A Phase IB and Randomized Open-Label Phase II Study of Berzosertib (M6620, VX-970) in Combination With Carboplatin/Gemcitabine/Pembrolizumab in Patients With Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer of Squamous Cell Histology
Phase: PHASE1
Conditions: Lung Non-Small Cell Squamous Carcinoma, Stage IV Lung Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)

SUMMARY OF CHANGES – Protocol 
For Protocol Amendment # 15 
NCI Protocol #: 10313 
Local Protocol #: 20-134 
 
NCI Version Date: 11/05/2024 
Protocol Date: 11/05/2024 
 
I. 
Comments requiring a response – Major Issues (submitted 11/05/24): 
 
# 
Section 
Change 
1. 
10.1.2 
Please remove the SPEER column for pembrolizumab as it is 
commercially supplied and the following related language: 
In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears 
in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI 
(except as noted below). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade 
noted in parentheses next to the AE in the SPEER. If this CAEPR is 
part of a combination protocol using multiple investigational agents and 
has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
PI Response: Updated 
2. 
4.1 
As previously requested, please replace the first paragraph with the 
updated language below: 
Food and Drug Administration (FDA) regulations require sponsors to 
select qualified investigators. National Cancer Institute (NCI) policy 
requires all individuals contributing to NCI-sponsored trials to register 
with their qualifications and credentials and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) 
account at https://ctepcore.nci.nih.gov/iam. In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator 
(NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
PI Response: Updated 

# 
Section 
Change 
3. 
8.1.1 
As previously requested, for M6620, please update the storage 
conditions to: 
Storage: Store intact vials protected from light inside cardboard boxes at 
room temperature, below 25°C (77°F), do not freeze with excursions 
allowed between 15 and 30°C (59 and 86°F). 
If a storage temperature excursion is identified, promptly return M6620 
to between 15 and 30°C below 25°C and quarantine the supplies. 
Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
PI Response: Updated 
4. 
ICD 
As previously requested, please update the gemcitabine and carboplatin 
side effects lists to the latest version available on the CTEP website: 
Tables of Possible Side Effects for Commonly-Used Oncology Drugs 
PI Response: Updated 
 
II. 
II. Response to RRA (submitted 10/30/24): 
 
# 
Section 
Change 
5. 
Cover Page 
Added: Amendment 15 / October 30, 2024 - Response to an RRA 
from Dr. Howard Streicher (streicherh@ctep.nci.nih.gov). 
6. 
10.3.3 
Revision of the AE Reporting Table - to version 08/30/2024 

# 
Section 
Change 
7. 
10.1.2 
Added New Risk: 
• 
Rare but Serious: Enterocolitis; Gastrointestinal disorders - Other 
(exocrine pancreatic insufficiency); Lipase increased; Myasthenia 
gravis; Myelitis; Nervous system disorders - Other (autoimmune 
neuropathy); Nervous system disorders - Other (demyelination); 
Nervous system disorders - Other (nerve paresis); Skin and 
subcutaneous tissue disorders - Other (Drug reaction with eosinophilia 
with systemic symptoms [DRESS]) 
Increase in Risk Attribution: 
• 
Changed to Less Likely from Rare but Serious: Infusion related 
reaction 
• 
Changed to Rare but Serious from Also Reported on Pembrolizumab 
MK-3475 Trials But With Insufficient Evidence for Attribution: Acute 
kidney injury; Blood and lymphatic system disorders - Other 
(autoimmune hemolytic anemia); Gastritis 
Decrease in Risk Attribution: 
• 
Changed to Rare but Serious from Less Likely: Pneumonitis 
• 
Changed to Also Reported on Pembrolizumab MK-3475 Trials But 
With Insufficient Evidence for Attribution from Less Likely: Cough 
Provided Further Clarification: 
• 
Hemolysis (under Also Reported on Pembrolizumab MK-3475 Trials 
But With Insufficient Evidence for Attribution) is now reported as 
Blood and lymphatic system disorders - Other (autoimmune hemolytic 
anemia) (under Rare but Serious). 
8. 
ICD 
Added New Risk: 
• 
Rare and Serious: Inability to digest food which may cause bloating; 
Swelling of the bowels; Skin rash developing 1-8 weeks after a drug is 
given which may be accompanied by fever, lymph node swelling and 
organ failure 
Decrease in Risk Attribution: 
• 
Changed to Rare and Serious from Occasional: Lung problems 
(pneumonitis and other conditions). Symptoms may include: new or 
worsening cough, chest pain, shortness of breath. 
• 
Changed to Also Reported on Pembrolizumab MK-3475 Trials But 
With Insufficient Evidence for Attribution from Occasional (i.e. 
Removed from Risk Profile): Cough 
Provided Further Clarification: 
• 
Reaction during or following a drug infusion which may cause fever, 
chills, rash (under Rare) is now reported as Reaction during or 
following a drug infusion which may cause fever, chills, rash, low 
blood pressure (under Occasional) 

# 
Section 
Change 
9. 
5.6.3 
EET Biobank Shipping Address updated to new address: 
EET Biobank 
2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
E-mail: BPCBank@nationwidechildrens.org 
10. 
5.6.4 
EET Biobank Contact Information for Assistance updated 
EET Biobank 
Toll-free Phone: (800) 347-2486 PH: (614) 722-2865 
E-mail: BPCBank@nationwidechildrens.org 

NCI Protocol #: 
10313 
 
Local Protocol #: 
20-134 
 
ClinicalTrials.gov Identifier: NCT04216316 
 
TITLE: 
A phase IB and randomized open-label phase II study of Berzosertib (M6620, VX- 
970) in combination with carboplatin/gemcitabine/ pembrolizumab in patients with 
chemotherapy-naïve advanced non-small cell lung cancer of squamous cell histology 
 
Corresponding Organization:  LAO-PA015 / UPMC Hillman Cancer Center LAO 
 
Principal Investigator: 
Liza C. Villaruz, M.D. 
University of Pittsburgh Cancer Institute 
UPMC Cancer Pavilion 
5150 Centre Avenue, 5th Floor, Room 564 
Pittsburgh, PA 15232 
412-648-6578 
412-648-6579 
villaruzl@upmc.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-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / UPMC Hillman Cancer Center LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
EDDOP / Early Drug Development Opportunity Program 
 
 
 
 
 
 
 
 
 
 
 
1 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
 
Statistician: 
Hong Wang, PhD 
UPMC Cancer Pavilion 
POB2, Suite 4C 
5150 Centre Ave 
Telephone: 412-383-1588 
Email: how8@pitt.edu 
Study Coordinator: 
Julie Urban, PhD 
UPMC Cancer Pavilion 
5150 Centre Avenue 
3rd Floor, Suite 301 
Pittsburgh, PA 15232 
Telephone: 412-623-7396 
E-mail: urbanj2@upmc.edu 
Study Team Email: 
ETCTN10313@upmc.edu 
 
 
NCI-Supplied Agents: Berzosertib (M6620, VX-970) (NSC #780162) 
 
Other Agent(s): Gemcitabine hydrochloride (NSC #613327, Commercial), Carboplatin (NSC 
#241240, Commercial), Pembrolizumab (NSC #776864, Commercial) 
 
 
IND #: 129800 
 
IND Sponsor: DCTD, NCI 
 
Protocol Type / Version # / Version Date: 
Original / August 2, 2019 
Revision 1 / October 3, 2019 
Revision 2 / November 7, 2019 
Revision 3a / January 3, 2020 
Revision 4 / January 31, 2020 
Revision 5 / February 19, 2020 
Amendment 1 / July 08, 2020 Response to CTEP 
and ETCTN Biorespository comments; response to 
a CTEP Amendment Request from Gary L. Smith, 
M.G.A; University of Pittsburgh changes 
Amendment 2 / September 04, 2020 (Changes made 
in response to an RA from CTEP) 
Amendment 3 / October 23, 2020 Changes made in 
response to CTEP recommendations, and to add 
windows and clarify response assessments 
Amendment 4 / December 18, 2020 Changes made 
in response to NCI CIRB comments. 
Amendment 5 / January 19, 2021 Changes made in 
response to CTEP comments dated 01/14/2021 
Amendment 6 / January 27, 2021 change made in 
response to CTEP comments dated 01/26/2021 
Amendment 7 / March 09, 2021 changes made in 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
response to CTEP and FDA comments 
Amendment 8 / May 14, 2021 changes made in 
response to a CTEP Notice dated 04/22/2021; 
changes to treatment administration 
Amendment 9 / June 24, 2021 changes made in 
response to CIRB stipulations; additional University 
of Pittsburgh Changes 
Amendment 10 / July 16, 2021 changes made in 
response to CTEP recommendations, received 
07/12/2021 
Amendment 11 / October 20, 2021 Changes in 
response to an RRA from Dr. Elad Sharon 
(sharone@mail.nih.gov) 
Amendment 12 / August 29, 2022 Response to an 
RRA from Dr. Stevenson Gore 
Amendment 13 / October 21, 2022 changes made in 
response to CTEP Request for Amendment dated 
10/06/2022 
Amendment 14 / February 23, 2023 Response to an 
RRA from Dr. Elad Sharon 
Amendment 15 / November 5, 2024 Response to an 
RRA from Dr. Howard Streicher and additional 
administrative updates 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
SCHEMA 
 
The projected study duration is 30 months from first to last enrolled evaluable patient, with an 
expected additional 12 months of follow-up from the last patient enrollment to ascertain 85 PFS 
events. 
 
Phase 1B Safety Lead-In (n = 6-18) 
Dose De-Escalation Schema 
Berzosertib 
(M6620, VX- 
Gemcitabine 
Carboplatin 
Pembrolizumab 
970) 
(mg/m2) 
(AUC) 
(mg) 
(mg/m2) 
Schedule 
Cycles 1-4 
(every 3 
weeks) 
Days 2 and 9 * 
Days 1 and 8 
Day 1 
Day 1 
Cycles 5-16 
(every 3 
weeks) 
Day 1 
- 
- 
Day 1 
Cycles 17-26 
(every 6 
weeks) 
- 
- 
- 
Day 1** 
Dose Level (Cycles 1-16) 
1 
135 mg/m2 
800 mg/m2 
5 
200 
-1 
135 mg/m2 
800 mg/m2 
4 
200 
-2 
90 mg/m2 
600 mg/m2 
3 
200 
We will start at dose level 1, as our patient population is chemotherapy-naïve, and would be expected to 
tolerate higher doses of platinum chemotherapy. 
The following treatment schedule will be used for a total of two years of treatment. Pembrolizumab 
administration should not exceed 2 years. 
• 
Cycles 1 to 4 (first 3 months of the first year): gemcitabine on D1 and D8, carboplatin and 
pembrolizumab on D1, and +/- berzosertib (M6620, VX-970) on D2 and D9, every three weeks 
• 
Cycles 5 to 16 (last 9 months of the first year): pembrolizumab +/- berzosertib (M6620, VX-970) on 
D1, every 3 weeks 
• 
Cycles 17 to 26 (second year): pembrolizumab on D1, every 6 weeks 
* Beyond 4 cycles (i.e., 3 months), when berzosertib (M6620, VX-970) and pembrolizumab administration 
continues without gemcitabine or carboplatin, the berzosertib (M6620, VX-970) and pembrolizumab may be 
dosed on the same day for patient convenience, where pembrolizumab is administered before berzosertib 
(M6620, VX-970). 
** Pembrolizumab will be administered as 200mg for Cycles 1-16 and 400mg for Cycles 17-26 and should 
not exceed 2 years of treatment. 
DLTs will be defined as grade 4 absolute neutrophil count for ≥ 7 days, grade 4 anemia, platelet count < 
25,000, or other non-hematologic events ≥ grade 3 as per NCI Common Terminology Criteria for Adverse 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
 
 
Events Version 5.0 (except fatigue, alopecia, anorexia, nausea, and emesis occurring despite optimal 
antiemetic therapy). Patients are allocated to doses by the following algorithm: 
Three patients will be treated at Level 1. 
1. 
If # DLT≤1/3, treat 3 more patients at Level 1, otherwise, go to step 2, below. 
a. 
If # DLT≤1/6, proceed to Phase 2 at Level 1, 
b. 
Else if # DLT=2/6 or 3/6, go to step 2, below, 
c. 
Else if # DLT>3/6, do not proceed to Phase 2. 
2. 
If # DLT≤1/3, treat 3 more patients at Level -1, otherwise, go to step 3, below. 
a. 
If # DLT≤1/6, proceed to Phase 2 at Level -1, 
b. 
Else if # DLT=2/6 or 3/6, go to step 3, below, 
c. 
Else if # DLT>3/6, do not proceed to Phase 2. 
3. 
Treat 3 patients at Level -2. 
a. 
If # DLT≤1/3, treat 3 more patients at Level -2, 
i. 
If #DLT≤1/6, proceed to Phase 2 at Level -2, 
ii. 
Else if #DLT≥2/6, do not proceed to Phase 2. 
b. If # DLT≥2/3, do not proceed to Phase 2. 
If the trial does not proceed to Phase 2, an internal DSMB consisting of the study investigators and medical 
monitor will meet to discuss potential protocol amendments. DLTs will be determined in cycle 1 of therapy, 
though accrual will not be halted for DLT evaluation. 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
Schema - Phase 2 (n = 88) 
 
 
 
 
 
 
 
 
 
 
 
 
** The following treatment schedule will be used for a total of two years of treatment. Pembrolizumab administration 
should not exceed 2 years. 
• 
Cycles 1 to 4 (first 3 months of the first year): gemcitabine on D1 and D8, carboplatin and pembrolizumab on 
D1, and +/- berzosertib (M6620, VX-970) on D2 and D9, every three weeks 
• 
Cycles 5 to 16 (last 9 months of the first year): pembrolizumab +/- berzosertib (M6620, VX-970) on D1, every 3 
weeks 
• 
Cycles 17 to 26 (second year): pembrolizumab on D1, every 6 weeks 
Beyond 4 cycles (i.e., 3 months), when berzosertib (M6620, VX-970) and pembrolizumab administration continues on D1 
only without gemcitabine or carboplatin, the berzosertib (M6620, VX-970) and pembrolizumab may be dosed on the same 
day (D1) for patient convenience, where pembrolizumab is administered before berzosertib (M6620, VX-970). 
 
Dose De-Escalation Schema 
 
Phase 2, Arm A (n = 44) 
Berzosertib 
(M6620, VX-970) 
(mg/m2) 
Gemcitabine 
(mg/m2) 
Carboplatin (AUC) 
Pembrolizumab 
(mg) 
Schedule 
Cycles 1-4 
(every 3 weeks) 
Days 2 and 9 
Days 1 and 8 
Day 1 
Day 1 
Cycles 5-16 
(every 3 weeks) 
Day 1 
- 
- 
Day 1 
Cycles 17-26 
(every 6 weeks) 
- 
- 
- 
Day 1* 
Dose Level (Cycles 1-16) 
1 
135 
800 
5 (or 4) 
200 
-1 
135 
800 
4 (or 3) 
200 
-2 
90 
600 
3 
200 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
*Pembrolizumab will be administered as 200mg for Cycles 1-16 and 400mg for Cycles 17-26 and should not exceed 2 years of 
treatment. 
* Pembrolizumab will be administered as 200mg for Cycles 1-16 and 400mg for Cycles 17-26 and should not 
exceed 2 years of treatment. 
Modifications are by dose level. 
 
 
 
 
 
 
Phase 2, Arm B (n = 44) 
Gemcitabine 
(mg/m2) 
Carboplatin 
(AUC) 
Pembrolizumab 
(mg) 
Schedule 
Cycles 1-4 (every 3 
weeks) 
Days 1 and 8 
Day 1 
Days 1 
Cycles 5-16 (every 3 
weeks) 
- 
- 
Day 1 
Cycles 17-26 (every 6 
weeks) 
- 
- 
Day 1* 
Dose Level (Cycles 1-16) 
1 
1250 
5 
200 
-1 
1000 
4 
200 
-2 
750 
3 
200 
Modifications are by individual agent. 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
TABLE OF CONTENTS 
SCHEMA ......................................................................................................................................... 4 
1. 
OBJECTIVES ....................................................................................................................11 
1.1 
Primary Objectives .................................................................................................11 
1.2 
Secondary Objectives .............................................................................................11 
1.3 
Exploratory Objectives ...........................................................................................11 
2. 
BACKGROUND ................................................................................................................12 
2.1 
Study Disease .........................................................................................................12 
2.2 
CTEP IND Agents ..................................................................................................14 
2.3 
Commercial Agents ................................................................................................17 
2.4 
Rationale ................................................................................................................19 
2.5 
Correlative Studies Background .............................................................................19 
3. 
PATIENT SELECTION ....................................................................................................20 
3.1 
Eligibility Criteria ..................................................................................................21 
3.2 
Exclusion Criteria ...................................................................................................22 
3.3 
Inclusion of Women and Minorities .......................................................................24 
4. 
REGISTRATION PROCEDURES ....................................................................................24 
4.1 
Investigator and Research Associate Registration with CTEP ..............................24 
4.2 
Site Registration .....................................................................................................25 
4.3 
Patient Registration ................................................................................................28 
4.4 
General Guidelines .................................................................................................30 
5. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .........................................30 
5.1 
Summary Table for Specimen Collection ..............................................................30 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies ..............32 
5.3 
Specimen Procurement Kits and Scheduling .........................................................33 
5.4 
Specimen Tracking System Instructions ................................................................33 
5.5 
Specimen Collection ..............................................................................................38 
5.6 
Shipping Specimens to the EET Biobank from the Clinical Site ...........................40 
5.7 
Shipping Specimens to Other Laboratories from the Clinical Site ........................42 
5.8 
Biomarker Plan .......................................................................................................45 
5.9 
Integrated Correlative Studies ................................................................................47 
5.10 
Exploratory/Ancillary Correlative Studies .............................................................48 
6. 
TREATMENT PLAN ........................................................................................................49 
6.1 
Agent Administration .............................................................................................49 
6.2 
Definition of Dose-Limiting Toxicity ....................................................................54 
6.3 
General Concomitant Medication and Supportive Care Guidelines ......................55 
6.4 
Duration of Therapy ...............................................................................................56 
6.5 
Duration of Follow-Up ...........................................................................................56 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................57 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
7.1 
Dosing Levels .........................................................................................................57 
7.2 
Dosing Modifications .............................................................................................57 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................76 
8.1 
CTEP IND Agents ..................................................................................................76 
8.2 
Commercial Agents ................................................................................................80 
9. 
STATISTICAL CONSIDERATIONS ...............................................................................82 
9.1 
Study Design ..........................................................................................................82 
9.2 
Analyses of Endpoints and Objectives ...................................................................85 
9.3 
Sample Size and Accrual Rate ...............................................................................86 
9.4 
Monitoring Rule for Toxicity .................................................................................87 
9.5 
Reporting and Exclusions .......................................................................................88 
9.6 
Data Safety Monitoring Board ...............................................................................88 
10. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................88 
10.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) ..................88 
10.2 
Adverse Event Characteristics ................................................................................95 
10.3 
Expedited Adverse Event Reporting ......................................................................96 
10.4 
Routine Adverse Event Reporting ..........................................................................98 
10.5 
Pregnancy ...............................................................................................................99 
10.6 
Secondary Malignancy ...........................................................................................99 
10.7 
Second Malignancy ................................................................................................99 
11. 
STUDY CALENDAR ......................................................................................................100 
12. 
MEASUREMENT OF EFFECT ......................................................................................102 
12.1 
Antitumor Effect – Solid Tumors.........................................................................102 
13. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS ...........................................................................................................109 
13.1 
Study Oversight ....................................................................................................109 
13.2 
Data Reporting .....................................................................................................109 
13.3 
Data Quality Portal ...............................................................................................112 
13.4 
Collaborative Agreements Language ...................................................................112 
13.5 
Genomic Data Sharing Plan .................................................................................114 
13.6 
Incidental/Secondary Findings Disclosure Procedure ..........................................114 
14. 
REFERENCES .................................................................................................................116 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .................................................121 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING 
SERUM CREATININE ...................................................................................................122 
APPENDIX C 
ACCEPTABLE BIRTH CONTROL METHODS ...................................124 
APPENDIX D 
PATIENT DRUG Interactions handout and wallet card ..........................126 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
PATIENT DRUG INTERACTION WALLET CARD ........................................................... 128 
APPENDIX E 
PRE-BIOPSY ASSESSMENT................................................................. 129 
APPENDIX F 
PHARMACOKINETICS (PK) SHEET DAY 1 AND 2 .......................... 130 
APPENDIX G - TISSUE BIOPSY VERIFICATION ................................................................. 132 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 Lead-in phase 1B only: To determine the recommended phase 2 dose (RP2D) of 
carboplatin in combination with berzosertib (M6620, VX-970) and 
gemcitabine/pembrolizumab, in patients with squamous cell non-small cell lung cancer 
(Sq-NSCLC). 
 
1.1.2 Phase 2 only: To compare progression-free survival (PFS) of 
carboplatin/gemcitabine/pembrolizumab with and without berzosertib (M6620, VX-970) 
in patients with Sq-NSCLC, as measured by a hazard ratio in an intent-to-treat analysis. 
 
1.2 
Secondary Objectives 
 
1.2.1 To compare progression-free survival (PFS) of carboplatin/gemcitabine/pembrolizumab 
with and without berzosertib (M6620, VX-970) in patients with Sq-NSCLC, as measured 
by a hazard ratio in an as-treated analysis. 
 
1.2.2 To compare PFS of carboplatin/gemcitabine/pembrolizumab with and without berzosertib 
(M6620, VX-970) in patients with ataxia telangiectasia mutated (ATM)-deficient Sq- 
NSCLC, as measured by a hazard ratio. 
 
1.2.3 To compare overall survival (OS) and overall response rate (ORR) of 
carboplatin/gemcitabine/pembrolizumab with and without berzosertib (M6620, VX-970), 
in patients with chemotherapy-naïve Sq-NSCLC. 
 
1.2.4 To determine the systemic drug exposure of berzosertib (M6620, VX-970) and 
gemcitabine, as correlates of efficacy and toxicity. 
 
1.2.5 To determine the safety and tolerability of berzosertib (M6620, VX-970) in combination 
with carboplatin/gemcitabine/pembrolizumab. 
1.2.6 To observe and record anti-tumor activity. Although the clinical benefit of these drugs 
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. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To identify molecular subpopulations of patients who have increased sensitivity to the 
berzosertib (M6620, VX-970)/carboplatin/gemcitabine/pembrolizumab combination. 
 
1.3.2 To explore the prognostic and predictive qualities of the ATM immunohistochemistry 
(IHC) assay for clinical response and PFS. 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
1.3.3 To explore inflammation-associated gene signatures and clinical response. 
 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Squamous cell non-small cell lung cancer (NSCLC) accounts for approximately 30% of all 
NSCLCs worldwide (Perez-Moreno et al., 2012). While significant therapeutic advances in non- 
squamous NSCLCs have been driven by the discovery of targetable oncogenic drivers, 
therapeutic advances in NSCLC of squamous histology have lagged behind. This therapeutic 
divide has been narrowed in recent years with the development of monoclonal antibodies 
targeting the Programmed Cell Death Protein 1/Programmed Death Ligand-1 (PD1/PD-L1) 
pathway, which have been associated with significant survival advantages in the previously 
treated metastatic non-squamous and squamous NSCLC settings compared with single-agent 
chemotherapy (Borghaei et al., 2015; Brahmer et al., 2015; Herbst et al., 2016; Rittmeyer et al., 
2017). In patients whose tumors express 50% or more PD-L1 (tumor proportion score; TPS 
≥50^%), which is observed in about 30% of newly diagnosed NSCLC patients, the immune 
checkpoint inhibitor pembrolizumab is associated with a significant improvement in progression- 
free survival (PFS) and overall survival (OS) compared with platinum-based chemotherapy in 
the 1st-line setting (Reck et al., 2016). While these findings have shifted the therapeutic 
landscape of squamous NSCLCs with high PD-L1 expression, the standard of care in the 
majority of patients with newly diagnosed advanced squamous NSCLC remains platinum-based 
chemotherapy. In this patient population, carboplatin-based doublet regimens are widely 
accepted as the standard of care in the US. A randomized phase 3 clinical trial identified the 
histology-specific benefit of gemcitabine-based doublet therapy when compared with 
pemetrexed-based doublet therapy in patients with squamous NSCLC (Scagliotti et al., 2008). 
Studies comparing cisplatin- and carboplatin-based doublets suggest comparable clinical efficacy 
with improved tolerability with carboplatin-based therapy in the advanced NSCLC setting 
(Schiller et al., 2002). More recently, two 
randomized phase 3 clinical trials 
demonstrated significant overall survival 
gains with the addition of pembrolizumab 
to carboplatin/pemetrexed and 
carboplatin/taxane in newly diagnosed 
non-squamous and squamous NSCLC, 
respectively (Gandhi et al., 2018; Paz-Ares 
et al., 2018). The survival benefit of a 
combined platinum doublet- 
immunotherapy approach was 
demonstrated across PD-L1 expression 
levels and in patients with a PD-L1 TPS 
<1%. An ongoing phase II is evaluating 
the combination of cisplatin, gemcitabine, 
Figure 1: ATR inhibition with AZD6738 in combination with cisplatin 
results in near complete response in ATM-deficient H23 NSCLC 
xenografts models 
cetuximab and avelumab in patients with squamous NSCLC (NCT03717155). 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia Rad3-related (ATR) protein 
kinases are the primary sensors of DNA damage and regulators of the DNA damage response 
(DDR). These DNA repair enzymes contribute to maintaining genomic integrity in response to 
cytotoxic chemotherapy, ultraviolet light, ionizing radiation (IR), or hypoxia (Fokas et al., 2014; 
Pitts et al., 2014; Yan et al., 2014). Vendetti et al. at the UPMC Hillman Cancer Center (HCC) 
have demonstrated that inhibition of ATR with the small molecule AZD6738 potentiates the 
cytotoxicity of cisplatin and gemcitabine in human NSCLC cell lines with intact ATM kinase 
signaling (Vendetti et al., 2015). In ATM-deficient NSCLC cell lines, AZD6738 potently 
synergizes with cisplatin (Vendetti et al., 2015). In NSCLC xenograft models, the combination 
of AZD6738 and cisplatin results in near complete response of ATM-deficient NSCLC tumors, 
suggesting ATM-deficient tumors are particularly sensitized to ATR inhibition in combination 
with platinum (Figure 1) (Vendetti et al., 2015). 
 
Berzosertib (M6620, VX-970) is a highly potent and selective ATP-competitive inhibitor of 
ATR, and it has been shown to potentiate the antitumor effects of cisplatin, gemcitabine, 
irinotecan, and IR in several mouse xenograft models derived from human lung cancer cell lines 
and primary human tumor cells in a dose- and schedule-dependent manner (Fokas et al., 2012; 
Jossé et al., 2014; Hall et al., 2014). Our lung cancer research group here in Pittsburgh has 
reported on the validation of a commercial antibody (ab32420) for the identification of ATM by 
immunohistochemistry and have shown that 41% (61 of 147; 95% CI 34%-50%) of lung 
adenocarcinomas are negative for ATM protein expression, identifying a significant proportion 
of lung cancer patients whose tumors may be exquisitely sensitized to ATR kinase inhibition 
(Villaruz et al., 2016). Further unpublished preliminary data found a similarly high rate (39%) 
of squamous cell carcinomas to be negative for ATM protein expression (36 of 93; 95% CI 29%- 
49%) (Figure 2). Our clinical research team has been working closely with NCI-CTEP on the 
clinical development of berzosertib (M6620, VX-970); Dr. Villaruz is currently the study chair 
of NCI P9938, a UM1-sponsored phase I study of M6620 and irinotecan in patients with solid 
tumors, which was developed as part of the NCI-CTEP M6620 Drug Project Team. 
A 
B 
 
 
Figure 2: ATM loss is identified in squamous cell carcinoma of the lung with the rabbit monoclonal anti-ATM antibody 
ab32420 (AstraZeneca, 20X). 
A. ATM positive squamous cell carcinoma of the lung, and B. ATM loss in squamous cell carcinoma of the lung. 

NCI Protocol #: 10313 
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2.2 
CTEP IND Agents 
 
2.2.1 Berzosertib (M6620, VX-970) 
 
2.2.1.1 Berzosertib (M6620, VX-970) Mechanism of Action 
 
Berzosertib (M6620, VX-970) (formerly VX-970) is a potent and selective ATP-competitive 
inhibitor of ataxia telangiectasia and Rad3-related protein (ATR) kinase, with an inhibition 
constant (Ki) <0.3 nM (berzosertib (M6620, VX-970) Investigator’s Brochure, 2018). In 
comparison, berzosertib (M6620, VX-970) was a >100-fold weaker inhibitor of ataxia- 
telangiectasia mutated (ATM) kinase (Ki=34 nM) and >1000-fold less effective against other 
closely related kinases, such as DNA-PK (Ki>4 mcM), mTOR (Ki>1 mcM), and PI3K-gamma 
(Ki=0.22 mcM) (Fokas et al., 2012). Overall, berzosertib (M6620, VX-970) was >50-fold more 
selective for ATR than for 290 of 291 kinases tested (berzosertib (M6620, VX-970) 
Investigator’s Brochure, 2018). Cellular 50% inhibitory concentration (IC50) of ATR was 0.019 
mcM, demonstrating good selectivity over ATM (IC50=2.1 mcM) and DNA-PK (IC50=18.1 
mcM) (Fokas et al., 2012). 
 
Berzosertib (M6620, VX-970) potentiates activity of multiple DNA-damaging agents in 
numerous cancer cell lines (berzosertib (M6620, VX-970) Investigator’s Brochure, 2018). In 
contrast, normal cells treated with DNA-damaging agents tolerated ATR inhibition with just a 
reversible increase in growth arrest. Treatment of cancer cell lines with berzosertib (M6620, 
VX-970) and various DNA-damaging agents led to sustained berzosertib (M6620, VX-970)- 
dose-dependent decreases in the levels of CHK1pS345 induced by chemotherapy; CHK1pS345 is 
the main substrate of ATR (Fokas et al., 2012; Hall et al., 2014). Radiosensitization of 
pancreatic ductal adenocarcinoma cells by berzosertib (M6620, VX-970) was associated with 
inhibition of homologous recombination (HR) repair (Fokas et al., 2012). Berzosertib (M6620, 
VX-970) caused persistent increase in γH2AX levels both in vitro and in vivo. Adding 
berzosertib (M6620, VX-970) to gemcitabine-based chemoradiation dramatically enhanced 
antitumor effects, resulting in early and late apoptosis and abrogation of radiation-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 HR 
repair of double-strand breaks (DSBs) and for survival. 
 
2.2.1.2 Berzosertib (M6620, VX-970) Nonclinical Data 
 
In tumor cell line and patient-derived tumor xenograft mouse models, berzosertib (M6620, VX- 
970) dose-dependently enhanced antitumor effects of multiple DNA-damaging drugs and 
radiation (berzosertib (M6620, VX-970) Investigator’s Brochure, 2018). Dose-schedule 
optimization studies in xenograft models demonstrated that timing of berzosertib (M6620, VX- 
970) administration was critical for maximum activity in combination with a DNA-damaging 
agent. In combination with cisplatin or gemcitabine, maximum activity was observed when 
berzosertib (M6620, VX-970) was given 12 to 24 hours after the DNA-damaging agent. In 
contrast, when combined with irinotecan, concurrent treatment was the most effective while 
delayed administration of berzosertib (M6620, VX-970) was completely ineffective. 

NCI Protocol #: 10313 
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Non-clinical Pharmacology: In non-clinical species, berzosertib (M6620, VX-970) had a high 
volume of distribution; tissue exposure, including tumor, was high (berzosertib (M6620, VX- 
970) Investigator’s Brochure, 2018). The blood to plasma concentration ratios ranged from 1.6 
to 1.79 in nonclinical species and was 1.36 in human blood. berzosertib (M6620, VX-970) had 
high plasma protein binding (mainly to albumin), and the free fraction in human blood was 
3.29%. In the whole blood, berzosertib (M6620, VX-970) half-life was 11.6 and 9.8 hours in 
rats and dogs, respectively. Berzosertib (M6620, VX-970) is primarily metabolized through 
cytochrome P450 (CYP) isoform 3A4 and thus strong inducers or inhibitors of CYP3A4 may 
alter berzosertib (M6620, VX-970) kinetics and blood levels. Berzosertib (M6620, VX-970) is a 
weak inhibitor of UDP-glucuronosyltransferases (UGTs) with IC50s >10 mcM, and a weak to 
moderate inhibitor of transporters such as P-glycoprotein (P-gp; IC50=14 mcM) and breast cancer 
resistance protein (BCRP; IC50=3.4 mcM). 
Non-clinical Toxicology: Berzosertib (M6620, VX-970) toxicology studies in rats and dogs 
identified the liver, testes, and peripheral blood cell populations as target organs following oral 
or IV administration (berzosertib (M6620, VX-970) Investigator’s Brochure, 2018). Liver and 
peripheral blood toxicities were reversed within 4 weeks of discontinuation of berzosertib 
(M6620, VX-970). Berzosertib (M6620, VX-970) had no hemolytic potential in human blood or 
compatibility issues in human plasma as a clinical IV formulation at 20 mg/mL. Berzosertib 
(M6620, VX-970) was not genotoxic in the in vitro Ames assay, but was genotoxic in an in vitro 
micronucleus screening test. Testicular degenerative changes were observed in rats and dogs. 
Based on these genotoxicity studies, a potential risk that berzosertib (M6620, VX-970) can affect 
maturing germ cells in humans cannot be excluded. No reproductive toxicity tests have been 
performed, but because of its inhibition of DNA-damage repair and in vitro genotoxicity, the 
potential for teratogenicity should be considered high. Berzosertib (M6620, VX-970) absorbs 
light in UV-visible spectrum and phototoxic effects on mouse fibroblasts were observed. 
 
Recently, the addition of berzosertib (M6620, VX-970) and avelumab to a carboplatin or 
cisplatin regimen was tested in MC38 murine colorectal tumor model (Alimzhanov et al., 2019). 
The triplet combination demonstrated a statistically significant improvement in the control of 
tumor growth, more frequent tumor regressions, and increased overall survival, relative to the 
doublet combination (berzosertib (M6620, VX-970) and avelumab only). Animals with 
complete tumor responses were re-challenged with MC38 tumor cells, and subsequently found to 
be refractory to the second tumor inoculation, suggesting the durability of the anti-tumor 
immunity in complete responders. Further, the triplet combination was found to be well- 
tolerated, as assessed by body weight and clinical signs. 
 
2.2.1.3 Berzosertib (M6620, VX-970) Clinical Data 
 
Clinical Pharmacokinetics: Berzosertib (M6620, VX-970) systemic exposures expressed as 
either maximum concentration (Cmax) or area under the concentration-time curve from time zero 
extrapolated to infinity (AUC0-∞) tended to increase proportionally with increasing dose after IV 
administration of berzosertib (M6620, VX-970) as a single agent at the doses tested (berzosertib 
(M6620, VX-970) Investigator’s Brochure, 2018). The mean terminal elimination half-life was 
approximately 17 hours across all dose groups. Mean berzosertib (M6620, VX-970) plasma 
exposures, when berzosertib (M6620, VX-970) was given 1 day after administration of 

NCI Protocol #: 10313 
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gemcitabine, cisplatin, or carboplatin, were largely similar to exposures observed for berzosertib 
(M6620, VX-970) administered alone at equivalent doses. 
 
Clinical Safety: Berzosertib (M6620, VX-970) appeared to be well-tolerated when administered 
as either single-agent therapy or in combination with 1 or 2 chemotherapeutic agents to subjects 
with solid tumors (berzosertib (M6620, VX-970) Investigator’s Brochure, 2018). No dose- 
limiting toxicities (DLTs) were observed when berzosertib (M6620, VX-970) was administered 
as single-agent therapy at doses from 18 mg/m2 to 480 mg/m2. Almost all patients who received 
berzosertib (M6620, VX-970) in combination with chemotherapy experienced at least one 
treatment-emergent adverse events (AEs). Frequency of grade ≥3 AEs, serious AEs (SAEs), and 
AEs leading to study drug discontinuation notably varied across different combinations. Fatal 
AEs were infrequent. 
 
Infusion-related reactions (local or systemic), nausea, and vomiting are considered adverse drug 
reactions (ADRs) for berzosertib (M6620, VX-970), and myelosuppression events are considered 
ADRs for berzosertib (M6620, VX-970) in combination with carboplatin (berzosertib (M6620, 
VX-970) Investigator’s Brochure, 2018). 
 
• 
Infusion-related reactions (local or systemic) for berzosertib (M6620, VX-970) are the 
following: 
 
o Systemic infusion-related reactions to berzosertib (M6620, VX-970) may 
include signs or symptoms such as pruritus, flushing, chills/rigors, 
urticaria/rash, headache, bronchospasm/dyspnea, and hypotension or 
hypertension, among others. 
 
o Some systemic infusion-related reactions to berzosertib (M6620, VX-970) 
have been serious, including those described as acute hypersensitivity 
reactions. In almost all cases, these reactions occurred within minutes of 
the second exposure to berzosertib (M6620, VX-970) and they included 
hypotension and mental status changes. All subjects fully recovered with 
standard care procedures. 
o Local infusion-related reactions to berzosertib (M6620, VX-970), 
sometimes described as infusion site reactions, may include signs or 
symptoms such as infusion site erythema, swelling, or pain. The IV 
catheter through which berzosertib (M6620, VX-970) is infused should be 
monitored for evidence of erythema, tenderness, or induration. To 
minimize the possibility of phlebitis, berzosertib (M6620, VX-970) should 
be administered through a large-bore catheter into a large-caliber 
peripheral vein. 
• 
Nausea and vomiting have occurred commonly in patients receiving berzosertib 
(M6620, VX-970) monotherapy. Many of the affected subjects experienced these 
events on the same day as berzosertib (M6620, VX-970) was administered, and there 
was some suggestion of a dose response. 

NCI Protocol #: 10313 
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• 
Hematologic AEs in subjects who received berzosertib (M6620, VX-970) in 
combination with carboplatin included neutropenia, thrombocytopenia, and febrile 
neutropenia. 
 
2.3 
Commercial Agents 
 
2.3.1 Pembrolizumab 
 
Pembrolizumab (Keytruda®), a humanized monoclonal antibody against the PD-1 protein, has 
been developed by Merck & Co. for the treatment of cancer. Pembrolizumab is approved for 
treatment of melanoma in several countries; in the United States (US) and European Union it is 
approved for the treatment of advanced (unresectable or metastatic) melanoma in adults. 
Pembrolizumab has also been approved for treatment of NSCLC in several countries; in the US 
it is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 
as determined by a Food and Drug Administration (FDA)-approved test and who have disease 
progression on or after platinum-containing chemotherapy. Patients with NSCLC and epidermal 
growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor 
aberrations should also have disease progression on FDA-approved therapy for these aberrations 
prior to receiving pembrolizumab. Pembrolizumab is approved in the US for the treatment of 
patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with 
disease progression on or after platinum-containing chemotherapy. 
 
Pembrolizumab has demonstrated initial clinical efficacy in single-arm monotherapy trials in 
patients with NSCLC, HNSCC, urothelial cancer, gastric cancer, triple negative breast cancer, 
and Hodgkin’s Lymphoma as determined by response rate. Ongoing clinical trials are being 
conducted in these tumor types as well as a number of other advanced solid tumor indications 
and hematologic malignancies. For study details please refer to the Investigator’s Brochure 
(2017). 
 
2.3.2 Gemcitabine 
 
Gemcitabine is a deoxycytidine chain-terminating nucleoside analogue that kills cells undergoing 
DNA synthesis and blocks the progression of cells through the G1/S-phase boundary 
(Gemcitabine FDA Package Insert, revised 5/2019). It is metabolized to the diphosphate and 
triphosphate metabolite forms. Gemcitabine diphosphate inhibits the enzymatic generation of 
deoxynucleoside triphosphates (dNTPs) for DNA synthesis, resulting in reductions in dNTP 
concentrations, including dCTP. Gemcitabine triphosphate competes with dCTP for 
incorporation into DNA. Together, these activities enhance the incorporation of gemcitabine 
triphosphate into DNA, blocking further DNA synthesis and resulting in apoptosis. Gemcitabine 
as a single agent or combined with other chemotherapies is FDA-approved for the treatment of 
relapsed ovarian cancer, metastatic breast cancer, non-small cell lung cancer, and pancreatic 
cancer. Gemcitabine combinations are also commonly used in the treatment of relapsed or 
refractory non-Hodgkins and Hodgkins lymphomas and are supported by the guidelines of the 
National Comprehensive Cancer Network. 

NCI Protocol #: 10313 
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2.3.3 Carboplatin 
 
The standard of care in the majority of patients with newly diagnosed advanced squamous 
NSCLC remains platinum-based chemotherapy. In this patient population, carboplatin-based 
doublet regimens are widely accepted as the standard of care in the US. A randomized phase 3 
clinical trial identified the histology-specific benefit of gemcitabine-based doublet therapy when 
compared with pemetrexed-based doublet therapy in patients with squamous NSCLC (Scagliotti 
et al., 2008). 
 
Studies comparing cisplatin- and carboplatin-based doublets suggest comparable clinical efficacy 
with improved tolerability with carboplatin-based therapy in the advanced NSCLC setting 
(Schiller et al., 2002). More recently, two randomized phase 3 clinical trials demonstrated 
significant overall survival gains with the addition of pembrolizumab to carboplatin/pemetrexed 
and carboplatin/taxane in newly diagnosed non-squamous and squamous NSCLC, respectively 
(Gandhi et al., 2018; Paz-Ares et al., 2018). The survival benefit of a combined platinum 
doublet-immunotherapy approach was demonstrated across PD-L1 expression levels and in 
patients with a PD-L1 TPS <1%. Ongoing clinical trials are exploring the safety and efficacy of 
the PD-L1 inhibitor, avelumab, alone and in combination with platinum-based chemotherapy in 
multiple tumor types, including newly diagnosed NSCLC (NCT02576574, NCT03317496). An 
ongoing phase II is evaluating the combination of cisplatin, gemcitabine, cetuximab and 
avelumab in patients with squamous NSCLC in study disease background (NCT03717155). 
 
Carboplatin use has previously been described in patients with “anaplastic” or “aggressive 
variant” prostate cancer (Aparicio et al., 2013). More recently, carboplatin has been shown to be 
an active agent in cancers with homologous recombination repair deficiency, with demonstrated 
activity in prostate cancer patients with known inherited BRCA2 mutations (Cheng et al., 2016; 
Pomerantz et al., 2017). However, now that olaparib has demonstrated responses in patients 
with mCRPC with alterations in genes involved in homologous recombination repair, PARP 
inhibitors have already been incorporated in clinical practice for off-label use and are often 
preferentially prescribed over carboplatin at centers where detection of these alterations is 
feasible. Nonetheless, many questions remain in the utility of PARP inhibitors, including a 
better understanding of patients likely to respond, the proper sequencing/combination of this 
agent with others, and mechanisms of resistance. 
 
A variety of mechanisms have been proposed for how tumors that are resistant to PARP 
inhibition could remain sensitive to platinum agents, including loss of 53BP1, which leads to 
increased double strand break resection and thus leads to resistance to PARP inhibition in Brca1- 
null cells, but maintenance of sensitivity to DNA-crosslinking agents (Bunting et al., 2012); 
BRCA1 mutations that lead to defects in alternate DNA repair pathways such as nucleotide 
excision repair but retain proficiency in homologous recombination repair (Johnson et al., 2016); 
and mutation of other genes involved in nucleotide excision repair such as ERCC6 and ERCC4 
(Ceccaldi et al., 2015). As such, carboplatin remains a relevant agent in mCRPC and may lead 
to clinical responses even in patients who progress on a PARP inhibitor. 

NCI Protocol #: 10313 
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2.4 
Rationale 
 
In this protocol, we propose a phase 2 clinical trial aimed at the evaluation of berzosertib 
(M6620, VX-970) in combination with carboplatin and gemcitabine and pembrolizumab in 
patients with non-small cell lung cancer (NSCLC) of squamous cell histology (Sq). 
 
NCI P9948, investigating this same triplet combination in an ovarian cancer population, has 
identified the MTD to be berzosertib (M6620, VX-970) 90 mg/m2 in combination with 
gemcitabine 800 mg/m2 and carboplatin AUC 5 in patients previously treated with platinum- 
based chemotherapy. In this study, the target population will be platinum-naïve (or +1 year out 
from platinum-based treatment) Sq-NSCLC patients. In general, these patients are expected to 
tolerate higher doses of berzosertib (M6620, VX-970) than ovarian cancer patients who have 
progressed after cytotoxic chemotherapy. A lead-in phase 1B study will, therefore, be first 
conducted to assess the safety and tolerability of the established triplet RP2Ds of gemcitabine 
(800 mg/m2) and carboplatin (AUC 5) in combination with a higher dose of berzosertib (M6620, 
VX-970) (135 mg/m2). 
 
Although most of the berzosertib (M6620, VX-970) (ATRi) combination data has been 
generated with cisplatin, clinical responses have been observed with gemcitabine alone (3/18 
partial responses in NSCLC, including 1 squamous NSCLC, 15 stable disease) and with 
carboplatin alone (1/21 PR, 14 SD). Moreover, carboplatin shows similar synergistic effects 
with berzosertib (M6620, VX-970) when tested in a panel of human NSCLC cell lines (see 
berzosertib (M6620, VX-970) Investigator’s Brochure, 2018). Taken together, these findings 
suggest that similar synergistic effects would be observed between berzosertib (M6620, VX-970) 
and carboplatin in the clinical setting. 
 
2.5 
Correlative Studies Background 
 
2.5.1 ATM expression 
 
Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia Rad3-related (ATR) protein 
kinases are the primary sensors of DNA damage and regulators of the DNA damage response 
(DDR). These DNA repair enzymes contribute to maintaining genomic integrity in response to 
cytotoxic chemotherapy, ultraviolet light, ionizing radiation (IR), or hypoxia (Fokas et al., 2014; 
Pitts et al., 2014; Yan et al., 2014). Investigators at the UPMC Hillman Cancer Center (HCC) 
have demonstrated that inhibition of ATR with the small molecule AZD6738 potentiates the 
cytotoxicity of cisplatin and gemcitabine in human NSCLC cell lines with intact ATM kinase 
signaling (Vendetti et al., 2015). In ATM-deficient NSCLC cell lines, AZD6738 potently 
synergizes with cisplatin (Vendetti et al., 2015). In NSCLC xenograft models, the combination 
of AZD6738 and cisplatin results in near complete response of ATM-deficient NSCLC tumors, 
suggesting ATM-deficient tumors are particularly sensitized to ATR inhibition in combination 
with platinum (Vendetti et al., 2015). 
 
berzosertib (M6620, VX-970) is a highly potent and selective ATP-competitive inhibitor of 
ATR, and it has been shown to potentiate the antitumor effects of cisplatin, gemcitabine, 
irinotecan, and IR in several mouse xenograft models derived from human lung cancer cell lines 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
and primary human tumor cells in a dose- and schedule-dependent manner (Josse et al., 2014; 
Hall et al., 2014). Our lung cancer research group here in Pittsburgh has reported on the 
validation of a commercial antibody (ab32420) for the identification of ATM by 
immunohistochemistry and have shown that 41% (61 of 147; 95% CI 34%-50%) of lung 
adenocarcinomas are negative for ATM protein expression, identifying a significant proportion 
of lung cancer patients whose tumors may be exquisitely sensitized to ATR kinase inhibition 
(Villaruz et al., 2016). Further unpublished preliminary data found a similarly high rate (39%) 
of squamous cell carcinomas to be negative for ATM protein expression (36 of 93; 95% CI 29%- 
49%). 
 
We will test the hypothesis that berzosertib (M6620, VX-970) in combination with 
carboplatin/gemcitabine/pembrolizumab is associated with superior progression-free survival 
(PFS) when compared with carboplatin/gemcitabine/pembrolizumab alone in patients with 
chemotherapy-naïve ATM-deficient Sq-NSCLC. 
 
2.5.2 Whole Exome Sequencing 
 
Tumors harboring pre-existing defects in the DNA damage response (mutations in p53, ATM, 
FANCA, FANCC, and FANCG, or BRCA) may demonstrate enhanced sensitivity to the 
combination of ATR inhibition with berzosertib (M6620, VX-970) and 
carboplatin/gemcitabine/pembrolizumab. 
 
We will test the hypothesis that molecularly defined subpopulations may be particularly sensitive 
to the addition of berzosertib (M6620, VX-970) to chemo-immunotherapy. 
 
2.5.3 RNASeq 
 
Expression of inflammation-associated gene signatures in tumor infiltrating lymphocytes may be 
useful indicators of response to immune checkpoint inhibition. We will test the hypothesis that 
inflammation-associated gene expression may correlate with response to berzosertib (M6620, 
VX-970) and carboplatin/gemcitabine/pembrolizumab. 
 
2.5.4 PK of Gemcitabine and berzosertib (M6620, VX-970) 
Berzosertib (M6620, VX-970) is a novel agent, and the proposed PK studies will further define 
the properties in a homogeneous population. Gemcitabine PK, though more established, has 
been proposed for therapeutic drug monitoring (Kozo et al., 2017), and after defining the PK in 
this trial, we will explore correlations with toxicity and response. Cytidine deaminase (CDA) is 
the main enzyme responsible for gemcitabine and cytarabine degradation. CDA serum activity 
has been reported as a predictive marker for gemcitabine related toxicity (Ciccolini et al., 2010; 
Peters et al., 2014). 
 
3. PATIENT SELECTION 
 
All eligibility and exclusion criteria apply to Phase 1B and Phase 2 patients. 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
3.1 
Eligibility Criteria 
 
3.1.1 Patients must have histologically confirmed NSCLC of predominantly squamous cell 
histology, Stage IV (AJCC 8th edition). 
 
3.1.2 Patients must have measurable disease, as defined by RECIST v1.1 (See Section 12.1). 
 
3.1.3 Patients must have tumor tissue available at time of enrollment or be willing to undergo a 
biopsy for integrated biomarker studies. 
 
3.1.4 Patients with a history of prior platinum-based systemic chemotherapy given as 
neoadjuvant, adjuvant, or consolidation therapy for early stage or loco-regionally 
advanced NSCLC are eligible, if therapy is completed one year prior to initiation of 
treatment. Patients must not have had prior systemic chemotherapy or immunotherapy 
for metastatic disease. 
 
3.1.5 Patients with prior immunotherapy given as neoadjuvant, adjuvant, or consolidation 
therapy for early stage or loco-regionally advanced disease are eligible, if treatment is 
completed one year prior to initiation of treatment. 
 
3.1.6 Patients must have ECOG performance status of 0-1 (Karnofsky >60%, see Appendix A). 
 
3.1.7 Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of these drug combinations in patients <18 years of age, children are excluded from 
this study, but will be eligible for future pediatric trials. 
 
3.1.8 Patients must have adequate organ and marrow function as defined below: 
 
− 
leukocytes 
≥3,000/mcL 
− 
absolute neutrophil count 
> lower limit of normal (LLN) 
− 
platelets 
> LLN 
− 
total bilirubin 
≤ institutional upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
≤3 × institutional ULN 
− 
creatinine 
≤ institutional ULN 
OR 
− 
glomerular filtration rate (GFR)  ≥60 mL/min/1.73 m2 unless data exists supporting 
safe use at lower kidney function values, no lower 
than 30 mL/min/1.73 m2 (see Appendix B) 
 
3.1.9 Patients with human immunodeficiency virus (HIV) infection are eligible if they are on 
effective anti-retroviral therapy with undetectable viral load within 6 months, provided 
there is no expected drug-drug interaction. 
 
3.1.10 Patients with evidence of chronic hepatitis B virus (HBV) infection are eligible if the 
HBV viral load is undetectable on suppressive therapy (if indicated), provided there is no 

NCI Protocol #: 10313 
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expected drug-drug interaction. 
 
3.1.11 Patients with a history of hepatitis C virus (HCV) infection are eligible if they have been 
treated and cured. For patients with HCV infection who are currently on treatment, they 
are eligible if they have an undetectable HCV viral load. 
 
3.1.12 Patients with treated brain metastases are eligible if clinically stable, i.e., on stable doses 
of anti-convulsant therapy and/or stable doses of corticosteroids which are not to exceed 
10 mg/day of prednisone, or an equivalent corticosteroid. 
 
 
3.1.13 Patients with a prior or concurrent malignancy whose natural history or treatment does 
not have the potential to interfere with the safety or efficacy assessment of the 
investigational regimen are eligible for this trial. 
 
3.1.14 Patients with known history or current symptoms of cardiac disease, or history of 
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac 
function using the New York Heart Association Functional Classification. To be eligible 
for this trial, patients should be class 2B or better. 
 
3.1.15 Patients must be willing to comply with birth control requirements: The effects of the 
agents in this study (or similar agents) on the developing human fetus are either 
unknown, or known to be teratogenic, embryotoxic, and fetotoxic in mice and rabbits. 
For this reason, 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, for the duration of study participation, and for 6 months after completing treatment 
administration. Should a woman become pregnant or suspect she is pregnant while she 
or her partner is participating in this study, she should inform her treating physician 
immediately. Men treated or enrolled on this protocol must also agree to avoid donating 
sperm for during the study period, and to use adequate contraception prior to the study, 
for the duration of study participation, and for 6 months after completion completing 
treatment administration. Acceptable contraceptives are further described in Appendix C. 
 
3.1.16 Patients must have the ability to understand and willingness to sign a written informed 
consent document. Participants with impaired decision-making capacity who have a 
legally-authorized representative and/or family member available will also be eligible. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients with severe intercurrent illness or comorbidity are not eligible. 
 
3.2.2 Patients with contraindications to immunotherapy (e.g., solid organ transplant or active 
autoimmune disease requiring immunosuppressant therapy within 2 years of enrollment) 
are not eligible. 

NCI Protocol #: 10313 
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3.2.3 Patients with prior systemic chemotherapy for metastatic disease are not eligible. 
 
3.2.4 Patients who are receiving any other investigational agents are not eligible. 
 
3.2.5 Patients with a history of allergic reactions attributed to compounds of similar chemical 
or biologic composition to berzosertib (M6620, VX-970), pembrolizumab, gemcitabine, 
carboplatin, or other agents used in study are not eligible. 
 
3.2.6 Patients with severe bone marrow depression or significant bleeding are not eligible. 
 
3.2.7 Patients with psychiatric illness/social situations that would limit compliance with study 
requirements are not eligible. 
 
3.2.8 Berzosertib (M6620, VX-970) is primarily metabolized by CYP3A4; therefore, 
concomitant administration with strong inhibitors of CYP3A4 (e.g. clarithromycin, 
itraconazole, ketoconazole, HCV and HIV protease inhibitors, nefazodone, posaconazole, 
telithromycin, voriconazole) or strong inducers of CYP3A4 (e.g. carbamazepine, 
rifampin, phenobarbital, phenytoin, St. John’s Wort) should be avoided. Because the 
lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated medical reference. 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. Appendix D should be provided to patients. 
 
3.2.9 Pregnant women are excluded from this study because the agents in this study may have 
the potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with the study agents, breastfeeding should be discontinued if the mother is treated with 
the study agents berzosertib (M6620, VX-970), pembrolizumab, gemcitabine, or 
carboplatin. 
 
3.2.10 Berzosertib (M6620, VX-970) should be used with caution in patients with clinical 
evidence of germline defects in their DNA damage repair pathway (for example, patients 
with Li-Fraumeni syndrome or ataxia telangiectasia) due to a possible increase in the 
toxicity of DNA-damaging agents when paired with berzosertib (M6620, VX-970). 
3.2.11 Patients must not have received or be scheduled to receive radiation therapy within 7 
days or less from gemcitabine administration. 
 
3.2.12 Current or prior use of immunosuppressive medication within 28 days before the first 
dose of pembrolizumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of 
prednisone, or an equivalent corticosteroid. 
 
3.2.13 Patients must not have received an allogeneic stem cell transplant. 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
3.2.14 Patients must not have active, uncontrolled infections or recently received active 
vaccinations. 
 
3.3 
Inclusion of Women and Minorities 
 
NIH policy requires that women and members of minority groups and their subpopulations be 
included in all NIH-supported biomedical and behavioral research projects involving NIH- 
defined clinical research unless a clear and compelling rationale and justification establishes to 
the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate 
with respect to the health of the subjects or the purpose of the research. Exclusion under other 
circumstances must be designated by the Director, NIH, upon the recommendation of an IC 
Director based on a compelling rationale and justification. Cost is not an acceptable reason for 
exclusion except when the study would duplicate data from other sources. Women of 
childbearing potential should not be routinely excluded from participation in clinical research. 
Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to NCI- 
sponsored trials to register with their qualifications and credentials and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account at https://ctepcore.nci.nih.gov/iam. In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five person registration types. 
• IVR: MD, DO, or international equivalent, 
• NPIVR: advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD), 
• AP: clinical site staff (e.g., RN or CRA) with data entry access to CTSU such as the 
Roster Update Management System (RUMS), OPEN, Rave, acting as a primary site 
contact, or with consenting privileges, 
• Associate (A): other clinical site staff involved in the conduct of NCI-sponsored trials, 
and 
• Associate Basic (AB): individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• Addition to a site roster, 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN, 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval 
• 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). 
 
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 IRB Manager to indicate 
their intent to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact the CTSU 
Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying 
NCI CIRB approvals across their Signatory Network. Site preferences can be set at the network 
or protocol level. Questions about establishing site preferences can be addressed to the CTSU 
Regulatory Office by emailing the email address above or calling 1-888-651-CTSU (2878). 
 
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: 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
• 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, 
• 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. One way to search for a protocol is listed below. 
• Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password, 
• Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select LAO-PA015, and 
protocol number 10313, 
• Click on Documents, select Site Registration, and download and complete the forms 
provided. (Note: For sites under the CIRB initiative, IRB data will load automatically to 
the CTSU.) 
4.2.2 Protocol Specific Requirements For 10313 Site Registration 
 
• A Study Initiation Visit (SIV) or Site Initiation Teleconference (SIT) is required for each 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
participating site prior to activation. The local site PI must participate on the call. To 
schedule a SIV or SIT, please email the study coordinator listed on the front pages of the 
protocol. 
• Specimen Tracking System Training Requirement: 
o All data entry users (Clinical Research Associate role) at each participating site will 
need to complete the Theradex-led training. 
o Theradex will provide a certificate of completion, which will need to be submitted to 
the CTSU through the Regulatory Submission Portal. 
o The training is a one-time only requirement per individual. If an individual has 
previously completed the training for another ETCTN study, the training does not 
need to be completed again nor does the certificate of completion need to be 
resubmitted to the CTSU. However, new versions of the Specimen Tracking System 
may require new training. 
o This training will need to be completed before the first patient enrollment at a given 
site. 
o Please contact STS Support at Theradex for training, STS.Support@theradex.com. 
Theradex phone: 609-799-7580. 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office using 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. 
 
Delegation of Tasks Log (DTL) 
 
Each site must complete a protocol-specific DTL using the DTL application in the Delegation 
Log section on the CTSU members’ website. The Clinical Investigator (CI) is required to review 
and electronically sign the DTL prior to the site receiving an Approved site registration status 
and enrolling patients to the study. To maintain an approved site registration status the CI must 
re-sign the DTL at least annually and when a new version of the DTL is released; and activate 
new task assignments requiring CI sign-off. Any individual at the enrolling site on a 
participating roster may initiate the site DTL. Once the DTL is submitted for CI approval, only 
the designated DTL Administrators or the CI may update the DTL. Instructions on completing 
the DTL are available in the Help Topics button in the DTL application and include a Master 
Task List, which describes DTL task assignments, CI signature, and CTEP registration 
requirements. 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
4.2.4 Checking Site Registration Status 
 
Site’s registration status may be verified on the CTSU website. 
• Click on Regulatory at the top of the screen, 
• Click on Site Registration, and 
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
 
4.3 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or Theradex Interactive Web Response System (IWRS) for 
retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access: 
• A valid CTEP-IAM account. 
• To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an Associate Plus (AP) registration type. 
• 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 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. IWRS system also sends an email confirmation of the registration. You 
may 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 (Phase 1B 
only) 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. 
 
4.3.2 Special Instructions for Patient Enrollment 
 
This Study will use the ETCTN Specimen Tracking System (STS). 
 
• All biospecimens collected for this trial must be submitted using the ETCTN Specimen 
Tracking System (STS) unless otherwise noted. 
• The system is accessed through special Rave user roles: “CRA Specimen Tracking” for 
data entry at the treating institutions and “Biorepository” for users receiving the 
specimens for processing and storage at reference labs and the Biorepository. 
• Please refer to the Medidata Account Activation and Study Invitation Acceptance link on 
the CTSU website in the Data Management section under the Rave Home tab and then 
under Rave Resource Materials. 
• Important: Failure to complete required fields in STS may result in a delay in 
sample processing. Any case reimbursements associated with sample submissions will 
not be credited if samples requiring STS submission are not logged into STS. 
Detailed instructions can be found in Section 5.4. 
 
To register a patient, the following documents must be submitted to the Coordinating Center at 
least 48 hours prior to planned start of protocol therapy: 
 
• Completed Eligibility Checklist 
• Copy of required laboratory tests 
• Copy of signed and dated Informed Consent Form (ICF) 
• Copy of signed and dated HIPAA Authorization form (if separate from ICF) 
• Copy of all required scan reports 
• Copy of pathology report(s) 
• Copy of History and Physical and or Progress Notes (including oncologic treatment 
history, vital signs, height, weight, performance status, concurrent medications) 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
• Copy of EKG 
 
All registration source documents should be properly de-identified prior to submitting to the 
Coordinating Center. Registration documents may be submitted to the Coordinating Center via 
fax (412-647-0949) or e-mail (phase1@upmc.edu). Upon receipt of the required source 
documentation, authorized staff at the Coordinating Center will confirm all eligibility 
requirements. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
Theradex has developed a Slot Reservations and Cohort Management User Guide, which is 
available on the Theradex website: http://www.theradex.com/clinicalTechnologies/?National- 
Cancer-Institute-NCI-11. This link to the Theradex website is also on the CTSU website OPEN 
tab. For questions about the use of IWRS for slot reservations, contact the Theradex Helpdesk at 
855-828-6113 or Theradex main number 609-799-7580; CTMSSupport@theradex.com. 
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 7 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. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
5.1 
Summary Table for Specimen Collection 
 
Time Point 
Specimen 
Send Specimens To: 
Archival 
• 
4 slides (charged unstained 
slides with 5-micron thick 
sections), freshly cut1 
(mandatory) 
Sanja Dacic 
UPMC Pathology 
dacics@upmc.edu 
• Formalin-fixed paraffin- 
embedded (FFPE) tumor tissue 
block (preferred)1 (mandatory) 
If a block is not available, then 
submit: 
EET Biobank 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
 
• 
1 H&E stained slide (3-5 µm) 
• 
20 unstained, uncharged, air- 
dried slides (10 µm) 
Baseline (specimens to be collected only if archival tissue is insufficient or unavailable) 
• 
4 slides (charged unstained 
slides with 5-micron thick 
sections), freshly cut2 
(mandatory) 
Sanja Dacic 
UPMC Pathology 
dacics@upmc.edu 
• Formalin-fixed paraffin- 
embedded (FFPE) tumor tissue 
block (preferred)2 (mandatory) 
If a block is not available, then 
submit: 
• 
1 H&E stained slide (3-5 µm) 
• 
20 unstained, uncharged, air- 
dried slides (10 µm) 
EET Biobank 
Baseline 
• 
10 mL blood in EDTA Tube 
(mandatory) 
EET Biobank 
• 
Peripheral blood serum (red 
top tube, 3-4 mL) (mandatory) 
Jan Beumer 
Cancer Pharmacokinetics and 
Pharmacodynamics Facility, 
UPMC 
beumerjh@upmc.edu 
Cycle 1, Day 1 
• pre-dose 
• 25 minutes (-5 min) post 
start of gemcitabine (~5 
min before end of 
infusion) 
• 1 x 4 mL blood in purple top 
EDTA tube spiked with THU 
for each PK time point 
(mandatory) 
Jan Beumer 
Cancer Pharmacokinetics and 
Pharmacodynamics Facility, 
UPMC 
beumerjh@upmc.edu 
Cycle 1, Day 2 
• pre-dose 
• 30 minutes (+/-5 min) 
post start of berzosertib 
(M6620, VX-970) 
• 55 minutes (+/-5 min) 
post start of berzosertib 
(M6620, VX-970) (~5 
• 1 x 4 mL blood in purple top 
EDTA tube spiked with THU 
for each PK time point 
(mandatory for patients 
receiving M6620) 
Jan Beumer 
Cancer Pharmacokinetics and 
Pharmacodynamics Facility, 
UPMC 
beumerjh@upmc.edu 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
 
min before end of 
infusion) 
• 15 min (+/-5 min) post 
end of berzosertib 
(M6620, VX-970) 
• 30 min (+/-5 min) post 
end of berzosertib 
(M6620, VX-970) 
• 1h (+/-5 min) post end of 
berzosertib (M6620, VX- 
970) 
1For archival tissue, a copy of the corresponding anatomic pathology report must be sent with the tissue 
and uploaded to Rave. If submitting slides, then slides must be processed in order, and numbered 
sequentially (e.g., H&E stained slide is created first and labeled 1, unstained slides are then created and 
numbered 2 – 51). 
2For new biopsies, a completed copy of the Tissue Biopsy Verification Form (Appendix G), a copy of the 
radiology report or operative report from the biopsy procedure and, if available, the diagnostic pathology 
report must be sent to the EET Biobank. If the corresponding pathology report becomes available, then it 
should be uploaded to RAVE and a copy should be provided to the EET Biobank. 
 
5.2 
Summary Table(s) for Interventional Radiologist for Research Biopsies 
 
Biopsy #: 1 
Trial Time Point: Baseline (To be conducted only if no archival tissue is available). 
IR Biopsy Definition: Research – No Clinical Impact 
Core 
Priority 
Use in the 
Trial 
Biomarker 
Name(s) 
Tumor 
Content 
Required 
Post-Biopsy Processing 
1 
Integrated 
ATM expression 
>50% 
• 
FFPE. 
• 
4 slides needed for the ATM IHC 
assay (four charged unstained 
slides with 5-micron thick 
sections), freshly cut 
2 
Integrated 
WES 
>50% 
• 
FFPE. 
• 
tumor tissue block (preferred) or: 
• 
1 H&E stained slide, and 
• 
20 unstained, uncharged, air-dried 
slides (10 µm) 
3 
Exploratory 
RNAseq 
(to be conducted using tissue from WES assay) 
 
Note: Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within 
the CTEP Medidata Rave system. 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
 
5.3 
Specimen Procurement Kits and Scheduling 
 
5.3.1 Specimen Procurement Kits 
 
Kits are not provided for this protocol. Sites will use institutional supplies for specimen 
collection and shipment. 
 
5.3.2 Scheduling of Specimen Collections (for specimens being sent to the EET Biobank) 
 
Please adhere to the following guidelines when scheduling procedures to collect tissue: 
• FFPE tissue may collected any day. 
• Fresh blood specimens may be collected and shipped Monday through Friday. 
5.3.3 Scheduling of Specimen Collections (for specimens being sent to the University of 
Pittsburgh) 
 
Beumer Laboratory: Blood samples will be collected at the timepoints specified in 
Section 5.1. Frozen plasma/serum will be shipped overnight on either Monday, Tuesday, 
or Wednesday (and not before a federal or university holiday) to the Beumer Laboratory 
at the University of Pittsburgh. 
 
UPMC Pathology: Tumor tissue specimens collected during biopsy procedures and fixed 
in formalin, after sectioning, must be shipped within 1 business day of completion of 
fixation. Slides may be shipped overnight Monday through Thursday for arrival on 
Tuesday through Friday at UPMC Pathology. 
 
 
5.4 
Specimen Tracking System Instructions 
5.4.1 Specimen Tracking System (STS) Overview and Enrollment Instructions 
For the ETCTN STS, the following information will be requested: 
• Protocol Number 
• Investigator Identification 
o Institution and affiliate name 
o Investigator’s name 
• Eligibility Verification: Patients must meet all the eligibility requirements listed 
in Section 3. 
• Additional Requirements: 
o Patients must provide a signed and dated, written informed consent form. 
Upon enrolling a patient, IWRS will communicate with OPEN, assigning two separate 
and unique identification numbers to the patient, a Universal patient ID (UPID) and a 
Treatment patient ID. The UPID is associated with the patient and used each and every 
time the patient engages with the portion of this or any other protocol that uses the 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
ETCTN Specimen Tracking System. The UPID contains no information or link to the 
treatment protocol. IWRS will maintain an association between the UPID for ETCTN 
biobanking and molecular characterization and any treatment protocols the patient 
participates in, thereby allowing analysis of the molecular characterization results with 
the clinical data. 
 
Immediately following enrollment, the institutional anatomical pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into Rave. The 
report must include the surgical pathology ID (SPID), collection date, block number, and 
the IWRS-assigned UPID and patient study ID for this trial. For newly acquired biopsies, 
the radiology and operative report(s) must also be uploaded into Rave. Important: 
Remove any personally identifying information, including, but not limited to, the 
patient’s name, date of birth, initials, medical record number, and patient contact 
information from the institutional pathology report prior to submission. 
 
Additionally, please note that the STS software creates pop-up windows when reports are 
generated, so you will need to enable pop-ups within your web browser while using the 
software. 
 
For questions regarding the Specimen Tracking System, please contact STS Support at 
STS.Support@theradex.com. 
 
The Shipping List report must be included with all sample submissions. 
 
5.4.2 Specimen Labeling 
 
5.4.2.1 Blood Specimen Labels 
 
Include the following on blood specimens (including whole blood and frozen, processed 
blood products – like serum and plasma): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., blood, serum) 
• Collection date and time (to be added by hand) 
5.4.2.2  Tissue Specimen Labels (for WES/RNAseq samples going to the Biorepository) 
Include the following on all tissue specimens or containers (e.g., formalin jar): 
• Patient Study ID 
• Universal Patient ID (UPID) 
• Specimen ID (automatically generated by Rave) 
• Time point 
• Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
Formalin Fixed Tissue, Fresh Tissue in Media, etc.) 
• Tissue type (P for primary, M for metastatic or N for normal) 
• Surgical pathology ID (SPID) number 
• Block number from the corresponding pathology report 
• Collection date (to be added by hand) 
• Slide section number (only if archival or baseline tissue is submitted as slides) 
(to be added by hand) 
5.4.2.3  Tissue Specimen Labels (for ATM expression samples going to UPMC Pathology) 
Include the following on all tissue specimens: 
• Patient Study ID 
• Specimen type (e.g., formalin-fixed paraffin-embedded [FFPE] Block, 
Formalin Fixed Tissue, Fresh Tissue in Media, etc.) 
• Fixation Time 
• Surgical pathology ID (SPID) number 
• Block number from the corresponding pathology report (archival only) 
• Collection date 
• Date slides were cut 
5.4.2.4 Example of Specimen Label Generated by STS 
 
 
STS includes a label printing facility, accessed via the Print Label CRF in the All 
Specimens folder. A generated PDF is emailed to the user as a result of saving that form. 
The following image is an example of a tissue specimen label printed on a label that is 
0.5” high and 1.28” wide. 
 
 
 
The QR code in the above example is for the Specimen ID shown on the second line. 
 
Labels may be printed on a special purpose label printer, one label at a time, or on a 
standard laser printer, multiple labels per page. Theradex recommends the use of these 
low temperature waterproof labels for standard laser printers: 

NCI Protocol #: 10313 
Version Date: 11/05/2024 
 
https://www.labtag.com/shop/product/cryo-laser-labels-1-28-x-0-5-cl-23-colors- 
available/ 
 
The last line item on the label includes the following data points joined together: 
1. Tissue only: Primary (P), Metastatic (M), Normal (N) tissue indicated at the 
beginning of the specimen ID; this field is blank if not relevant (e.g., for 
blood) 
2. Block ID or blank if not relevant 
3. SPID (Surgical Pathology ID) or blank if none 
4. An optional alpha-numeric code that is protocol specific and is only included 
if the protocol requires an additional special code classification 
 
Space is provided at the bottom of the label for the handwritten date and optional 
time. The last line on the example label is for the handwritten date and optional time. 
 
 
5.4.3 Overview of Process at Treating Site 
 
5.4.3.1 OPEN Registration 
 
All registrations will be performed using the Oncology Patient Enrollment Network 
(OPEN) system. OPEN communicates automatically with the Interactive Web Response 
System (IWRS) which handles identifier assignments, any study randomization, and any 
prescribed slot assignments. 
 
Registration without eligibility specimen analysis: 
 
1. Site enters registration data into OPEN during one or more steps. 
2. IWRS receives data from OPEN, generates the Patient Study ID and the Universal 
Patient ID, both of which are sent back to OPEN. 
3. IWRS sends all applicable registration data directly to Rave at the end of the final 
registration step. 
Any data entry errors made during enrollment should be corrected in Rave. 
5.4.3.2 Rave Specimen Tracking Process Steps 
 
Step 0: Log into Rave via your CTEP-IAM account, then navigate to the appropriate 
participant. 
 
Step 1: Complete the Histology and Disease form (but do not upload reports until a 
specimen label can be applied to them) and the Baseline forms regarding Prior 
Therapies. Enter the initial clinical specimen data: 
• Specimen Tracking Enrollment CRF: Enter Time Point, Specimen Category, 
Specimen Type, Block number, Tissue type, Surgical Path ID, and number of 

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labels needed (include extra labels to apply to reports to be uploaded). CRF 
generates unique Specimen ID. 
 
Step 2: Print labels using the Print Labels CRF located in the All Specimens folder, 
then collect specimen. 
• Label specimen containers and write collection date on each label. 
• After collection, store labeled specimens as described in Section 5.4.2. 
Apply an extra specimen label to each report before scanning. Return to the 
Histology and Disease form to upload any initial Pathology, Radiology, 
Molecular Reports (up to 4), Surgical (or Operative) reports. Return to Specimen 
Tracking Enrollment CRF to upload any molecular report (one per specimen) 
and/or specimen specific pathology or related report (one per specimen) and/or 
the Tissue Biopsy Verification form (when applicable, Appendix G). Uploaded 
reports should have protected health information (PHI) data, like name, date of 
birth, mailing address, medical record number or social security number (SSN), 
redacted. Do not redact SPID, block number, diagnosis or relevant dates 
(such as collection date), and include the UPID and patient study ID on each 
document (either by adding a label or hand writing). 
 
Step 3: Complete specimen data entry. 
• Specimen Transmittal Form: Enter collection date and time and other required 
specimen details. 
Step 4: When ready to ship, enter shipment information. 
• Shipping Status CRF: Enter tracking number, your contact information, 
recipient, number of sample containers and ship date once for the first specimen 
in a shipment. 
• Copy Shipping CRF: In the specimen folders for additional specimens (if any) 
that will be shipped with the initial specimen, please use the Copy Shipping form 
to derive common data into additional Shipping Status forms. A few unique 
fields will still need to be entered in Shipping Status. 
 
Step 5: Print shipping list report and prepare to ship. 
• Shipping List report is available at the site level. 
• Print two copies of the shipping list, one to provide in the box, the other for your 
own records. 
• Print pathology or other required reports to include in the box. Be sure the printed 
copy includes the specimen label. 
Step 6: Send email notification. 
• For only one of the specimens in the shipment, click “Send Email Alert” 
checkbox on the Shipping Status CRF to email recipient. 
Step 7: Ship the specimen(s). 

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Step 8: Monitor the Receiving Status form located in each specimen folder for 
acknowledgment of receipt and adequacy. 
 
 
5.5 
Specimen Collection 
 
See Section 5.4.2 for labeling instructions. 
 
5.5.1 Archival or Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimen for WES and 
RNAseq 
If archival FFPE tissue will be submitted, then the following criteria must be met: 
• Tissue must have been collected within 3 months prior to registration 
• FFPE tumor tissue block(s) must be submitted. The optimal block is at least >50% 
tumor. Specimen size requirements are as follows: 
o Surface area: 25 mm2 is optimal. Minimum is 5 mm2. 
o Volume: 1 mm3 optimal. Minimum volume is 0.2 mm3, however the success 
of DNA extraction decreases at suboptimal tissue volume. 
If an existing block cannot be submitted, the following are requested, if available: 
• One (1) H&E slide, (3-5 µm) 
• Twenty (20) (10 µm) unstained air-dried uncharged slides. 
o Process and number slides sequentially (e.g., H&E stained slide should be created 
first and labeled with “1,” and additional unstained slides should be processed 
next and be labeled 2 – n. 
 
5.5.2 Archival Tumor Specimen for ATM Expression 
 
• Four freshly-cut charged, unstained slides from FFPE tissue, 5 microns (mcm) thick. 
• Fixation time should be between 6-12 hours (Lindeman et al., 2013). 
5.5.3 Collection of Blood in EDTA Tube for WES/RNAseq Germline Control 
 
1. Label EDTA tubes according to the instructions in Section 5.4.2. 
2. Collect 10 mL of blood in EDTA tube(s) and gently invert tube to mix. 
3. Ship on day of collection (whenever possible) according to instructions in Section 
5.6. 
4. If blood cannot be shipped on the day of collection (e.g., a late scheduled collection), 
then refrigerate until shipment. 
 
5.5.4 Collection of Blood in Red Top Tube for Serum Processing for PK Studies 

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Document exact start and stop times of each infusion and exact times of blood draws per 
Appendix F. 
 
1. Label one 3-4 mL red-top tube according to the instructions in Section 5.4.2.1. (e.g. 
BD vacutainer 367812 plastic 13 x 75 4 mL tube), note that no tetrahydrouridine (NO 
THU) shall be added to this tube. 
2. Collect 3-4 mL of whole blood in red-top tube. 
3. Allow blood to clot upright at room temperature for at least 30 minutes (maximum 60 
minutes) prior to processing. If the blood is not immediately processed after the 
clotting period, then tubes should be stored (after the 30-60 minutes of clotting time) 
at 4°C for no longer than 4 hours. Process serum from red top tubes by centrifuging 
for 10 minutes at 1,200 × g at room temperature. 
4. Using a clean transfer pipette, aliquot serum into the labeled (using the label printed 
from the ETCTN Specimen Tracking System or following the instructions in Section 
5.4.2) cryovials at an aliquot volume of 1 mL per tube. Avoid picking up red blood 
cells when aliquoting by keeping the pipet above the red blood cell layer and leaving 
a small amount of serum in the tube. Tightly secure the cap of the vials before 
storage. Aliquoting and freezing of serum specimens should be completed within 1 
hour of centrifugation. 
5. Store serum cryovials upright in a specimen box or rack in an -70°C to -90°C or 
colder freezer prior to delivering to laboratory. Do not allow specimens to thaw after 
freezing. 
 
5.5.5 Collection of Blood in EDTA Tubes for Plasma Processing for PK Studies 
 
General Considerations 
 
Blood samples to be obtained through a peripheral or central line blood draw. Samples 
should be drawn from the opposite arm if infusion is a peripheral infusion. Samples 
should NOT be drawn from the infusion line. EDTA Vacutainer tubes shall be prepared 
by addition of THU solution to prevent ex vivo degradation of gemcitabine. 
 
Preparation of Tubes with THU 
Prepare an aqueous stock solution of tetrahydrouridine (THU) at 10 mg/mL. THU can be 
added to Vacutainer tubes up to several days in advance without causing significant loss 
of vacuum (keep in fridge, no more than 1-2 weeks). 
1. Using a 3/10 cc insulin syringe or other similar sized syringe with a fine needle, 
draw up 10 mcL of the THU solution for each 1 mL of blood to be drawn and 
transfer it to a Vacutainer tube by piercing the stopper. 
2. Do not draw up THU solution for more than one tube at a time. You will not be 
able to control the volume of THU solution that leaves the needle, as it is sucked 
out by the vacuum. 

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3. Because of the fine needle, you will not lose the vacuum (apart from the volume 
added) in the collection tube. 
 
Drawing and Processing 
 
1. Label EDTA tube(s) (e.g., BD vacutainer 367861 plastic 13 x 75 4 mL tube) 
according to the instructions in Section 5.4.2. 
2. Collect 3-4 mL of whole blood in EDTA (purple top) tube(s). 
3. Process plasma by centrifuging for 10 minutes at approximately 1,200 × g at room 
temperature. 
4. Using a clean transfer pipette, transfer 1 mL of plasma into each of the labeled 
cryovials (using the label printed from the ETCTN Specimen Tracking System or 
following the instructions in Section 5.4.2.1). Avoid picking up the blood cells when 
aliquoting by keeping the pipet above the cell layers and leaving a small amount of 
plasma in the tube. Tightly secure the cap of the vials before storage. Aliquoting and 
freezing of plasma specimens should be completed within 1 hour of centrifugation. 
5. Store plasma cryovials upright in a specimen box or rack in an -70°C to -90°C or 
colder freezer prior to delivering to laboratory. Do not allow specimens to thaw after 
freezing. 
 
5.6 
Shipping Specimens to the EET Biobank from the Clinical Site 
 
5.6.1 General Shipping Information 
 
For all archival tissue, the corresponding anatomical clinical pathology report is required 
both in the package and uploaded in the ETCTN specimen tracking system. If this is not 
available at the time of shipment, then it must sent to the EET Biobank as soon as 
possible and be uploaded to the ETCTN specimen tracking system, or the specimen will 
not be processed. The pathology report must state the disease diagnosis made by the 
reviewing pathologist. 
For new biopsies, include a completed copy of the Tissue Verification Form (Appendix 
G), and a copy of the radiology or operative report, and, if available, the diagnostic 
pathology report with the shipment. 
5.6.1.1 Required Forms for Specimen Submissions 
Each document submitted with the specimen must be labeled with a label 
printed from the STS, or the Universal ID and Patient Study ID. 
 
Tissue 
Required Forms 
Archival 
1. Shipping List 
2. Corresponding Pathology Report 

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Tissue 
Required Forms 
New Biopsy 
1. Shipping List 
2. Tissue Biopsy Verification Form 
3. Diagnostic Pathology Report 
4. Surgical and/or Radiology Report 
Blood 
1. Shipping List 
 
 
 
5.6.2 Specimen Shipping Instructions 
 
Archival or Baseline (FFPE) tissue may be shipped on Monday through Thursday. 
Fresh blood may be shipped on Monday through Friday. Please select “Saturday 
Delivery” when shipping fresh blood on a Friday. 
5.6.2.1 Shipping of FFPE Blocks or Glass Slides 
 
1. Before packaging blocks or slides, verify that each specimen is labeled according to 
Section 5.4.2.2. 
2. Blocks should be placed in a special block holder, if possible. Glass slides are to be 
placed in plastic slide holders. Place tissue paper on top of the separated slides prior 
to closing the slide holder to reduce slide movement during shipment. 
3. Place the blocks or slides in a reinforced cardboard shipping box with appropriate 
packaging filler to minimize movement of specimens within the shipping box. 
4. Include a copy of the corresponding pathology report, if available, and a shipping 
manifest from the Specimen Tracking System with each shipment. 
5. Please include a cold pack when shipping on hot days and extra insulation on cold 
days. 
6. Ship specimens to the address listed below. FedEx Priority Overnight is strongly 
recommended to prevent delays in package receipt. 
5.6.2.2 
Shipping Blood in Your Own Container 
1. Before packaging specimens, verify that each specimen is labeled according to the 
instructions in section 5.4.2. 
2. Place the blood collection tube(s) in a zip-lock bag. 
3. Place blood into a biohazard envelope with absorbent material. Expel as much air as 
possible and seal the envelope securely. 
4. Place the biohazard envelope into a Tyvek envelope. Expel as much air as possible 
and seal securely. 
5. Place packaged blood collection tube(s) and a copy of the shipping manifest from the 
Sample Tracking System into a sturdy shipping container. In winter months, please 
use an insulated container and include extra insulation, such as bubble wrap, inside 
the shipping container to prevent specimens from freezing. 
6. Close the container and tape shut. 

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7. Attach a shipping label to the top of the shipping container. 
8. Attach an Exempt Human Specimen sticker to the side of the container. 
9. Ship specimens via overnight courier to the address below. FedEx Priority Overnight 
is strongly recommended to prevent delays in package receipt. 
 
5.6.3 
Shipping Address 
 
Ship to the address below. Ship formalin-fixed and fresh blood specimens the same day 
of specimen collection. Do not ship specimens the day before a holiday. 
 
EET Biobank 
2200 International Street 
Columbus, OH 43228 
PH: (614) 722-2865 
FAX: (614) 722-2897 
E-mail: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred. 
 
NOTE: The EET Biobank FedEx Account will not be provided to submitting 
institutions. 
 
5.6.4 
Contact Information for Assistance 
For all queries, please use the contact information below: 
EET Biobank 
PH: (614) 722-2865 
E-mail: BPCBank@nationwidechildrens.org 
 
 
 
5.7 
Shipping Specimens to Other Laboratories from the Clinical Site 
 
5.7.1 
Shipping of Specimens to UPMC Pathology 
5.7.1.1 Specimen Shipping Instructions 
Samples should be labeled according to Section 5.4.2.3. 
For all archival tissue, the corresponding anatomical clinical pathology report is 
required in the package. If this is not available at the time of shipment, then it must 
be sent to the address below when it becomes available. The pathology report must 
state the disease diagnosis made by the reviewing pathologist. 
 
For formalin-fixed biopsies, if the corresponding anatomical pathology report is not 

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available at the time of shipment, then it must be sent to the address below if it 
becomes available. The pathology report, if available, must state the disease 
diagnosis made by the reviewing pathologist. 
 
Unstained slides should be placed into an appropriately labeled transport container. 
Ship using 4°C cool packs. Do not freeze the specimen. Ship specimens via overnight 
courier to the address below. FedEx Priority Overnight is strongly recommended to 
prevent delays in package receipt. 
 
5.7.1.2 Shipping Address 
 
Sanja Dacic, M.D., Ph.D. 
Professor of Pathology 
Rm. PUH C608 
UPMC-PUH 
200 Lothrop St. 
Pittsburgh, PA 15213 
5.7.1.3 Contact Information for Assistance 
Office Telephone: 412-647-8694 
Email Laboratory Director: dacics@upmc.edu 
 
5.7.2 
Shipping of Specimens to Cancer Pharmacokinetics and Pharmacodynamics Facility, 
UPMC (Beumer PK Laboratory) 
 
5.7.2.1 Specimen Shipping Instructions 
Preparing the shipment: 
1. Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, L x W x H). 
2. Organize the samples by Patient and Time point in the box. 
3. Do not store in plastic bags (they break on dry-ice and labels will detach). 
4. A copy of each of the pharmacokinetic sample collection forms for the respective 
patients should be included with each shipment (see Appendix F). 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 the 
samples so that receipt can be acknowledged. 
5. Please notify the lab by email (pitt-pk@upmc.edu), telephone (412-623-3248), or 
fax (412-623-1212) at least 24 hours prior to shipment. 

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Regulations: 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. 
 
Shipping Restrictions: All samples should be shipped via overnight express courier 
in insulated containers with enough dry ice to maintain the samples in a frozen state. 
All specimens are to be shipped on either Monday, Tuesday, or Wednesday, and not 
before federal or university holidays. 
 
5.7.2.2 
Shipping Address 
 
Jan Beumer, University of Pittsburgh 
Cancer Pharmacokinetics and Pharmacodynamics Facility 
UPMC Hillman Cancer Center 
Room G27 Hillman Research Laboratories 
5117 Centre Avenue 
Pittsburgh, PA 15213 
5.7.2.3 
Contact Information for Assistance 
Lab phone: 412-623-3248 
Lab fax: 412-623-1212 
PK Lab email: PITT-PK@upmc.edu 
PK director email: beumerjh@upmc.edu 

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5.8 
Biomarker Plan 
 
List of Biomarker Assays in Order of Priority 
Note for participating sites: Please see Section 5.1 for details on specimens to collect. The specimens tested are not always the same 
specimens that are submitted by the site, as processing of blood and tissue will occur at the Biobank prior to testing 
Priority Biomarker 
Name 
Assay 
CLIA: Y/N 
Use in the 
Trial and 
Purpose 
Specimens 
Tested 
Collection Time Points 
M/O Assay Laboratory and 
Lab PI 
Tissue-based Biomarkers 
1 
ATM 
expression 
Chromogenic 
IHC 
CLIA: Y 
Integrated 
Correlate with 
PFS 
FFPE Tumor 
Archival, within 3 months prior to 
treatment (or baseline if archival tissue 
is insufficient or unavailable) 
M 
UPMC Pathology 
Sanja Dacic 
dacics@upmc.edu 
2 
Whole Exome 
Sequencing 
NGS 
CLIA: N 
Integrated 
Correlate with 
Response 
DNA from 
FFPE Tumor 
Archival, within 3 months prior to 
treatment (or baseline if archival tissue 
is insufficient or unavailable) 
M 
NCLN Genomics 
Laboratory 
Mickey Williams, Ph.D. 
mickey.williams@nih.gov 
3 
RNAseq 
NGS 
CLIA: N 
Exploratory 
To identify 
TIL 
signatures and 
correlate 
response 
RNA from 
FFPE Tumor 
Archival, within 3 months prior to 
treatment (or baseline if archival tissue 
is insufficient or unavailable) 
O 
NCLN Genomics 
Laboratory 
Mickey Williams, Ph.D. 
mickey.williams@nih.gov 
Blood-based Biomarkers 

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Priority Biomarker 
Name 
Assay 
CLIA: Y/N 
Use in the 
Trial and 
Purpose 
Specimens 
Tested 
Collection Time Points 
M/O Assay Laboratory and 
Lab PI 
Tissue-based Biomarkers 
1 
PK of 
gemcitabine and 
Berzosertib 
(M6620, VX- 
970) 
LC/MS 
CLIA: N 
Integrated 
Correlate drug 
levels with 
toxicity and 
efficacy 
Blood 
All: Cycle 1, Day 1: pre-dose and 25 
min (-5 min) post start of gemcitabine 
(~ 5 min before end of infusion) 
Patients receiving M6620 only: Cycle 
1, Day 2: pre-dose, 30 min (+/-5 min) 
post start of berzosertib (M6620, VX- 
970), 55 min (+/-5 min) post start of 
berzosertib (M6620, VX-970) (~ 5 min 
before end of infusion), 15 min (+/-5 
min) post end of berzosertib (M6620, 
VX-970), 30 min (+/-5 min) post end 
of berzosertib (M6620, VX-970), 1 hr 
(+/-5 min) post end of berzosertib 
(M6620, VX-970). 
M 
Cancer Pharmacokinetics 
and Pharmacodynamics 
Facility, UPMC 
Jan Beumer 
beumerjh@upmc.edu 
2 
Whole Exome 
Sequencing 
NGS 
CLIA: N 
Integrated 
Correlate with 
Response 
DNA from 
Blood in 
EDTA 
(Germline 
Control) 
Baseline 
M 
NCLN Genomics 
Laboratory 
Mickey Williams, Ph.D. 
mickey.williams@nih.gov 

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47 
 
 
5.9 
Integrated Correlative Studies 
5.9.1 ATM Expression 
5.9.1.1 Specimen Receipt and Processing at UPMC Pathology 
Each case upon receipt in the pathology laboratory at UPMC Pathology will be 
assigned a unique accession number (PHR) in the pathology electronic records. 
Cases will be sent for staining with 1 business day of receipt. ATM IHC as 
developed and validated by the UPMC Hillman Cancer Center and UPMC Pathology 
will be performed as previously reported (Villaruz et al., 2016). 
 
5.9.1.2 Site Performing Correlative Study 
 
Sanja Dacic, M.D., Ph.D. 
Professor of Pathology 
Rm. PUH C608 
UPMC-PUH 
200 Lothrop St. 
Pittsburgh, PA 15213 
 
Office Telephone: 412-647-8694 
Email Laboratory Director: dacics@upmc.edu 
 
5.9.2 PK of Gemcitabine and Berzosertib (M6620, VX-970) 
 
5.9.2.1 Specimen Receipt and Processing at UMPC Cancer Pharmacokinetics and 
Pharmacodynamics Facility 
 
Frozen Plasma aliquots will be received at the Beumer laboratory for processing and 
storage. 
 
The LC-MS/MS assay for berzosertib (M6620, VX-970) was developed and validated 
at the UPMC Hillman Cancer Center, Cancer Pharmacokinetics and 
Pharmacodynamics Facility (Kiesel et al., 2017). An LC-MS/MS assay to quantitate 
gemcitabine and metabolite dFdU and CDA activity (Stoller et al., 2017) is currently 
available in the UPMC Hillman Cancer Center, Cancer Pharmacokinetics and 
Pharmacodynamics Facility. The study team will use accepted assay characteristics 
for each test. 
 
5.9.2.2 Site Performing Correlative Study 
 
Jan Beumer, University of Pittsburgh 
Cancer Pharmacokinetics and Pharmacodynamics Facility 
UPMC Hillman Cancer Center 
Room G27 Hillman Research Laboratories 

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48 
 
 
5117 Centre Avenue 
Pittsburgh, PA 15213 
Lab phone: 412-623-3248 
Lab fax: 412-623-1212 
5.9.3 Whole Exome Sequencing 
5.9.3.1 Specimen Receipt and Processing at the EET Biobank 
• 
Tumor tissue received in formalin will be paraffin-embedded. All FFPE blocks 
will be sectioned to generate an initial hematoxylin and eosin (H&E)-stained slide 
for pathology QA assessment, and unstained slides for macrodissection (if needed) 
for nucleic acid extractions. 
• DNA and RNA will be co-extracted from tumor tissue. The nucleic acids will be 
analyzed to determine concentration and quality. Aliquots of DNA will be 
shipped to the central sequencing laboratory for analysis. 
• DNA will be extracted from the whole blood collected in EDTA tube(s) 
5.9.3.2 Site Performing Correlative Study 
 
NCLN Genomics Laboratory 
Dr. Mickey Williams 
mickey.williams@nih.gov 
 
5.9.3.3 Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
 
Specimens will be shipped from the EET Biobank to: 
NCLN Genomics Laboratory at The University of Texas MD Anderson Cancer 
Center 
Attn: Jincy Veliyathu or Khushali Rajendra Patel 
Zayed Building 
CTLU Z3.4020 
6565 MD Anderson Blvd 
Houston, TX 77030 
 
5.9.3.4 Contact Information for Notification of Specimen Shipment 
Thomas Forbes (NCLNGenomicsReceiving@nih.gov) 
5.10 Exploratory/Ancillary Correlative Studies 

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Regimen Description 
(Phase 1B and Phase 2) 
5.10.1 RNA Sequencing 
5.10.1.1 
Specimen Receipt and Processing at the EET Biobank 
• 
Tumor tissue received in formalin will be paraffin-embedded. All FFPE blocks 
will be sectioned to generate an initial hematoxylin and eosin (H&E)-stained 
slide for pathology QA assessment and unstained slides for nucleic acid 
extractions 
• DNA and RNA will be co-extracted from tumor tissue. The nucleic acids will 
be analyzed to determine concentration and quality. Aliquots of RNA will be 
shipped to the central sequencing laboratory for analysis. 
5.10.1.2 
Site Performing Correlative Study 
NCLN Genomics Laboratory 
Dr. Mickey Williams 
mickey.williams@nih.gov 
 
5.10.1.3 
Shipment of Specimens from the EET Biobank to Site Performing Correlative Study 
Specimens will be shipped from the EET Biobank to: 
NCLN Genomics Laboratory at The University of Texas MD Anderson Cancer 
Center 
Attn: Jincy Veliyathu or Khushali Rajendra Patel 
Zayed Building 
CTLU Z3.4020 
6565 MD Anderson Blvd 
Houston, TX 77030 
 
5.10.1.4  Contact Information for Notification of Specimen Shipment 
Thomas Forbes (NCLNGenomicsReceiving@nih.gov) 
 
6. TREATMENT PLAN 
 
6.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 10. Appropriate dose modifications are described in Section 7. No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 

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50 
 
 
 
Agent* 
Order of 
Admin- 
istration 
Pre- 
medications 
& 
Precautions** 
Route 
Schedule 
Cycles 1- 
4 (every 
3 weeks) 
Schedule 
Cycles 5- 
16 (every 
3 weeks) 
Schedule 
Cycles 
17-26 
(every 6 
weeks) 
Cycle 
Length 
Pre- 
IV over 30 
min 
(± 10 
minutes) 
medications 
should be 
Pembrolizumab 
1 
administered 
D1 
D1 
D1 
per 
institutional 
guidelines. 
Antiemetics 
should be 
IV over 30 
Cycles 1- 
Gemcitabine 
2 
administered 
per 
min 
(± 10 
D1 and 
D8 
- 
- 
16: 
21 days 
institutional 
minutes) 
(3 weeks) 
guidelines. 
Antiemetics 
Cycles 
should be 
IV over 30 
17-26: 
Carboplatin 
3 
administered 
per 
min 
(± 10 
D1 
- 
- 
42 days 
(6 weeks) 
institutional 
minutes) 
guidelines. 
No pre- 
Berzosertib 
(M6620, VX- 
970) 
-- 
medications 
required 
unless 
clinically 
IV over 60 
min 
(± 10 
minutes) 
D2 and 
D9 
D1 
- 
indicated. 
*Doses as appropriate for assigned dose level. 
**All pre-medications will be given prior to starting infusions. 

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51 
 
 
 
Phase 1B Safety Lead-In (n = 6-18) 
Dose De-Escalation Schema 
Berzosertib 
(M6620, VX- 
Gemcitabine 
Carboplatin 
Pembrolizumab 
970) 
(mg/m2) 
(AUC) 
(mg) 
(mg/m2) 
Schedule 
Cycles 1-4 
(every 3 
weeks) 
Days 2 and 9 
Days 1 and 8 
Day 1 
Day 1 
Cycles 5-16 
(every 3 
weeks) 
Day 1 
- 
- 
Day 1 
Cycles 17-26 
(every 6 
weeks) 
- 
- 
- 
Day 1* 
Dose Level (Cycles 1-16) 
1 
135 mg/m2 
800 mg/m2 
5 
200 
-1 
135 mg/m2 
800 mg/m2 
4 
200 
-2 
90 mg/m2 
600 mg/m2 
3 
200 
• 
All study drugs will be administered IV. 
• 
Dosing will begin at DL 1. 
• 
Plans for dose de-escalation to DL -1 are described in Section 7. 
*Pembrolizumab will be administered as 200mg for Cycles 1-16 and 400mg for Cycles 17-26 and should not 
exceed 2 years of treatment. 
 
Phase 2 Expansion, Arm A (n = 44) 
Treatment Schema 
Berzosertib (M6620, 
VX-970) 
135 or 90 mg/m2 
Gemcitabine 
800 or 600 mg/m2 
Carboplatin 
AUC 3, 4 or 5 
Pembrolizumab 
200 mg* 
Cycles 1-4 
(every 3 weeks) 
Days 2 and 9 
Days 1 and 8 
Day 1 
Days 1 
Cycles 5-16 
(every 3 weeks) 
Day 1 
- 
- 
Day 1 
Cycles 17-26 
(every 6 weeks) 
- 
- 
- 
Day1 
• 
All study drugs will be administered IV. 
• 
Arms will be randomized 1:1. 
*Pembrolizumab will be administered as 200mg for Cycles 1-16 and 400mg for Cycles 17-26 and should not 
exceed 2 years of treatment. 

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52 
 
 
 
Phase 2 Expansion, Arm B (n = 44) 
Treatment Schema 
Gemcitabine 
1250 mg/m2 
Carboplatin 
AUC 5 
Pembrolizumab 
200 mg* 
Cycles 1-4 (every 3 
weeks) 
Days 1 and 8 
Day 1 
Days 1 
Cycles 5-16 (every 3 
weeks) 
Day 1 
Cycles 17-26 (every 6 
weeks) 
Day1 
• 
All study drugs will be administered IV. 
• 
Arms will be randomized 1:1. 
* Pembrolizumab will be administered as 200mg for Cycles 1-16 and 400mg for Cycles 17-26 and should not 
exceed 2 years of treatment. 
The following treatment schedule will be used for a total of two years of treatment. 
Pembrolizumab administration should not exceed 2 years. 
• Cycles 1 to 4 (first 3 months of the first year): gemcitabine on D1 and D8, carboplatin 
and pembrolizumab on D1, and +/- berzosertib (M6620, VX-970) on D2 and D9, every 
three weeks 
• Cycles 5 to 16 (last 9 months of the first year): pembrolizumab +/- berzosertib (M6620, 
VX-970) on D1, every 3 weeks 
• Cycles 17 to 26 (second year): pembrolizumab on D1, every 6 weeks 
Beyond 4 cycles (i.e., 3 months), when berzosertib (M6620, VX-970) and pembrolizumab 
administration continues on D1 only without gemcitabine or carboplatin, the berzosertib 
(M6620, VX-970) and pembrolizumab may be dosed on the same day (D1) for patient 
convenience, where pembrolizumab is administered before berzosertib (M6620, VX-970). 
6.1.1 CTEP IND Agents 
6.1.1.1 Berzosertib (M6620, VX-970) 
 
Berzosertib (M6620, VX-970) will be supplied as a 20 mg/mL solution provided in 20% betadex 
sulfobutyl ether sodium (w/v) and 86 mM acetate buffer. Berzosertib (M6620, VX-970) must be 
diluted with 5% dextrose in water solution before intravenous infusion as detailed in Section 
8.1.1. 
 
An appropriate volume of concentrated drug product solution is diluted before use, according to 
the dose indicated in the dose administration table in Section 6.1. The total dose of berzosertib 
(M6620, VX-970) is not to exceed 800 mg/dose. The dose of berzosertib (M6620, VX-970) in 
dextrose in water solution will be infused IV over 60 minutes (± 10 minutes). 
 
Infuse using an infusion set containing low-sorption or non-PVC, DEHP-free tubing and bags 

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and an in-line 0.2-micron filter. 5% dextrose in water solution must be used for IV line priming 
and flushing. Berzosertib (M6620, VX-970) should not come in contact with 0.9% Sodium 
Chloride due to incompatibility. 
 
6.1.2 Commercial Agents 
For General Concomitant Medication Guidelines for commercial agents, please refer to the FDA 
package inserts for gemcitabine, carboplatin, and pembrolizumab. 
6.1.2.1 Pembrolizumab 
 
Trial treatment of pembrolizumab will be administered on Day 1 of each 3-week treatment cycle 
after all procedures/assessments have been completed. Pembrolizumab will be administered 
using a 30-minute IV infusion for all cycles, and the dose will be 200 mg for Cycles 1-16 and 
400 mg for Cycles 17-26. Pembrolizumab administration should not exceed 2 years. Infusion 
timing should be as close to 30 minutes as possible; however, a window of ±10 minutes is 
permitted. 
 
6.1.2.2 Gemcitabine 
 
Gemcitabine is administered intravenously over 30 minutes (± 10 minutes) on Days 1 and 8 of 
each 21-day cycle. 
 
Infusion time should not exceed 60 minutes. In clinical trials evaluating the maximum tolerated 
dose of gemcitabine, prolongation of the infusion time beyond 60 minutes or more frequent than 
weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu- 
like symptoms, myelosuppression, and asthenia. 
 
Prior to each dose of gemcitabine, obtain a complete blood count (CBC) with a differential and a 
platelet count. Modify the dosage as recommended. Myelosuppression manifested by 
neutropenia, thrombocytopenia, and anemia occurs with gemcitabine as a single agent, and the 
risks are increased when gemcitabine is combined with other cytotoxic drugs. 
 
Gemcitabine is a hazardous agent, and double gloving, a gown, and (if dosage form allows) 
Closed System Drug-Transfer Devices (CSTDs) should be used during administration (NIOSH 
2016). 
 
6.1.2.3 Carboplatin 
 
Carboplatin, as a single agent, has been shown to be effective in patients with recurrent ovarian 
carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks. In general, however, single 
intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 
2000 and the platelet count is at least 100,000. 
 
Carboplatin is administered intravenously (IV) as a diluted solution over 30 minutes (± 10 

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minutes) through an IV line. Do not co-administer other drugs in the same IV line. 
The subject-specific dose should be calculated using the Calvert formula per institutional policy 
for AUC calculation. Carboplatin should be administered per institutional standards. 
Anti-emetics and supportive therapies will be administered or dispensed to subjects for use in 
combination with carboplatin according to individual site SOC. Anti-emetics and growth factors 
can be used per institutional guidelines for standard chemotherapy. If a participant has an 
infusion reaction to carboplatin, standard of care for re-challenge should be followed. 
6.2 
Definition of Dose-Limiting Toxicity 
 
Toxicities will be graded according to the NCI Common Toxicity Criteria for Adverse Events 
version 5.0 (CTCAE version 5.0). DLT is defined as the occurrence of any of the treatment-related 
events listed below during the first cycle (21 days) of study treatment and is felt to be possibly, 
probably, or definitely related to the study drug. Approaches for dose modification are presented 
Section 7. 
 
Patients who fail to complete cycle 1 of therapy (i.e., fail to receive carboplatin, pembrolizumab, 
and two full doses of gemcitabine and berzosertib (M6620, VX-970)) for reasons unrelated to 
treatment (e.g., rapid disease progression) will be deemed to be non-evaluable for DLT and be 
replaced. Patients who fail to complete cycle 1 at the prescribed dose level due to treatment 
related adverse side effects (i.e., dose modification per Section 7.2.1 are required) will be 
classified as having a DLT. 
 
DLTs will be defined as grade 4 absolute neutrophil count for ≥7 days, grade 4 anemia, platelet 
count <25,000, or other non-hematologic events ≥grade 3 as per NCI Common Terminology 
Criteria for Adverse Events Version 5.0 (except fatigue, alopecia, anorexia, nausea and emesis 
occurring despite optimal antiemetic therapy). 
Patients are allocated to doses by the following algorithm: 
Three patients will be treated at Level 1. 
1. If # DLT≤1/3, treat 3 more patients at Level 1, otherwise, go to step 2, below. 
a. If # DLT≤1/6, proceed to Phase 2 at Level 1, 
b. Else if # DLT=2/6 or 3/6, go to step 2, below, 
c. Else if # DLT>3/6, do not proceed to Phase 2. 
2. If # DLT≤1/3, treat 3 more patients at Level -1, otherwise, go to step 3, below. 
a. If # DLT≤1/6, proceed to Phase 2 at Level -1, 
b. Else if # DLT=2/6 or 3/6, go to step 3, below, 
c. Else if # DLT>3/6, do not proceed to Phase 2. 
3. Treat 3 patients at Level -2. 
a. If # DLT≤1/3, treat 3 more patients at Level -2, 
i. 
If #DLT≤1/6, proceed to Phase 2 at Level -2, 
ii. 
Else if #DLT≥2/6, do not proceed to Phase 2. 

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b. If # DLT≥2/3, do not proceed to Phase 2 
 
6.3 
General Concomitant Medication and Supportive Care Guidelines 
 
6.3.1 Berzosertib (M6620, VX-970) is primarily metabolized by cytochrome P450 (CYP) 3A4 
(CYP3A4); exposure of berzosertib (M6620, VX-970) may be affected by concomitant 
administration of drugs that are strong inhibitors or inducers of CYP3A4. Concomitant 
administration with potent inhibitors or inducers of CYP3A4 is prohibited in this study. 
Berzosertib is a weak inhibitor of CYP3A4. Based on in vitro data, berzosertib has the 
potential to be an inhibitor of BCRP and OATP1B3 at clinically relevant concentrations 
and may increase exposure of BCRP and OATP1B3 substrates. Concomitant 
administration with sensitive CYP3A4 substrates with a narrow therapeutic index, and 
substrates of BCRP and OATP1B3 with berzosertib (M6620, VX-970) should be 
considered with caution and careful monitoring for safety. 
6.3.2 While taking berzosertib (M6620, VX-970), if any patient develops phlebitis or signs of 
inflammation which 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. If any patient develops pruritus or evidence of an 
allergic reaction, standard measures may be employed to ameliorate these symptoms or 
prevent recurrence (e.g., premedication with acetaminophen 325 mg, PO approximately 
30 minutes before the infusion, 200 mg hydrocortisone IV approximately 60 minutes 
before infusion, and 25 mg diphenhydramine IV approximately 30 minutes before 
infusion). Alternative antihistamine and steroid combinations may be considered, as long 
as they are not prohibited by protocol. If standard procedures to limit symptoms of 
injection site reaction or pruritus are insufficient, the infusion time may be extended 
beyond 60 minutes, but no more than 90 minutes. 
 
6.3.3 To decrease the risk of phlebitis, berzosertib (M6620, VX-970) 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. 
 
6.3.4 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. 
 
6.3.5 Current or prior use of immunosuppressive medication within 28 days before the first 
dose of pembrolizumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of 
prednisone, or an equivalent corticosteroid. Higher doses of steroids given as 

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premedications on day 1 and 8 of therapy are permitted. 
6.4 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment will continue according to 
the following schedule for a total of 2 years of therapy. Pembrolizumab administration should 
not exceed 2 years. 
• Cycles 1 to 4 (first 3 months of the first year): gemcitabine on D1 and D8, carboplatin 
and pembrolizumab on D1, and +/- berzosertib (M6620, VX-970) on D2 and D9, every 
three weeks 
• Cycles 5 to 16 (last 9 months of the first year): pembrolizumab +/- berzosertib (M6620, 
VX-970) on D1, every 3 weeks 
• Cycles 17 to 26 (second year): pembrolizumab on D1, every 6 weeks 
Or treatment will continue until one of the following criteria applies: 
• 
Disease progression. In patients with disease progression, treatment may continue if 
there is clear ongoing clinical benefit, after discussion with the PI. 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
• 
Clinical progression 
• 
Patient non-compliance 
• 
Pregnancy 
o All women of childbearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation. 
o The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor 
• 
The drug manufacturer can no longer provide the study agent 
 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
 
6.5 
Duration of Follow-Up 

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Patient follow-up will occur via standard of care or a phone call every 3 months +/- (2 weeks) for 
12 months following removal from study. Patients removed from study for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
7.1 
Dosing Levels 
 
Dose Levels for Carboplatin, Gemcitabine, and Berzosertib (M6620, VX-970) 
(Phase 1B and Phase 2, Arm A)* 
Dose Level 
Carboplatin (AUC) 
Gemcitabine 
Berzosertib 
(M6620, VX-970) 
1 
5 (or 4) 
800 mg/m2 
135 mg/m2 
-1 
4 (or 3) 
800 mg/m2 
135 mg/m2 
-2 
3 
600 mg/m2 
90 mg/m2 
*Modifications are by dose level and not by individual agent. 
 
Dose Levels for Carboplatin and Gemcitabine (Phase 2, Arm B)* 
Dose Level 
Carboplatin (AUC) 
Gemcitabine 
1 
5 
1250 mg/m2 
-1 
4 
1000 mg/m2 
-2 
3 
750 mg/m2 
*Modifications are by individual agent. 
 
 
7.2 
Dosing Modifications 
 
7.2.1 Gemcitabine should be permanently discontinued in patients who experience or develop 
the following: 
• Unexplained dyspnea, with or without bronchospasm, or severe pulmonary toxicity 
• Hemolytic uremic syndrome (HUS) or severe renal impairment 
• Severe hepatic toxicity 
• Capillary leak syndrome (CLS) 
• Posterior reversible encephalopathy (PRES) 
 
7.2.2 Dose Modification Tables for Phase 1B and Phase 2, Arm A 

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7.2.2.1 Dose Modifications for Neutropenia on Day 1 at Time of Treatment of Any Cycle 
Modifications are by dose level and not by individual agent. 
Neutropenia 
Management/Next Dose for Berzosertib (M6620, VX-970)***, 
Gemcitabine and Carboplatin 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. 
Resume at same dose level. 
Grade 3 
Hold* until ≤ Grade 1. Resume at one dose level lower. 
Second recurrence, reduce by one dose level, if indicated** 
Grade 4 
Hold* until ≤ Grade 1. Resume at one dose level lower, if indicated.** 
*Patients with a grade 3 toxicity requiring a delay of >2 weeks should be discussed with the PI. 
Patients may continue therapy if receiving benefit. In patients with a grade 4 toxicity requiring a 
delay of >2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
*** Berzosertib (M6620, VX-970) dose is given on day 2; however, the CBC from day 1 will be 
used to determine the day 2 dose 
 
 
7.2.2.2 Dose Modifications for Neutropenia at Time of Treatment on Day 8 and Day 9 of Any 
Cycle 
 
Neutropenia 
Management/ 
Next Dose for 
Berzosertib (M6620, 
VX-970)* 
Management/ 
Next Dose for 
Gemcitabine 
Management/ Next 
Dose for 
Carboplatin** 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Omit current cycle day 
9 dose 
Omit current cycle day 
8 dose 
No change in dose 
Grade 4 
Omit current cycle day 
9 dose 
Omit current cycle day 
8 dose 
No change in dose 
* Berzosertib (M6620, VX-970) dose is given on day 9; however, the CBC from day 8 will be 
used to determine the day 9 dose 
**Carboplatin is not given on day 8 or day 9 of the cycle. 
 
7.2.2.3 Dose Modifications for Thrombocytopenia at Time of Treatment on Day 1 of Any 
Cycle 
Modifications are by dose level and not by individual agent. 
Thrombocytopenia 
Management/Next Dose for Berzosertib (M6620, VX-970)***, 

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Gemcitabine, and Carboplatin 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. 
Resume at same dose level. 
Grade 3 
Hold* until ≤ Grade 1. Resume at one dose level lower. 
Second recurrence, reduce by one dose level, if indicated** 
Grade 4 
Hold* until ≤ Grade 1. Resume at one dose level lower, if indicated.** 
*Patients with a grade 3 toxicity requiring a delay of >2 weeks should be discussed with the PI. 
Patients may continue therapy if receiving benefit. In patients with a grade 4 toxicity requiring a 
delay of >2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
*** Berzosertib (M6620, VX-970) dose is given on day 2; however, the CBC from day 1 will be 
used to determine the day 2 dose 
 
 
7.2.2.4 Dose Modifications for Thrombocytopenia at Time of Treatment on Day 8 and 9 of Any 
Cycle 
 
Thrombocytopenia 
Management/ 
Next Dose for 
Berzosertib (M6620, 
VX-970)* 
Management/ 
Next Dose for 
Gemcitabine 
Management/ Next 
Dose for 
Carboplatin** 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Omit current cycle day 
9 dose 
Omit current cycle day 
8 dose 
No change in dose 
Grade 4 
Omit current cycle day 
9 dose 
Omit current cycle day 
8 dose 
No change in dose 
* Berzosertib (M6620, VX-970) dose is given on day 9; however, the CBC from day 8 will be 
used to determine the day 9 dose 
**Carboplatin is not given on day 8 or day 9 of the cycle. 
 
7.2.2.5 Dose Modifications for Other Non-Hematological Toxicities at Time of Treatment on 
Days 1, 2, 8 or 9* 
 
On days 1 and 2, modifications are by dose level and not by individual agent. 
Event 
Management/ Next 
Dose for Berzosertib 
(M6620, VX-970) 
(VX-970)**** 
Management/ Next 
Dose for 
Gemcitabine 
Management/ Next 
Dose for Carboplatin 
≤ Grade 1 
No change in dose 
No change in dose 
No change in dose 

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Grade 2 
No change in dose 
No change in dose 
No change in dose 
Grade 3 
Day 2: Hold** until ≤ 
Grade 2 
Resume at one dose 
lower*** 
Day 9: Omit current 
cycle dose 
Day 1: Hold** until ≤ 
Grade 2 
Resume at one dose 
lower*** 
Day 8: Omit current 
cycle dose 
Day 1: Hold** until ≤ 
Grade 2 
Resume at same dose 
Grade 4 
Day 2: Hold** until ≤ 
Grade 2 
Resume at one dose 
lower*** 
Day 9: Omit current 
cycle dose 
Day 1: Hold** until ≤ 
Grade 2 
Resume at one dose 
lower*** 
Day 8: Omit current 
cycle dose 
Day 1: Hold** until ≤ 
Grade 2 
Resume at same dose 
* Does not include alopecia and fatigue 
** Patients with a grade 3 toxicity requiring a delay of >2 weeks should be discussed with the PI. 
Patients may continue therapy if receiving benefit. In patients with a grade 4 toxicity requiring a 
delay of >2 weeks, study should be discontinued. 
*** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
**** Berzosertib (M6620, VX-970) dose is on day 2, 9, but dose can be determined based on 
toxicity assessment performed on day 1 and 8 as well as on days 2 and 9. 
 
7.2.3 Dose Modification Tables for Phase 2, Arm B 
 
7.2.3.1 Dose Modifications for Neutropenia on Day 1 at Time of Treatment of Any Cycle 
 
Modifications are by individual agent. 
Neutropenia 
Management/Next Dose for 
Carboplatin 
Management/Next Dose for 
Gemcitabine 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. Resume at 
same dose level. 
Hold until ≤ Grade 1. Resume at 
same dose level. 
Grade 3 
Hold* until ≤ Grade 1. First 
recurrence, resume at same dose 
level. Second recurrence, reduce by 
one dose level, if indicated** 
Hold* until ≤ Grade 1. 
Resume at one dose level lower, if 
indicated. ** 
Grade 4 
Hold* until ≤ Grade 1. Resume at 
one dose level lower, if indicated.** 
Hold* until ≤ Grade 1. Resume at 
one dose level lower if indicated.** 
* Patients with a grade 3 toxicity requiring a delay of >2 weeks should be discussed with PI. 
Patients may continue therapy if receiving benefit. In patients with a grade 4 toxicity requiring a 
delay of >2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 

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7.2.3.2 Dose Modifications for Neutropenia on Day 8 at Time of Treatment of Any Cycle 
 
Neutropenia Management/ Next Dose for Gemcitabine 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Administer one dose level lower than administered on day 1 of that cycle. Resume 
next cycle based on the day 1 dose of gemcitabine. 
Grade 4 
Omit current cycle day 8 dose 
 
 
7.2.3.3 Dose Modifications for Thrombocytopenia on Day 1 at Time of Treatment of Any 
Cycle 
 
Modifications are by individual agent. 
Thrombocytopenia 
Management/Next Dose for 
Carboplatin 
Management/Next Dose for 
Gemcitabine 
≤ Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3 
Hold* until ≤ Grade 2. Resume at 
same dose at first recurrence. 
Second recurrence, resume at one 
dose lower, if indicated.** 
Hold* until ≤ Grade 2. Resume at 
one dose level lower, if 
indicated.** 
Grade 4 
Hold* until ≤ Grade 2. Resume at 
one dose level lower, if 
indicated.** 
Hold* until ≤ Grade 2. Resume at 
one dose level lower, if 
indicated.** 
* Patients with a grade 3 toxicity requiring a delay of >2 weeks should be discussed with the 
PI. Patients may continue therapy if receiving benefit. In patients with a grade 4 toxicity 
requiring a delay of >2 weeks, study should be discontinued. 
** Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
 
 
7.2.3.4 Dose Modifications for Thrombocytopenia on Day 8 at Time of Treatment of Any 
Cycle 
 
Thrombocytopenia 
Management/Next Dose for Gemcitabine 
≤ Grade 1 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Administer one dose level lower than the dose administered on day 1 of 
the cycle. 
Resume next cycle based on the day 1 dose of gemcitabine. 
Grade 4 
Administer one dose level lower than the dose administered on day 1 of 
the cycle. 

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7.2.3.5 Dose Modifications for Other Non-hematological Toxicities at Time of Treatment* 
Modifications are by individual agent. 
Event 
Management/Next Dose for 
Carboplatin 
Management/Next Dose for 
Gemcitabine 
Grade 1 or 2 
No change in dose 
No change in dose 
Grade 3 
Day 1: Hold** until ≤ Grade 2 
Resume at same dose 
Day 1: Hold** until ≤ Grade 2 
Resume at one dose lower*** 
Day 8: Omit current cycle dose 
Grade 4 
Day 1: Hold** until ≤ Grade 2 
Resume at same dose 
Day 1: Hold** until ≤ Grade 2 
Resume at one dose lower*** 
Day 8: Omit current cycle dose 
*Excluding alopecia and fatigue 
**Patients with a grade 3 toxicity requiring a delay of >2 weeks should be discussed with the PI. 
Patients may continue therapy if receiving benefit. In patients with a grade 4 toxicity requiring a 
delay of >2 weeks, study should be discontinued. 
***Patients requiring > two dose reductions should be discussed with PI. Patients may continue 
therapy if receiving benefit. 
 
7.2.4 Pembrolizumab Dose Modification and Supportive Care Guidelines for Drug- 
Related Adverse Events (revised 1-10-2023) 
 
7.2.4.1 Dose Modifications 
 
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These AEs may occur shortly after the first dose or several 
months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as described in Section 7.2.4.3. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Patients should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the patient's study record. 
 
7.2.4.2 Supportive Care Guidelines 
 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are also outlined in the table in Section 7.2.4.3. Where appropriate, these 
guidelines include the use of oral or IV treatment with corticosteroids as well as additional anti- 
inflammatory agents if symptoms do not improve with administration of corticosteroids. Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive care. 
The treatment guidelines are intended to be applied when the investigator determines the events to 

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be related to pembrolizumab. 
 
Note: If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of the evaluation of the event. 
7.2.4.3 Dose Modification and Toxicity Management for Immune-related Adverse Events 
Associated with Pembrolizumab 
 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may 
be included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. Pembrolizumab may cause severe or 
life-threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely 
within 24 hours of completion of infusion. Dose modification and toxicity management 
guidelines for irAEs and infusion reactions associated with pembrolizumab are provided in the 
table below. 
 
Note that non-irAEs will be managed as appropriate, following clinical practice 
recommendations 

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Dose Modification and Toxicity Management Guidelines for Immune-related AEs and Infusion Reactions Associated with 
Pembrolizumab 
 
General instructions: 
1. For non-endocrine-related severe and life-threatening irAEs, investigators should consider the use of IV corticosteroids 
followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids. Some non-endocrine irAEs do not require steroids. For example, celiac disease induced by pembrolizumab 
can be controlled by diet alone. 
2. For non-endocrine-related toxicities, pembrolizumab must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. Generally, when corticosteroids are used, investigators should begin a taper when the irAE is ≤Grade 1 and continue at least 
4 weeks. 
4. If pembrolizumab has been withheld due to a non-endocrine irAE, pembrolizumab may generally resume after the irAE has 
decreased to ≤Grade 1 after a corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies 
Monitoring and follow-up 
Pneumonitis 
Grade 2 
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Add prophylactic antibiotics 
for opportunistic 
infections 
Monitor participants for signs 
and symptoms of 
pneumonitis 
Evaluate participants with 
suspected pneumonitis 
with radiographic 
imaging and initiate 
corticosteroid treatment 
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue 
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Monitor participants for signs 
and symptoms of 
enterocolitis (i.e., 
diarrhea, abdominal pain, 
blood or mucus in stool 

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Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 
Patients who do not respond 
to corticosteroids should 
be seen by a 
gastroenterologist for 
confirmation of the 
diagnosis and 
consideration of 
secondary immune 
suppression 
with or without fever) and 
of bowel perforation (i.e. 
peritoneal signs and ileus) 
Specifically assess for celiac 
disease serologically, and 
exclude Clostridium 
difficile infection 
Participants with ≥Grade 2 
diarrhea suspecting 
enterocolitis should 
consider GI consultation 
and performing 
endoscopy to rule out 
enterocolitis and assess 
mucosal severity 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. 
If sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted via 
IV infusion 
AST or ALT 
elevation or Increased 
Bilirubin 
Grade 2 a 
Withhold 
Administer corticosteroids 
(initial dose of 0.5 to 1 
mg/kg prednisone or 
equivalent) followed by 
taper 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable) 

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Grade 3 b or 4 c 
Permanently 
discontinue 
Administer corticosteroids 
(initial dose of 1 to 2 
mg/kg prednisone or 
equivalent) followed by 
taper 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Grade 1 or 2 
Continue 
Investigate for diabetes. In 
the absence of 
corticosteroids or diabetes 
medication non- 
adherence, any grade 
hyperglycemia may be an 
indication of beta-cell 
destruction and 
pembrolizumab-induced 
diabetes akin to type 1 
diabetes. This should be 
treated as a Grade 3 
event. Given this risk, 
exercise caution in 
utilizing non-insulin 
hypoglycemic agents in 
this setting. After a 
thorough investigation of 
other potential causes, 
which may involve a 
referral to an 
endocrinologist, follow 
institutional guidelines. 
Monitor glucose control. 

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New onset T1DM 
(evidence of -cell 
failure) or 
Grade 3 or 4 
hyperglycemia 
Withhold d 
Resume 
pembrolizumab 
when symptoms 
resolve and glucose 
levels are stable 
Initiate treatment with 
insulin 
If patient is found to have 
diabetic ketoacidosis or 
hyperglycemic 
hyperosmolar syndrome, 
treat as per institutional 
guidelines with 
appropriate management 
and laboratory values 
(e.g. anion gap, ketones, 
blood pH, etc.) reported 
Monitor for glucose control 
Strongly consider referral to 
endocrinologist 
Obtain C-peptide level paired 
with glucose, 
autoantibody levels (e.g. 
GAD65, islet cell 
autoantibodies), and 
hemoglobin A1C level 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids 
and initiate hormonal 
replacements as 
clinically indicated 
Monitor for signs and 
symptoms of hypophysitis 
(including 
hypopituitarism and 
adrenal insufficiency) 
Provide adrenal insufficiency 
precautions including 
indications for stress dose 
steroids and medical alert 
jewelry 
Strongly consider referral to 
endocrinologist 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 

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Hyperthyroidism 
Grade 2 
Consider 
withholding. 
Resume 
pembrolizumab 
when symptoms 
are controlled, and 
thyroid function is 
improving 
Treat with nonselective 
beta-blockers (e.g., 
propranolol) or 
thionamides as 
appropriate 
Initiate treatment with anti- 
thyroid drug such as 
methimazole or 
carbimazole as needed 
Monitor for signs and 
symptoms of thyroid 
disorders 
Strongly consider referral to 
endocrinologist 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
Initiate thyroid replacement 
hormones (e.g., 
levothyroxine or 
liothyronine) per 
standard of care 
Monitor for signs and 
symptoms of thyroid 
disorders 
Nephritis: 
grading according to 
increased creatinine 
or acute kidney injury 
Grade 2 
Withhold 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg 
or equivalent) followed 
by taper 
Monitor changes of renal 
function 
Strongly consider referral to 
nephrologist 
Grade 3 or 4 
Permanently 
discontinue 

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Cardiac Events 
(including 
myocarditis, 
pericarditis, 
arrhythmias, impaired 
ventricular function, 
vasculitis) 
Asymptomatic 
cardiac enzyme 
elevation with clinical 
suspicion of 
myocarditis 
(previously CTCAE 
v4.0 Grade 1), or 
Grade 1 
Withhold 
Based on severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Strongly consider referral to 
cardiologist and cardiac 
MRI 
Consider endomyocardial 
biopsy 
If event resolves to Grade 1 
or better, taper 
corticosteroids over ≥1 
month 

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Grade 2, 3 or 4 
Permanently 
discontinue 
Initiate treatment with 
corticosteroids 
equivalent to 1-2 
mg/kg/day IV 
methylprednisolone and 
convert to 1-2 
mg/kg/day oral 
prednisone or equivalent 
upon improvement 
If event does not improve 
within 48 hours after 
initiating corticosteroids, 
consider adding an 
immunosuppressive 
agent 
Initiate treatment per 
institutional guidelines 
and consider 
antiarrhythmic drugs, 
temporary pacemaker, 
extracorporeal 
membrane oxygenation 
(ECMO), ventricular 
assist device (VAD), or 
pericardiocentesis as 
appropriate 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Strongly consider referral to 
cardiologist and cardiac 
MRI 
Consider endomyocardial 
biopsy 
If event resolves to Grade 1 
or better, taper 
corticosteroids over ≥1 
month 
Exfoliative 
Dermatologic 
Suspected SJS, TEN, 
or DRESS 
Withhold 
Based on severity of AE 
Ensure adequate evaluation to 

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Conditions 
Confirmed SJS, TEN, 
or DRESS 
Permanently 
discontinue 
administer 
corticosteroids 
confirm etiology or 
exclude other causes 
Strongly consider referral to 
dermatologist 
Consider skin biopsy for 
evaluation of etiology 
All Other irAEs 
Persistent Grade 2 
Withhold 
Based on severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology or 
exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the event e 
Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue 
 
 
Infusion-Related Reactions 
Infusion Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated 
Grade 1 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 

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Infusion Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications indicated 
for ≤24 hrs. 
Grade 2 
• Stop Infusion. 
• Additional appropriate medical therapy 
may include but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
• If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr. to 50 mL/hr.). 
Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 
Participant 
 may  
 be 
premedicated 
1.5h 
(± 
30 
minutes) prior to infusion of 
study intervention with: 
Diphenhydramine 50 mg PO 
(or 
equivalent  
dose 
 of 
antihistamine). 
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic). 

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Infusion Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary infiltrates) 
Grade 3 
• Stop Infusion. 
• Additional appropriate medical therapy 
may include but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids (e.g. methylprednisolone 2 
mg/kg/day or dexamethasone 10 mg every 
6 hours) 
• Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
• Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing. 

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Infusion Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Life-threatening; 
pressor or ventilator 
support indicated 
Grade 4 
Admit participant to intensive care unit (ICU) and 
initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as 
needed. Monitor other organ function closely. 
Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
Follow Grade 3 recommendations as applicable. 
No subsequent dosing. 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; ECMO=extracorporeal membrane oxygenation; GI=gastrointestinal; ICU=intensive care unit; IO=immuno-oncology; 
ir=immune related; IV=intravenous; MRI=magnetic resonance imaging; PO=per os; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic 
Epidermal Necrolysis; ULN=upper limit of normal; VAD=ventricular assist device. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if 
baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
If control achieved or ≤Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (e.g. vasculitis 
and sclerosing cholangitis). 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov. 

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Neurological Toxicities 
 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue pembrolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 2 
• Withhold pembrolizumab for up to 12 weeks after event onset. a 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume 
pembrolizumab. b 
o If event does not resolve to Grade 1 or better while 
withholding pembrolizumab, permanently discontinue 
pembrolizumab. c 
• For facial paresis: 
o If event resolves fully, resume pembrolizumab. b 
o If event does not resolve fully while withholding 
pembrolizumab, permanently discontinue 
pembrolizumab. c 
Immune-mediated 
neuropathy, 
including facial 
paresis, Grade 3 or 4 
• Permanently discontinue pembrolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis 
and Guillain-Barré 
syndrome (any 
grade) 
• Permanently discontinue pembrolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 
mg/kg/day oral or IV prednisone. 
a Pembrolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day 
oral prednisone. The acceptable length of the extended period of time must be based on an 
assessment of benefit−risk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before pembrolizumab can be resumed. 
c Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefit−risk and 
documented by the investigator (or an appropriate delegate). 
 
Event 
Management 
Immune-mediated myelitis, 
• 
Continue pembrolizumab unless symptoms worsen or 

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Event 
Management 
Grade 1 
do not improve. 
• 
Investigate etiology and refer patient to a neurologist. 
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue pembrolizumab. 
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue pembrolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
• Permanently discontinue pembrolizumab. a 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month. 
a Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefit−risk and 
documented by the investigator (or an appropriate delegate). 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 10.1. 
 
8.1 
CTEP IND Agents 
 
8.1.1 M6620 (NSC # 780162) 
 
Other Names: VRT-0768079, MSC2527093A, VX-970 
 
Chemical Name: 5-(4-(isopropylsulfonyl)phenyl)-3-(3-(4- 
((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2- amine 
 
Classification: ATR inhibitor 
CAS Registry Number: 1232416-25-9 

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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. Berzosertib (M6620, VX-970) disrupts ATR-mediated DNA damage response 
signaling and leads to sustained accumulation of DNA damage in cancer cells co-treated with DNA- 
damaging agents. 
 
Description: The drug substance for berzosertib (M6620, VX-970) is the free base. 
 
How Supplied: Berzosertib (M6620, VX-970) is supplied by Merck KGaA/EMD Serono, Inc. and 
distributed by the Pharmaceutical Management Branch, CTEP/DCTD/NCI as single-use 200 mg 
vials containing a sterile solution (20 mg/mL). Berzosertib (M6620, VX-970) solution for 
injection is a yellow liquid formulated in 20% betadex sulfobutyl ether sodium (w/v) and 86 mM 
acetate buffer, 10 mL total volume, supplied in clear glass vials in cardboard boxes with foam 
inserts. 
 
Preparation: Berzosertib (M6620, VX-970) solution for injection must be diluted with 5% dextrose 
in water solution prior to administration. Do not use 0.9% Sodium Chloride due to incompatibility 
with berzosertib (M6620, VX-970). To prepare the infusion solution add the dose volume of 
berzosertib (M6620, VX-970) to a non-polyvinyl chloride (non-PVC), di(2-ethylhexyl) phthalate 
(DEHP)-free EVA infusion bag containing 5% dextrose in water. Gently invert the IV bag 5-10 
times to mix the solution. Confirm the solution is clear and free of precipitates and/or particulates. 
The final concentration must be between 0.075 mg/mL to 1 mg/mL. Place the IV bag into an 
opaque cover to protect from light. 
 
Storage: Store intact vials protected from light inside cardboard boxes at room temperature, below 
25°C (77°F), do not freeze. 
 
If a storage temperature excursion is identified, promptly return berzosertib (M6620, VX-970) 
to below 25°C and quarantine the supplies. Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability: Stability testing of the intact vials is on-going. Prepared solutions must be protected from 
light and used within 4 hours from time of preparation if stored at room temperature or 24 hours if 
stored refrigerated (2-8°C). 
 
Route of Administration: Intravenous (IV) infusion. 
Method of Administration: Prior to administration the solution should be given one hour at ambient 
temperature to warm up if stored refrigerated following preparation. Infuse over 60 minutes using an 
infusion set containing low-sorption or non-PVC, DEHP-free tubing and an in-line 0.2 micron filter. 
5% dextrose in water solution must be used for IV line priming and flushing. Berzosertib (M6620, 

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VX-970) 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, berzosertib (M6620, 
VX-970) 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. 
Berzosertib (M6620, VX-970) absorbs in the UV-visible radiation spectrum and is widely 
distributed including skin, so patients receiving berzosertib (M6620, VX-970) 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 berzosertib (M6620, VX-970). 
Potential Drug Interactions: Berzosertib (M6620, VX-970) is primarily metabolized by 
CYP3A4. Berzosertib (M6620, VX-970) 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 
berzosertib (M6620, VX-970) 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. 
 
Berzosertib (M6620, VX-970) is a weak/moderate inhibitor of UGT1A1, UGT1A14, UGT1A9, 
UGT2B15, and UGT2B17. UGT2B7, UGT1A3, and UGT1A6 were weakly or not inhibited. 
Berzosertib (M6620, VX-970) is predicted to not inhibit significantly the metabolic clearance of 
SN-38 (active metabolite of irinotecan) at therapeutic exposures. 
 
Berzosertib (M6620, VX-970) 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. 
 
 
8.1.2 CTEP IND Agent Ordering, Accountability, Further Information, and Contacts 
 
8.1.2.1 Agent Ordering 
 
NCI-supplied agents may be requested by eligible participating Investigators (or their 
authorized designee) at each participating institution. The CTEP-assigned protocol 
number must be used for ordering all CTEP-supplied investigational agents. The 
eligible participating investigators at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form 
(FDF). If there are several participating investigators at one institution, CTEP- 
supplied investigational agents for the study should be ordered under the name of one 
lead participating investigator at that institution. 

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79 
 
 
Sites can place orders for PMB-supplied agents only after enrollment 
onto the study. Please provide the patient ID# in the comment box 
when placing orders. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status, a “current” password, and active person registration status. For questions 
about drug orders, transfers, returns, or accountability, call or email PMB any time. 
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
8.1.2.2 Agent Inventory Records 
 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation 
and ordering investigator on this protocol. 
 
8.1.2.3 Investigator Brochure Availability 
 
The current versions of the IBs for the agents will be accessible to site investigators 
and research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password and active person registration status. Questions about IB 
access may be directed to the PMB IB Coordinator via email. 
 
8.1.2.4 Useful Links and Contacts 
• CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP 
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 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) 

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8.2 
Commercial Agents 
 
8.2.1 Pembrolizumab (NSC 776864) 
 
Product Description: Pembrolizumab is a humanized MAb of the IgG4/kappa isotype. 
 
Solution Preparation: Pembrolizumab solution for infusion must be diluted prior to 
administration. Allow the required number of vials to equilibrate to room temperature. 
Do not shake the vials. Do not use if opaque or extraneous particulate matter other than 
translucent to white proteinaceous particles is observed. Do not use if discolored. To 
prepare the infusion solution add the dose volume of pembrolizumab to an infusion bag 
containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Gently 
invert the bag 10-15 times to mix the solution. The final concentration must be between 
1 mg/mL to 10 mg/mL. 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, 
or PE lined polyolefin 
 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F). Do not freeze. Protect from 
light by storing in the original box. 
 
Administer prepared solutions immediately after preparation. If not administered 
immediately, prepared solutions may be stored refrigerated for up to 24 hours. 
Pembrolizumab solutions may be stored at room temperature for a cumulative time of up 
to 6 hours. This includes room temperature storage of liquid drug product solution in 
vials, room temperature storage of infusion solution in the IV bag, and the duration of 
infusion. 
 
Route of Administration: IV infusion only. Do not administer as an IV push or bolus 
injection. Infuse over approximately 30 minutes (±10 minutes) using an infusion set 
containing a low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone or 
polysulfone. Infusion rate should not exceed 6.7 mL/min. A central line is not required; 
however if a subject has a central venous catheter in place, it is recommended that it be 
used for the infusion. Do not co-administer other drugs through the same infusion line. 
Following the infusion, flush the IV line with normal saline. 
 
Agent ordering: Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
 
8.2.2 Gemcitabine (NSC 613327) 
 
Product description: Gemcitabine (gemcitabine for injection, USP) is a nucleoside 
metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2´-deoxy-2´,2´- 
difluorocytidine monohydrochloride (β-isomer). The empirical formula for gemcitabine 
HCl is C9H11F2N3O4 • HCl. It has a molecular weight of 299.66. 

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Gemcitabine HCl is soluble in water, slightly soluble in methanol, and practically 
insoluble in ethanol and polar organic solvents. 
 
Gemcitabine is supplied in a sterile form for intravenous use only. Vials of gemcitabine 
contain either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with 
mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, 
respectively) as a sterile lyophilized powder. Hydrochloric acid and/or sodium hydroxide 
may have been added for pH adjustment. 
 
Unopened vials of gemcitabine are stable until the expiration date indicated on the 
package when stored at controlled room temperature 20° to 25°C (68° to 77°F) and that 
allows for excursions between 15° and 30°C (59° and 86°F). 
Exercise caution and wear gloves when preparing gemcitabine solutions. Immediately 
wash the skin thoroughly or rinse the mucosa with copious amounts of water if 
gemcitabine contacts the skin or mucus membranes. Death has occurred in animal 
studies due to dermal absorption. 
 
Solution preparation: Reconstitute the vials with 0.9% Sodium Chloride Injection 
without preservatives. 
 
Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a 
Gemcitabine concentration of 38 mg/mL. Complete withdrawal of the vial contents will 
provide 200 mg or 1 g of gemcitabine. Prior to administration the appropriate amount of 
drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be 
as low as 0.1 mg/mL. 
 
Reconstituted gemcitabine is a clear, colorless to light straw-colored solution. Inspect 
visually prior to administration and discard for particulate matter or discoloration. 
Gemcitabine solutions are stable for 24 hours at controlled room temperature of 20° to 
25°C (68° to 77°F). Do not refrigerate as crystallization can occur. No incompatibilities 
have been observed with infusion bottles or polyvinyl chloride bags and administration 
sets. 
 
Route of administration: Gemcitabine is supplied in a sterile form for intravenous use 
only. 
 
Agent ordering: Commercially available from various manufacturers. See package 
insert for further information. 
 
8.2.3 Carboplatin (NSC #241240) 
 
Product description: Commercially available for injection as solution: 10 mg/mL (5 
mL, 15 mL, 45 mL, 60 mL) 
 
Solution preparation: Refer to package insert for complete preparation and dispensing 

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instructions. 
 
Storage requirements: Store intact vials at room temperature and protect from light. 
 
Stability: Further dilution to a concentration as low as 0.5 mg/mL is stable at room 
temperature for 8 hours in 0.9% NaCl; stable at room temperature or under refrigeration 
for at least 9 days in D5W, although the manufacturer states to use within 8 hours due to 
lack of preservative. Multidose vials are stable for up to 14 days after opening when 
stored at room temperature. 
 
Route of administration: Refer to the treatment section for specific administration 
instructions. When administered as sequential infusions, taxane derivatives (docetaxel, 
paclitaxel) should be administered before the carboplatin to limit myelosuppression and 
to enhance efficacy. 
Agent ordering: Commercial supplies. Pharmacies or clinics shall obtain supplies from 
normal commercial supply chain or wholesaler. 
 
 
9. STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design 
 
9.1.1 Overview of the Design 
 
A phase 1B lead-in study will be conducted to establish the safety and tolerability of the 
combination RP2Ds of gemcitabine and berzosertib (M6620, VX-970) with carboplatin at a dose 
of AUC 5 and pembrolizumab. A randomized phase 2 clinical trial aimed at the evaluation of 
berzosertib (M6620, VX-970) in combination with carboplatin/gemcitabine/pembrolizumab, 
compared with carboplatin/gemcitabine/pembrolizumab alone in patients with chemotherapy- 
naïve Sq-NSCLC will then be conducted. Eligible patients will be randomized to 
carboplatin/gemcitabine/pembrolizumab with or without berzosertib (M6620, VX-970). Patients 
will adhere to the following treatment schedule for a total of 2 years of treatment or until disease 
progression, unacceptable treatment-related toxicity, or withdrawal of consent. Pembrolizumab 
administration should not exceed 2 years. 
• Cycles 1 to 4 (first 3 months of the first year): gemcitabine on D1 and D8, carboplatin 
and pembrolizumab on D1, and +/- berzosertib (M6620, VX-970) on D2 and D9, every 
three weeks 
• Cycles 5 to 16 (last 9 months of the first year): pembrolizumab +/- berzosertib (M6620, 
VX-970) on D1, every 3 weeks 
• Cycles 17 to 26 (second year): pembrolizumab on D1, every 6 weeks 
The primary endpoint of this clinical trial is PFS. Patients will be required to have tumor tissue 
at the time of enrollment in order to conduct a secondary analysis of ATM-deficiency and PFS 
with carboplatin/gemcitabine/pembrolizumab with and without berzosertib (M6620, VX-970) 
and exploratory analyses of other mediators of the DNA damage response and inflammation- 

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associated gene expression that may be associated with response to berzosertib (M6620, VX- 
970) and carboplatin/gemcitabine/pembrolizumab. 
 
9.1.2 Phase 1B Safety Lead-In 
We will start at dose level 1, as our patient population is chemotherapy-naïve, and would be 
expected to tolerate higher doses of platinum chemotherapy. Patients who fail to complete cycle 
1 (i.e., fail to receive carboplatin, pembrolizumab, and two full doses of gemcitabine and 
berzosertib (M6620, VX-970) of therapy for reasons unrelated to toxicities or treatment side 
effects) will be non-evaluable for DLT and will be replaced. Patients who fail to complete cycle 
1 for reasons of toxicities or treatment side effects will be classified as having a DLT. 
 
Patients who fail to complete cycle 1 of therapy (i.e., fail to receive carboplatin, pembrolizumab, 
and two full doses of gemcitabine and berzosertib (M6620, VX-970)) for reasons unrelated to 
treatment (e.g., rapid disease progression) will be deemed to be non-evaluable for DLT and be 
replaced. Patients who fail to complete cycle 1 at the prescribed dose level due to treatment 
related adverse side effects (i.e., dose modification per Section 7.2.1 are required) will be 
classified as having a DLT. 
DLTs will be defined as grade 4 absolute neutrophil count for ≥ 5 days, grade 4 anemia, platelet 
count < 25,000, or other non-hematologic events ≥ grade 3 as per NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 (except fatigue, alopecia, and anorexia). 
Patients are allocated to doses by the following algorithm (Dixon and Mood, 1948): 
Three patients will be treated at Level 1. 
1. If # DLT≤1/3, treat 3 more patients at Level 1, otherwise, go to step 2, below. 
a. If # DLT≤1/6, proceed to Phase 2 at Level 1, 
b. Else if # DLT=2/6 or 3/6, go to step 2, below, 
c. Else if # DLT>3/6, do not proceed to Phase 2. 
2. If # DLT≤1/3, treat 3 more patients at Level -1, otherwise, go to step 3, below. 
a. If # DLT≤1/6, proceed to Phase 2 at Level -1, 
b. Else if # DLT=2/6 or 3/6, go to step 3, below, 
c. Else if # DLT>3/6, do not proceed to Phase 2. 
3. Treat 3 patients at Level -2. 
a. If # DLT≤1/3, treat 3 more patients at Level -2, 
i. If #DLT≤1/6, proceed to Phase 2 at Level -2, 
ii. Else if #DLT≥2/6, do not proceed to Phase 2. 
b. If # DLT≥2/3, do not proceed to Phase 2. 
If the trial does not proceed to Phase 2, an internal DSMB consisting of the study investigators 
and medical monitor will meet to discuss potential protocol amendments. DLTs will be 
determined in cycle 1 of therapy, though accrual will not be halted for DLT evaluation. 
The operating characteristics for the run-in study are shown in the table below (“Probabilities of 
Dose Selection”), using the algorithm stated above and assuming the true probabilities of DLT 
stated in the first two rows. 

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Probabilities of Dose Selection 
True P(DLT) at Level 1 
0.050 
0.100 
0.150 
0.200 
0.250 
0.300 
0.400 
True P(DLT) at Level -1 
0.025 
0.050 
0.075 
0.100 
0.125 
0.150 
0.200 
P(Select Level 1) 
0.968 
0.895 
0.794 
0.670 
0.525 
0.413 
0.226 
P(Select Level -1) 
0.029 
0.091 
0.167 
0.265 
0.329 
0.376 
0.397 
P(Do Not Proceed to 
Phase 2) 
0.003 
0.041 
0.035 
0.065 
0.146 
0.211 
0.377 
 
9.1.3 Phase 2 
The goal of the phase 2 study is to detect improvement in PFS with the addition of berzosertib 
(M6620, VX-970) to carboplatin/gemcitabine/pembrolizumab. A secondary analysis will 
examine the potential association between ATM deficiency and benefit of berzosertib (M6620, 
VX-970) in combination with carboplatin/gemcitabine/pembrolizumab. Patients will not be 
stratified by or selected based on ATM mutation status, as efficacy of berzosertib (M6620, VX- 
970) in the ATM-deficient population is a secondary endpoint and is not being used to power the 
primary endpoint. In order to control for drifts in patient selection and treatment outcomes and 
to prepare for assessment of ATM as a predictive biomarker, a randomized phase 2 trial is the 
selected design (Gan et al., 2010). The median PFS for patients with chemotherapy-naïve 
advanced NSCLC of squamous cell histology (unselected by ATM status) is expected to be 
about 6 months in the control (carboplatin/gemcitabine/pembrolizumab) arm (Scagliotti et al., 
2008; Thatcher et al., 2015; Sederholm et al., 2005). A promising hazard ratio for PFS would be 
0.75 (approximate observed median PFS of 10 months in the +berzosertib (M6620, VX-970) 
arm). 
 
The sample size is justified in terms of the primary endpoint: progression-free survival. It is 
assumed that: the median PFS is 6 months in the control arm and 10 months in the experimental 
arm, resulting in a hazard ratio of 0.6 (assuming exponentially-distributed survival times); 88 
participants will be randomized 1:1 over 30 months; the futility analysis will be performed when 
40 events have been observed; the final analysis will be performed when 85 events have been 
observed. According to Monte Carlo simulation, it is anticipated that the futility analysis will 
take place 24 months after accrual starts and the final analysis will take place 38 months after 
accrual begins, and there is a 0.056 probability that the trial will be stopped at the futility 
analysis. The one-sided hypothesis test at α=0.1 has 82.4% power; this calculation includes the 
probability that the trial will be halted at the futility analysis. Phase 1B participants will not be 
included in the Phase 2 analysis. 
 
9.1.4 Safety and Tolerability 
The NCI CTCAE 5.0 will be used to evaluate toxicity, and we will consider a toxicity to be an 
adverse event that is possibly, probably, or definitely related to treatment. The maximum grade 
of toxicity for each category of interest will be recorded for each patient, and the summary 

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results will be tabulated by category, grade, and dose level. Serious (≥ Grade 3) toxicities will be 
described on a per patient basis and will include any relevant baseline data. 
 
9.2 
Analyses of Endpoints and Objectives 
For purposes of analysis, PFS is defined as the duration of time from the date of randomization 
to time of progression or death, whichever occurs first. 
 
9.2.1 Primary Endpoints 
 
1. Phase 1B: The RP2D will be the dose selected as described in the description of the dose 
de-escalation schema. 
2. Phase 2: Proportional hazards (Cox) regression will be used to estimate the hazard ratio 
and the primary null hypothesis, that PFS is identical between arms, will be tested by a 
one-sided likelihood ratio test at α=0.10. The hazard ratio will be estimated with a 95% 
confidence interval. The assumption of proportionality of hazards will be checked 
graphically and by the method of Therneau and Grambsch. If it is found that the 
assumption is violated, the log-rank test will be used to compare the product-limit 
estimates of the survival functions. The analysis will take place when 85 events have 
been observed. This analysis will be on an intent-to-treat basis, that is, participants will 
be analyzed as they were randomized. 
 
9.2.2 Secondary Objectives in Phase 2 
1. The Phase 2 primary objective analysis will be repeated on an as-treated basis, that is, 
participants will be analyzed as they were actually treated. 
2. PFS will be analyzed as in the Primary Phase 2 Objective in the subset of patients with 
ATM-deficient Sq-NSCLC. 
3. Overall survival will be analyzed in the same fashion as PFS. Overall response will be 
analyzed by means of Fisher’s exact test. The odds ratio will be estimated with a 95% 
confidence interval. 
4. Objective response, overall survival, progression-free survival, and worst grade of 
adverse event experienced of the participants in the berzosertib (M6620, VX-970) arm 
will be modeled as a function of total berzosertib (M6620, VX-970) exposure using 
logistic regression, proportional hazards (Cox) regression and cumulative logit models, as 
appropriate. 
5. Adverse events will be tabulated according to CTCAE v5.0 type, grade and relation to 
treatment. The worst grade of adverse event will be determined for each participant, and 
the distributions of worst grades will be compared between arms using a cumulative logit 
model. 

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9.2.3 Exploratory Objectives in Phase 2 
 
1. Sparse modeling (e.g., the lasso) will be used to determine if any features of whole 
exome and RNA sequencing are predictive of OR, OS or PFS. 
2. Proportional hazards (Cox) regression will be used to assess the relationship between the 
ATM assay and OS and PFS. 
3. Logistic regression and proportional hazards (Cox) regression will be used to explore the 
relationship between inflammation-associated gene signatures and OR, OS and PFS. 
 
9.2.4 Futility Analysis: A futility analysis will be conducted after 40 events have been 
observed. At this time, the hazard ratio will be calculated, and the trial will be closed if 
the hazard ratio is greater than 1. 
 
9.3 
Sample Size and Accrual Rate 
This study is projected to last 30 months from first to last enrolled evaluable patient, with an 
expected additional 12 months of follow-up from the last patient enrollment to ascertain 85 PFS 
events. Monthly accrual is estimated at 3-4 patients per month (range: 94-106 patients). Sample 
size will be 6-18 patients for Phase 1B, and 88 patients for Phase 2. 
 
The sample size is justified in terms of the primary endpoint, progression-free survival. It is 
assumed that: the median PFS is 6 months in the control arm and 10 months in the experimental 
arm, resulting in a hazard ratio of 0.6 (assuming exponentially-distributed survival times); 88 
participants will be randomized 1:1 over 30 months; the futility analysis will be performed when 
40 events have been observed. At this time, the hazard ratio will be calculated, and the trial will 
be closed if the hazard ratio is greater than 1. The final analysis will be performed when 85 
events have been observed. According to Monte Carlo simulation, it is anticipated that the 
futility analysis will take place 24 months after accrual starts and the final analysis will take 
place 38 months after accrual begins, and there is a 0.056 probability that the trial will be 
stopped at the futility analysis if the hazard ratio is 0.6 with a median PFS of 6 months in the 
control arm and 10 months in the experimental arm, per the primary hypothesis. The one-sided 
hypothesis test at α=0.1 has 82.4% power; this calculation includes the probability that the trial 
will be halted at the futility analysis. Phase 1B participants will not be included in the Phase 2 
analysis. 
 
PLANNED ENROLLMENT REPORT 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 

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87 
 
 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African 
American 
0 
1 
0 
0 
1 
White 
52 
49 
1 
1 
103 
More Than One Race 
1 
0 
0 
0 
1 
Total 
53 
51 
1 
1 
106 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015) 
OMB No. 0925-0001/0002 
 
 
9.4 
Monitoring Rule for Toxicity 
 
Toxicity will be monitored after every 10 participants have been treated. For the purpose of 
monitoring, a participant experiences toxicity if he or she experiences an adverse event of Grade 
≥3 at least probably related to treated. If πX and πC are the probabilities a participant experiences 
toxicity in the experimental and control arms, then the trial will be paused for toxicity if P(πX - 
πC>0.1)>0.75. A Beta(1,1) (uninformative) prior distribution is assigned to both πX and πC. This 
stopping rule is expressed in the following table, where it is assumed the numbers of participants 
in both arms are equal, nX is the number of participants experiencing toxicity in the experimental 
arm and nC is the number of participants experiencing toxicity in the control arm 
 
Total # Participants Stop if nX-nC ≥ 
10 
2 
20 
3 
30 
4 
40 
5 
50 
5 
60 
6 
70 
6 
80 
7 
90 
7 

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88 
 
 
9.5 
Reporting and Exclusions 
 
9.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with the study 
drugs. 
 
9.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories: 1) CR, 2) PR, 3) SD 4) PD, 5) early death from malignant disease, 6) 
early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data). [Note: By arbitrary convention, category 9 usually designates the “unknown” 
status of any type of data in a clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be 
protocol specific. 
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported. The 95% confidence intervals should also be provided. 
 
9.6 
Data Safety Monitoring Board 
 
The conduct of this study will be overseen by the ETCTN DSMB. The DSMB will be 
responsible for recommendations to the Principal Investigator and NCI regarding possible trial 
closure and/or early reporting of the study. The study team (with the exception of the study 
statistician) will not have access to the summary outcome data until released by the DSMB. 
 
10. 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 10.1) and the characteristics of an observed AE (Sections 10.2 and 
10.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
10.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 

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The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
10.1.1 CAEPRs for CTEP IND Agents 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
M6620 (VX-970, berzosertib, NSC 780162) 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in 
the SPEER. If this CAEPR is part of a combination protocol using multiple investigational agents and has 
an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
Version 2.0, July 13, 20221 
Adverse Events with Possible 
Relationship to M6620 (VX-970, berzosertib) 
(CTCAE 5.0 Term) 
[n= 323] 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Anemia (Gr 3) 
GASTROINTESTINAL DISORDERS 
Constipation 
Diarrhea 
Diarrhea (Gr 2) 
Nausea 
Nausea (Gr 2) 
Vomiting 
Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
Fatigue (Gr 2) 
Fever 
Flu like symptoms 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
Infusion related reaction 
Infusion related reaction (Gr 2) 
INVESTIGATIONS 
Alanine aminotransferase 
increased 
Alanine aminotransferase 
increased (Gr 2) 
Aspartate aminotransferase 
increased 
Aspartate aminotransferase 
increased (Gr 2) 

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Adverse Events with Possible 
Relationship to M6620 (VX-970, berzosertib) 
(CTCAE 5.0 Term) 
[n= 323] 
Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
Lymphocyte count decreased 
Lymphocyte count decreased (Gr 
2) 
Neutrophil count decreased 
Neutrophil count decreased (Gr 2) 
Platelet count decreased 
Platelet count decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Anorexia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
Dizziness 
Headache 
Headache (Gr 2) 
VASCULAR DISORDERS 
Flushing 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all Principal 
Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
Adverse events reported on M6620 (VX-970, berzosertib) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that M6620 (VX-970, berzosertib) caused the adverse event: 
 
CARDIAC DISORDERS - Cardiac arrest; Palpitations 
EAR AND LABYRINTH DISORDERS - Tinnitus 
GASTROINTESTINAL DISORDERS - Abdominal pain; Ascites; Colonic obstruction; Dyspepsia; Mucositis oral 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (lower respiratory tract infection); 
Otitis externa; Sepsis; Soft tissue infection; Urinary tract infection 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Creatinine increased; GGT 
increased; Hemoglobin increased; Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperglycemia; Hypokalemia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (malignant neoplasm progression); Tumor pain 
NERVOUS SYSTEM DISORDERS - Lethargy; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Atelectasis; Cough; Dyspnea; 
Respiratory, thoracic and mediastinal disorders - Other (hemotypsis) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Pruritus; Rash maculo-papular 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event; Vascular disorders - Other 
(hypovolemic shock) 
Note: M6620 (VX-970, berzosertib) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 

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10.1.2 Adverse Event Lists for Commercial Agents 
 
Refer to the package inserts for a comprehensive list of adverse events. 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Pembrolizumab (MK-3475, NSC 776864) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 3793 patients. Below is the CAEPR for Pembrolizumab 
(MK-3475). 
 
 
Version 2.8, August 14, 20241 
Adverse Events with Possible 
Relationship to Pembrolizumab (MK-3475) 
(CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia2 
Blood and lymphatic system 
disorders - Other (immune 
thrombocytopenic purpura)2 
Blood and lymphatic system 
disorders - Other (autoimmune 
hemolytic anemia)2 
Lymph node pain2 
CARDIAC DISORDERS 
Myocarditis2 
Pericarditis2 
ENDOCRINE DISORDERS 
Adrenal insufficiency2 
Endocrine disorders - Other 
(hypoparathyroidism)2 
Endocrine disorders - Other 
(thyroiditis)2 
Hyperthyroidism2 
Hypophysitis2 
Hypopituitarism2 
Hypothyroidism2 
EYE DISORDERS 
Eye disorders - Other (Vogt- 
Koyanagi-Harada syndrome) 
Uveitis2 
GASTROINTESTINAL DISORDERS 

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Adverse Events with Possible 
Relationship to Pembrolizumab (MK-3475) 
(CTCAE 5.0 Term) 
[n= 3793] 
Abdominal pain 
Colitis2 
Diarrhea2 
Enterocolitis2 
Gastritis2 
Gastrointestinal disorders - 
Other (exocrine pancreatic 
insufficiency) 
Mucositis oral2 
Nausea 
Pancreatitis2 
Small intestinal mucositis2 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
Fatigue 
Fever2 
HEPATOBILIARY DISORDERS 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
Hepatobiliary disorders - Other 
(sclerosing cholangitis) 
IMMUNE SYSTEM DISORDERS 
Anaphylaxis2 
Cytokine release syndrome2 
Immune system disorders - 
Other (acute graft-versus-host- 
disease)2,3 
Immune system disorders - 
Other (hemophagocytic 
lymphohistiocytosis)2 
Immune system disorders - 
Other (sarcoidosis)2 
Serum sickness2 
INFECTIONS AND INFESTATIONS 
Myelitis2 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
Infusion related reaction 
INVESTIGATIONS 
Alanine aminotransferase 
increased2 
Alkaline phosphatase increased 
Aspartate aminotransferase 
increased2 
Blood bilirubin increased 
GGT increased 
Lipase increased 
Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 

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Adverse Events with Possible 
Relationship to Pembrolizumab (MK-3475) 
(CTCAE 5.0 Term) 
[n= 3793] 
Hyponatremia 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
Metabolism and nutrition 
disorders - Other (type 1 
diabetes mellitus)2 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia2 
Arthritis2 
Back pain 
Joint range of motion decreased
Myalgia2 
Myositis2 
NERVOUS SYSTEM DISORDERS 
Guillain-Barre syndrome2 
Myasthenia gravis 
Nervous system disorders - 
Other (autoimmune 
neuropathy)2 
Nervous system disorders - 
Other (demyelination)2 
Nervous system disorders - 
Other (myasthenic syndrome)2 
Nervous system disorders - 
Other (nerve paresis)2 
Nervous system disorders - 
Other (neuromyopathy)2 
Nervous system disorders - 
Other (non-infectious 
encephalitis)2 
Nervous system disorders - 
Other (non-infectious 
meningitis)2 
Nervous system disorders - 
Other (non-infectious myelitis) 
Nervous system disorders - 
Other (optic neuritis) 
Nervous system disorders - 
Other (polyneuropathy)2 
Paresthesia 
Peripheral motor neuropathy2 
RENAL AND URINARY DISORDERS 
Acute kidney injury 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Pneumonitis2 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Bullous dermatitis2 

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Adverse Events with Possible 
Relationship to Pembrolizumab (MK-3475) 
(CTCAE 5.0 Term) 
[n= 3793] 
Erythema multiforme2 
Erythroderma 
Palmar-plantar 
erythrodysesthesia syndrome 
Pruritus2 
Rash acneiform2 
Rash maculo-papular2 
Skin and subcutaneous tissue 
disorders - Other (Drug reaction 
with eosinophilia with systemic 
symptoms [DRESS])2 
Skin and subcutaneous tissue 
disorders - Other (dermatitis)2 
Skin hypopigmentation2 
Stevens-Johnson syndrome2 
Toxic epidermal necrolysis2 
Urticaria2 
VASCULAR DISORDERS 
Vasculitis2 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving Pembrolizumab (MK- 
3475). Adverse events potentially related to Pembrolizumab (MK-3475) may be manifestations of 
immune-mediated adverse events. In clinical trials, most immune-mediated adverse reactions were 
reversible and managed with interruptions of Pembrolizumab (MK-3475), administration of corticosteroids 
and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with Pembrolizumab (MK-3475) 
who received hematopoeitic stem cell transplants. 
 
 
Adverse events reported on Pembrolizumab (MK-3475) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that Pembrolizumab (MK-3475) 
caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal 
hemorrhage; Dysphagia; Gastrointestinal disorders - Other (intussusception); Gastrointestinal disorders - 
Other (diverticulitis); Gastrointestinal disorders - Other (intestinal obstruction); Oral pain; Rectal 
hemorrhage; Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; 
Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general 

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physical health deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - CPK increased; Cholesterol high; Creatinine increased; Fibrinogen decreased; 
Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White 
blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Joint effusion2; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in 
extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders 
- Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Nephrotic syndrome; Proteinuria; Renal and urinary disorders - 
Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pleuritic pain2; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 
Note: Pembrolizumab (MK-3475) 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. 
 
 
10.1.2.1 Gemcitabine 
 
The most common adverse reactions for gemcitabine (≥20%) are nausea/vomiting, anemia, 
increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), 
neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, 
thrombocytopenia, dyspnea, and edema. 
 
10.1.2.2 Carboplatin 
 
The following adverse events have been associated with carboplatin: 
 
Very common side effects (>10%): abdominal pain, anemia, decreased kidney 
function/kidney toxicity, high blood uric acid levels, infection, abnormal liver function tests, 
electrolyte imbalance, low platelets, leukopenia, nausea, vomiting. 
Less common side effects (<10%): allergic reaction (rash and hives), bleeding, diarrhea, 
constipation, hearing impairment, infection, neuropathy (numbness or pain of the hands 
and/or feet). 
10.2 Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found 

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in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only: 
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 10.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
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. 
 
10.3 Expedited Adverse Event Reporting 
 
10.3.1 Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP- 
AERS) integration enables evaluation of post-baseline AEs entered in Rave to determine 
whether they require expedited reporting and facilitates entry in CTEP-AERS for those 
AEs requiring expedited reporting. 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period and is used to 
collect AEs that start during the period or persist from the previous reporting period. 
CRA will enter AEs that occur prior to the start of treatment on a baseline form that is not 
included in the Rave-CTEP-AERS integration. AEs that occur prior to enrollment must 
begin and end on the baseline Adverse Event form and should not be included on the 
standard Adverse Events form that is available at treatment unless there has been an 
increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct, and 
• AEs are recorded and complete (no missing fields) and the form is query-free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 

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that meet reporting requirements. The CRA completes the report by accessing CTEP- 
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
In the rare occurrence that Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the CTSU 
website: 
• Study specific documents: Protocols > Documents > Education and Promotion, 
and 
• Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information > User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website: 
• NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid 
elines.pdf. 
 
10.3.2 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. 
 
10.3.3 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 as long as the death occurred within 30 days after the last administration 
of the investigational agent. 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. 
 
Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse 

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Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration 
of the Investigational Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY SAEs, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64). 
An AE is considered serious if it results in ANY of the following outcomes: 
1) 
Death 
2) 
A life-threatening AE 
3) 
An AE that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours. 
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) 
A congenital anomaly/birth defect. 
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6). 
ALL SAEs that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within the 
timeframes detailed in the table below. 
Grade 1-2 Timeframes 
Grade 3-5 Timeframes 
24-Hour notification, 10 Calendar Days 
24-Hour notification, 5 Calendar Days 
NOTE: Protocol-specific exceptions to expedited reporting of SAEs are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timeframes are defined as: 
o 
“24-Hour notification, 5 Calendar Days” - The SAE must initially be reported via CTEP-AERS within 
24 hours of learning of the SAE, followed by a complete expedited report within 5 calendar days of 
the initial 24-hour report. 
o 
“24-Hour notification, 10 Calendar Days” - The SAE must initially be reported via CTEP-AERS within 
24 hours of learning of the SAE, followed by a complete expedited report within 10 calendar days of 
the initial 24-hour report. 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-Hour notifications are required for all SAEs followed by a complete report 
• 
Within 5 calendar days for Grade 3-5 SAEs 
• 
Within 10 calendar days for Grade 1-2 SAEs 
2For studies using nuclear medicine or molecular imaging IND agents (NM, SPECT, or PET), the SAE 
reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered. Footnote “1” above applies after this reporting period. 
Effective Date: August 30, 2024 
 
 
10.4 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 CTEP-AERS. For this trial the Adverse Event CRF is used for routine AE 
reporting in Rave. 
 
10.5 Pregnancy 
 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 90 days after the last dose of study drug must be reported and then followed for 
outcome. Newborn infants should be followed until 30 days old. Please see the “NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and 
CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to 
report pregnancy and its outcome to CTEP. 
 
10.6 Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to 
describe the event: 
• 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. 
 
10.7 Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 

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11. STUDY CALENDAR 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy. Scans 
and x-rays must be done <4 weeks prior to the start of therapy. A window of -1 week is allowed 
for scans and x-rays. In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. A 
window of ±48 hours is allowed for all assessments in the Study Calendar. 

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Study Calendar 
 
Baseline 
Cycles 1-4 
(1 Cycle = 21 days) 
Cycles 5-16 
(1 Cycle = 21 days) 
Cycles 17-26 
(1 Cycle = 42 days) 
Disease 
Progression 
or 
End of 
Treatment 
Follow Upj 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Every 3 
months 
Berzosertib 
(M6620, VX- 
970) a 
X 
X 
X a* 
Pembrolizumab 
a 
X 
X 
X 
Gemcitabine a 
X 
X 
Carboplatin a 
X 
Archival Tumor 
Collection b 
X 
Blood 
Collection for 
WES c 
X 
Blood 
Collection for 
PK c 
X 
X 
Response 
Assessments d 
X 
Tumor measurements and radiologic evaluation to occur at 6, 12, and 18 weeks, 
then every 9 weeks thereafter. 
X 
Comprehensive 
Chemistry 
Panel & CBC e 
X 
X 
X 
X 
X 
Thyroid 
Function Test f 
X 
X 
X 
X 
General Health 
Exam g 
X 
X 
X 
X 
EKG h 
X 
Adverse Event 
Evaluation 
X 
X 
X 
Concurrent 
Medications 
X 
X 
X 
X 
Informed 
Consent, 
Demographics, 
and Medical 
History 
X 
Pregnancy Test 
i 
X 
a Dose as assigned. The following treatment schedule will be used for a total of 2 years of treatment. Pembrolizumab 
administration should not exceed 2 years: 
• 
Cycles 1 to 4 (first 3 months of the first year): gemcitabine on D1 and D8, carboplatin and pembrolizumab on D1, and 
+/- berzosertib (M6620, VX-970) on D2 and D9, every three weeks 
• 
Cycles 5 to 16 (last 9 months of the first year): pembrolizumab +/- berzosertib (M6620, VX-970) on D1, every 3 weeks 
• 
Cycles 17 to 26 (second year): pembrolizumab on D1, every 6 weeks 
a* Beyond 4 cycles (i.e., 3 months), when berzosertib (M6620, VX-970) and pembrolizumab administration continues on D1 only 

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Baseline 
Cycles 1-4 
(1 Cycle = 21 days) 
Cycles 5-16 
(1 Cycle = 21 days) 
Cycles 17-26 
(1 Cycle = 42 days) 
Disease 
Progression 
or 
End of 
Treatment 
Follow Upj 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Day 
1 
Day 
2 
Day 
8 
Day 
9 
Every 3 
months 
without gemcitabine or carboplatin, the berzosertib (M6620, VX-970) and pembrolizumab may be dosed on the same day 
(D1) for patient convenience, where pembrolizumab is administered before berzosertib (M6620, VX-970). 
b Archival Tumor Collection: The use of archival tumor tissue for ATM Expression and Whole Exome Sequencing is mandatory. 
The use of archival tissue for RNA Sequencing is optional. Tissue must be collected within 3 months prior to beginning 
treatment. 
c Blood Collection for Studies: All study blood samples are mandatory and will be taken at the following times: 
• 
Baseline (for germline control for WES) 
• 
Cycle 1, Day 1: pre-dose and 25 min post start of gemcitabine (~ 5 min before end of infusion). 
• 
Cycle 1, Day 2: pre-dose, 30 min (+/-5 min) post start of berzosertib (M6620, VX-970), 55 min (+/-5 min) post start of 
berzosertib (M6620, VX-970) (~ 5 min before end of infusion), 15 min (+/-5 min) post end of berzosertib (M6620, VX- 
970), 30 min (+/-5 min) post end of berzosertib (M6620, VX-970), 1 hr (+/-5 min) post end of berzosertib (M6620, VX- 
970). 
d Response Assessments: Response to treatment will be assessed by tumor measurement and radiologic evaluation at 6, 12, 
and 18 weeks, then every 9 weeks thereafter. Radiologic documentation must be provided for patients to be removed from 
study for progressive disease. The same modality for all known sites of disease should be used throughout the study. This 
includes a CT scan of the chest, abdomen ± pelvis (as clinically indicated) or an MRI of the brain (as clinically indicated). 
e Comprehensive Chemistry Panel & CBC: Assessments to be conducted twice during each cycle (Weeks 1 and 2) or as 
medically indicated. Assessment to include CBC with a differential and platelet count. Serum Chemistry to include albumin, 
alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium. 
f Thyroid Function Test: Assessment to be conducted baseline, then at the start of every cycle, or as medically indicated . To 
include TSH and Free T4. 
g General Health Exam: To consist of a physical exam and evaluation of vital signs, weight, and performance status. To be 
evaluated at the beginning of each cycle, or as medically indicated. 
h EKG: To be conducted at baseline, then as clinically indicated. 
I Pregnancy Test: Women of childbearing potential will also receive a pregnancy test within 7 days prior to registration. 
j Follow Up: Patient follow-up will occur via standard of care or a phone call every 3 months +/- (2 weeks) for 12 months following 
removal from study. 
 
12. MEASUREMENT OF EFFECT 
Although the clinical benefit of these drug 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. For the purposes of this study, 
patients will be re-evaluated at 6, 12, and 18 weeks, then every 9 weeks thereafter. In addition to 
a baseline scan, confirmatory scans will also be obtained ≥ 4 weeks following initial 
documentation of an objective response. 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients will be re-evaluated at 6, 12, and 18 weeks, then every 9 
weeks thereafter. In addition to a baseline scan, confirmatory scans should also be obtained not 
less than 4 weeks following initial documentation of objective response. 

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Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 
12.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with berzosertib (M6620, VX-970), pembrolizumab, gemcitabine, or carboplatin. 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions. 
 
12.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might be considered 
measurable, if biopsy-proven progression within the radiation field. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, 
only the short axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not 

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be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up. 
 
12.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
 
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice 

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thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of 
MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-CT 
is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) 
and PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J 
Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 
92:1534-1535, 2000]. 

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Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG- 
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG- 
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.4 Response Criteria 
 
12.1.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm (<1 cm). 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 

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20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). 
(Note: the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
12.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
12.1.4.3 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 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation 
CR 
Non-CR/Non- 
PD 
No 
PR 
≥4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non- 
No 
PR 

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

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PFS is defined as the duration of time from the date of randomization to time of progression or 
death, whichever occurs first. 
 
 
13. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 10 
(Adverse Events: List and Reporting Requirements). 
 
13.1 Study Oversight 
This protocol is monitored at several levels, as described in this section. The Protocol Principal 
Investigator is responsible for monitoring the conduct and progress of the clinical trial, including 
the ongoing review of accrual, patient-specific clinical and laboratory data, and routine and 
serious adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s). The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal. 
 
For the Phase 1 portion of this study, all decisions regarding dose escalation/expansion/de- 
escalation require sign-off by the Protocol Principal Investigator through the CTMS/IWRS. In 
addition, for the Phase 1 portion, 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. 
 
For a Phase 1/2 trial, enrollment to the Phase 2 portion of the trial will not begin until a protocol 
amendment has been submitted which summarizes the Phase 1 results, the recommended Phase 2 
dose, and the rationale for selecting it. The amendment must be reviewed and approved by 
CTEP before enrollment to the Phase 2 portion can begin. 
 
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. 
 
13.2 Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 
Requirements to access Rave via iMedidata: 
• 
A valid account, and 

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• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role, must have a minimum of an 
Associate Plus (AP) registration type, 
o Rave Investigator role, must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR), and 
o Rave Read Only role, site staff must have at a minimum an Associates (A) 
registration type. 
• 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
If the study has a DTL, individuals requiring write access to Rave must also be assigned the 
appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password, and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff will not be 
able to access the study in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the link in the upper right pane of the iMedidata screen. If an eLearning 
is required and has not yet been taken, the link to the eLearning will appear under the study name 
in iMedidata instead of the Rave EDC link; once the successful completion of the eLearning has 
been recorded, access to the study in Rave will be granted, and a Rave EDC link will display 
under the study name. 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
13.2.1 Method 
 
CTMS Comprehensive Monitoring: 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS). Data will be 
submitted to CTMS at least once every two weeks via Medidata Rave (or other modality if 
approved by CTEP). Information on CTMS reporting is available at 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11. On-site 
audits will be conducted three times annually (one annual site visit and two data audits). For 

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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. 
 
13.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all investigators at 
the ETCTN Sites understand the procedures for data submission for each ETCTN protocol and 
that protocol specified data are submitted accurately and in a timely manner to the CTMS via the 
electronic data capture system, Medidata Rave. 
 
Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less than once 
every 2 weeks. The timeliness of data submissions and timeliness in resolving data queries will 
be tracked by CTMS. Metrics for timeliness will be followed and assessed on a quarterly basis. 
For the purpose of Institutional Performance Monitoring, data will be considered delinquent if it 
is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing basis as 
data is received. Queries will be issued by CTMS directly within Rave. The queries will appear 
on the Task Summary Tab within Rave for the CRA at the ETCTN to resolve. Monthly web- 
based reports are posted for review by the Drug Monitors in the IDB, CTEP. Onsite audits will 
be conducted by the CTMS to ensure compliance with regulatory requirements, GCP, and NCI 
policies and procedures with the overarching goal of ensuring the integrity of data generated 
from NCI-sponsored clinical trials, as described in the ETCTN Program Guidelines, which may 
be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm) and 
CTSU websites. 
 
CTMS will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics- 
resources/interoperability-and-semantics/metadata-and-models). Customized eCRFs will be 
included when appropriate to meet unique study requirements. The PI is encouraged to review 
the eCRFs, working closely with CTMS to ensure prospectively that all required items are 
appropriately captured in the eCRFs prior to study activation. CTMS will prepare the eCRFs 
with built-in edit checks to the extent possible to promote data integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried out by 
the CTMS contractor, Theradex. CDUS submissions are performed by Theradex on a monthly 
basis. The trial’s lead institution is responsible for timely submission to CTMS via Rave, as 
above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm). 

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13.3 
Data Quality Portal 
 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics. 
 
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, and 
timeliness reports. Review the DQP modules on a regular basis to manage specified 
queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct 
link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
 
13.4 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. 

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

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releases and other media presentations must also be forwarded to CTEP prior to release. 
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
13.5 Genomic Data Sharing Plan 
The investigators and statistician and/or bioinformaticians for a study will have access to all data 
on mutations and variants stored in the Theradex Data Base and the GDC. This information will 
be sequestered from access throughout the study until it is analyzed for purposes of reporting and 
publishing of the study results. As specified in the CRADA for the agents used in the clinical 
study, the pharmaceutical collaborator will have at least 6 months, longer if needed for a 
regulatory filing, to review the data and or receive copies of the data once the study is completed 
and analyzed, or sooner, if specified for purposes of generating Intellectual Property. Once these 
timeframes have been exceeded, the data will be available through a Data Access Committee 
(DAC) in the GDC following NCI and Collaborator review of the proposals. 
 
13.6 Incidental/Secondary Findings Disclosure Procedure 
 
Given the potential clinical implications conferred by detecting a germline and/or somatic 
mutation in one of the proven cancer susceptibility genes, this protocol will use the following 
disclosure procedure, consistent with the recommendations of the American College of Medical 
and Genomics (ACMG) (Green et al., 2013 and Kalia et al., 2016): 
 
The NCI Molecular Characterization Laboratory will review the mutations/variants once at the 
time of initial specimen evaluation according to the most recent version of the ACMG guidance 
on variants. The NCI Molecular Characterization Laboratory will not re-review all specimens 
received if a new version of the ACMG guidance is published after the initial review. 
 
For each participant with a pathogenic or likely pathogenic germline and/or somatic variant 
detected in the WES of blood (as defined in the ACMG guidance), the NCI Molecular 
Characterization Laboratory will report to the Program Director or Scientific Officer the UPID 
and variant(s) identified. The Program Director or Scientific Officer will contact Theradex to 
obtain the name of the protocol, investigator treating the patient, and the Principal Investigator of 
the grant. The treating physician will be contacted by phone and in writing to ask the patient 
whether he or she is interested in learning more about the finding. 
 
If the patient wants to know more, the physician should contact the Program Director for more 
information about the mutation/variant. The treating physician and a medical genetics counselor 
should meet with the patient to discuss the importance and meaning of the finding, but not the 
finding itself, and notify the patient that this research finding must be confirmed by Sanger 
sequencing at the patient’s/patient insurer’s expense in a Clinical Laboratory Improvement 

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Amendments (CLIA)-approved laboratory. The treating physician and genetic counselor should 
inform the patient of the confirmed result and its meaning and significance to the patient. If 
desired, the patient may elect to undergo genetic counseling and confirmatory CLIA-approved 
clinical testing on his or her own. Neither the research laboratory nor the National Cancer 
Institute will be responsible for the costs incurred for any confirmatory genetic testing or 
counseling. 

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advanced tumors. Ann Oncol. 28:2002-2008. 

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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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1. Estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) (Levey et al., 2009). 
 
Formulae: 
SCr in mg/dL; Output is in mL/min/1.73 m2 and needs no further conversions. 
2.  eGFR using the Modification of Diet in Renal Disease (MDRD) Study (Levey et al., 2006). 
 
175 x SCr–1.154 × age–0.203 × 0.742 (if female) × 1.212 (if black) 
Output is in mL/min/1.73 m2 and needs no further conversions. 
APPENDIX B 
FORMULA TO ESTIMATE RENAL FUNCTION USING SERUM CREATININE 
 
Formulas to estimate renal function using serum creatinine provided by the NCI’s Investigational Drug Steering Committee (IDSC) 
Pharmacological Task Force in table below. 
 
 
 
 
 
 
Race and 
Sex 
Serum Creatinine (SCr), 
µmol/L (mg/dL) 
Equation 
Black 
Female 
≤62 (≤0.7) 
GFR = 166 × (SCr/0.7)−0.329 × (0.993)Age 
>62 (>0.7) 
GFR = 166 × (SCr/0.7)−1.209 × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 163 × (SCr/0.9)−0.411 × (0.993)Age 
>80 (>0.9) 
GFR = 163 × (SCr/0.9)−1.209 × (0.993)Age 
White or 
other 
Female 
≤62 (≤0.7) 
GFR = 144 × (SCr/0.7)−0.329 × (0.993)Age 
>62 (>0.7) 
GFR = 144 × (SCr/0.7)−1.209 × (0.993)Age 
Male 
≤80 (≤0.9) 
GFR = 141 × (SCr/0.9)−0.411 × (0.993)Age 
>80 (>0.9) 
GFR = 141 × (SCr/0.9)−1.209 × (0.993)Age 

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

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APPENDIX C 
ACCEPTABLE BIRTH CONTROL METHODS 
 
Patients of child-bearing potential and their partners, who are sexually active, must agree to the use of two highly effective forms of 
contraception throughout their participation in the study, and for 6 months after completing treatment administration. Acceptable birth 
control methods are listed below. 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 avoid 
donating sperm for during the study period, and to use adequate contraception prior to the study, for the duration of study participation, 
and for 6 months after completion completing treatment administration. 
Acceptable combinations of birth control methods include: 
Condom with spermicide and one of the following: 
• 
Oral contraceptive or hormonal therapy (e.g. hormone implants) 
• 
Placement of an intra-uterine device 
 
Acceptable non-hormonal birth control methods include: 
• 
Total sexual abstinence. Abstinence must be for the total duration of the study and the drug washout period. 
• 
Vasectomised sexual partner plus male condom. With participant assurance that partner received post-vasectomy 
confirmation of azoospermia 
• 
Tubal occlusion plus male condom with spermicide 
• 
Intrauterine Device (IUD) plus male condom+spermicide. Provided coils are copper-banded 
 
Acceptable hormonal methods: 
• 
Etonogestrel implants (eg, Implanon, Norplan)+male condom with spermicide 
• 
Normal and low dose combined oral pills+male condom with spermicide 

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• 
Norelgestromin/ethinyl estradiol (EE) transdermal system+male condom with spermicide 
• 
ntravaginal device+male condom with spermicide (eg, EE and etonogestrel) 
• 
Cerazette (desogestrel)+male condom with spermicide. Cerazette is currently the only highly efficacious progesterone 
based pill. 

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APPENDIX D 
PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible Interactions with Other Drugs and 
Herbal Supplements 
 
Patient 
Name: 
Diagnosis: 
Trial #: 
Study 
Doctor: 
Study Doctor 
Phone #: 
Study 
Drug(s) 
: 
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse practitioners, pharmacists), and tell them 
you are taking part in a clinical trial sponsored by the National Cancer Institute. 
These are the things that your healthcare providers need to know: 
Berzosertib (M6620, VX-970) 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. Berzosertib (M6620, VX-970) 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. Berzosertib (M6620, VX- 
970) 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 berzosertib (M6620, VX-970), 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 

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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. 
 
Version Apr2021 
 
(Next page: Patient Drug Interaction Wallet Card) 

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

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APPENDIX E 
PRE-BIOPSY ASSESSMENT 
A pre-biopsy lesion assessment can increase trial safety and efficiency. By agreement between 
all investigators, an attempt at biopsy will be made if the clinical trial team determines that a 
biopsy poses minimal relative risk, provides potential clinical gain to the participant, and will 
likely yield sufficient tissue for analysis. 
Pre-biopsy assessments will be reported and tracked through a trial-specific CRF within the 
CTEP Medidata Rave system. Additional information can be found in the Investigational 
Radiology SOP available at: 
https://ctep.cancer.gov/initiativesPrograms/docs/ETCTN_IR_Research_Biopsy_SOP.pdf. 
 
Individual Patient Pre-Biopsy Assessment. IR co-investigators are encouraged to apply this 
pre-biopsy scoring and correlation system to assist in the determination of biopsy 
appropriateness. 
• IR co-investigators assign a subjective score of 1-3 based on likelihood of success due to 
lesion characteristics. 
1. Biopsy should not be done 
A. Due to safety concerns 
B. Due to lack of suitable lesion for biopsy 
 
2. Uncertainty about success 
A. Due to access path to lesion 
B. Due to lesion characteristics 
 
3. Likely successful 
• Lesion characteristics to be considered 
• Size (small) (<2 cm) 
• Location/path to lesion 
• Morphologic features (necrosis, sub-solid, sclerosis, ill-defined/infiltrative) 
• PET (+/-), avidity 
• Organ/site (sclerotic bone is low yield; fine needle aspiration to be used) 

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APPENDIX F 
PHARMACOKINETICS (PK) SHEET DAY 1 AND 2 
NCI 10313 (M6620, gemcitabine in Plasma): A phase IB and randomized open-label phase II study of M6620 in combination with 
carboplatin/gemcitabine/pembrolizumab in patients with chemotherapy-naïve advanced non-small cell lung cancer of squamous cell histology 
Study Sample Collection Log 
Subject Initials: 
(First_Middle_Last) 
Subject ID: 
Date: 
BSA: 
(m2) 
Site Name: 
Pharmacokinetic (PK) Sample Collection 
At each time point, ~4-5 mL of peripheral blood will be collected in a purple-topped (EDTA), mix by inversion, and place sample immediately on ice after collection; samples 
must be processed within 30 minutes. After sample processing, store plasma samples at -70°C or below until shipment. See Section 5 of the protocol for more specific 
processing instructions and shipping instructions. At the time of sample transfer, the dosing information must be transferred also. 
Note the start and stop times of infusions in this form. Whenever the timing of drawing samples is dependent on the recent start or end of an infusion, a green arrow indicates 
which time-point starts the clock on subsequent blood draws. 
M6620, gemcitabine (GEM) 
Protocol Sample and Time 
Point 
Projected Sample Due 
Time 
(24 hr 
clock) 
Actual Time 
(24 hr 
clock) 
Comments 
Cycle 1 Day 1 
Gemcitabine infusion (nominal 30 min) GEM Dose (mg/m2): 
 
pre sample 
Also draw the serum sample without THU at this time 
GEM infusion start 
25 min post GEM start 
(~5 min prior to EOI) 
GEM infusion end 
 

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NCI 10313 (M6620, gemcitabine in Plasma): A phase IB and randomized open-label phase II study of M6620 in combination with 
carboplatin/gemcitabine/pembrolizumab in patients with chemotherapy-naïve advanced non-small cell lung cancer of squamous cell histology 
Study Sample Collection Log 
Subject Initials: 
(First_Middle_Last) 
Subject ID: 
Date: 
BSA: 
(m2) 
Site Name: 
Pharmacokinetic (PK) Sample Collection 
At each time point, ~4-5 mL of peripheral blood will be collected in a purple-topped (EDTA), mix by inversion, and place sample immediately on ice after collection; samples 
must be processed within 30 minutes. After sample processing, store plasma samples at -70°C or below until shipment. See Section 5 of the protocol for more specific 
processing instructions and shipping instructions. At the time of sample transfer, the dosing information must be transferred also. 
Note the start and stop times of infusions in this form. Whenever the timing of drawing samples is dependent on the recent start or end of an infusion, a green arrow indicates 
which time-point starts the clock on subsequent blood draws. 
M6620, gemcitabine (GEM) 
Protocol Sample and Time 
Point 
Projected Sample Due 
Time 
(24 hr 
clock) 
Actual Time 
(24 hr 
clock) 
Comments 
Cycle 1 Day 2 
M6620 infusion (nominal 60 min) M6620 Dose (mg/m2): 
 
pre sample 
M6620 infusion start 
30 min post M6620 start 
55 min post M6620 start 
(~5 min prior to EOI) 
M6620 infusion end 
15 min post end M6620 
30 min post end M6620 
60 min post end M6620 

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