and tumor 
penetration could also help direct efforts in other intra-cranial histologies including 
high-grade gliomas. 
 
M6620 (VX-970, berzosertib) plasma PK will be performed to add to the present 
knowledge base of M6620 (VX-970, berzosertib) PK, to correlate exposure to PD 
metrics and to document any accumulation due to the more frequent administration of 
M6620 (VX-970, berzosertib) (twice weekly). 
 
9.1.1.2  
Assay Validity and Appropriateness for Study 
 
Plasma, CSF and tissue concentrations of M6620 (VX-970, berzosertib) will be 
measured with a method developed by Vertex and currently being implemented in the 
University of Pittsburgh cancer Institute (UPCI) PK core by Dr. Jan Beumer. SOPs 
for the methods will be included as an appendix to this protocol document, once 
available.  
 
 
9.1.1.3 
Performance Site 
 
The pk assay will be performed at the UPCI PK core by Dr. Jan Beumer. Per the facts 
noted at the facility’s website, the UPCI Cancer Pharmacokinetics and 
Pharmacodynamics Facility (CPPF) provides accessible, economical, comprehensive, 
and state-of-the-art pharmacology research services that support preclinical and 
clinical research programs at UPCI and medical institutions nationwide. The CPPF 
has developed, validated and implemented assays for (but not limited to): abiraterone, 
alisertib, ATRA, belinostat, bortezomib, busulfan, cabozantinib, celecoxib, DMS612, 
docetaxel, erlotinib, fluorouracil, imatinib, indenoisoquinoline 400, 776, 744, iso-
fludelone, ixabepilone, lapatinib, nilotinib, paclitaxel, phenyl-isothiocyanate, 
platinating agents carboplatin, cisplatin and oxaliplatin, temozolomide, 
tetrahydrouridine, vitamin D3, veliparib, vincristine, vorinostat, zebularine, and 
zileuton. The CPPF supports clinical research through multiple programs at UPCI, 
including studies within the Cancer Therapeutics Program, Melanoma Program and 

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Lung Cancer Program. Most prominent is the role of the CPPF in the successful re-
competition of the CTEP phase I grant (NCI ET-CTN with Phase I Emphasis at 
UPCI; UM1-CA186690).Outside of UPCI, the facility's quality and capacity has been 
recognized through its designation as the central reference analytical and 
pharmacokinetic modeling resource for phase IV clinical studies of imatinib, 
nilotinib, dasatinib, and ixabepilone, and its continued serving as the pharmacology 
core laboratory for NRG and Alliance. In addition, the CPPF has served as the NCI 
reference laboratory to support phase 1 studies involving veliparib and vorinostat, and 
is currently serving as the reference laboratory for a belinostat hepatic dysfunction 
study (quantitating belinostat and 5 metabolites), and a veliparib hepatic and renal 
dysfunction study (quantitation of veliparib and major metabolite M8).    
 
9.1.1.4 
Justification of the Number of Patients and Samples 
Meaningful conclusions regarding the impact of drug exposure can only be drawn for 
those patients in whom the assays are performed.  Accordingly, the plan is to measure 
serum pharmacokinetics in all six patients of the group 2. The low number was 
chosen considering the logistics of arranging for a study screening, consent, 
registration prior to the craniotomy, which may need to be performed on an 
urgent/emergent basis limiting the number of potentially eligible patients. This is an 
exploratory cohort with the primary goal to assess in vivo CSF and tumor penetration 
of the drug and to measure the proportion of cases with elevated DNA damage repair 
biomarkers. With a sample size of N=6, we will have 80% power to reject the null 
hypothesis of a true marker response rate of 40% at the 5% significant level if we 
observe zero patients with a marker response among the six.   
 
  
9.1.1.5 
Description of Biological Samples Required for Assay 
 
Sample Collection Schedule 
Plasma, CSF and tumor samples will be collected 2-4 hours after M6620 (VX-970, 
berzosertib) administration during the craniotomy procedure. Plasma samples will 
also be collected on both days of M6620 (VX-970, berzosertib) administration in 
week 1 of subsequent WBRT only at pre-infusion and 2h 50 min after start of M6620 
(VX-970, berzosertib) infusion. Blood samples to be collected through a peripheral 
blood draw. Samples should be drawn from the opposite arm if infusion is a 
peripheral infusion.  
 
Handling of Specimens 
 
Blood samples: Collect blood samples in EDTA vacutainer tubes.  Invert the tubes 
several times to mix blood with anticoagulant and place on ice.  Samples should be 
centrifuged within 20 min at approximately 1000 x g in a refrigerated tabletop 
centrifuge so as to produce plasma. The resulting plasma should be aspirated from the 
tubes, placed into appropriately-labeled microcentrifuge tubes, and stored at -70 °C. 
 

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CSF and Tumor Tissue: CSF and tumor may be collected in cryovials.  Document 
the exact start and stop times of each infusion and exact times of sample draws.  CSF 
and tumor collected in cryovials should be stored at stored at -70 °C. 
 
Shipment of Specimens 
Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, L x W x H). 
Please organize the samples by patient and time point in the box.  Do not store in 
plastic bags (they break on dry-ice and labels will detach).  A copy of each of the 
pharmacokinetic sample collection forms for the respective patients or a sample list 
should be included with each shipment.  To prevent problems with illegible writing 
on tubes, consider numbering them and numbering samples on the sample sheet.  
Note the study number, PI, and the drugs used/to be measured.  A name, phone 
number and email address should be included with samples so that receipt can be 
acknowledged. 
 
Please notify the lab by telephone (412-623-3248) or fax (412-623-1212) at least 24 
hours prior to shipment. 
  
All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain the samples in a frozen state (if samples are to be 
shipped frozen).  Shipment of samples must comply with appropriate regulations as 
specified by the carrier. At a minimum, all samples must be packaged within two 
containers with absorbent material between containers to control any spill or leakage. 
The outer container must be puncture-resistant (e.g. cardboard mailing tube, 
corrugated cardboard box). A biohazard sticker must be affixed to both the inner and 
outer containers. 
 
All specimens are to be shipped on Monday, Tuesday or Wednesday to: 
 
Cancer Pharmacokinetics and Pharmacodynamics Facility 
University of Pittsburgh Cancer Institute 
Room G27 Hillman Research Laboratories 
5117 Centre Avenue 
Pittsburgh, PA 15213. 
 
 
 
9.1.2 pATR T1989, pCHK1 S345 and RAD51 multiplex 
 
9.1.2.1 
Hypothesis and Rationale 
 
Hypothesis: M6620 (VX-970, berzosertib) is expected to inhibit ATR 
autophosphorylation which will impact expression of pATR T1989 
(autophosphorylation site critical for ATR function), pCHK1 S345 (an additional 
marker of baseline replication stress and downstream ATR activity) and RAD51 

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(which plays a key role in the homologous recombination repair pathway) in brain 
metastases from NSCLC. 
 
Rationale: Due to the extreme and unjustifiable risk of obtaining intra-cranial tumor 
biopsy prior to M6620 (VX-970, berzosertib) administration, this study will have a 
novel exploratory cohort (group 2) wherein a single dose of M6620 (VX-970, 
berzosertib) will be administered 2-4 hours prior to the planned craniotomy followed 
by obtaining tumor sample at the time of craniotomy. This will allow assessment of 
assess drug pharmacodynamic (PD) effect in vivo within the tumor and to correlate 
with the CSF and tumor penetration. 
 
It is noted that a definite PD relationship through the measurement of pATR T1989, 
pCHK1 S345 and RAD51 foci without baseline estimate of their expression is 
difficult to establish. As an alternate, a parallel study at the PI’s institution would be 
conducted wherein fresh tumor biopsies from 12 matched control patients who are 
scheduled to undergo a craniotomy but not accrued to the proposed study will be 
collected as a separate IRB approved study for assessments of pATR T1989, pCHK1 
S345 and RAD51 multiplex foci. Expression of these markers will be compared with 
the data from 6 patients in the group 2 of the proposed study.  The samples will be 
forwarded to the same central laboratories that will be performing study on the 
current protocol.. Depending on the evolving understanding of drug effects in 
combination with other chemotherapy agents or radiation, additional biomarkers may 
be added in future, pending approval and funding.     
 
9.1.2.2 
Assay Validity and Appropriateness for Study 
pATR T1989, pCHK1 S345 and RAD51 levels will be measured by multiplex 
immunofluorescence assay. Details regarding the assay validity and appropriateness 
for the study will be made available once the sequencing core has been confirmed by 
the M6620 (VX-970, berzosertib) Project Team leadership. 
 
9.1.2.3 
Performance Site 
Multiplex immunofluorescence assay will be performed in the laboratory of Dr 
Deborah Wilsker at PADIS, DCTD/NCI. 
 
9.1.2.4 
Justification of the Number of Patients and Specimens 
Being an ancillary/exploratory study, meaningful conclusions regarding the impact of 
drug exposure can only be drawn for those patients in whom the assays are 
performed.  Accordingly, the plan is to measure expression of these PD markers in all 
the 6 patients from group 2.  As noted above in PK measurements for group 2, the 
low number was chosen considering the logistics of arranging for a study screening, 
consent, registration prior to the craniotomy, which may need to be performed on an 
urgent/emergent basis limiting the number of potentially eligible patients. Even if a 
definite PD-PK relationship is difficult to discern due to small patient number and the 
challenges as noted above, the mere observation of CSF and tumor penetration could 
also help direct efforts in other intra-cranial histologies including high-grade gliomas. 

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9.1.2.5 
Description of Biological Samples Required for Assay 
Baseline (pre-treatment) tumor tissue samples will be obtained by using archived 
samples or a fresh biopsy samples that will be obtained only as part of standard of 
care clinical process.  Tumor samples will be collected 2-4 hours after M6620 (VX-
970, berzosertib) administration during the craniotomy procedure. This will be 
performed on formalin-fixed, paraffin-embedded cell pellets. No additional biopsy 
will be done specifically for the correlative studies; there is no additional risk to the 
patient. 
 
Information on handling and shipment of specimens will be made available once the 
sequencing core has been assigned by the M6620 (VX-970, berzosertib) Project Team 
leadership. Appropriate SOPs will be provided as an appendix. 
 
 

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10. 
STUDY CALENDAR 
 
Pre-treatment tests and exams must be completed, eligibility confirmed and the patient registered 
within 6 weeks; baseline imaging evaluations are to be conducted within 4 weeks before the start 
of the study treatment.  Study treatment should begin within 2 weeks after registration.  Vital 
signs including performance status should be obtained 1 week prior to the start of study 
treatment.  In the event that the patient’s condition is deteriorating, laboratory evaluations should 
be repeated within 48 hours prior to initiation of the next dose of M6620 (VX-970, berzosertib). 
 
Group 1: 
 
Pre- 
study 
Week  
1 
Week  
2 
Week  
3 
End of 
Week 6 4 
Follow 
Up 
Visits g 
Off-
Study e 
Informed Consent 
X 
 
 
 
 
 
 
Radiation  
Planning 1 
X 
 
 
 
 
 
 
WBRT 
 
X a 
X 
X 
 
 
 
M6620 (VX-970, 
berzosertib) 
 
V b 
V 
V 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Physical  
Exam 2 
X 
X 
X 
X 
X 
X 
X e 
CBC with diff, 
platelets 
X 
 
X 
 
X 
 
 
Serum chemistry c 
X 
 
X 
 
X 
 
 
Serum or urine 
pregnancy test  3 
X 
 
 
 
 
 
 
ECG 5  
X 
 
 
 
 
 
 
Neurocognitive  
Testing R 
X 
 
 
 
X 
X h 
 
Quality of Life 
evaluation R 
X 
 
 
 
X 
X h 
 
Adverse event 
evaluation 
 
X 
X 
X 
X 
X 
X e 
MRI f 
X 
 
 
 
 
X d 
X e 
Patient Steroid Diary i 
X 
X 
X 
X 
X 
 
 

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1.   Radiation planning may be performed prior to study registration as per standard of care. 
Patients can receive WBRT at a community site/satellite location within the health system 
where the study is approved as long as the study agent is received at the site approved to 
dispense/administer the study drug, and patient can be monitored closely for toxicities and 
undergo necessary HVLT-R and FACT-BR testing. 
2.   Physical exam includes medical history, concurrent medications, vital signs (pulse, blood 
pressure, temperature), weight, performance status and at pre-treatment only, height. 
3.   Perform for females of child bearing potential only. 
4.   The end of week 6 is the DLT assessment period and has a window of ± 3 days. 
5.   Perform as clinically indicated 
a. WBRT schedule as noted in the protocol, to be started on Day 0 
b. M6620 (VX-970, berzosertib) dose and administration as assigned in the schedule of the 
dose-escalation schema.  The first dose of M6620 (VX-970, berzosertib) is to start 18-30 
hours after first fraction WBRT but before the second fraction of WBRT.  It is recommended 
to keep as close to 24 hours gap as possible between the first fraction of radiation and the 
first dose of M6620 (VX-970, berzosertib).  Record the time of administration of radiation 
and M6620 (VX-970, berzosertib).  The second and subsequent doses of M6620 (VX-970, 
berzosertib) will be administered after the day’s administration of radiation treatment with no 
specified time interval.  The timing of radiation and M6620 (VX-970, berzosertib) will be 
strictly recorded and monitored by the data monitoring committee.   
The study protocol will allow a Monday through Thursday start of WBRT, with M6620 (VX-
970, berzosertib) administered as follows: 
• Monday or Thursday WBRT start: M6620 (VX-970, berzosertib) administered Tuesday 
and Friday 
• Tuesday WBRT start: M6620 (VX-970, berzosertib) administered Wednesday and Friday 
in week 1 followed by Tuesday and Friday from week 2 onwards  
• Wednesday WBRT start: M6620 (VX-970, berzosertib) administered Thursday in week 1 
and then Monday and Thursday from week 2 onwards. 
c. Comprehensive metabolic profile (liver function tests including total bilirubin, serum 
albumin, total protein,  AST, ALT, alkaline phosphatase, BUN and serum creatinine) 
therapy.   
d. Follow-up MRI at 6 months (± 2 weeks) from the completion of WBRT is required.  As per 
institutional standard practices, MRIs are also recommended during follow-up visits every 2 
months (± 1 week) for the first 6 months and every 3-4 months (± 2 weeks) for the next 6 
months from the completion of WBRT. 
e. To be performed only if feasible if the patient is removed from the study. 
f. 
For patients accrued to dose level 3 and higher, please send anonymized pre- and post-
treatment scans via FTP or hard copy CD to the study PI for central review of response 
(Section 11.1.7). 
g. From the date of completion of WBRT, follow-up visits are performed every 2 months (± 1 
week) for the first 6 months and are recommended  every 3-4 months (± 2 weeks) for the 

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next 6 months then every 6 months (± 3 weeks) for the next one year. After the DLT 
assessment visit at the end of week 6, the clinic visits can be performed at an outside 
institution if appropriate clinical staff is available to complete adverse event, neurocognitive 
testing and QOL assessments. Neurocognitive testing may also be performed by the study 
team through videoconferencing, if feasible. After the first 6 months of follow up, clinic 
visits may be replaced by phone calls or videoconference or visits at an outside institution.  
Follow up notes or documentation of phone calls or videoconferences must be included in the 
study chart.     
h. Neurocognitive and quality of life evaluation performed during follow-up visits every 2 
months (± 1 week) for the first 6 months from the completion of WBRT (for patients without 
intracranial progression). 
i. 
Patients must record steroid use from the time informed consent is signed throughout the 
DLT assessment period at the end of week 6 using the steroid medication dairy in Appendix 
D. 
R.    Research funded    
 
 

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Group 2: 
 
Pre-
study 
Pre-
Cranio-
tomy 
(Day 
0) 
Cranio-
tomy 
(Day 
0) 
Week 
2 k 
Week 
3 
Week 
4 
Week 
5 
End 
of 
Week 
8 4   
Follow 
Up 
Visits j 
Off-
Study 
e 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
M6620 (VX-
970, 
berzosertib) 
 
A a 
 
 
A b 
A 
A 
 
 
 
Craniotomy 
 
 
X 
 
 
 
 
 
 
 
Radiation 
Planning 1 
 
 
 
X 
 
 
 
 
 
 
WBRT 
 
 
 
 
X b 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Physical  
Exam 2 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
CBC with diff, 
platelets 
X 
 
 
X 
 
X 
 
X 
 
 
Serum 
chemistry c 
X 
 
 
X 
 
X 
 
X 
 
 
Serum or urine 
pregnancy test 3  
X 
 
 
 
 
 
 
 
 
 
ECG 5 
X 
 
 
 
 
 
 
 
 
 
Neurocognitive 
Testing R 
X 
 
 
 
 
 
 
X 
X k 
X 
Quality of life 
evaluation R 
X 
 
 
 
 
 
 
X 
X k 
X 
Adverse event 
evaluation 
 
 
 
X 
X 
X 
X 
X 
X 
X 
MRI h 
X 
 
 
 
 
 
 
 
X d 
X 
Archived  
biopsy tissue 
sample i 
X 
 
 
 
 
 
 
 
 
 
Fresh biopsy 
tissue sample 
 
 
X 
 
 
 
 
 
 
 
Pk  R 
 
 
X f 
 
X g 
 
 
 
 
 
Patient Steroid 
Diary l 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

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1. Radiation planning may be performed prior to study registration as per standard of care. 
2.   Physical exam includes medical history, concurrent medications, vital signs (pulse, blood 
pressure, temperature), weight, performance status and at pre-treatment only, height. 
3.   Perform for females of child bearing potential only. 
4.   The end of week 8 is the DLT assessment period and has a window of ± 3 days. 
5.   Perform as clinically indicated 
a.  First dose of M6620 (VX-970, berzosertib) to be administered at the identified RP2D, 2-4 
hours prior to the craniotomy 
b. WBRT to preferably start 10-20 days after surgery or as clinically indicated. M6620 (VX-
970, berzosertib) is to be administered during WBRT at the identified RP2D.  The first dose 
of M6620 (VX-970, berzosertib) is to start18-30 hours after first fraction WBRT but before 
the second fraction.   It will be recommended to keep as close to 24 hours gap as possible 
between the first fraction of radiation and the first dose of M6620 (VX-970, berzosertib).  
The timing of radiation and M6620 (VX-970, berzosertib) will be strictly recorded and 
monitored by the data monitoring committee.   See study calendar for group 1 for schedule of 
M6620 (VX-970, berzosertib) depending on the day of start of WBRT. 
c. Comprehensive metabolic profile (liver function tests including total and direct bilirubin, 
serum albumin, total protein, AST, ALT and alkaline phosphatase; BUN and serum 
creatinine)  
d. Follow up MRI at 6 months (± 2 weeks) from the completion of WBRT is required. As per 
institutional standard practices, MRIs are also recommended during follow-up visits every 2 
months (± 1 week) for the first 6 months then every 3-4 months (± 2 weeks) for the next 6 
months from the completion of WBRT. 
e. To be performed only if feasible if the patient is removed from the study. 
f. During the craniotomy procedure, tumor, plasma and CSF samples will be collected  
g.  Plasma samples will be collected for the first 2 doses of M6620 (VX-970, berzosertib) 
administered while on WBRT only.  Collect samples at these timepoints: before the start of 
M6620 (VX-970, berzosertib) infusion and at 2h 50 min after start of M6620 (VX-970, 
berzosertib) infusion. 
h. For patients who have a defined target lesion (other than the lesion surgically resected), 
please send anonymized pre- and post-treatment scans via FTP or hard copy CD to the study 
PI for central review of response (Section 11.1.7). 
i. Confirm availability of archived/fresh tissue sample available from the non-craniotomy site 
and will have fresh tumor tissue available from the planned craniotomy. 
j. From the date of completion of WBRT, follow-up visits performed every 2 months (± 1 
week) for the first 6 months then every 3-4 months (± 2 weeks) for the next 6 months then 

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79 
 
 
 
every 6 months (± 3 weeks) for the next one year. After DLT assessment visit, the clinic 
visits can be performed at an outside institution if appropriate clinical staff is available to 
complete adverse event, neurocognitive testing and QOL assessments. Neurocognitive 
testing may also be performed by the study team through videoconferencing, if feasible.  
After the first 6 months of follow-up, clinic visits may be replaced by phone calls or 
videoconference or visits at an outside institution.  Follow up notes or documentation of 
phone calls or videoconferences must be included in the study chart. 
k.  Neurocognitive and quality of life evaluation performed during follow-up visits every 2 
months (± 1 week) for the first 6 months from the completion of WBRT (for patients without 
intracranial progression) and M6620 (VX-970, berzosertib). 
l.  Patients must record steroid use from the time informed consent is signed throughout the 
DLT assessment period at the end of week 8 using the steroid medication dairy in Appendix 
D. 
 
R.   Research funded    
 
 
 
 

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10.1  Neurocognitive Evaluation  
 
10.1.1 Hopkins Verbal Learning Test (HVLT-R)  
The HVLT-R incorporates 6 different forms, helping to mitigate practice effects of 
repeated administrations.  Each form includes 12 nouns (targets) for memorization with 4 
words drawn from 3 semantic categories, which differ across the 6 forms.  Patients will 
be asked to recall from the list of 12 targets for 3 consecutive trials (immediate recall), 
identify the 12 targets from a list of semantically related or unrelated items (immediate 
recognition), and recall the 12 targets after a 20-minute delay (delayed recall).  Raw 
scores will be derived for total recall, delayed recall, retention (percentage retained), and 
a recognition discrimination index.  Each patient will serve as his/her own control, as the 
difference in scores obtained at baseline and at pre-specified post-treatment intervals will 
be calculated.  The HVLT-R is owned and copyright protected by Psychological 
Assessment Resources, Inc. (PAR).   Electronic distribution of the HVLT is not currently 
permitted by PAR; please send an email to the study PI, Dr Mohindra, University of 
Maryland, to request a paper copy of the HVLT prior to enrolling any patients (or to get 
information regarding procuring institutional copies for the study).  Future updates 
regarding electronic handling of these forms if allowed will be provided directly to the 
study teams, when available. Based on the copyright agreement with PAR, completed 
HVLT-R forms can be uploaded to NCI’s secure, password protected online portal, 
iMedidata RAVE (“web portal”). The uploaded forms should contain the original 
copyright notice on the form.  Access to the web portal shall be limited to authorized 
study personnel at the study site.  Completed HVLT-R forms shall not be printed or 
downloaded from the web portal.  Once uploaded to iMedidata RAVE, a hard copy of the 
completed HVLT-R forms should be mailed to the study PI.  
 
Study personnel administering the HVLT must be previously credentialed in performing 
neurocognitive testing through existing mechanisms within cooperative groups including 
but not limited to participation in a prior NRG or Alliance or any other cooperative 
group/multi-institutional study.  The PI may also approve other measures as applicable.  
Email a copy of the credential to the study PI, Dr Mohindra, at the University of 
Maryland.   This requirement is necessary before any patients can be enrolled into the 
study at the site, see Site Registration, section 4.2.2.  These assessments can be 
performed at an outside institution if appropriate research staff (credentialed and 
registered as a study team member prior to the evaluations) is available to complete 
adverse event and neurocognitive evaluation. 
 
Scoring of HVLT-R 
1. HVLT-R Delayed Recall 
Patient scores on the HVLT-R delayed recall section have an integer range from 0 
to 12 with lower scores indicating declining cognitive function.  The score is the 
number of words a patient can recall from a list of 12 words.  The change in score 
from baseline to 2-, 4- and 6- months ranges from - 12 to 12.  Change scores from 
1 to 12 indicate declining cognitive function.  A change score of 0 indicates 
preserved cognitive function.  Change scores from -1 to -12 indicate improved 

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cognitive function and are not expected. 
 
2. HVLT-R Free Recall 
Patient scores on the HVLT-R free recall section have an integer range from 0 to 
36 with lower scores indicating declining cognitive function. The score is the 
number of words a patient can recall from a list of 12 words in three trials. 
 
3. HVLT-R Delayed Recognition 
Patient scores on the HVLT-R delayed recognition section have an integer range 
from -12 to 12 with lower scores indicating declining cognitive function. The 
score is the number of correctly identified words from the list of 12 words minus 
the number of incorrectly identified words from the list of 12 words. 
 
10.2 
Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR) for Quality of 
Life (QOL) 
 
10.2.1 The FACT-BR  
 
The FACT-BR is a multidimensional, self-report QOL instrument specifically designed 
and validated for use with brain malignancy patients.  It is written at the 4th grade 
reading level and can be completed in 5 to 10 minutes with little or no assistance in 
patients who are not neurologically incapacitated.  It measures quality of life related to 
symptoms or problems across 5 scales: physical well-being (7 items); social/family well-
being (7 items); emotional well-being (6 items); functional well-being (7 items); and 
concerns relevant to patients with brain tumors (23 items).  Items are rated on a five-point 
scale: 0-“not at all”, 1- “a little bit”, 2-“somewhat”, 3-“quite a bit” and 4-“very much”. 
The measure yields information about total QOL, as well as information about the 
dimensions of physical well-being, social/family well-being, emotional well-being, 
functional well-being, and disease-specific concerns.  Six additional experimental items 
request information regarding how much each dimension affects QOL, using a "0" (not at 
all) to "10" (very much so) rating scale.  Patient scores on the FACT-Br will range from 0 
to 92 with lower scores indicating declining quality of life.  FACT-BR is self-
administered and does not require precertification.  It has been translated into 26 
languages and is available free of charge to institutions with the completion of an 
agreement to share data, accessible at: http://www.facit.org/facitorg/questionnaires.  
The assessments will be scored centrally by a blinded reviewer to avoid potential bias.  
The self-report of quality of life can be completed by the patient or the examiner and does 
not require pre-certification. 
 
Scoring of FACT-BR Assessments 
The change scores from pretreatment from baseline to 2, 4 and 6 months will be 
estimated.  A mean difference of 5 points represents a clinically meaningful change 
(CMC).  A difference of less than 5 will not be considered meaningful, even if it has 
statistical significance.   
  

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11. 
MEASUREMENT OF EFFECT 
 
Although the clinical benefit of M6620 (VX-970, berzosertib) has not yet been established, the 
intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient 
will be carefully monitored for tumor response and symptom relief in addition to safety and 
tolerability.  Patients with measurable disease will be assessed by standard criteria noted below.  
For the purposes of this study, patients should be evaluated at baseline and at 6 months (± 2 week) 
from the completion of WBRT. As guided by institutional practices, MRIs are also recommended during 
follow-up visits every 2 months (± 1 week) for the first 6 months and every 3-4 months (± 2 weeks) for 
the next 6 months from the completion of WBRT.  
 
All patients accrued in group 1 (except the first three dose-levels) will be included in the 
imaging objective. Based on the EWOC dose algorithm, patients accrued in the cohorts 
beyond the dose level 3, are anticipated to be treated at a dose very close to the final RP2D. 
Thus, patients will likely receive effective or near-effective doses and hence, heterogeneity 
in response due to sub-optimal dose is avoided. 
 
Patients in the group 2 who have defined target lesions (other than the lesion surgically 
resected) will also be included in the imaging objective. 
 
11.1 
Antitumor Effect – Intracranial Metastases 
 
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).  
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one bi-weekly dose of M6620 (VX-970, 
berzosertib), and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions 
stated below.  (Note: Patients who exhibit objective disease progression prior to the end 
of 1st week of M6620 (VX-970, berzosertib) 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 bi-weekly dose of M6620 (VX-970, berzosertib), 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 ≥ 10 mm (≥ 1 

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cm) with MRI.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter < 10 mm [< 1 cm] are considered non-measurable disease.   
 
Target lesions.  All measurable lesions up to a maximum of 3 lesions will 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 
intracranial metastases, 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.  Bidimensional 
product for each of the 1-3 largest brain metastases will be identified at baseline.  The 
bidimensional product is defined as the largest dimension multiplied by the second 
largest dimension that is perpendicular to it (the largest dimension).  This value will be 
recorded on the baseline form and every subsequent follow-up form.  The appearance 
(yes/no) of any new brain metastases will be recorded on all follow-up forms.  A sum of 
the bidimensional product for all target lesions will be calculated and reported as the 
baseline sum diameters.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
Volume of the three target lesions will also be estimated by segmentation of the lesions; 
using auto-segmentation software with appropriate manual editing or manual delineation 
by the same investigator(s) when auto-segmentation is not feasible.  For consistency in 
measurements, MRI data for all patients (baseline and follow up) from other participating 
institutions will be collected and analyzed at the PI’s institution under the supervision of 
the Radiology Co-chairs.  
 
Non-target lesions.  All other lesions including any measurable lesions over and above 
the 3 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 target lesion at baseline and during follow-up.  
 
Conventional MRI.  MRI-scan based response evaluation is based on the assumption that 

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MRI slice thickness is 5 mm (0.5 cm) or less.  If MRI scans have slice thickness greater 
than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice the slice 
thickness.   
 
It is recommended that MRI sequences be followed per the consensus recommendations 
as detailed in the article: “Consensus recommendations for standardized brain tumor 
imaging protocol in clinical trials. Benjamin M. Ellingson et al. Neuro Oncol. 2015 Sep; 
17(9):1188-98. doi: 10.1093/neuonc/nov095. Epub 2015 Aug 5.” 
 
Please contact the study PI or the radiology co-investigators with any questions. 
 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Patients will undergo gadolinium contrast-enhanced brain MRI prior to the 
study entry (within 4 weeks of start of therapy), and prior to the start of SRS 
or systemic therapy or at 2 months post-WBRT (whichever is earlier). 
Thereafter, MRI will be done every 2 months after WBRT completion for the 
first 6 months, and every 3 months after WBRT completion for the next 6 
months.   
 
Complete Response (CR):  Disappearance of all target lesions.   
 
Partial Response (PR):  At least a greater than a 50% decrease in the sum of 
the bidimensional product of target lesions, taking as reference the baseline 
measurement. 
 
Progressive Disease (PD):  At least a 25% increase in the sum of the 
bidimensional product of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on study).  For 
lesions < 1cm in maximum diameter, a minimum increase of 50% of 
perpendicular bidimensional treatment area will be necessary to score as 
progression. This caveat is included to account for potential variability in 
measurement, which will be most susceptible to proportionate errors at 
smaller sizes. (Note:  the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions. 

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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 Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
Non-CR/Non-PD 
No 
PR 
SD 
Non-CR/Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
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* 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 

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 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD 
is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
The date at which CNS progression is identified will be used to calculate the intra-cranial 
PFS.  Survival will be measured from the date of start of treatment to time of progression 
or death, whichever occurs first.  Deaths due to non-neurological causes will be censored. 
 
11.1.7 Response Review 
 
All responses will be reviewed by the radiology investigator of the study at the study’s 
completion to allow simultaneous review of the patients’ files and radiological images.  
Raw data from baseline and follow up MRI will be obtained from the participating 
institutions for volumetric, perfusion and diffusion-based response assessments.  Sites 
should send anonymized pre- and post-treatment scans via FTP or as a hard copy CD to  
the study PI, Dr. Mohindra, at the University of Maryland as listed on the title page.  The 
scans and data will be stored in HIPAA compliant secure servers within the Department 
of Radiology.  Each patient will be identified only with the patient number assigned by 
the study. 
 
 
11.2 
Other Response Parameters (Optional) 
 
In addition to morphological criteria noted above, the current study will also assess changes in 
magnetic susceptibility (T2-Dynamic Susceptibility Contrast Enhanced MRI, DSC-MRI) that 
provides information about the perfusion characteristics of the tumoral micro-environment.  The 
most robust and widely used parameter derived from DSC-MRI is rCBV (relative Cerebral 
Blood Volume). Additionally, measurement of the Apparent Diffusion Coefficient (ADC) of 
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such as cellularity, which may not be readily estimated by conventional MR imaging methods 
[41,42].  Specific details of a standard protocol DSC-MRI and standard diffusion weighted 
imaging protocol may be found in Appendix E.  The published literature regarding these novel 
end-points is described in section 2.7.  
 
Correlative  Objective 
(Name of Correlate,  
Lead PI and Site) 
Imaging 
Technique 
 
Organ(s) Scanned 
and Timing of Scans 
M/O 
MRI contrast morphological 
assessment, perfusion and DWI 
imaging 
PIs: Prashant Raghavan/Rao 
Gullapalli 
MRI 
Brain. See Study 
Calendar for Timing 
of scans 
Optional 
 
MRI protocol 
attached  
(Appendix E) 
 
 
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.   
 
All decisions regarding dose escalation/expansion/de-escalation require sign-off by the 
Protocol Principal Investigator through the CTMS/IWRS.  In addition, during this phase 
1 study, the Protocol Principal Investigator will have at least monthly, or more frequently, 
conference calls with the Study Investigators and the CTEP Medical Officer(s) to review 
accrual, progress, and adverse events and unanticipated problems.   
 
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. 

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12.2 
Data Reporting 
 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study.  Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  To access Rave via iMedidata: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account, and  
• 
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. 
 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata.  To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page.  Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed.  Trainings will be in the form of electronic learnings (eLearnings), and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen.  If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account.  Account activation instructions are located on the CTSU 
website in the Rave section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance).  Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
 

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12.1.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  On-
site audits will be conducted three times annually (one annual site visit and two data 
audits).  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. 
 
 
12.1.2 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. 
 
An End of Study CRF is to be completed by the PI, and is to include a summary of study 
endpoints not otherwise captured in the database, such as (for phase 1 trials), the 
recommended phase 2 dose (RP2D), and a description of any dose-limiting toxicities 
(DLTs).  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 

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required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
). 
 
12.4 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov.. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 

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by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator. (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to  
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 

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13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a phase 1 dose escalation trial in patients with brain metastases NSCLC to determine the 
recommended phase 2 dose (RP2D) of twice weekly i.v. M6620 (VX-970, berzosertib) 
administered concurrent with conventionally fractionated WBRT.   
 
13.1.1 Primary Endpoint 
Dose-limiting toxicity defined as any grade 3 or more non-hematological toxicity 
requiring more than 5-day interruption in therapy or any grade 4 or higher hematological 
toxicity that is attributable to the M6620 (VX-970, berzosertib) and/or WBRT.  
 
Study population. All patients experiencing a DLT will be retained in the study 
population irrespective of what proportion of the planned dose was actually administered 
to that patient. Patients who have to stop treatment because of patient withdrawal, disease 
progression or any other reason unrelated to treatment-related toxicity will be withdrawn 
from the analysis group and will be replaced by another patient enrolled at the same dose 
level. 
 
13.1.2 Secondary Endpoints 
1. Incidence of delayed neurological toxicity at 2, 4 and 6-months post-completion 
of WBRT (for patients without intracranial progression) including:  
a. Delayed-recall through HVLT-R  
b. Quality of life as measured by the FACT-BR. 
 
2. Radiological RR at 6 months based on morphological criteria described in section 
11.1.4.  All patients accrued in group 1 (except the first three dose-levels) will be 
included in the imaging objective.   
 
3. Intracranial 6-month PFS. 
 
13.1.3 Exploratory Endpoints 
Group 1 for patients accrued beyond dose-level 3: Changes in DSC-MRI) perfusion, 
mean ADC measurements in DWI 
 
Group 2:  
a. Pharmacokinetic measurements: Intra-operative blood and CSF M6620 (VX-970, 
berzosertib) levels  and  craniotomy tumor specimen M6620 (VX-970, 
berzosertib) concentration  
b. Biomarker (Pharmacodynamic) end-point: Percentage pATR-Thr1989, pCHK1 
S345 and RAD51 multiplex in post-M6620 (VX-970, berzosertib) administration 
intra-cranial tumor tissue specimen   
c. MRI end-points (For patients with identifiable target lesion, other than the 
resected lesion): Changes in DSC-MRI perfusion,  mean ADC measurements in 

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iii) Accrual will be stopped and the data will be analyzed and published if the 
relative width from the lower bound of the Bayesian 90% credible interval to 
the estimated RP2D is less than 20%. This early stopping rule could be activated 
if the dose-response relationship is unexpectedly steep.  
 
iv) Alternatively, if 9 patients have been enrolled at three dose levels without a 
change in dose varying by more than 10 mg, the IDMC will be tasked with 
deciding whether accrual should be stopped. This decision will be made 
considering also the estimate from ii) above. Also in this case, RP2D will be 
estimated as the median of the marginal posterior distribution of the RP2D.  
 
v) If the convergence toward the RP2D is unexpectedly slow, i.e. the dose-
response relationship is very shallow, accrual will be halted and the dose-
response data will be analyzed and published once the maximum sample size 
of 40 patients is reached. 
 
Late neurotoxicity will be reviewed by the independent DSMB who will be charged 
with considering cessation of the trial if the long term (6 months) grade 3 
symptomatic neurotoxicity is >20%. A formal stopping rule will not be defined, 
mainly due to the lack of good clinical data to build on.  
 
13.2.3 
Group 2 (Correlative Pre-Craniotomy Cohort) 
 Six patients will be accrued in this group.  The low number was chosen considering 
the logistics of arranging for a study screening, consent, registration prior to the 
craniotomy, which may need to be performed on an urgent/emergent basis limiting 
the number of potentially eligible patients.  This is an exploratory cohort with the 
primary goal to assess in vivo CSF and tumor penetration of the drug and to measure 
the proportion of cases with elevated DNA damage repair biomarkers.  With a sample 
size of N=6, we will have a “proof of principle” of a PD effect if at least 2 PD 
responses are seen among the 6 patients.  This allows rejection of the null hypothesis 
of no PD response at a significance level of .02-.03, allowing for a 4-5% false 
positive rate for individual biopsies.  It yields 77% power to detect a 40% PD 
response rate and 89% power to detect a 50% rate. The proportion of responders for 
various biomarkers will be reported.   
 
No formal hypothesis will be tested in relation to the parallel cohort of 12 craniotomy 
cases without M6620 (VX-970, berzosertib) (see 2.6.3) and the 6 patients in Group 2, 
but distributions of biomarkers will summarized in box-and-whiskers plots and be 
compared using the Mann-Whitney test. 
 
13.2.4 
Accrual Rate and Study Duration 
The anticipated accrual rate is two to six evaluable patients per month.  Therefore, the 
accrual period for this study is expected to be approximately 18 months.  Analysis for 
DLTs will be done regularly through the course of study duration, since this will be 
an integral component for the estimation of next dose level through the EWOC 

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13.3 
Stratification Factors 
None. 
 
 
13.4 
Analysis of Secondary and Exploratory Endpoints 
 
Because of the non-randomized nature of the phase-I trial, all analyses of secondary end-
points will be exploratory.  Since this is a first-in-class drug that has never been tested in 
combination with WBRT (or radiation at any other body site) in humans, there is no 
estimate of the potential positive and negative effects of the combination.  The results 
from these exploratory analyses will help determine the statistical power calculations for 
a future randomized comparison.  All treatment effect and toxicity endpoints will be 
reported separately from analyses including all cases vs. evaluable patients only.  We will 
give a full account of all dose modifications or treatment interruptions that occurred 
during the trial. 
 
13.4.1. Incidence of events will be expressed as proportions with exact 95% confidence 
limits.  
 
13.4.2. For end-points that are being compared from pre-treatment baseline (e.g. 
delayed-recall, FACT-BR score, changes in DSC-MRI perfusion or ADC 
measurements, pharmacodynamic biomarker assessments), descriptive statistics 
of the actual change scores will also be provided. The median change score and 
quartiles will be reported. Where relevant the proportion of patients 
experiencing a clinically significant change in score will be reported with 95% 
confidence limits. 
 
13.4.3 
Kaplan-Meier estimates of 6 month intracranial PFS (icPFS) and 12 month 
overall survival (OS) will be calculated.  For estimation of icPFS, patients alive 
without intracranial progression at last follow-up will be censored at the date of 
the last radiologic assessment whereas intracranial progression or death will be 
scored as events.  The icPFS estimates at 2, 4, and 6 months with their standard 
error of the estimate will be reported.  For calculation of OS, patients alive at 
last follow-up will be censored.  An exploratory Cox regression analysis with 
M6620 (VX-970, berzosertib) dose as a covariate will be performed if judged 
reasonable in view of our sample size.  
 
 
 

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REFERENCES 
 
1.  Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE. Incidence 
proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan 
Detroit Cancer Surveillance System. J Clin Oncol 2004;22:2865-2872. 
2.  DeAngelis LM, Posner JB. Intracranial metastases. New York: Oxford University Press; 
2009. 
3.  Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Current oncology reports 
2012;14:48-54. 
4.  Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery 
WR, Macdonald JS, Young B. A randomized trial of surgery in the treatment of single 
metastases to the brain. N Engl J Med 1990;322:494-500. 
5. Patchell RA, Tibbs PA, Regine WF, Dempsey RJ, Mohiuddin M, Kryscio RJ, Markesbery 
WR, Foon KA, Young B. Postoperative radiotherapy in the treatment of single metastases to 
the brain: a randomized trial. JAMA 1998;280:1485-1489. 
6.  Scott C, Suh J, Stea B, Nabid A, Hackman J. Improved survival, quality of life, and quality-
adjusted survival in breast cancer patients treated with efaproxiral (Efaproxyn) plus whole-
brain radiation therapy for brain metastases. Am J Clin Oncol 2007;30:580-587. 
7.  Meyers CA, Smith JA, Bezjak A, Mehta MP, Liebmann J, Illidge T, Kunkler I, Caudrelier 
JM, Eisenberg PD, Meerwaldt J, Siemers R, Carrie C, Gaspar LE, Curran W, Phan SC, 
Miller RA, Renschler MF. Neurocognitive function and progression in patients with brain 
metastases treated with whole-brain radiation and motexafin gadolinium: results of a 
randomized phase III trial. J Clin Oncol 2004;22:157-165. 
8.  Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-
Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, 
Collette S, Collette L, Mueller RP. Adjuvant whole-brain radiotherapy versus observation 
after radiosurgery or surgical resection of one to three cerebral metastases: results of the 
EORTC 22952-26001 study. J Clin Oncol 2011;29:134-141. 
9.  Brown PD, Asher AL, Ballman KV, Farace E, Cerhan JH, Anderson SK, Carrero XW, 
Barker FG, Deming RL, Burri S, Menard C, Chung C, Stieber VW, Pollock BE, Galanis E, 
Buckner JC, Jaeckle KA. NCCTG N0574 (Alliance): A phase III randomized trial of whole 
brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 
brain metastases. ASCO Annual Meeting. Chicago. 2015. 
10. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy 
for brain metastases correlates with survival and improved neurocognitive function. J Clin 
Oncol 2007;25:1260-1266. 
11. Mehta MP, Shapiro WR, Phan SC, Gervais R, Carrie C, Chabot P, Patchell RA, Glantz MJ, 
Recht L, Langer C, Sur RK, Roa WH, Mahe MA, Fortin A, Nieder C, Meyers CA, Smith JA, 
Miller RA, Renschler MF. Motexafin gadolinium combined with prompt whole brain 
radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients 

NCI Protocol #: 9952 
Local Protocol #: HP-00068292 
Version Date: June 21, 2021 
99 
 
 
 
with brain metastases: results of a phase III trial. Int J Radiat Oncol Biol Phys 2009;73:1069-
1076. 
12. Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown 
PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto 
CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for 
patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 
patients. Int J Radiat Oncol Biol Phys 2010;77:655-661. 
13. Qin H, Pan F, Li J, Zhang X, Liang H, Ruan Z. Whole brain radiotherapy plus concurrent 
chemotherapy in non-small cell lung cancer patients with brain metastases: a meta-analysis. 
PloS one 2014;9:e111475. 
14. Lee SM, Lewanski CR, Counsell N, Ottensmeier C, Bates A, Patel N, Wadsworth C, Ngai Y, 
Hackshaw A, Faivre-Finn C. Randomized trial of erlotinib plus whole-brain radiotherapy for 
NSCLC patients with multiple brain metastases. J Natl Cancer Inst 2014;106. 
15. Gadgeel SM, Gandhi L, Riely GJ, Chiappori AA, West HL, Azada MC, Morcos PN, Lee 
RM, Garcia L, Yu L, Boisserie F, Di Laurenzio L, Golding S, Sato J, Yokoyama S, Tanaka 
T, Ou SH. Safety and activity of alectinib against systemic disease and brain metastases in 
patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): 
results from the dose-finding portion of a phase 1/2 study. The Lancet Oncology 
2014;15:1119-1128. 
16. Fokas E, Prevo R, Hammond EM, Brunner TB, McKenna WG, Muschel RJ. Targeting ATR 
in DNA damage response and cancer therapeutics. Cancer Treat Rev 2014;40:109-117. 
17. Weber AM, Ryan AJ. ATM and ATR as therapeutic targets in cancer. Pharmacol Ther 
2015;149:124-138. 
18. Zeman MK, Cimprich KA. Causes and consequences of replication stress. Nature cell 
biology 2014;16:2-9. 
19. Pitts TM, Davis SL, Eckhardt SG, Bradshaw-Pierce EL. Targeting nuclear kinases in cancer: 
development of cell cycle kinase inhibitors.  Pharmacol Ther 2014;142:258-269. 
20. Yan S, Sorrell M, Berman Z. Functional interplay between ATM/ATR-mediated DNA 
damage response and DNA repair pathways in oxidative stress. Cell Mol Life Sci 
2014;71:3951-3967. 
21. Dickson MA, Schwartz GK. Development of cell-cycle inhibitors for cancer therapy. Current 
oncology 2009;16:36-43. 
22. Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA, Golec JM, 
Pollard JR. Selective killing of ATM- or p53-deficient cancer cells through inhibition of 
ATR. Nature chemical biology 2011;7:428-430. 
23. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, 
Hammond EM, Olcina MM, Gillies McKenna W, Muschel RJ, Brunner TB. Targeting ATR 
in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic 
tumors to radiation. Cell Death and Disease 2012;3:e441. 

NCI Protocol #: 9952 
Local Protocol #: HP-00068292 
Version Date: June 21, 2021 
100 
 
 
 
24. Hall AB, Newsome D, Wang Y, Boucher DM, Eustace B, Gu Y, Hare B, Johnson MA, 
Milton S, Murphy CE, Takemoto D, Tolman C, Wood M, Charlton P, Charrier JD, Furey B, 
Golec J, Reaper PM, Pollard JR. Potentiation of tumor responses to DNA damaging therapy 
by the selective ATR inhibitor M6620 (VX-970, berzosertib). Oncotarget 2014;5:5674-5685. 
25. Kuo LJ, Yang LX. Gamma-H2AX - a novel biomarker for DNA double-strand breaks. In 
Vivo 2008;22:305-309. 
26. White D, Rafalska-Metcalf IU, Ivanov AV, Corsinotti A, Peng H, Lee SC, Trono D, Janicki 
SM, Rauscher FJ, 3rd. The ATM substrate KAP1 controls DNA repair in heterochromatin: 
regulation by HP1 proteins and serine 473/824 phosphorylation. Molecular cancer research : 
MCR 2012;10:401-414. 
27. Suh JH, Stea B, Nabid A, Kresl JJ, Fortin A, Mercier JP, Senzer N, Chang EL, Boyd AP, 
Cagnoni PJ, Shaw E. Phase III study of efaproxiral as an adjunct to whole-brain radiation 
therapy for brain metastases. J Clin Oncol 2006;24:106-114. 
28. Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik 
M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ, Jr. Whole 
brain radiation therapy with or without stereotactic radiosurgery boost for patients with one 
to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 
2004;363:1665-1672. 
29. Viani GA, Manta GB, Fonseca EC, De Fendi LI, Afonso SL, Stefano EJ. Whole brain 
radiotherapy with radiosensitizer for brain metastases. J Exp Clin Cancer Res 2009;28:1. 
30. Eich M, Roos WP, Nikolova T, Kaina B. Contribution of ATM and ATR to the resistance of 
glioblastoma and malignant melanoma cells to the methylating anticancer drug 
temozolomide. Molecular cancer therapeutics 2013;12:2529-2540. 
31. Lin NU, Lee EQ, Aoyama H, Barani IJ, Baumert BG, Brown PD, Camidge DR, Chang SM, 
Dancey J, Gaspar LE, Harris GJ, Hodi FS, Kalkanis SN, Lamborn KR, Linskey ME, 
Macdonald DR, Margolin K, Mehta MP, Schiff D, Soffietti R, Suh JH, van den Bent MJ, 
Vogelbaum MA, Wefel JS, Wen PY, Response Assessment in Neuro-Oncology g. 
Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient 
population, response, and progression. A report from the RANO group. The Lancet 
Oncology 2013;14:e396-406. 
32. Lin NU, Wefel JS, Lee EQ, Schiff D, van den Bent MJ, Soffietti R, Suh JH, Vogelbaum MA, 
Mehta MP, Dancey J, Linskey ME, Camidge DR, Aoyama H, Brown PD, Chang SM, 
Kalkanis SN, Barani IJ, Baumert BG, Gaspar LE, Hodi FS, Macdonald DR, Wen PY, 
Response Assessment in Neuro-Oncology g. Challenges relating to solid tumour brain 
metastases in clinical trials, part 2: neurocognitive, neurological, and quality-of-life 
outcomes. A report from the RANO group. The Lancet Oncology 2013;14:e407-416. 
33. Lin NU, Lee EQ, Aoyama H, Barani IJ, Barboriak DP, Baumert BG, Bendszus M, Brown 
PD, Camidge DR, Chang SM, Dancey J, de Vries EG, Gaspar LE, Harris GJ, Hodi FS, 
Kalkanis SN, Linskey ME, Macdonald DR, Margolin K, Mehta MP, Schiff D, Soffietti R, 
Suh JH, van den Bent MJ, Vogelbaum MA, Wen PY, Response Assessment in Neuro-
Oncology g. Response assessment criteria for brain metastases: proposal from the RANO 

NCI Protocol #: 9952 
Local Protocol #: HP-00068292 
Version Date: June 21, 2021 
101 
 
 
 
group. The Lancet Oncology 2015;16:e270-278. 
34. Cha S. Update on brain tumor imaging: from anatomy to physiology. AJNR Am J 
Neuroradiol 2006;27:475-487. 
35. Weber MA, Thilmann C, Lichy MP, Gunther M, Delorme S, Zuna I, Bongers A, Schad LR, 
Debus J, Kauczor HU, Essig M, Schlemmer HP. Assessment of irradiated brain metastases 
by means of arterial spin-labeling and dynamic susceptibility-weighted contrast-enhanced 
perfusion MRI: initial results. Invest Radiol 2004;39:277-287. 
36. Hoefnagels FW, Lagerwaard FJ, Sanchez E, Haasbeek CJ, Knol DL, Slotman BJ, Vandertop 
WP. Radiological progression of cerebral metastases after radiosurgery: assessment of 
perfusion MRI for differentiating between necrosis and recurrence. J Neurol 2009;256:878-
887. 
37. Mitsuya K, Nakasu Y, Horiguchi S, Harada H, Nishimura T, Bando E, Okawa H, Furukawa 
Y, Hirai T, Endo M. Perfusion weighted magnetic resonance imaging to distinguish the 
recurrence of metastatic brain tumors from radiation necrosis after stereotactic radiosurgery. 
J Neurooncol 2010;99:81-88. 
38. Chiang IC, Kuo YT, Lu CY, Yeung KW, Lin WC, Sheu FO, Liu GC. Distinction between 
high-grade gliomas and solitary metastases using peritumoral 3-T magnetic resonance 
spectroscopy, diffusion, and perfusion imagings. Neuroradiology 2004;46:619-627. 
39. Gasparetto EL, Pawlak MA, Patel SH, Huse J, Woo JH, Krejza J, Rosenfeld MR, O'Rourke 
DM, Lustig R, Melhem ER, Wolf RL. Posttreatment recurrence of malignant brain neoplasm: 
accuracy of relative cerebral blood volume fraction in discriminating low from high 
malignant histologic volume fraction. Radiology 2009;250:887-896. 
40. Barajas RF, Chang JS, Sneed PK, Segal MR, McDermott MW, Cha S. Distinguishing 
recurrent intra-axial metastatic tumor from radiation necrosis following gamma knife 
radiosurgery using dynamic susceptibility-weighted contrast-enhanced perfusion MR 
imaging. AJNR Am J Neuroradiol 2009;30:367-372. 
41. Jakubovic R, Sahgal A, Soliman H, Milwid R, Zhang L, Eilaghi A, Aviv RI. Magnetic 
resonance imaging-based tumour perfusion parameters are biomarkers predicting response 
after radiation to brain metastases. Clin Oncol (R Coll Radiol) 2014;26:704-712. 
42. Jakubovic R, Sahgal A, Ruschin M, Pejovic-Milic A, Milwid R, Aviv RI. Non Tumor 
Perfusion Changes Following Stereotactic Radiosurgery to Brain Metastases. Technology in 
cancer research & treatment 2015;14:497-503. 
43. Hayashida Y, Hirai T, Morishita S, Kitajima M, Murakami R, Korogi Y, Makino K, 
Nakamura H, Ikushima I, Yamura M, Kochi M, Kuratsu JI, Yamashita Y. Diffusion-
weighted imaging of metastatic brain tumors: comparison with histologic type and tumor 
cellularity. AJNR Am J Neuroradiol 2006;27:1419-1425. 
44. Nadal Desbarats L, Herlidou S, de Marco G, Gondry-Jouet C, Le Gars D, Deramond H, Idy-
Peretti I. Differential MRI diagnosis between brain abscesses and necrotic or cystic brain 
tumors using the apparent diffusion coefficient and normalized diffusion-weighted images. 
Magn Reson Imaging 2003;21:645-650. 

NCI Protocol #: 9952 
Local Protocol #: HP-00068292 
Version Date: June 21, 2021 
102 
 
 
 
45. Meyer HJ, Fiedler E, Kornhuber M, Spielmann RP, Surov A. Comparison of diffusion-
weighted imaging findings in brain metastases of different origin. Clin Imaging 2015;39:965-
969. 
46. Provenzale JM, Mukundan S, Barboriak DP. Diffusion-weighted and perfusion MR imaging 
for brain tumor characterization and assessment of treatment response. Radiology 
2006;239:632-649. 
47. Tomura N, Narita K, Izumi J, Suzuki A, Anbai A, Otani T, Sakuma I, Takahashi S, Mizoi K, 
Watarai J. Diffusion changes in a tumor and peritumoral tissue after stereotactic irradiation 
for brain tumors: possible prediction of treatment response. J Comput Assist Tomogr 
2006;30:496-500. 
48. Huang CF, Chou HH, Tu HT, Yang MS, Lee JK, Lin LY. Diffusion magnetic resonance 
imaging as an evaluation of the response of brain metastases treated by stereotactic 
radiosurgery. Surg Neurol 2008;69:62-68; discussion 68. 
49. Mahmood F, Johannesen HH, Geertsen P, Opheim GF, Hansen RH. The effect of region of 
interest strategies on apparent diffusion coefficient assessment in patients treated with 
palliative radiation therapy to brain metastases. Acta Oncol 2015;54:1529-1534. 
50. Zakaria R, Das K, Radon M, Bhojak M, Rudland PR, Sluming V, Jenkinson MD. Diffusion-
weighted MRI characteristics of the cerebral metastasis to brain boundary predicts patient 
outcomes. BMC medical imaging 2014;14:26. 
51. Essig M, Waschkies M, Wenz F, Debus J, Hentrich HR, Knopp MV. Assessment of brain 
metastases with dynamic susceptibility-weighted contrast-enhanced MR imaging: initial 
results. Radiology 2003;228:193-199. 
52. Lee CC, Wintermark M, Xu Z, Yen CP, Schlesinger D, Sheehan JP. Application of diffusion-
weighted magnetic resonance imaging to predict the intracranial metastatic tumor response to 
gamma knife radiosurgery. J Neurooncol 2014;118:351-361. 
53. Sperduto PW, Shanley R, Luo X, Andrews D, Werner-Wasik M, Valicenti R, Bahary JP, 
Souhami L, Won M, Mehta M. Secondary analysis of RTOG 9508, a phase 3 randomized 
trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients 
with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int J 
Radiat Oncol Biol Phys 2014;90:526-531. 
54. DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of 
brain metastases. Neurology 1989;39:789-796. 
55. Regine WF, Schmitt FA, Scott CB, Dearth C, Patchell RA, Nichols RC, Jr., Gore EM, 
Franklin RL, 3rd, Suh JH, Mehta MP. Feasibility of neurocognitive outcome evaluations in 
patients with brain metastases in a multi-institutional cooperative group setting: results of 
Radiation Therapy Oncology Group trial BR-0018. Int J Radiat Oncol Biol Phys 
2004;58:1346-1352. 
56. Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, 
Shiu AS, Maor MH, Meyers CA. Neurocognition in patients with brain metastases treated 
with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. 

NCI Protocol #: 9952 
Local Protocol #: HP-00068292 
Version Date: June 21, 2021 
103 
 
 
 
The Lancet Oncology 2009;10:1037-1044. 
57. Welzel G, Fleckenstein K, Mai SK, Hermann B, Kraus-Tiefenbacher U, Wenz F. Acute 
neurocognitive impairment during cranial radiation therapy in patients with intracranial 
tumors. Strahlenther Onkol 2008;184:647-654. 
58. Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, Rowley H, Kundapur V, 
DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Shah S, Shi W, Wendland M, Kachnic 
L, Mehta MP. Preservation of memory with conformal avoidance of the hippocampal neural 
stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): 
a phase II multi-institutional trial. J Clin Oncol 2014;32:3810-3816. 
59. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with 
overdose control. Stat Med 1998;17:1103-1120. 
60. Xu Z, Tighiourart M, Rogatko A. EWOC 2.0: interactive software for dose escalation in 
cancer phase I clinical trials. Drug Inf J 2007;41:221-228. 
61. Rogatko A, Tighiouart M, Cook-Wiens G, Quanlin L. Escalation with overdose control. 
User's guide. Version 3.1.2012. In: Editor, editor^editors. Book Escalation with overdose 
control. User's guide. Version 3.1.2012; 2012. 
 
 
 
 
 

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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: GRADED PROGNOSTIC ASSESSMENT (GPA) SCORE FOR BRAIN 
METASTASES FON NON-SMALL CELL LUNG CANCER (NSCLC)  
 
Prognostic 
Factor 
GPA Scoring Criteria 
0 
0.5 
1.0 
Age (Years) 
>60 
50-60 
<50 
KPS 
<70 
70-80 
90-100 
Extracranial 
Metastases 
Present 
 
Absent 
Number of 
Brain 
Metastases  
>3 
2-3 
1 
Sum Total 
 
 
 
Total: 
 
 
Median Overall Survival (months) by GPA: 
 
GPA 
 
Median Survival 
      0-1.0 
 
3.0 months 
 
1.5-2.0 
 
5.5 months 
 
2.5-3.0 
 
9.4 months 
 
3.5-4.0 
 
14.8 months 
 
From: Sperduto, P. Kased, N., and Roberge, D. et al. Summary report on the graded prognostic 
assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with 
brain metastases. J Clin Oncol 2012 30(4): p. 419-25.  
 
 

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APPENDIX C: PATIENT DRUG INFORMATION HANDOUT AND WALLET 
CARDInformation 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. 
 
• 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.  
• Make sure your doctor knows to avoid certain prescription medications.  
• 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: PATIENT DEXAMETHASONE DIARY 
 
Please take the dexamethasone tablets as instructed by your doctor.  Record the date and total 
number of dexamethasone tablets you took for each day.  If you have any comments, please 
record them in the comments column.  If you should make a mistake on the diary, draw through 
the mistake with one line and then sign your initials.  Thank you. 
 
Day 
Date 
Number of  
Dexamethasone 
Tablets Taken 
Dose of 
Dexamethasone 
Tablets Taken 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 

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Patient’s Signature___________________________________   Date ________________________ 

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APPENDIX E: MRI PROTOCOL  
 
MRI sequences will be followed per the consensus recommendations as detailed in the article: 
Consensus recommendations for standardized brain tumor imaging protocol in clinical trials. 
Benjamin M. Ellingson et al. Neuro Oncol. 2015 Sep; 17(9):1188-98. doi: 
10.1093/neuonc/nov095. Epub 2015 Aug 5. 
 
There is no defined consensus describing the perfusion sequences. Attached below are the 
perfusion sequences for 1.5T and 3T MRI used at the University of Maryland, Baltimore. 
Though defined for the Siemens machine, the parameters noted here are vendor non-specific and 
should be reproduced at the participating institution.  Please contact the PI or the Radiology Co-
Investigator on the protocol with any questions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.5 T MRI, Perfusion Sequence, University of Maryland, Baltimore 
 

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3T MRI: Perfusion Sequence, University of Maryland, Baltimore