Conditions: Carcinoma, Non-Small -Cell Lung Ovarian Neoplasms Small Cell Lung Carcinoma Uterine Cervical Neoplasms Carcinoma, Neuroendocrine Extrapulmonary Small Cell Cancer
Keywords: RB1 Inactivation Kinase Inhibitor DNA Damage Response Network MYC And CCNE1 Activation Defective ATM-p53 Signaling Pathway
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 62
Healthy volunteers: no

Brief summary:
Background:

Chemotherapy damages cancer cell deoxyribonucleic acid (DNA) so the cells die, and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. VX-970 (M6620) may stop cancer cells from preventing the repair of DNA damaged by chemotherapy. The purpose of this study is to see if using the chemotherapy drug topotecan along with the drug VX-970 (M6620) will improve the response to chemotherapy.

Objective:

To study the safety and efficacy of VX-970 (M6620) and topotecan in treating small cell lung cancer.

Eligibility:

Adults at least 18 years old with small cell lung cancer.

Design:

Participants will be screened with medical history, physical exam, blood and heart tests, and scans. Most of these tests are part of their routine care. Most of these tests will be repeated throughout the study.

The study is set in 21-day cycles. Participants will get topotecan intravenous (IV) on days 1 through 5. They will get VX-970 (M6620) IV on day 5 alone or on day 5 and day 2.

Participants doctors will monitor them weekly for the first cycle, every 3 weeks after that.

For Part 1 of this Study the doses of topotecan and VX-970 (M6620) will be increased (according to the Protocol) to determine the maximum safe dose of the combination. The maximum safe dose of the combination is the dose at which no more than 1 in 6 people have an intolerable side effect.

More participants will join in Phase 2. They will take the drugs at the maximum safe dose, on the same schedule as the drugs were taken in Phase 1.

Participants will give samples of blood, hair, and tumor tissue (optional) at different times. They will discuss side effects at every visit.

A month after stopping taking the drugs, participants will have a physical exam and blood drawn. They will have follow-up phone calls every 3 months.

Detailed description:
Background:

Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis.

Although highly responsive to chemotherapy initially, SCLC typically relapses quickly and becomes refractory to treatment within a few months.

There is only one Food and Drug Administration (FDA) approved treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated single-strand deoxyribonucleic acid (DNA) breaks leading to lethal double-strand DNA breaks.

The survival of some SCLC cells despite initial tumor sensitivity to chemotherapy suggests the existence of a highly effective DNA damage response network.

SCLC is characterized by high replication stress (RB transcriptional corepressor 1 (RB1) inactivation, MYC and cyclin E1 (CCNE1) activation) and defective ataxia-telangiectasia mutated tumor protein p53 (ATM-p53) signaling pathway, which cause an excessive reliance on ataxia-telangiectasia rad 3-related (ATR) for survival following DNA damage.

We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents such as topotecan will provide an attractive synthetically lethal therapeutic option for SCLC.

VX-970 is a potent and selective kinase inhibitor of ATR, and in vitro data support the hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents.

Primary objectives:

Phase 1: To identify the maximum tolerated dose (MTD) of topotecan in combination with VX-970.

Phase 2: To assess the efficacy with respect to clinical response rate of a combination of topotecan and VX-970 in the second-line treatment of patients with SCLC.

Eligibility:

Both Phase 1 and 2: Subjects must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG) less than or equal to 2. Subjects must not have received chemotherapy or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment.

Phase 1: Subjects with histologically confirmed SCLC, non-small cell cancer (NSCLC), ovarian cancer, cervical cancer, and neuroendocrine cancers, and at least one prior chemotherapy. Patients with other histologies will be allowed if no standard treatment options exist. Patients with evaluable, but not measurable disease will be eligible for Phase I.

Phase 2: Subjects with histological confirmation of SCLC and one prior platinum-based chemotherapy. Patients with both platinum-sensitive and platinum-refractory disease will be eligible. Patients must have measurable disease to be eligible for Phase II.

Design:

Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970 administered every 21 days (1 cycle), until disease progression or development of intolerable side effects.

Blood and hair samples will be collected at multiple time points during cycle 1 (pre-treatment on day 1, post treatment on days 2, and 3) for pharmacodynamic (PD) analyses.

Tumor biopsies, which are optional, will be obtained at baseline, during the first treatment cycle (approximately 15 hours after the first dose of VX-970 on day 3) and at disease progression except for subjects at the first dose level.

Participants at the first dose level will undergo biopsies on day 3 prior to third dose of topotecan.

Participants will be monitored weekly during the first cycle by clinic visit and basic labs.

Toxicity will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and tumor assessments will be made using computed tomography (CT) scans (chest, abdomen and pelvis) at baseline and after every 2 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1.

Follow-up for survival will be carried out every 3 months.

Arms:
arm 1: VX-970 (M6620) + topotecan at escalating doses arm 2: VX-970 (M6620) + topotecan at maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D)

Interventions: intervention 1: Topotecan intervention 2: VX-970 (M6620)
Intervention descriptions: intervention 1: Topotecan (in combination with VX-970 (M6620) administered by intravenous (IV) Days 1-5 in a 21 day cycle, until disease progression or development of intolerable side effects. intervention 2: VX-970 (M6620 (in combination with Topotecan) administered by intravenous (IV) Day 5 or Days 2 and 5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title: Topotecan + M6620 in Sm Cell 
Version Date: 06/12/2020 
 
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Abbreviated Title: Topotecan + M6620 in Sm Cell 
CC Protocol #: 15-C-0150 M 
Version Date: 06/12/2020 
NCT Number:  NCT02487095 
A Phase I/II Trial of Topotecan with VX-970 (M6620), an ATR Kinase Inhibitor in Small 
Cell Cancers 
 
 
Investigational Agent:     
Drug Name: 
VX-970 (M6620) 
IND Number: 
126291 
Sponsor: 
Center for Cancer Research, National Cancer Institute 
Manufacturer: 
EMD Serono 
Commercial Agent: topotecan 
NCI Principal Investigator: Anish Thomas, MBBS, M.D.  
Developmental Therapeutics Branch (DTB) 
Center for Cancer Research 
National Cancer Institute 
10 Center Drive, Room 4-5330 
Bethesda, MD 20892 
Phone: 240-760-7343 
E-mail: anish.thomas@nih.gov  


Abbreviated Title: Topotecan + M6620 in Sm Cell 
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PRÉCIS  
Background: 
• Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. 
• Although highly responsive to chemotherapy initially, SCLC relapses quickly and 
becomes refractory to treatment within a few months. 
• There is only one FDA approved treatment for patients with relapsed SCLC after first-
line chemotherapy: topotecan, which inhibits religation of topoisomerase I-mediated 
single-strand DNA breaks leading to lethal double-strand DNA breaks.  
• The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the 
existence of a highly effective DNA damage response network. 
• SCLC is characterized by high replication stress (RB1 inactivation, MYC and CCNE1 
activation) and defective ATM-p53 signaling pathway, which cause an excessive reliance 
on ATR for survival following DNA damage. 
• We hypothesize that a combination of ATR kinase inhibition with DNA damaging agents 
will provide an attractive synthetically lethal therapeutic option for SCLC. 
• VX-970 (M6620) is a potent and selective kinase inhibitor of ATR, and in vitro data 
support the hypothesis that ATR inhibition can improve SCLC responses to DNA 
damaging agents. 
Primary objectives: 
• Phase I: To identify the maximum tolerated dose (MTD) of topotecan in combination 
with VX-970 (M6620). 
• Phase II: To assess the efficacy with respect to clinical response rate of a combination of 
topotecan and VX-970 (M6620) in previously treated patients with SCLC and extra-
pulmonary small cell carcinomas. 
Eligibility: 
• Both Phase I and II: Subjects must be ≥ 18 years of age and have a performance status 
(ECOG) ≤ 2. Subjects must not have received chemotherapy, or undergone major surgery 
within 2 weeks and radiotherapy within 24 hours prior to enrollment.  
• Phase I: Subjects with histologically confirmed SCLC, NSCLC, ovarian cancer, cervical 
cancer, and neuroendocrine cancers, and at least one prior chemotherapy. Patients with 
other histologies will be allowed if no standard treatment options exist.  Patients with 
evaluable, but not measurable disease will be eligible for Phase I. 
• Phase II: Subjects with histological confirmation of SCLC and extra-pulmonary small 
cell carcinomas. Patients with both platinum-sensitive and platinum-refractory disease 
will be eligible.  Patients must have measurable disease to be eligible for Phase II. 


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Design: 
• Participants meeting inclusion and exclusion criteria will receive topotecan and VX-970 
(M6620) administered every 21 days (1 cycle), until disease progression or development 
of intolerable side effects.   
• Blood and hair samples will be collected at multiple time points during cycle 1 (pre-
treatment on day 1, post treatment on days 2, and 3) for PD analyses.  
• Blood for pharmacokinetic analysis, which is optional, may be collected before and after 
topotecan and VX-970 (M6620) on days 1 and 2 during cycle 1, if feasible with regard to 
scheduling. 
• Tumor biopsies, which are optional, will be obtained at baseline, during the first 
treatment cycle (approximately 15 hours after the first dose of VX-970 (M6620) on day 
3) and at disease progression except for subjects at the first dose level.  
• PBMCs will be collected cycle 1 days 1 and 2 (pre-treatment), post-treatment on cycle 1 
day 5 (optional) and cycle 2 day 1 (pre-treatment).  
• Participants at the first dose level will undergo biopsies on day 3 prior to third dose of 
topotecan. 
• Participants will be monitored weekly during the first cycle by clinic visit and basic labs. 
• Toxicity will be graded according to CTCAE version 4.0, and tumor assessments will be 
made using CT scans (chest, abdomen and pelvis) at baseline and after every 2 cycles 
according to RECIST version 1.1.  
• Follow-up for survival will be carried out every 3 months.  
VX970+ topotecan-Phase I/II trial schema 
0
1
2
3
4
5
Days
Topotecan
VX970
Biopsy
Dose level
Topotecan- mg/m2 IV
(days 1-5)
VX970- mg/m2 IV
1
1
140 on day 5
2
1
140  on days 2,5
3
1.25
140 on days 2,5
4
1.25
210 on days 2,5
21 day cycles
PD
 


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TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1 
INTRODUCTION .................................................................................................................. 9 
1.1 
Study Objectives .............................................................................................................. 9 
1.1.1 
Primary Objectives.................................................................................................... 9 
1.1.2 
Secondary Objectives................................................................................................ 9 
1.1.3 
Exploratory Objectives ............................................................................................. 9 
1.2 
Background and Rationale ............................................................................................... 9 
1.2.1 
Hypothesis............................................................................................................... 11 
1.2.2 
VX-970 (M6620) .................................................................................................... 12 
1.2.3 
Topotecan ................................................................................................................ 16 
1.2.4 
Rationale ................................................................................................................. 16 
1.2.5 
Topotecan plus VX-970 (M6620) Phase I summary .............................................. 16 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 17 
2.1 
Eligibility Criteria .......................................................................................................... 17 
2.1.1 
Inclusion Criteria .................................................................................................... 17 
2.1.2 
Exclusion Criteria ................................................................................................... 18 
2.1.3 
Recruitment Strategies ............................................................................................ 19 
2.2 
Screening Evaluation...................................................................................................... 19 
2.3 
Participant Registration and Status Update Procedures ................................................. 20 
2.4 
Treatment Assignment Procedures................................................................................. 20 
3 
STUDY IMPLEMENTATION ............................................................................................ 20 
3.1 
Study Design .................................................................................................................. 20 
3.1.1 
Phase I: Dose Limiting Toxicity ............................................................................. 21 
3.1.2 
Phase I: Dose Escalation ......................................................................................... 22 
3.1.3 
Phase II.................................................................................................................... 23 
3.2 
Drug Administration ...................................................................................................... 23 
3.2.1 
VX-970 (M6620) Administration ........................................................................... 24 
3.2.2 
Topotecan Administration ...................................................................................... 24 
3.3 
Dose Modifications ........................................................................................................ 24 
3.3.1 
VX-970 (M6620) dose modification ...................................................................... 24 


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3.3.2 
Topotecan dose modification .................................................................................. 25 
3.4 
Study Calendar ............................................................................................................... 27 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 28 
3.5.1 
Criteria for removal from protocol therapy ............................................................ 28 
3.5.2 
Off-Study Criteria ................................................................................................... 28 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 29 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 29 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 29 
5.1.1 
γ-H2AX Detection in Tumor Biopsies, hair follicles and PBMC .......................... 30 
5.1.2 
Sample Collection ................................................................................................... 31 
5.1.3 
Genomic analysis .................................................................................................... 32 
5.1.4 
Circulating Nucleic Acids ....................................................................................... 33 
5.1.5 
Circulating Tumor Cells ......................................................................................... 33 
5.1.6 
Immune Subsets ...................................................................................................... 33 
5.1.7 
Pharmacokinetic Studies ......................................................................................... 33 
5.2 
Sample Storage, Tracking and Disposition .................................................................... 34 
5.2.1 
Laboratory of Jane Trepel ....................................................................................... 35 
5.2.2 
Blood Processing Core (Laboratory of Dr. William Figg) ..................................... 35 
5.2.3 
Future Use/IRB Reporting/Protocol Completion/Sample Destruction ................... 36 
5.3 
Samples for Genetic/Genomic Analysis ........................................................................ 37 
5.3.1 
Description of the scope of genetic/genomic analysis ............................................ 37 
5.3.2 
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized ............................................................................................... 37 
5.3.3 
Certificate of Confidentiality .................................................................................. 37 
5.3.4 
Management of Results........................................................................................... 37 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 38 
6.1 
Data Collection ............................................................................................................... 38 
6.1.1 
Genomic Data Sharing Plan .................................................................................... 38 
6.2 
Response Criteria ........................................................................................................... 38 
6.2.1 
Definitions............................................................................................................... 39 
6.2.2 
Disease Parameters ................................................................................................. 39 
6.2.3 
Methods for Evaluation of Measurable Disease ..................................................... 40 


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6.2.4 
Response Criteria .................................................................................................... 42 
6.2.5 
Duration of Response .............................................................................................. 44 
6.2.6 
Progression-Free Survival ....................................................................................... 44 
6.2.7 
Response Review .................................................................................................... 44 
6.3 
Toxicity Criteria ............................................................................................................. 44 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 45 
7.1 
Definitions ...................................................................................................................... 45 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 45 
7.2.1 
Expedited Reporting ............................................................................................... 45 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review ................................... 45 
7.3 
NCI Clinical Director Reporting .................................................................................... 45 
7.4 
NIH Required Data and Safety Monitoring Plan ........................................................... 45 
7.4.1 
Principal Investigator/Research Team .................................................................... 45 
8 
SPONSOR SAFETY REPORTING ..................................................................................... 46 
8.1 
Definitions ...................................................................................................................... 46 
8.1.1 
Adverse Event ......................................................................................................... 46 
8.1.2 
Serious Adverse Event (SAE) ................................................................................. 46 
8.1.3 
Life-threatening....................................................................................................... 46 
8.1.4 
Severity ................................................................................................................... 46 
8.1.5 
Relationship to Study Product ................................................................................ 47 
8.2 
Assessment of Safety Events.......................................................................................... 47 
8.3 
Reporting of Serious Adverse Events ............................................................................ 47 
8.4 
Safety Reporting Criteria to the Pharmaceutical Collaborators ..................................... 48 
8.4.1 
EMD-Serono ........................................................................................................... 48 
8.5 
Reporting Pregnancy ...................................................................................................... 49 
8.5.1 
Maternal exposure ................................................................................................. 49 
8.5.2 
Paternal exposure .................................................................................................... 49 
8.6 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND .................. 49 
9 
CLINICAL MONITORING ................................................................................................. 49 
10 STATISTICAL CONSIDERATIONS.................................................................................. 50 
10.1 Determination of Sample Size........................................................................................ 51 
11 COLLABORATIVE AGREEMENTS ................................................................................. 51 


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11.1 Cooperative Research and Development Agreement (CRADA) ................................... 51 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................... 51 
12.1 Rationale For Subject Selection ..................................................................................... 51 
12.2 Participation of Children ................................................................................................ 51 
12.3 Participation of Subjects Unable to Give Consent ......................................................... 51 
12.4 Evaluation of Benefits and Risks/Discomforts .............................................................. 52 
12.4.1 Risks ........................................................................................................................ 52 
12.4.2 Benefits ................................................................................................................... 54 
12.5 Risks/Benefits Analysis for Subjects Able and Unable To Provide Consent ................ 54 
12.6 Consent Process and Documentation ............................................................................. 55 
13 PHARMACEUTICAL INFORMATION ............................................................................. 55 
13.1 VX-970 (M6620)............................................................................................................ 55 
13.1.1 Source ..................................................................................................................... 55 
13.1.2 VX-970 (M6620) (NSC 780162) Other Names...................................................... 56 
13.1.3 Classification........................................................................................................... 56 
13.1.4 Molecular Formula: C24H26ClN5O3S M.W.: 500.01 Da ..................................... 56 
13.1.5 Mode of Action ....................................................................................................... 56 
13.1.6 Description .............................................................................................................. 57 
13.1.7 How Supplied.......................................................................................................... 57 
13.1.8 Preparation .............................................................................................................. 57 
13.1.9 Storage .................................................................................................................... 57 
13.1.10 Stability ................................................................................................................... 57 
13.1.11 Route of Administration ......................................................................................... 57 
13.1.12 Method of Administration....................................................................................... 57 
13.1.13 Patient Care Implications ........................................................................................ 58 
13.1.14 Potential Drug Interactions ..................................................................................... 58 
13.1.15 Incompatibilities ..................................................................................................... 58 
13.2 Topotecan ....................................................................................................................... 58 
13.2.1 Administration Procedures...................................................................................... 58 
14 REFERENCES ..................................................................................................................... 59 
15 APPENDICES ...................................................................................................................... 60 
15.1 Appendix A- PERFORMANCE STATUS CRITERIA ................................................. 60 


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15.2 Appendix B- STRONG INHIBITORS AND INDUCERS OF CYP3A ........................ 61 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 
Primary Objectives 
• Phase I: To identify the maximum tolerated dose (MTD) of topotecan in combination 
with VX-970 (M6620). 
• Phase II: To assess the efficacy with respect to clinical response rate of a combination of 
topotecan and VX-970 (M6620) in previously treated patients with SCLC and extra-
pulmonary small cell carcinomas.  
1.1.2 
Secondary Objectives 
• To determine the progression-free survival (PFS) and overall survival (OS) of a 
combination of topotecan and VX-970 (M6620) in SCLC.  
• To assess safety and tolerability of a combination of topotecan and VX-970 (M6620). 
• To identify pharmacodynamic markers of response. 
• To assess duration of response to the combination in both platinum sensitive and 
refractory patients.  
1.1.3 
Exploratory Objectives 
• To characterize gene expression and mutations which predict response and changes 
associated with development of chemoresistance.  
• To characterize circulating tumor cells (CTC) and circulating DNA bearing tumor-
specific mutations.   
• To characterize the immunomodulatory effects of DNA damage-inducing cytotoxic 
therapy. 
1.2 
BACKGROUND AND RATIONALE 
Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. Annually there are 
approximately 34,000 new cases of SCLC in the United States. SCLC is characterized by rapid 
doubling time, high growth fraction and early and widespread metastatic involvement. 
Approximately two thirds of patients present with extensive-stage disease with tumor 
involvement of contralateral lung, liver, adrenal glands, brain, bones and/or bone marrow.  
The primary treatment modality for patients with extensive-stage SCLC (ES-SCLC) is systemic 
chemotherapy consisting of platinum and etoposide followed by prophylactic cranial irradiation 
in patients with a response [1]. Although highly responsive to chemotherapy initially, SCLC 
relapses quickly and becomes refractory to treatment within a few months. The median survival 
for patients with ES-SCLC ranges from 8 to 13 months. Less than 5% of patients survive two 
years and less than 2% are alive five years after diagnosis. There is only one FDA approved 
treatment for patients with relapsed SCLC after first-line chemotherapy: topotecan, which 
inhibits religation of topoisomerase I-mediated single-strand DNA breaks leading to lethal 


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double-strand DNA breaks. In patients with disease that is refractory to or relapsed after first-line 
chemotherapy, the median survival ranges from 2 to 6 months. 
The standard treatment of ES-SCLC today reflects the prevailing state-of-the-art from the early 
1980s. Among the many strategies that have been evaluated unsuccessfully over the last three 
decades are dose-dense chemotherapy regimens, addition of a third drug to standard two drug 
chemotherapies, alternating non-cross resistant chemotherapy regimens, maintenance therapy 
and more recently targeted therapies. Not unexpectedly, the outcomes for these patients have 
also largely remained poor. Clearly there is a critical need for newer therapeutic approaches for 
patients with SCLC and patients with extrapulmonary small cell carcinomas. 
DNA damaging agents are the cornerstone of SCLC treatment, yet they provide only transient 
benefit. The inability to destroy residual SCLC cells despite initial chemosensitivity suggests the 
existence of a highly effective DNA damage response network. The DNA damage response 
pathways may therefore have a role in chemotherapy resistance in SCLC.  
The DNA damage response pathway is depicted in Figure 1[2]. Apical kinases ataxia-
telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) are recruited via 
DNA damage sensors. In addition to single-stranded DNA breaks, ATR responds to genotoxic 
stress that is caused by DNA replication stress, caused by oncogenes. Eventually via 
phosporylation of a number of mediators, DNA damage response signaling converges on 
downstream effectors such as p53 and the cell division cycle 25 (CDC25) phosphatases. 
Figure 1. DNA damage response pathway 
 
Despite the importance of the DNA damage response for cell survival following DNA damage, 
defects in this pathway are common in cancer. For example, loss of ATM signaling capacity is 
frequently observed, either through loss of expression of ATM itself, or through defects in 


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upstream regulators and downstream effectors such as p53. Although they appear to confer a 
growth advantage, defects in ATM signaling cause an excessive reliance on remaining DNA 
damage response components, such as ATR, and thus provide an ‘Achilles’ heel’ that could be 
targeted by drugs.  
Most frequently mutated genes in SCLC are shown in Figure 2 [3]. SCLC is remarkable for the 
high frequency of alterations in the ATM pathway. SCLC is characterized by high frequency of 
alterations in p53, a key downstream effector of the ATM pathway. Furthermore, SCLC is also 
characterized by the widespread expression of oncogenes that drive replication stress. This 
combination of high replication stress and defective ATM-p53 signaling pathway may provide a 
strong reliance on ATR for survival following DNA damage in SCLC. 
Consequently, the combination of an inhibitor of ATR kinase with DNA damaging agents could 
be an attractive synthetic lethal therapeutic option for SCLC. 
Figure 2. Most frequently mutated genes in SCLC 
 
Durable clinical response from synthetic lethal interactions between the two DNA damage 
response pathways was recently reported in a patient with small cell cancer of the urothelial tract 
[4]. The patient with metastatic disease was treated with a combination of irinotecan and an 
experimental CHK1 inhibitor resulting in a complete response which was ongoing at three years 
at the time of the report. Functional studies revealed somatic mutations that impaired Mre11 
function, which likely resulted in synthetically lethal activity of the combination of CHK1 
inhibitor with a DNA damaging agent.  
1.2.1 
Hypothesis 
The inability to destroy residual SCLC cells despite initial chemo-sensitivity to DNA damaging 
agents suggests the existence of a highly effective DNA damage response. SCLC is characterized 
by high replication stress (RB1 inactivation, MYC and CCNE1 activation) and defective ATM-
p53 signaling pathway. SCLC therefore relies strongly on ATR for survival following DNA 
damage. We hypothesize that a combination of ATR kinase inhibition with DNA damaging 
agents will provide an attractive synthetically lethal therapeutic option for SCLC.  


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1.2.2 
VX-970 (M6620) 
VX-970 (M6620) is an adenosine triphosphate (ATP)-competitive, highly potent, tightly binding 
inhibitor of ATR with an inhibition constant (Ki) <300 pM (range <0.1 to 0.3 nM) that blocks 
ATR activity in cells, with a concentration associated with 50% inhibition (IC50) of 20 nM [5]. 
VX-970 (M6620) is very selective in inhibiting ATR; it showed >100-fold selectivity against the 
closely related DDR proteins, ATM (Ki 38 ± 30 nM [mean ± SD]) and DNA-dependent protein 
kinase (Ki >4000 nM). ATR and ATM have overlapping functions in the cellular response to 
dsDNA breaks and replication stress. Accordingly, cells with defects in ATM signaling, for 
example from loss of p53, have been shown to be especially sensitive to ATR inhibition by VX-
970 (M6620). Minimal inhibitory activity was observed against a large panel of unrelated protein 
kinases, with 278 of 291 kinases tested having a measured IC50 of >400 nM and a measured Ki 
>200 nM, corresponding to >500-fold selectivity for ATR. For 12 of the remaining 13 kinases, 
the Ki was >15 nM (>50- fold selectivity for ATR) and ≥8 nM for one of the 13 kinases, Flt4 
kinase (>25-fold selectivity for ATR). 
1.2.2.1 Pre-Clinical Toxicology and Compound Safety 
Good laboratory practices (GLP) toxicology studies have been performed with both oral and 
intravenous formulations of VX-970 (M6620). VX-970 (M6620) administered orally to dogs for 
28 days at doses of 30, 60, and 90 mg/kg/day, given every other day, resulted in cachexia and 
overall deterioration of animals requiring early termination at all doses; however, all findings 
showed evidence of reversibility after termination of dosing. Pathologic findings included 
periportal vacuolation, bile duct hyperplasia, and cholestasis in the liver and testicular 
degeneration, as well as effects on peripheral blood cell populations. Oral administration of VX-
970 (M6620) to rats for 28 days at doses of 50, 150, and 300 mg/kg/day, every other day, 
resulted in mortality in 9 of 50 animals at the highest dose only with decreases in red blood cell 
mass and testicular atrophy. The animal-to-human exposure multiple calculated on a weekly area 
under the concentration versus time curve (AUC) basis at the MTD (150 mg/kg/day) was 107-
fold to the weekly projected human exposure at the estimated efficacious dose [6].  
VX-970 (M6620) was administered to dogs intravenously for 28 days at dosages of 7.5, 15, and 
20 mg/kg/day on a twice a week schedule. No mortality or adverse clinical findings were 
observed; decreases in hematocrit, and increases in reticulocytes, and transient elevations in 
alanine aminotransferase (ALT) were noted at the 20 mg/kg/day dose, but there were no 
correlative findings on pathologic examination. The highest non-severely toxic dose (HNSTD) 
was determined to be 20 mg/kg/day. The animal-to-human exposure coverage for safety was 
calculated based upon weekly AUC parameter estimates at the HNSTD (19-fold the weekly 
projected human exposure at the efficacious dose). VX-970 (M6620) was administered 
intravenously twice weekly to rats for 28 days at doses of 5, 10, and 30 mg/kg/day. At the 
highest dose, animals had mild increases in reticulocytes and platelets, and there was mortality in 
4 of 48 animals. Animals at the 10- and 30-mg/kg/day dose exhibited chronic phlebitis and 
animals at all doses exhibited extramedullary hematopoiesis in the spleen. The severely toxic 
dose in 10% of animals (STD10) was considered to be 30 mg/kg/day. The animal-to-human 
exposure multiple calculated on a weekly AUC basis at the STD10 was 13-fold to the weekly 
projected human exposure at the estimated efficacious dose [6].  
1.2.2.2 Clinical Studies 


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At this time, the following studies of VX970 are ongoing: 1) VX12 970 001 (Study 001), Phase 
1 First in human 2) VX13 970 002 (Study 002) Phase 1 3) 9771 16-C-0087 NCI 160087 
ClinicalTrials.gov Identifier: NCT02723864 Phase I Study of Veliparib (ABT-888), an Oral 
PARP Inhibitor, and VX 970, an ATR Inhibitor, in Combination With Cisplatin in Patients With 
Refractory Solid Tumors 4) 9938 NCI-2015-01915 UPCI 15-164 ClinicalTrials.gov Identifier: 
NCT02595931 Phase I Clinical Trial of VX-970 in Combination With the Topoisomerase I 
Inhibitor Irinotecan in Patients With Advanced Solid Tumors 5) DF/HCC Protocol 16 322 NCI 
Protocol 9944 ClinicalTrials.gov Identifier: NCT02595892 Phase 2 Study of VX 970 (NSC# 
780162) in Combination with Gemcitabine versus Gemcitabine Alone in Subjects with Platinum-
Resistant Recurrent Ovarian or Primary Peritoneal Fallopian Tube Cancer 6) PhII 135 NCI 
Protocol 9947 ClinicalTrials.gov Identifier: NCT02567409 Phase 2 A Randomized Phase 2 Trial 
of Cisplatin/Gemcitabine with or without VX 970 in Metastatic Urothelial Carcinoma. 
1.2.2.3 Clinical Safety 
Single-agent Therapy  
VX-970 (M6620) was administered as a single agent in the lead-in periods of Study 001 Parts A 
and B (doses of 18 mg/m2 to 210 mg/m2, lead-in periods of 7 to 21 days); during 
Study 002 Part A1 (once weekly, doses of 60 mg/m2 to 480 mg/m2) and Part A1 (twice weekly, 
doses of 240 mg/m2); and during the single-agent phase of Study 002 Part C (doses of 
240 mg/m2). 
VX-970 (M6620) was generally well tolerated as a single agent. There were no dose-limiting 
toxicities (DLTs), few adverse events (AEs) leading to study drug discontinuation, and 1 AE 
leading to death. Most subjects receiving single-agent VX-970 (M6620) had AEs. The System 
Organ Classes (SOCs) in which AEs occurred most frequently were Gastrointestinal Disorders 
and General Disorders and Administration Site Conditions. The most commonly occurring AE 
was nausea. 
The SOCs in which serious adverse events (SAEs) occurred most frequently were Neoplasms 
Benign, Malignant, and Unspecified; Respiratory, Thoracic, and Mediastinal Disorders; and 
Gastrointestinal Disorders. SAEs that occurred in more than 1 subject receiving single-agent 
VX-970 (M6620) were metastases to central nervous system, malignant neoplasm progression, 
dyspnea, nausea, and blood creatinine increased. Most of the SAEs were assessed as not related 
to study drug. 
Combination Therapy 
VX-970 (M6620) + Gemcitabine 
In Study 001 Part A1, 49 of 50 subjects (98.0%) had at least 1 AE. AEs of nausea, fatigue, 
alanine transaminase (ALT) increased, and anemia occurred in more than 50% of subjects. 
Twenty-four subjects (48.0%) had at least 1 SAE. The SAEs that occurred in more than 1 subject 
were pyrexia (6 subjects, 12.0%) and cellulitis, dehydration, musculoskeletal pain, 
thrombocytopenia, and vomiting (each in 2 subjects, 4.0%). Thirty-eight subjects (76.0%) had at 
least 1 Grade ≥3 AE. Grade ≥3 AEs that occurred in at least 10% of subjects were neutropenia, 
anemia, thrombocytopenia, ALT increased, and fatigue. DLTs occurred in 4 of 45 subjects 
(8.9%) in the DLT Evaluable Set and included ALT increased and aspartate transaminase (AST) 
increased, each in 2 subjects (4.4%) and blood alkaline phosphatase increased, 


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thrombocytopenia, and fatigue, each in 1 subject (2.2%). Nine subjects (18.0%) had AEs leading 
to study drug discontinuation. One subject (2.0%) had a fatal SAE of disease progression of 
NCSLC that was unrelated to either study drug. 
In Study 001 Part C1, 31 of 33 subjects (93.9%) had at least 1 AE. The most common AEs were 
anemia (15 subjects, 45.5%) and fatigue (14 subjects, 42.4%). Seventeen subjects (51.5%) had at 
least 1 SAE. The SAEs that occurred in more than 1 subject were vomiting, fatigue, pneumonia, 
sepsis, and dyspnea (each in 2 subjects, 6.1%). Nineteen subjects (57.6%) had at least 
1 Grade ≥3 AE. Grade ≥3 AEs that occurred in at least 10% of subjects were fatigue and 
neutropenia. Two subjects (6.1%) had AEs leading to study drug discontinuation, which included 
vomiting and fatigue, each in 1 subject. One subject (3.0%) had an AE leading to death (coded as 
abdominal pain). 
VX-970 (M6620) + Cisplatin 
In Study 001 Part B, 29 of 30 subjects (96.7%) had at least 1 AE, and the most common AE was 
nausea (15 subjects, 50.0%). Eleven subjects (36.7%) had at least 1 SAE. The SAEs that 
occurred in more than 1 subject were infusion-related reaction, ALT increased, and AST 
increased (each in 2 subjects, 6.7%). Twenty-one subjects (70.0%) had at least 1 Grade ≥3 AE. 
Grade ≥3 AEs that occurred in at least 10% of subjects were neutropenia and anemia. DLTs 
occurred in 2 of 29 subjects (6.9%) in the DLT Evaluable Set and included ALT increased and 
flushing, each in 1 subject. Six subjects (20.0%) had AEs leading to study drug discontinuation. 
There were no AEs leading to death.  
In Study 001 Part C2, 34 of 35 subjects (97.1%) had at least 1 AE. AEs of nausea and fatigue 
occurred in more than 50% of subjects. Seven subjects (20.0%) had at least 1 SAE. The SAEs 
that occurred in more than 1 subject were vomiting (3 subjects, 8.6%) and nausea and pyrexia 
(each in 2 subjects, 5.7%). Eighteen subjects (51.4%) had at least 1 Grade ≥3 AE. Grade ≥3 AEs 
that occurred in at least 10% of subjects were neutropenia, anemia, and vomiting. Eight subjects 
(22.9%) had AEs leading to study drug discontinuation. There were no AEs leading to death.  
In Study 001 Part C3, 2 subjects received VX-970 (M6620) in combination with cisplatin. 
Both subjects had at least 1 AE. The AEs that occurred in both subjects were constipation and 
fatigue. Neither subject had an SAE. One subject (50.0%) had 3 Grade ≥3 AEs, including 
2 events of Grade 4 thrombocytopenia and 1 event of Grade 3 neutropenia. Neither subject had 
an AE leading to study drug discontinuation or to death. 
VX-970 (M6620) + Carboplatin 
In Study 002 Part B1, all 23 subjects (100%) had at least 1 AE. AEs of nausea and anemia 
occurred in more than 50% of subjects. Eight subjects (34.8%) had at least 1 SAE. The only SAE 
that occurred in more than 1 subject was pyrexia (3 subjects, 13.0%). Eleven subjects (47.8%) 
had at least 1 Grade ≥3 AE. Neutropenia was the only Grade ≥3 AE that occurred in at least 10% 
of subjects. DLTs occurred in 3 of 23 subjects (13.0%) in the DLT Evaluable Set and included 
febrile neutropenia, neutropenia, thrombocytopenia, hypersensitivity, and lower respiratory tract 
infection. Four subjects (17.4%) had AEs leading to study drug discontinuation. There were no 
AEs leading to death. 
In Study 001 Part C3, 8 subjects (80.0%) had at least 1 AE, and the most common AEs were 
thrombocytopenia and fatigue (each in 4 subjects, 40.0%). Two subjects (20.0%) had at least 


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1 SAE; SAEs were superior vena cava syndrome and failure to thrive. Six subjects (60.0%) had 
at least 1 Grade ≥3 AE. The Grade ≥3 AEs that occurred in more than 1 subject were 
thrombocytopenia, neutropenia, anemia, and platelet count decreased. One subject (10.0%) had 
an AE leading to study drug discontinuation. There were no AEs leading to death. 
In Study 002 Part C, all 11 subjects (100.0%) in the Combination Safety Set had at least 1 AE, 
and the most common AE was anemia (5 subjects, 45.5%). Five subjects (45.5)% had at least 
1 SAE. The only SAE that occurred in more than 1 subject was thrombocytopenia (2 subjects, 
18.2%). Seven subjects (63.6%) had at least 1 Grade ≥3 AE. Grade ≥3 AEs that occurred in more 
than 1 subject were thrombocytopenia (3 subjects, 27.3%) and neutropenia and anemia (each in 
2 subjects, 18.2%). Four subjects (36.4%) had AEs leading to study drug discontinuation, and 
1 subject (9.1%) had a fatal AE of bronchitis. 
VX-970 (M6620) + Gemcitabine + Cisplatin 
In Study 001 Part A2, all 8 subjects in the Combination Safety Set had at least 1 AE. AEs that 
occurred in more than 50% of subjects were fatigue, nausea, and neutropenia. Five subjects 
(62.5%) had at least 1 SAE, and no SAE occurred in more than 1 subject. All 8 subjects 
(100.0%) had at least 1 Grade ≥3 AE. The only Grade ≥3 AEs that occurred in more than 
1 subject were neutropenia (5 subjects, 62.5%) and thrombocytopenia (3 subjects, 37.5%). Three 
subjects (37.5%) had DLTs, including neutropenia, febrile neutropenia, and thrombocytopenia. 
One subject had AEs leading to study drug discontinuation. No subject had a fatal AE. 
VX-970 (M6620) + Carboplatin + Paclitaxel 
In Study 002 Part B2, 8 of 9 subjects (88.9%) had at least 1 AE. AEs that occurred in more than 
50% of subjects were neutropenia and fatigue. Two subjects (22.2%) had at least 1 SAE; SAEs 
were febrile neutropenia and thrombocytopenia. Seven subjects (77.8%) had at least 
1 Grade ≥3 AE. Grade ≥3 AEs that occurred in more than 1 subject were neutropenia (6 subjects, 
66.7%), anemia (3 subjects, 33.3%), and thrombocytopenia (2 subjects, 22.2%). One subject 
(11.1%) had a DLT of thrombocytopenia. Two subjects (22.2%) had AEs leading to study drug 
discontinuation, including neutropenia, thrombocytopenia, and drug hypersensitivity. No subject 
had a fatal AE. 
1.2.2.4 Adverse Drug Reactions 
After careful assessment, infusion-related reactions, nausea, and vomiting are considered adverse 
drug reactions (ADRs) for VX-970 (M6620), and myelosuppression events are considered ADRs 
for VX-970 (M6620) in combination with carboplatin. 
Infusion-related reactions are common with IV administration of drugs used to treat cancer. 
These reactions occur during or shortly after administration of the drug, may be local and/or 
systemic, and are diverse. 
Systemic infusion-related reactions to VX-970 (M6620) may include signs or symptoms such as 
pruritus, flushing, chills/rigors, urticaria/rash, headache, bronchospasm/dyspnea, and 
hypotension or hypertension, among others. Some systemic infusion-related reactions to VX-970 
(M6620) have been serious, including those described as acute hypersensitivity reactions. Local 
infusion-related reactions to VX-970 (M6620), sometimes described as infusion site reactions, 
may include signs or symptoms such as infusion site erythema, swelling, or pain. 


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Nausea and vomiting have occurred commonly in patients receiving VX-970 (M6620) 
monotherapy. Many of the affected subjects experienced these events on the same day as VX-
970 (M6620) was administered, and there was some suggestion of a dose response. 
Myelosuppression AEs for subjects who received VX-970 (M6620) in combination with 
carboplatin have included neutropenia, thrombocytopenia, platelet count decreased, and febrile 
neutropenia. 
1.2.3 
Topotecan 
Topotecan has been approved by the FDA for the treatment of metastatic carcinoma of the ovary 
after failure of initial or subsequent chemotherapy, small cell lung cancer sensitive disease after 
failure of first-line chemotherapy, and as a combination therapy with cisplatin for Stage IV-B, 
recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with 
surgery and/or radiation therapy. Topotecan is a semi-synthetic derivative of camptothecin and is 
an anti-tumor drug with topoisomerase I-inhibitory activity. Topotecan binds to the 
topoisomerase I-DNA complex and prevents religation of these single-strand breaks. The 
cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during 
DNA synthesis, when replication enzymes interact with the ternary complex formed by 
topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double 
strand breaks. Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of 
topotecan.  
1.2.4 
Rationale 
VX-970 (M6620) is a potent and selective kinase inhibitor of ATR. In vitro data support the 
hypothesis that ATR inhibition can improve SCLC responses to DNA damaging agents. 
Specifically, VX-970 (M6620) markedly sensitized SCLC cell lines, but not normal cells, to 
multiple DNA damaging drugs. In matched NSCLC cell lines differing only in p53 status, p53 
loss of function, through deletion, influenced cell sensitivity to ATR inhibition [7, 8]. The 
Pommier lab has shown that VX-970 (M6620) potentiates the cytotoxicity of both camptothecins 
and the non-camptothecin LMP-400 [8]. In NSCLC and colon cancer models, VX-970 (M6620) 
enhanced the in vivo tumor response to a broad range of DNA damaging agents without 
additional toxicity. 
Although our goal is to assess the activity of the combination primarily in SCLC, we propose to 
include NSCLC, neuroendocrine cancers, cervical and ovarian cancers in the phase I trial to 
expedite the determination of the MTD of the combination and to assess for any potential early 
signals of activity in these other tumors. Topotecan is an approved agent for previously treated 
cervical and ovarian cancers. Although not an approved treatment, topotecan has activity in 
NSCLC where a phase III trial has found that topotecan was not inferior to docetaxel [9].  
Patients with other histologies will be allowed if no standard treatment options exist.  
1.2.5 
Topotecan plus VX-970 (M6620) Phase I summary  
Between September 2016 and February 2017, 21 patients (DL1: 6; DL2: 6; DL3: 3; DL4: 6) 
were treated. M/F: 9/12, ECOG PS 1/2: 19/2, median age: 61 years (range 27-69), primary 
tumor: small cell 6 (small cell lung 5, small cell cervix 1), mesothelioma 4, non-small cell lung 
cancer, pancreatic, rectal neuroendocrine carcinoma 2 each, others 4), median prior lines of 
systemic therapies 3 (range 1-6). VX-970 (M6620) was generally well tolerated in combination 


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with topotecan with mainly Gr1-2 toxicities. One patient each at DL1, DL2 and DL4 had DLTs 
(Gr4 neutropenia > 7 days, Gr4 thrombocytopenia requiring transfusion, Gr3 elevation of 
AST/ALT; Gr4 thrombocytopenia requiring transfusion, Gr3 febrile neutropenia; Gr4 
thrombocytopenia requiring transfusion). DL4 was determined to be the MTD. Gr 3/4 toxicities 
in ≥10% of patients included neutropenia (n=3/8), lymphopenia (n=7/2), anemia (9/0), 
thrombocytopenia (2/3), and leucopenia (8/2). Of 19 evaluable patients, 2 had partial responses, 
8 had stable disease and 9 had progressive disease. Among 6 evaluable patients with small cell 
cancer, all of whom had platinum resistant or refractory disease, 1 patient had a partial response, 
2 patients had prolonged stable disease (11 months and ongoing at 3 months).  In summary, VX-
970 (M6620) was generally well tolerated in combination with topotecan. The MTD of the 
combination was VX-970 (M6620) 210 mg/m2 on days 2 and 5 with topotecan 1.25 mg/m2 on 
days 1-5. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
2.1.1 
Inclusion Criteria 
2.1.1.1 Both Phase I and Phase II:  
2.1.1.1.1 Male and female subjects ≥ 18 years of age. Because no dosing adverse event data are 
currently available on the use of topotecan in combination with VX-970 (M6620) in 
subjects <18 years of age, children are excluded from this study, but will be eligible 
for future pediatrics trials.  
2.1.1.1.2 ECOG performance status ≤2 (See Appendix A)  
2.1.1.1.3 Patients must have measurable disease, per RECIST 1.1.  See Section 6.2 for the 
evaluation of measurable disease. Subjects with evaluable, but not measurable disease 
will be eligible for Phase I.  
2.1.1.1.4 Subjects must not have received chemotherapy, or undergone major surgery within 2 
weeks and radiotherapy within 24 hours prior to enrollment. 
2.1.1.1.5 Adequate organ functions 
• 
Hemoglobin ≥ 9.0 g/dL 
• 
Absolute neutrophil count ≥ 1.5x109/L 
• 
Platelets ≥ 100x109/L 
• 
Total Bilirubin ≤ 2.0 mg/dL 
• 
Transaminases ≤ 2 x ULN or if liver metastases were present, ≤ 3 x ULN  
• 
Creatinine ≤ 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula ≥ 60 
mL/min 
2.1.1.1.6 Ability of subject to understand and the willingness to sign a written informed consent 
document. 
2.1.1.1.7 The effects of VX-970 (M6620) on the developing human fetus are unknown.  For this 
reason and because topotecan is known to be teratogenic, women of child-bearing 


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potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry, during study participation 
and for 6 months after the last dose study therapy.  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. 
2.1.1.2 Phase I:  
2.1.1.2.1 Subjects with histologically confirmed SCLC, NSCLC, ovarian cancer, cervical 
cancer, and neuroendocrine cancers will be eligible. Pathological confirmation of 
diagnosis will be done at NCI Laboratory of Pathology.  Patients with other 
histologies will be allowed if no standard treatment options exist. 
2.1.1.2.2 At least one prior chemotherapy 
2.1.1.2.3 NSCLC subjects with EGFR mutations or ALK translocations should have previously 
received appropriate FDA approved therapies in addition to prior chemotherapy 
2.1.1.3 Phase II: 
2.1.1.3.1 Histological confirmation of SCLC or extrapulmonary small cell cancer. Although NCI 
confirmation of pathology is not required prior to starting treatment, every effort will be 
made to obtain outside pathology to be reviewed by an NCI pathologist. 
2.1.1.3.2 Subjects with both platinum-sensitive and platinum-refractory disease will be eligible 
2.1.2 
Exclusion Criteria 
2.1.2.1 Subjects with tumor amenable to potentially curative therapy. 
2.1.2.2 Subjects who are receiving any other investigational agents. 
2.1.2.3 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to (study agent) or other agents used in study. 
2.1.2.4 Subjects with symptomatic brain metastases will be excluded from trial secondary 
to poor prognosis.  However, subjects who have had treatment for their brain 
metastasis and whose brain disease is stable without steroid therapy for 1 week or 
on physiologic doses of steroids may be enrolled. 
2.1.2.5 Subjects requiring any medications or substances that are strong inhibitors or 
inducers of CYP3A during the course of the study are ineligible.  Lists including 
strong inhibitors and inducers of CYP 3A4 are provided in Appendix B (Strong 
Inhibitors and Inducers of CYP3A). 
2.1.2.6 Subjects with evidence of severe or uncontrolled systemic disease, or any 
concurrent condition, which could compromise participation in the study, including, 
but not limited to, active or uncontrolled infection, immune deficiencies, Hepatitis 
B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic 
congestive heart failure, unstable angina pectoris, myocardial infarction within the 
past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident 
within the past 6 months, or psychiatric illness/social situations which would 
jeopardize compliance with the protocol.   


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2.1.2.7 HIV-positive subjects on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with VX-970 (M6620).  In 
addition, these subjects are at increased risk of lethal infections when treated with 
marrow-suppressive therapy.   
2.1.2.8 Pregnant women are excluded from this study because topotecan  is a Class D  
agent with the potential for teratogenic or abortifacient effects and because the 
effects of VX-970 (M6620) on the developing human fetus are currently unknown.  
In addition, because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with topotecan or VX-970 
(M6620), breastfeeding should be discontinued if the mother is treated with these 
agents.   
2.1.3 Recruitment Strategies 
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms.   
2.2 
SCREENING EVALUATION 
Screening evaluation testing/procedures are conducted under the separate screening protocol, 01-
C-0129 (Eligibility Screening and Tissue Procurement for the NIH Intramural Research Program 
Clinical Protocols). Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a patient has signed 
the consent. 
Screening must be completed within 2 weeks (except viral markers screen that could be 
performed within 4 months) prior to enrolling subjects onto the protocol.  
1. History and physical exam (including height, weight, and vital signs) 
2. Blood tests (for organ function): 
• Complete blood count (CBC/Diff) 
• Acute care panel 
• Hepatic panel 
• Mineral panel 
• Prothrombin time (PT) 
• Partial thromboplastin time (PTT) 
3. Viral Markers Protocol Screen (HBsAg, anti-HCV, anti-HIV) 
4. Confirmation of diagnosis by the NCI Laboratory of Pathology (can be done prior to the 
two-week screening window) Note:  NCI confirmation of pathology is not required prior 
to starting treatment, but every effort should be made to obtain outside pathology to be 
reviewed by an NCI pathologist. 
5. CT scan of disease sites 
6. Electrocardiogram (12 lead) 


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7. Urine or serum HCG for women of child-bearing potential (to be performed within 5 
days prior to C1D1) 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g. when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here  
2.4 
TREATMENT ASSIGNMENT PROCEDURES 
Cohorts 
Number 
Name 
Description 
1 
Phase I 
Patients with measurable or evaluable SCLC, NSCLC, ovarian 
cancer, cervical cancer, and neuroendocrine cancer. Other 
histologies allowed if no standard treatment exists 
2 
Phase II (SCLC) 
Patients with measurable SCLC.  
3 
Phase II (extrapulmonary 
small cell cancer) 
Patients with measurable SCLC or extrapulmonary small cell 
cancer. 
Arms 
Number 
Name 
Description 
1 
Phase I 
VX-970 (M6620) + topotecan at escalating doses 
2 
Phase II 
VX-970 (M6620) + topotecan at MTD/RP2D 
Arm Assignment 
Up to 24 subjects in cohort 1 will be directly assigned to arm 1. 
Up to 25 subjects with Small Cell Lung Cancer and up to 15 subjects with extrapulmonary small 
cell cancers in cohorts 2 and 3 respectively will be directly assigned to arm 2. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a Phase I/II, open label clinical trial. The objectives of this study are to identify the 
maximum tolerated dose (MTD) of topotecan in combination with VX-970 (M6620) in a phase I 
trial, and to assess the efficacy with respect to clinical response rate of a combination of 
topotecan and VX-970 (M6620) in the second-line treatment of subjects with SCLC in a phase II 
trial. Participants meeting inclusion and exclusion criteria (Section 2.1) will receive topotecan 
(on days 1-5) and VX-970 (M6620) (on day 5 or 2 and 5) administered every 21 days (1 cycle), 
either in the in-patient or out-patient setting, until disease progression or development of 
intolerable side effects. Subjects will be monitored weekly during the first cycle by basic labs 
(CBC with differential on days 8 and 15; chemistries- acute panel, hepatic panel, mineral panel 
and troponin on days 8 and 15).  During the first cycle, basic labs may be performed at patient’s 


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local physician and faxed to the research team. For the following cycles, subjects will be seen 
every 3 weeks.  After study treatment, follow-up for survival will be carried out every 3 months.  
Blood and hair samples will be collected at multiple time points during cycle 1 (pre-treatment, 
day on day 1, post treatment on days 2 and 3) for PD analyses. Tumor biopsies which are 
optional will be obtained at baseline, during the first treatment cycle (approximately 15 hours 
after the first dose of VX-970 (M6620) on day 3) and at disease progression except for subjects 
at the first dose level. Subjects at the first dose level will undergo biopsies on day 3 prior to third 
dose of topotecan.  
3.1.1 
Phase I: Dose Limiting Toxicity  
Subjects will be monitored for DLTs during the first cycle. DLTs will be defined using the 
National Cancer Institute (NCI) CTCAE (Version 4). 
A DLT is defined as related or possibly drug-related:  
• Neutropenia Grade 4 for >7 days duration*  
• Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection)  
• Infection (documented clinically or microbiologically) with Grades 3 or 4 neutropenia 
(absolute neutrophil count <1.0 x 109/L)  
• Thrombocytopenia Grade 3: 
o associated with clinically significant bleeding 
o requiring platelet transfusion 
• Thrombocytopenia Grade 4 for >7 days duration* 
• Grades 3 or 4 toxicity to organs other than the bone marrow including Grades 3 and 4 
biochemical AEs and DLTs, excluding the following: 
o Grade 3 nausea 
o Grade 3 vomiting in subjects who have not received optimal treatment with 
antiemetics 
o Grade 3 diarrhea in subjects who have not received optimal treatment with 
antidiarrheal 
o Grade 3 fatigue 
o Grades 3 or 4 mucositis in subjects who have not received optimal therapy for 
mucositis 
• Death due to drug related adverse events 
• Cardiac: 
o QTcF prolongation (any QTcF interval ≥500 msec or any change in QTcF interval 
≥60 msec from baseline) on ECG, unless related to an electrolyte abnormality and 
prolongation resolves with correction of electrolyte abnormality 


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o Any of the following (CTCAE criteria): Grade 2 or greater ventricular arrhythmia 
(second or third degree atrioventricular (AV) block), severe 
sustained/symptomatic sinus bradycardia less than 45 beats per minute (bpm) or 
sinus tachycardia >120 bpm not due to other causes (e.g., fever), persistent 
supraventricular arrhythmia (e.g., uncontrolled/new atrial fibrillation, flutter, 
atrioventricular nodal tachycardia, etc.) lasting more than 24 hours, ventricular 
tachycardia defined as >9 beats in a row or any length of torsades de pointes 
(polymorphic ventricular tachycardia with long QTcF), or unexplained recurrent 
syncope 
o Symptoms suggestive of congestive heart failure with confirmed Ejection 
Fraction (EF) <40% (by 2D-echocardiogram or Multiple Gated Acquisition 
[MUGA] scan) or a relative decrease >20% from historical assessment of EF 
performed within 12 months 
o Troponin-T: level which is consistent with myocardial infarction 
• Any drug related toxicity that causes interruption of treatment for >3 weeks (21 
successive days). If a subject is deemed fit to restart treatment on Day 21then this is not a 
DLT. 
*Note: In the event of a Grade 4 neutropenia or thrombocytopenia, a full blood count must be 
performed no more than 7 days after the onset of the event to determine if a DLT has occurred. 
The subject will be closely monitored until resolution to Grade 3 or less. 
3.1.2 
Phase I: Dose Escalation 
The starting dose of VX-970 (M6620) is based on the safety information from the trial of single-
agent VX-970 (M6620) and preliminary data from trials combining VX-970 (M6620) with 
gemcitabine, cisplatin or carboplatin. The study will follow a 3+3 design: dose will be escalated 
in cohorts of 3 patients with the individual dose of VX-970 (M6620) and topotecan increased in 
successive dose levels as outlined in the dose escalation table below. In case there is safety 
problem with the first dose, there will be a dose de-escalation to 105 mg/m2 of VX-970 (M6620) 
(25%), as indicated in the table below. 
The MTD is the dose level at which no more than 1 of up to 6 subjects experience DLT during 
one cycle of treatment, and the dose below that at which at least 2 (of ≤6) subjects have DLT as a 
result of the drug. If a subject did not experience DLT and did not finish treatment, he or she will 
not be evaluable for toxicity and will be replaced in the dose level.  
Table 1. Dose Escalation Schedule 
Dose Level 
Topotecan – mg/m2 IV 
(days 1-5) 
VX-970 (M6620) – mg/m2 IV 
Level -1 
1 
105 on day 5 
Level 1 
1 
140 on day 5 
Level 2 
1 
140 on days 2,5 
Level 3 
1.25 
140 on days 2,5 


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Dose escalation will follow the rules outlined in the Table below. 
Table 2. Dose Escalation rules 
3.1.3 
Phase II 
The study will initially enroll 16 evaluable subjects. If 2 or more of the first 16 subjects have a 
response, then accrual would continue to a total of 25 subjects. Subjects will be treated at the 
identified MTD. 
3.2 
DRUG ADMINISTRATION  
Study drug may be dispensed only under the supervision of the investigator or an authorized 
designee and only for administration to the study subjects.  The drugs will be administered 
sequentially, with topotecan followed 15 minutes later by VX-970 (M6620). 
Level 4 
1.25 
210 on days 2,5 
21 day cycles 
Number of Subjects with 
DLT 
at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 subjects at the next dose level 
> 2 
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose 
(highest dose administered).  Up to three (3) 
additional subjects will be entered at the next lowest 
dose level if only 3 subjects were treated previously 
at that dose. 
1 out of 3 
Enter up to 3 more subjects at this dose level. 
• If 0 of these 3 subjects experience DLT, proceed 
to the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose.  UP to three (3) 
additional subjects will be entered at the next 
lowest dose level if only 3 subjects were treated 
previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD and is generally the recommended 
phase 2 dose.  At least 6 subjects must be entered at 
the recommended phase 2 dose. 


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3.2.1 
VX-970 (M6620) Administration 
VX-970 (M6620) will be supplied as 20 mg/mL VX-970 (M6620) to be diluted with 5% 
dextrose in water solution before intravenous infusion as detailed in section 13.1.12. 
An appropriate volume of concentrated drug product solution is diluted before use, according to 
the dose indicated in Table 1. Total dose is not to exceed 800 mg of VX-970 (M6620)/dose.  
The dose of VX-970 (M6620) in dextrose in water solution will be infused intravenously over 60 
minutes (+/- 10 minutes). 
To minimize the possibility of phlebitis, VX-970 (M6620) should be administered through a 
large bore catheter into a large caliber peripheral vein or via central venous access. The 
intravenous infusion site should be monitored closely for the development of erythema, 
induration, purulence, tenderness, or warmth. 
If any subject develops phlebitis or signs or symptoms of inflammation that may progress to 
phlebitis or which the subject cannot tolerate, standard measures should be employed to 
ameliorate these symptoms, including removal of the infusion catheter and resumption of 
infusion through a different vein.  If any subject develops pruritus or evidence of allergic 
reaction, standard measures may be employed to ameliorate these symptoms or to prevent 
recurrence of these symptoms (e.g., premedication with acetaminophen 325 mg PO 
approximately 30 minutes before the infusion, 200 mg hydrocortisone intravenously 
approximately 60 minutes before infusion, and 25 mg diphenhydramine intravenously 
approximately 30 minutes before infusion; alternative antihistamine and steroid combinations 
may be considered, as long as not prohibited by protocol). If standard procedures to limit 
symptoms of injection site reaction or pruritus are insufficient, then the infusion time may be 
extended beyond 60 minutes, but no more than 90 minutes. 
3.2.2 
Topotecan Administration 
Topotecan is a cytotoxic anticancer drug. Prepare topotecan under a vertical laminar flow hood 
while wearing gloves and protective clothing. If topotecan solution contacts the skin, wash the 
skin immediately and thoroughly with soap and water. If topotecan contacts mucous membranes, 
flush thoroughly with water. Use procedures for proper handling and disposal of anticancer 
drugs.  
Each 4-mg vial of topotecan is reconstituted with 4 mL Sterile Water for Injection. Then the 
appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride 
Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.  Topotecan 
will be administered as an intravenous infusion over 30 minutes. 
3.3 
DOSE MODIFICATIONS 
3.3.1 
VX-970 (M6620) dose modification 
No dose modifications of VX-970 (M6620) may be made during Cycle 1. 
The dose of VX-970 (M6620) may be reduced other than in Cycle 1 for toxicity using the 
following guidelines depending on the toxicities (and drug deemed to be responsible for toxicity) 
observed: 
1. For Grade 4 hematologic toxicity: The dose of VX-970 (M6620) will be reduced by 25%. 


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2. For Grade 3 non-hematologic toxicity (except disease related hyponatremia for which dose 
reduction will only be made for grade 4): The dose of VX-970 (M6620) will be reduced by 25%. 
3. For Grade 4 non-hematologic toxicity: The dose of VX-970 (M6620) will be reduced by 50%. 
Based on the criteria above, a maximum of 2 dose reductions will be permitted. If a grade 4 non-
hematologic toxicity were to recur, treatment will be discontinued. Please see table below 
indicating VX-970 (M6620) dose reductions within each dose level.  
Dose 
Level 
Dosage Schedule 
100% 
75% 
50% 
1 
140 mg/m2 on Day 5 
105 mg/m2 on Day 5 
70 mg/m2 on Day 5 
2 & 3 
140 mg/m2 per dose, 
Days 2 and 5 
105 mg/m2 per dose, 
Days 2 and 5 
70 mg/m2 per dose, 
Days 2 and 5 
4 
210 mg/m2 per dose, 
Days 2 and 5 
158 mg/m2 per dose, 
Days 2 and 5 
105 mg/m2 per dose, 
Days 2 and 5 
- 1 
105 mg/m2 on Day 5 
79 mg/m2 on Day 5 
Exceeds 2 dose reductions 
In addition, in case of Grade 3 or higher toxicity during any cycle beyond Cycle 1, treatment 
may be interrupted and may be resumed when all toxicities have returned to Grade 2 or less, at 
the discretion of the investigator. Treatment interruptions may occur for a maximum of 21 days.  
Subjects who have a DLT for VX-970 (M6620) will continue on topotecan. 
3.3.2 
Topotecan dose modification 
No dose modifications of topotecan may be made during cycle 1.  
The dose of topotecan may be reduced other than in Cycle 1 for toxicity using the following 
guidelines depending on the toxicities (and drug deemed to be responsible for toxicity) observed, 
see Table 3.  Topotecan dose reductions will be accomplished by decreasing the dose of 
topotecan for each of the 5 days. 
To initiate subsequent cycles of topotecan the day 1 ANC should be >1500/mm3 and platelets 
>100,000/mm3. Treatment interruptions may occur for a maximum of 21 days. 
Based on the below criteria, a maximum of 2 dose reductions will be permitted.  
Table 3. Dose Adjustments 
A. Dose adjustments for renal functions 
Creatinine clearance  
(Cockcroft-Gault formula) 
Dose adjustment (% decrease in topotecan dose) 
DL1 and 2 
DL3 and 4 
>60 
no adjustment 
no adjustment 
40-59 
-20% 
-20% 
20-39 
-25% 
-25% 


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<20 
Discontinue 
Discontinue 
 
B. Dose adjustments for non-hematologic toxicities 
Non-hematologic toxicity 
Dose adjustment (% decrease in topotecan dose) 
DL1 and 2 
DL3 and 4 
Grades 1 and 2 
no adjustment 
no adjustment 
Grades 3 and 4 (except grade 3 nausea) 
-20% 
-20% 
 
C. Dose adjustments for hematologic toxicities 
Hematologic toxicity 
Dose adjustment (topotecan mg/m2) 
DL1 and 2 
DL3 and 4 
Grades 1 and 2 
no adjustment 
no adjustment 
Grade 3 neutropenia persisting after day 21 
-20% 
-20% 
Grade 4 thrombocytopenia or Grade 4 neutropenia 
with fever or infection or of duration ≥ 7 days 
-20% 
-20% 
In addition, in case of Grade 3 or higher toxicity during any cycle beyond Cycle 1, treatment 
may be interrupted and may be resumed when all toxicities have returned to Grade 2 or less, at 
the discretion of the investigator.  
Subjects who develop intolerance to topotecan, but who may be benefiting from therapy, may 
continue on single agent VX-970 (M6620), administered once weekly (on days 1, 8, 15 of 21 day 
cycle) at the same dose they have received in combination therapy, until disease progression. 


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3.4 
STUDY CALENDAR 
On-study assessments can be performed within ±7 days of the specified time, unless otherwise 
indicated. 
Next cycle treatment may be delayed up to 7 days to accommodate scheduling conflicts. 
Procedure 
Screening 
Cycles = 21 days1 
End of 
Treatment17/ 
Disease 
Progression 
Post Therapy 
Follow-up4 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
8 
Day 
15 
Day 
21 
History 
x 
 
 
 
 
 
 
 
 
x 
 
Physical exam3 
x 
x 
 
 
 
x 
 
 
 
x 
 
PT, PTT 
x 
 
 
 
 
 
 
 
 
 
 
Viral Markers Protocol 
Screen 
x 
 
 
 
 
 
 
 
 
 
 
CBC diff5 
x 
x 
 
 
 
 
x18 
x18 
 
x 
 
Acute Care Panel6 
x 
x 
 
 
 
 
x15 
x15 
 
x 
 
Hepatic pannel7 
x 
x 
 
 
 
 
x15 
x15 
 
x 
 
Mineral panel16 
x 
x 
 
 
 
 
x15 
x15 
 
x 
 
Troponin 
 
x 
 
 
 
 
x15 
x15 
 
 
 
Pregnancy test14 
x 
x 
 
 
 
 
 
 
 
 
 
CT scan 
x 
 
 
 
 
 
 
 
x12 
 
 
Clinical disease 
assessment 
 
 
 
 
 
 
 
 
x12 
x 
 
ECG 
x 
 
x13 
 
 
x13 
 
 
 
 
 
Correlative Studies2: 
 
 
 
 
 
 
 
 
 
 
 
Blood 
 
x 
x 
x 
 
 
 
 
 
 
 
Hair 
 
x 
x 
x 
 
 
 
 
 
 
 
Circulating Nucleic Acids 
 
x9 
 
 
 
 
 
 
 
x 
 
Circulating Tumor Cells 
 
x9 
 
 
 
 
 
 
 
x 
 
PBMC19 
 
x 
x 
 
 
x20 
 
 
 
 
 
PK21 
 
x 
 
 
 
 
 
 
 
 
 
Biopsies10 (optional) 
 
x 
 
x 
 
 
 
 
 
x 
 
Topotecan 
 
x 
x 
x 
x 
x 
 
 
 
 
 
VX-970 (M6620)11 
 
 
x 
 
 
x 
 
 
 
 
 
Follow-up phone call 
 
 
 
 
 
 
 
 
 
 
x 
 
1 Number of cycles depends on disease progression and development of intolerable side effects.  
2  Correlative studies are only performed during cycles 1, 2 and at disease progression. 
3  Symptom-directed physical examinations will be performed as clinically indicated in the investigator’s 
judgment 
4  Follow-up for survival will be carried out every 3 months 
5  Includes Neutrophils, Lymphs, Monos, Eos, Basos, WBC, RBC, Hemoglobin, Hematocrit, RBC 
Indices, MCV, RDW, Platelet 


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6  Includes Sodium (NA), Potassium (K), Chloride (CL) Total CO2 (Bicarbonate), Creatinine, Glucose, 
Urea nitrogen, eGFR 
7  Includes Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin 
8  Only for women of child-bearing potential 
9  Will be collected at cycle 2 day 1 in addition to cycle 1 day 1. 
10  Will be obtained at baseline (pre-treatment), on day 3 before topotecan and at disease progression, 
except for subjects at the first dose level. 
11  Taken on day 5, or day 2 and 5, as indicated in Section 3.1.2 
12  Performed after every 2 cycles 
13 ECG will be performed predose (within the 120 minutes before the start of VX-970 (M6620) infusion) 
on the first treatment day during cycle 1 and immediately after end of VX-970 (M6620) infusion 
(within the next 120 minutes) on the first day of treatment during Cycle 1. For subsequent cycles, ECG 
will be performed pre VX-970 (M6620) only on both days 2 and 5 (within the 120 minutes before the 
start of VX-970 (M6620) infusion).   
14  Only for women of child-bearing potential 
15  Only done in cycle 1 
16 Includes Albumin, Calcium, Magnesium (Mg), Phosphorus 
17  Approximately 4 weeks after treatment discontinuation 
18  Only done in cycles 1 and 2 
19  Will be collected pre-treatment on cycle 1 days 1 and 2; post-treatment on cycle 1 day 5 (within 3 
hours of completion of topotecan) and pre-treatment on cycle 2 day 1 as indicated in Section 5.1.6.  
20  Collection at this time point may be omitted due to scheduling conflicts. 
21  Topotecan: may be collected at pre, end of infusion (EOI), and 0.5, 1, 2, 4, 8, 24 hr post EOI; VX-970 
(M6620) collected at pre, end of infusion (EOI), and 0.5, 1, 4, 8, 24, and 48 hr post EOI when feasible 
with regard to patient scheduling; ex., when the treatment is administered Mon-Fri, and may be 
omitted when the treatment runs through the weekend when the PK collection is not feasible. 
   
3.5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
3.5.1 
Criteria for removal from protocol therapy  
• Progressive disease  
• Participant requests to be withdrawn from active therapy 
• Unacceptable Toxicity as defined in Sections 3.1.1 and 3.3 
• Toxicity related dose delay lasting longer than 21 days 
• Investigator discretion 
• Requirement for any of the prohibited study drugs as described in Section 4 and 
Appendix B (Strong Inhibitors and Inducers of CYP3A) 
• The subject becomes pregnant 
3.5.2 
Off-Study Criteria 
• Participant lost to follow up 
• Participant requests to be withdrawn from study 


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• Death 
 
4 
CONCOMITANT MEDICATIONS/MEASURES 
In vitro drug metabolism studies suggest that VX-970 (M6620) is a substrate of CYP3A and its 
systemic exposure may be affected by concomitant medications that are strong CYP3A inhibitors 
and inducers. Please see a list of CYP3A inhibitors and inducers in Appendix B (Strong 
Inhibitors and Inducers of CYP3A) or at http://medicine.iupui.edu/clinpharm/ddis/. Prior and 
concomitant medication/food restrictions are provided in Table 4. Based upon in vitro data, VX-
970 (M6620) is not a potent inhibitor or inducer of human CYP enzymes in isolated enzyme 
systems, therefore the probability of VX-970 (M6620) interaction with other medications that are 
substrates of CYP metabolism is expected to be low.  
Table 4. Study Restrictions 
 
Medications taken from 28 days before the first dose of study drug will be documented as a prior 
medication. Medications taken after the first dose of study drug through the end of the study will 
be documented as concomitant medications. All medications must be recorded with indication, 
route of administration, and start and stop dates of administration. All subjects will be questioned 
about concomitant medication at each clinic visit.  
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
Table 5. Summary of Collection of Correlative Samples 
Test/assay 
Volume blood 
(approx) 
Type of 
tube 
Collection point  
(+/- 5 days) 
Location of 
specimen analysis 
Tumor 
(optional) 
N/A 
N/A 
(1) Baseline (pretreatment) 
(2) C1 D3 before 
topotecan 
(3) Disease Progression 
Trepel lab to p/u 
Hair Follicles 
(15-30) 
N/A 
N/A 
(1) Pretreatment C1D1 
(2) C1D2 Post treatment  
(3) C1D3 Post treatment 
Redon 
(To be done at same 
time as green top tubes) 


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Blood 
 
6 mL 
Green Top 
(1) Pretreatment C1D1 
(2) C1D2 Post treatment  
(3) C1D3 Post treatment 
Redon 
(On ice) 
Circulating 
Nucleic Acids 
10 mL 
Lavender 
Top 
(1) Pretreatment C1D1 
(2) Pretreatment C2D1 
(3) Disease Progression 
Trepel 
(Room temperature) 
Circulating 
Tumor Cells 
10 mL (x2) 
Lavender 
Top 
(1) Pretreatment C1D1 
(2) Pretreatment C2D1 
(3) Disease Progression 
2.5 mL (x1) 
PAXgene 
RNA  
Immune 
Subsets 
(PBMC) 
8 mL (x2) 
CPT 
blue/black 
(1) Pretreatment C1D1 
(2) Pretreatment C1D2 
(3) Posttreatment C1D5 
w/in 3 hrs of topotecan 
(4) Pretreatment C2D1 
PK topotecan  
6 ml (x1) 
Sodium 
heparin 
tube 
C1D1: pre, end of 
infusion (EOI), and 0.5, 
1, 2, 4, 8, 24 hr post EOI 
(8 time points total).   
Blood Processing Core 
(Dr. Figg) 
(On ice) 
PK VX-970 
(M6620)  
6 ml (x1) 
Sodium 
heparin 
tube 
C1D1 pre, end of 
infusion (EOI), and 0.5, 
1, 4, 8, 24, and 48 hr 
post EOI (8 time points 
total).   
5.1.1 
 γ-H2AX Detection in Tumor Biopsies, hair follicles and PBMC 
Phosphorylated H2AX (γ-H2AX) plays an important role in the recruitment and/or retention of 
DNA repair and checkpoint proteins such as BRCA1, MRE11/RAD50/NBS1 complex, MDC1 
and 53BP1 (see Figure 1). DNA damage has been shown to increase H2AX phosphorylation in 
cancer cells following exposure to camptothecins. If VX-970 (M6620) is able to increase the 
degree of DNA damage due to topotecan, it may be detectable by measurement of H2AX 
phosphorylation. We have successfully employed an immunofluorescence assay in previous 
clinical studies. We plan to study γ-H2AX incidences in patient PBMCs, hair follicles, and in 
tumor biopsies if there is readily accessible disease. Tumor and hair follicles will be obtained if 
patients are suitable candidates and willing to allow such sampling.  
This analysis will be exploratory only and data will be used in planning biomarker endpoints in 
subsequent trials with the combination of VX-970 (M6620) and topotecan. This analysis will be 
exploratory only and data will be used in planning biomarker endpoints in subsequent trials with 
the combination of VX-970 (M6620) and topotecan. These studies are of interest in an early 
phase clinical trial and will be done primarily for Phase I part of the study. Additionally, these 
studies may be done in selected patients in Phase II. 


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5.1.2 
Sample Collection 
5.1.2.1 Tumor tissue (optional) 
Paired tumor biopsies will be obtained by minimally invasive methods such as CT guided 
percutaneous biopsies at baseline (pre-treatment), and after treatment (on day 3 before 
topotecan), and at disease progression. Patients on dose level 1 who will have the second biopsy 
on day 3 (before topotecan) will serve as "controls" to show the induction of γ-H2AX with 
topotecan alone.  
The site of biopsy will be determined in discussion with interventional radiologist. If it can be 
safely obtained, 4 cores of tumor tissue will be collected. Two cores will be sent to pathology- 
one for confirmation of diagnosis and another will be used for making an FFPE block. The other 
2 cores will be flash frozen at the time of biopsy.  When the patient is scheduled, the Trepel lab 
will be contacted [by email to trepelj@mail.nih.gov and Sunmin Lee lees@pop.nci.nih.gov]. 
Interventional Radiology will call the lab at 240-760-6330 when the patient arrives in IR and a 
lab member will be present at Interventional Radiology for the procedure.  The cores will be 
flash frozen, 2D barcoded, and stored in liquid nitrogen.  
5.1.2.2 Blood samples 
Blood will be collected in a 6-ml green top tube at the following time points during cycle 1: Pre-
treatment on cycle 1 day 1, and post treatment on day 2 and 3 within 3 hours of completion of 
topotecan. When the patient is scheduled, the Trepel lab will be contacted [by email to 
trepelj@mail.nih.gov  and Sunmin Lee lees@pop.nci.nih.gov]. Blood from heparinized syringe 
will be mixed with a 1:1 ratio of room temperature PBS and layered over a 1:1 blood-PBS/Ficoll 
ratio in a conical centrifuge tube. The conical centrifuge tube should be centrifuged 25 minutes at 
room temperature at approximately 1000 rpm. The cell layer resting above the Ficoll and 
containing the peripheral blood mononuclear cells (PBMCs) will be aspirated and transferred to 
a 15 ml conical tube for washing in 15 ml PBS. PBMCs will be fixed with paraformaldehyde, 
spun onto a microscope slide and stain for γH2AX detection. Images from γ-H2AX-stained 
PBMCs will be recorded by using a confocal microscope (Figure 3, image at the top). 
5.1.2.3 Hair follicles 
Hair follicles will be collected at multiple time points:  Pre-treatment on cycle 1 day 1, post 
treatment on cycle 1 days 2 and 3. At least 24 hours prior to the start of the study, the research 
nurse will contact Dr. Redon in Dr. Aladjem’s lab (LMP/CCR/NCI, Bldg 37/ Rm 5056) to 
inform him when samples will be taken (Tel: 240-760-7338 (L); 301-760-6275 (Cell); 
redonc@mail.nih.gov). Dr. Redon will provide tubes for collecting the plucked hairs. The tubes 
contain ice cold PBS labeled with the date/time of sampling, the protocol, and the unique 900 
identifier.  Dr. Redon will also provide forceps for plucking. Dr. Redon should be notified of 
when the samples should be picked up. 
 
Single hairs are plucked from the scalp with forceps. Plucked hairs from eyebrows will be 
collected only if scalp hairs cannot be provided. The aim is to acquire 15-30 hairs that contain a 
full intact follicle and sheath (Figure 3, image in the middle). If it is determined by Dr. Redon 
that the hairs collected at the first 2 time points do not contain a full intact follicle and sheath, 
hair collection at the third time-point may be omitted.  All the hairs from a patient are placed in 
microfuge tubes containing cold PBS and stored on ice. Upon delivery in Dr. Aladjem’s lab, 


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hairs will be fixed with paraformaldehyde and analyzed under a dissection microscope to select 
those containing a full intact follicle and sheath. Plucked hairs will be fluorescently stained for γ-
H2AX and images will be recorded by using a confocal microscope (Figure 3, image at the 
bottom). 
 
 
Figure 3 
5.1.3 
Genomic analysis 
Formalin fixed paraffin embedded tumor tissue (FFPE) from the new biopsies and or from 
archived FFPE tissue from prior biopsies/surgical procedures will be sent to the Trepel lab as 
described above. Genomic DNA and RNA will be extracted from the tumor. We will assess gene 
expression by Illumina sequencing, NanoString or droplet digital PCR technology and also 
perform whole exome sequencing on pre- and post-treatment samples.   
The tumor tissue obtained before start of treatment will be used for the following assessments: γ-
H2AX (as described before), depending on the availability of tissue in the following sequence of 
priority 1. genes expression including the following genes: SLFN11, RAD51, RAD54L, BLM, 
TOP1, ATM, ATR, TOPBP1, POLQ, MCM2, FANCI, MGMT, ATAD5, ASCL1, ESRP1, 
CAV1, CCNE1, MYCL, MYC, MYCN and RB1 expression, 2. If more tissue is available, it will 
be archived for whole exome sequencing.  
Tumor tissue obtained during and after treatment will be assessed for the following: γ-H2AX and 
gene expression studies.  


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5.1.4 
Circulating Nucleic Acids  
Circulating DNA will be isolated from plasma separated from peripheral blood drawn into 10-ml 
lavender top tubes pre-treatment on cycle 1 day 1, pre-treatment on cycle 2 day 1, and at disease 
progression. Mutations identified by analysis of patient tumor samples may be included as 
personalized tumor markers in the circulating nucleic acid analysis. Mutations will be assessed 
by the appropriate technology, i.e. nested PCR, droplet digital PCR, Sanger sequencing, or next 
generation sequencing on MiSeq (Illumina). These assessments will be performed by the Trepel 
lab.   
5.1.5 
Circulating Tumor Cells  
Circulating tumor cells (CTCs), which can be prevalent in SCLC, present a readily accessible 
'liquid biopsy'. Peripheral blood will be collected (pre-treatment on cycle 1 day 1, pre-treatment 
on cycle 2 day 1 and at disease progression) to correlate circulating tumor cell (CTC) levels at 
baseline or levels pre- and post-therapy with clinical response and survival. CTCs will be 
assessed using ferrofluidic enrichment and multiparameter flow cytometric detection. CTCs will 
be identified as viable, nucleated cells, that positively express one or more epithelial or tumor 
markers and are negative for expression of hematopoietic markers. CTCs will be enumerated and 
if sufficient, gene expression will be analyzed by droplet digital PCR. NanoString, whole 
transcriptome by Illumina or another platform as appropriate to the sample.  Peripheral blood 
will be drawn into two 10-ml lavender top tubes and one 2.5 ml PAXgene RNA tube for each 
time point. These assessments will be performed by the Trepel lab 
5.1.6 
Immune Subsets  
Little is known of the immunomodulatory effects of DNA damage-inducing cytotoxic therapy. 
Peripheral blood mononuclear cells (PBMC) obtained before and during treatment (pre-treatment 
on cycle 1 day 1, pre-treatment on cycle 1 day 2, post-treatment on cycle 1 day 5 within 3 hours 
of completion of topotecan (collection at this time point may be omitted due to scheduling 
conflicts), and pre-treatment on cycle 2 day 1) will be assessed by the Trepel Lab in the 
Developmental Therapeutics Branch using multiparameter flow cytometry for immune subsets 
including but not necessarily limited to Tregs, myeloid-derived suppressor cells, effector and 
exhausted CD4+ and CD8+ T-cells, and CD14+ monocytes. Assessment will include functional 
markers, i.e. PD-1, Tim-3, CTLA-4, CD40, HLA-DR, and/or PD-L1. Members of the lab will 
procure the peripheral blood samples, enter the samples in a secure patient database, process the 
samples for viable cell storage, label each sample with a unique 2D barcode, and viably store the 
samples. They will prepare the samples for staining, stain and run the samples by 
multiparametric flow cytometry (MACSQuant, Miltenyi Biotec, Bergisch Gladbach, DE), the 
data will be analyzed by FlowJo v.X.0.6. Peripheral blood will be drawn into two 8-ml CPT 
citrate blue/black tubes for each time point. These assessments will be performed by the Trepel lab. 
5.1.7 
Pharmacokinetic Studies 
Topotecan 
Blood samples for the determination of plasma levels of topotecan may be obtained from each 
patient, when feasible with regard to scheduling, via 6mL sodium heparin tube (BD, Franklin 
Lakes, NJ) collected on the first daily dose on cycle 1 day 1 at the following time points: pre, end 
of infusion (EOI), and 0.5, 1, 2, 4, 8, 24 hours post EOI (8 time-points total).  Bioanalytical 


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measurements will be conducted on an ultra HPLC-MSMS system using an assay developed and 
validated by the Blood Processing Core. 
VX-970 (M6620) 
Blood samples for the determination of plasma levels of VX-970 (M6620) may be obtained from 
each patient, when feasible with regard to scheduling, via 6mL sodium heparin tube (BD, 
Franklin Lakes, NJ) collected on the first daily dose on cycle 1 day 2 at the following time 
points: pre, end of infusion (EOI), and 0.5, 1, 4, 8, 24, and 48 hours post EOI (8 time-points 
total).  Bioanalytical measurements will be conducted on an ultra HPLC-MSMS system using an 
assay developed and validated by the Blood Processing Core (BPC). 
This data will be used to monitor topotecan and VX-970 (M6620) plasma concentrations in order 
to correlate to pharmacodynamic endpoints, clinical response, and toxicity. 
The samples will be placed immediately on wet ice and refrigerated. The date and exact time of 
each blood draw should be recorded on the sample tube and the PK sheet.  
Please e-mail mailto: BPC at NCIBloodcore@mail.nih.gov at least 24 hours before transporting 
samples (the Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact BPC by e-mail. 
Upon arrival in the Blood Processing Core, samples will be centrifuged and the plasma 
transferred into cryovials for storage at -80 °C until the time of analysis. In addition, samples 
will be barcoded as described in Section 5.2.2. 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
All samples (except the two cores of tissue which will be stored in the Laboratory of Pathology 
and the PK samples which will be processed by the Figg lab) will be sent to and stored in Jane 
Trepel's Lab at NCI, Bldg 10, Room 12C208, Bethesda, MD. Place all samples at room 
temperature, phone the Trepel Lab at 240-760-6330 and a laboratory member will come to pick 
up the sample.  
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. 
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required.  
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues. Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed.  
 If the subject withdraws consent the participants data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved. 


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The PI will record any loss or unanticipated destruction of samples as a deviation.  Reporting 
will be per the requirements of section 7.2. 
5.2.1 
Laboratory of Jane Trepel 
Tracking and disposition of samples will conform to the NCI CCR Biospecimen Guidelines. 
All samples will be barcoded and data entered and stored in the LabMatrix system utilized by the 
NIH Clinical Center. This is a secure system with access limited to defined personnel. All such 
personnel with access to subject information annually complete the NIH online Protection of 
Human Subjects course.  
LabMatrix creates a unique barcode ID for every sample which cannot be traced back to subjects 
without LabMatrix access. The data recorded for each sample includes the subject ID, name, trial 
name/protocol number, date/time drawn, as well as box and freezer location. Subject 
demographics associated with the clinical center patient number are provided in the system. For 
each sample, there are notes associated with the processing method (delay in sample processing, 
storage conditions on the ward, etc.). Access to personally identifiable information (PII) is 
limited to the PI and associate investigators.  
An additional layer of encryption will be added for samples undergoing genetic analysis in Dr. 
Trepel's lab where a separate clinically annotated unique sample ID will be generated linked with 
the sample ID in LabMatrix. As additional clinical information is generated and linked to the 
unique patient ID, it is also electronically linked via LabMatrix to the sample ID. Dr. Trepel's lab 
will proceed with sample analysis and record data under the unique sample ID.  
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C or in 
liquid nitrogen according to stability requirements. These freezers are located onsite, and access 
to stored clinical samples is restricted. Samples will be stored until requested by a researcher 
named on the protocol. All requests are monitored and tracked in the LabMatrix System. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the NCI. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Samples will be stored in a freezer at either -4° C or -70° C behind a door locked after working 
hours. Samples will be tracked by a designated member of the laboratory who is responsible for 
notifying the PI about requests for use of the material, for allocating the material to other 
members of the laboratory, for recording the disposition of the allocated material.   
5.2.2 
Blood Processing Core (Laboratory of Dr. William Figg) 
5.2.2.1 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in Labmatrix utilized by the BPC. This is a secure program, with access to Labmatrix 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
Labmatrix is limited to computers specified by Dr. Figg. These computers all have a password 
restricted login screen.  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without Labmatrix access. The data recorded for each sample includes the 


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patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
5.2.2.2 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). Any samples lost (in transit 
or by a researcher) or destroyed due to unknown sample integrity (i.e. broken freezer allows for 
extensive sample thawing, etc.) will be reported per 7.2.1. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
Labmatrix. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
5.2.3 
Future Use/IRB Reporting/Protocol Completion/Sample Destruction 
Blood and tissue specimens collected in the course of this research project may be banked and 
used in the future to investigate new scientific questions related to this study, including optional 
germline analysis.  However, this research may only be done if the risks of the new questions 
were covered in the consent document and the proposed research has undergone prospective IRB 
review and approval.  If new risks are associated with the research (e.g., analysis of germ line 
genetic mutations.) the Principal Investigator must amend the protocol and obtain informed 
consent from all research subjects. 
Following completion of this study, samples will remain in storage as detailed above only for 
those subjects that agreed to future use in the Optional Studies section of the consent form.  
Access to these samples will only be granted following IRB approval of an additional protocol, 
granting the rights to use the material.  Currently, there is no plan to use these samples outside of 
the use described in the protocol.  


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 If the subject withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not be 
able to be retrieved. 
 The PI will record any loss or unanticipated destruction of samples as a deviation.  Reporting 
will be per the requirements of section 7.2. 
5.3 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.3.1 
Description of the scope of genetic/genomic analysis 
One of the exploratory endpoints of this protocol is to characterize mutations which predict 
response and changes associated with the development of chemoresistance. To this end, whole 
and targeted exome sequencing will be performed on tumor samples collected pre-treatment 
and/or post-progression.  Since analysis of germline variants is essential to fully characterize the 
somatic mutations identified in exome sequencing, these assays will involve both somatic and 
germline DNA.  
5.3.2 
Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Please refer to Section 5.2. 
5.3.3 
Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study will obtain a 
Certificate of Confidentiality which helps to protect personally identifiable research information.  
The Certificate of Confidentiality allows investigators on this trial to refuse to disclose 
identifying information related to the research participants, should such disclosure have adverse 
consequences for subjects or damage their financial standing, employability, insurability or 
reputation.  The informed consent includes the appropriate coverage and restrictions of the 
Certificate of Confidentiality. 
5.3.4 
Management of Results 
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).  Subjects 
will be contacted at this time with a request to provide a blood sample to be sent to a CLIA 
certified laboratory. If the research findings are verified in the CLIA certified lab, the subject 
will be offered the opportunity to come to NIH (at our expense) to have genetic education and 
counseling to explain this result.  If the subject does not want to come to NIH, a referral to a 
local genetic healthcare provider will be provided (at their expense). 
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 


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6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D and Labmatrix) and ensuring data accuracy, consistency and timeliness. 
The principal investigator, associate investigators/research nurses and/or a contracted data 
manager will assist with the data management efforts.  All data obtained during the conduct of 
the protocol will be kept in secure network drives or in approved alternative sites that comply 
with NIH security standards. Primary and final analyzed data will have identifiers so that 
research data can be attributed to an individual human subject participant. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event.   
Document AEs from the first study intervention, Study Day 1 through 30 days after the agent 
was last administered. Serious adverse events that occur more than 30 days after the last 
administration of investigational agent/intervention and have an attribution of at least possibly 
related to the agent/intervention should be recorded.  
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the subject’s 
outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  
6.1.1 
Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.2 
RESPONSE CRITERIA 
For the purposes of this study, subjects should be re-evaluated for response every 2 cycles.  In 
addition to a baseline scan, confirmatory scans should also be obtained 6 weeks (not less than 4) 
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) [10].  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. 
6.2.1 
Definitions 
Evaluable for toxicity:  All subjects will be evaluable for toxicity from the time of their first 
treatment with topotecan. 
Evaluable for objective response: Only those subjects 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 subjects will have their response classified 
according to the definitions stated below.  (Note:  Subjects who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response:  Subjects 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.  
6.2.2 
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: 
• By chest x-ray: >20 mm  
• By CT scan:  
o Scan slice thickness 5 mm or under as >10 mm with CT scan  
o Scan slice thickness >5 mm: double the slice thickness 
• With calipers on clinical exam >10 mm.   
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  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 or pathological lymph nodes with ≥10 to <15 mm 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 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 


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‘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 subject, 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.  
6.2.3 
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 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 or less.  If CT scans have slice thickness 
greater than 5 mm, 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.  


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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 subject 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 [11-13].  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 [14]. 
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:  


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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. 
6.2.4 
Response Criteria 
6.2.4.1 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. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (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 of diameters while on study. 
6.2.4.2 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 short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
subject 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 


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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). 
6.2.4.3 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 subject's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
Table 6. For Subjects with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 


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disease progression. 
Note: 
Subjects 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. 
 
Table 7. For Subjects 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 
6.2.5 
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.  
6.2.6 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
6.2.7 
Response Review 
Tumor measurements will be performed by the Center for Cancer Research Radiology and 
Imaging Sciences image processing service.  
6.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
subject while on the study.  The descriptions and grading scales found in the revised NCI 


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Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 
Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.  
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to 
be reported per these policies. 
7.2.2 
IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 
Principal Investigator/Research Team  
The clinical research team will meet on a weekly basis when subjects are being actively treated 
on the trial to discuss each subject. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior subjects.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each subject to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
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8 
SPONSOR SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 
Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)). 
8.1.2 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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. 
8.1.3 
Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32). 
8.1.4 
Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 4. 


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8.1.5 
Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.   
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor. 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets  protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. 
All SAE reporting must include the elements described in 8.2. 
SAE reports will be submitted to the Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 


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Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible. 
8.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
8.4.1 
EMD-Serono 
8.4.1.1 The following reportable events must be submitted to EMD Serono by the 
Sponsor 
The following reportable events must be submitted to EMD Serono within 2 business days or 3 
calendar days (whichever comes first) using the mandatory MedWatch form 3500a or equivalent. 
The Sponsor will assume responsibility for submitting the reportable event(s) below to EMD 
Serono as well as ensuring that any local reporting requirements are completed in parallel. 
• Serious Adverse Events (refer to section 8.1.2) 
• Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse 
event) 
8.4.1.2  The following reportable events must be submitted to EMD Serono by the PI or 
designee  
• Occupational exposure (even if not associated with an adverse event) 
• Potential drug-induced liver injury (Hy’s Law cases): These events are considered 
important medical events and should be reported as SAEs.  
• In addition, all AEs will be collected in tabulated form and reported to EMD Serono as 
outlined in the Collaborative Agreement.  
• Reporting of Overdose of M6620: An overdose is defined as any dose 5% greater than 
the highest dose included in the clinical trial protocol. Any overdose must be recorded in 
the trial medication section of the eCRF. For monitoring purposes, any case of overdose, 
whether or not associated with an AE (serious or non-serious), must be reported. There 
are no known symptoms of M6620 overdose to date. The Investigator should monitor 
closely for AEs should an overdose occur and use his or her clinical judgment in 
providing symptomatic/supportive care as medically indicated. There is no known 
antidote for M6620. 
8.4.1.3 Contact information for submission of reportable events to EMD Serono: 
Fax: +49 6151 72 6914 
OR 
E-mail: ICSR_CT_GPS@merckgroup.com 
Specifying: 
PROTOCOL Number and/or Title 
EMD Serono assigned Study Number: MS201923-0023 
SUBJECT Number 
SITE Number/PI Name 


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8.5 
SAE/ONSET DATE REPORTING PREGNANCY  
8.5.1 
Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 
when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy become known, 
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (8.1.2) should be reported as SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented. 
8.5.2 
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for (6 
months) after the last dose of VX-970 (M6620). 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until (6 months) after the last 
dose should, if possible, be followed up and documented. 
8.6 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event.  CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
9 
CLINICAL MONITORING  
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary and secondary study endpoints; adherence to the protocol, 
regulations, ICH E6 and SOPs; and human subjects protection. This is done through independent 
verification of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
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This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
10 STATISTICAL CONSIDERATIONS   
Primary Objectives: 
• Phase I: To identify the maximum tolerated dose (MTD) of topotecan in combination 
with VX-970 (M6620). 
• Phase II: To assess the efficacy with respect to clinical response rate of a combination of 
topotecan and VX-970 (M6620) in previously treated subjects with SCLC and extra-
pulmonary small cell carcinomas. 
Secondary Objectives: 
• To determine the progression-free survival (PFS) and overall survival (OS) of a 
combination of topotecan and VX-970 (M6620) in SCLC.  
• To assess safety and tolerability of a combination of topotecan and VX-970 (M6620). 
• To identify pharmacodynamic markers of response. 
• To assess duration of response to the combination in both platinum sensitive and 
refractory patients.  
Exploratory Objectives: 
• Assess target modulation by VX-970 (M6620)  
• Characterize gene expression and mutations which predict response and changes 
associated with development of chemoresistance 
• Characterize CTC and ct-DNA 
The initial portion of the trial will be a phase I dose escalation study using a standard 3 + 3 
design to determine a MTD over increasing dose levels of VX-970 (M6620). The phase II trial 
will be conducted using a Simon two-stage Minimax design in order to rule out an unacceptably 
low 10% response rate (p0=0.10) in favor of a targeted response rate of 30% (p1=0.30). Based 
on historical controls, actually observing a response rate of 20% would be considered clinically 
meaningful in this setting. With alpha=0.10 and beta = 0.10, the study will initially enroll 16 
evaluable subjects. If 2 or more of the first 16 subjects have a response, then accrual would 
continue to a total of 25 subjects. If there were 2-4 responses in 25 subjects, this would not be 
considered promising in this population. If there were 5 or more subjects of the 25 (20.0%) who 
have a response, this would be sufficiently interesting to warrant further study of this 
combination in a future randomized trial of topotecan vs. topotecan+ VX-970 (M6620). The 
probability of early termination is 51.5% if the true response rate were 10%. In addition, with 
amendment B, up to 15 patients with extrapulmonary small cell cancers may be enrolled on the 
protocol. Response rates of these patients will not be included in the primary statistical analysis 
and will be described in an exploratory manner. 


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Overall survival will be determined from the on-study date until date of death or last follow-up. 
Progression free survival will be determined from the on-study date until date of progression. 
The probabilities of survival and of progression free survival will be determined by the Kaplan-
Meier method.  
10.1 DETERMINATION OF SAMPLE SIZE 
The theoretical maximum number of subjects required to determine the MTD in the phase I 
portion of the study is 24 subjects (6 per dose level), although it is expected that as few as 12 
subjects in 3 dose levels would be required to reach an MTD. As of amendment C, 21 subjects 
have been enrolled on the phase I portion of the study, and accrual for the phase I portion is 
complete. For the phase II portion of the study, 25 subjects with Small Cell Lung Cancer and 15 
subjects with extrapulmonary small cell cancers are to be recruited. To allow room for a small 
number of inevaluable subjects, an accrual ceiling of 70 will be set for this study.. The cohort of 
patients with extrapulmonary small cell cancers will have their response rate reported along with 
appropriate confidence intervals. 
We anticipate that it will take approximately 4 years to accrue 40 evaluable subjects to the phase 
II portion of the trial.  
11 COLLABORATIVE AGREEMENTS  
11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
The study drug VX-970 (M6620) was initially  provided under a CRADA (#2999) between the 
manufacturer, Vertex, and the Thoracic Gastrointestinal Oncology Branch, National Cancer 
Institute. 
Amendment 1 to the CRADA executed in July 2017 transfers EMD Serono as the manufacturer 
of the study drug.  
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
As previously described, the subjects for this study will include all subjects who meet the 
eligibility criteria outlined in section 2.1.  No gender, racial, or ethnic groups will be excluded 
from participation in this trial.  
12.2 PARTICIPATION OF CHILDREN 
Because no dosing adverse event data are currently available on the use of topotecan in 
combination with VX-970 (M6620) in subjects <18 years of age, children are excluded from this 
study, but will be eligible for future pediatrics trials. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 12.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 


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person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
12.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
12.4.1 
Risks  
12.4.1.1 Study drugs risks 
12.4.1.1.1 VX-970 (M6620)  
VX-970 (M6620) was generally well tolerated when administered as either single-agent therapy 
or in combination with 1 or 2 chemotherapeutic agents to subjects with solid tumors. There were 
no dose-limiting toxicities (DLTs), few adverse events (AEs) leading to study drug 
discontinuation, and 1 unrelated AE leading to death. Most subjects receiving VX-970 (M6620) 
as single-agent or combination therapy had AEs.  
Risks due to M6620 alone 
• Nausea 32% 
• Vomiting 12% 
• Infusion site reactions 9% 
• Systemic infusion reactions 17% 
Risks when M6620 is given with chemotherapy 
• Nausea 54% 
• Vomiting 33% 
• Infusion site reactions 10% 
• Systemic infusion reactions 15% 
Additional risks of M6620 given in combination with carboplatin 
• Anemia 52% 
• Low neutrophils 45% 
• Low platelets 38% 
In addition, the following very common adverse events were observed in at least 15% of subjects 
receiving M6620 monotherapy. There is not enough experience in M6620 whether these truly are 
side effects. 
• Diarrhea 15% 
• Fatigue 20% 


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There is a possibility that M6620 may make patient more sensitive to sunlight. VX-970 (M6620) 
absorbs in the UV-visible radiation spectrum and is widely distributed including skin, so patients 
receiving VX-970 (M6620) should take protective measures to minimize sun exposure.  
12.4.1.1.2 Topotecan 
Likely, some may be serious (experienced by more than 20% of subjects taking the drug) 
• Anemia which may require a blood transfusion 
• Low white blood cell counts 
• Constipation, diarrhea, nausea, vomiting 
• Fever 
• Pain 
• Bruising, bleeding 
• Infection, especially when white blood cell count is low 
• Tiredness 
• Shortness of breath 
Less likely, some may be serious (experienced by between 3 and up to 20% of subjects taking 
the drug) 
• Sores in mouth which may cause difficulty swallowing 
• Headache 
• Cough 
• Scarring of the lungs 
Rare but Serious (experienced by 3% of fewer of subjects taking the drug) 
• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat 
• Low white blood cell counts which may result in life-threatening infections 
12.4.1.2 Biopsy risks 
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. CT 
guidance may be used in obtaining biopsies. 
12.4.1.3 Radiation risks 
There will be a risk of exposure to radiation from 3 CT guided biopsies and 9 CT scans.  The 
amount of radiation exposure is 12.3 rem. The risk of getting cancer from the radiation exposure 
in this study is 1.2 out of 100 (1.2%) and of getting a fatal cancer is 0.6 out of 100 (0.6%). 
12.4.1.4  CT contrast risks 
Itching, hives or headaches are possible risks associated with contrast agents that may be used 
during CT imaging. Symptoms of a more serious allergic reaction include shortness of breath 
and swelling of the throat or other parts of the body. Very rarely, the contrast agents used in CT 
can cause kidney problems for certain patients, such as those with impaired kidney function. 
12.4.1.5 Release of medical records 
In the course of applying for certain types of insurance (e.g., medical insurance, life insurance, or 
disability insurance), people are often asked to sign forms that authorize insurance companies to 


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obtain their medical records.  If subjects sign such a release form at some point in the future, it is 
possible that the insurance company would present this signed release form to the Clinical Center 
of the National Institutes of Health.  In that event, the National Institutes of Health would comply 
with the subject’s request to provide the insurance company with their medical record.  It is 
possible that information contained in the subject’s medical record, including any diagnosis of 
cancer, might affect the willingness of the insurance company to sell them insurance.    
In addition, the genomic data generated from samples will be uploaded to a shared database such 
as dbGaP.  Such databases may be useful beyond the aims of this particular study, especially as 
various diseases turn out to have mechanisms in common.  The value of these data can increase 
when they are shared with the broader research community.  While no traditionally identifying 
information will be shared, it is possible that a subject or a family member may be identified. 
12.4.1.6 Risk of receiving unwanted information 
Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will 
be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers. 
12.4.1.7 Risk related to the possibility that information may be released 
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement 
agencies. Although there are no plans to release results to the patients, family members or health 
care providers, this risk will be included in the informed consent document. 
12.4.1.8 Risk to family or relatives 
Family members or relatives may or may not want to be aware of familial tendencies or genetic 
risks of disease which may cause anxiety about possible future health problems. As previously 
noted, patients will be notified of any medically significant and actionable incidental findings. 
Study results will not be shared with patients. 
12.4.1.9 Risks related to blood sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
12.4.1.10 
Risk related to hair collection 
The only risk associate with hair collection is pain.  
12.4.2 
Benefits 
The benefits include a possible decrease in the size of the tumor and the scientific knowledge 
that could be acquired through this trial. 
12.5 RISKS/BENEFITS ANALYSIS FOR SUBJECTS ABLE AND UNABLE TO PROVIDE CONSENT 
Small cell cancer is an aggressive cancer with a poor prognosis. Patients are in continuous need 
of improved therapy options. This is especially true for patients who have progressed on standard 
therapy such as the patient population that will be eligible for this trial. Phase I clinical data (see 
section 1.2) suggest that Topotecan plus VX-970 (M6620) may improve outcomes in patients 
with small cell cancers, particularly in those with platinum resistant or refractory disease. A 


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number of clinically appropriate strategies to minimize risk to patients have been built into the 
protocol through the means of inclusion/exclusion criteria, monitoring strategies, and 
management guidelines. Overall, the study presents more than minimal risk due to protocol-
related procedures and interventions with the prospect of direct benefit due to the potential for 
protocol treatment to reduce tumor burden.  
12.6 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
the parent/guardian if participant is a minor, legally authorized representative [LAR] if 
participant is an adult unable to consent) for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person in a 
private area (e.g., clinic consult room) or remotely (e.g., via telephone or other NIH approved 
remote platforms) per discretion of the designated study investigator and with the agreement of 
the participant/consent designee(s).  
13 PHARMACEUTICAL INFORMATION   
13.1 VX-970 (M6620) 
13.1.1 
Source  
VX-970 (M6620) was initially  manufactured and provided by Vertex Pharmaceuticals Inc. As of 
July 2018, the drug is manufactured and provided by EMD Serono.  Toxicity 
13.1.1.1 Pre-clinical toxicity 
VX-970 (M6620) was administered by both oral and IV routes to rats and dogs for up to 28 days. 
The oral studies used a frequent dosing regimen (every other day) to define the toxicity profile, 
while the IV dosing regimen in the GLP 28-day studies (biw) were more representative of the 
planned clinical dosing schedule (intravenously, once per week). The rat STD10 was determined 
to be 30 mg/kg/day and the dog HNSTD was determined to be 20 mg/kg/day, both administered 
via 3-hour IV infusion. Major toxicities in the dog included cholestasis, bile duct hyperplasia and 
periportal vacuolation of the liver, which were reflected by increases in AST, ALT, bilirubin and 
alkaline phosphatase; changes in red cell mass in the periphery without corresponding bone 
marrow pathology; and testicular atrophy. Major toxicities in the rat also included alterations in 
red cell mass, without microscopic correlates in the bone marrow and testicular atrophy, as well 
as phlebitis. No corresponding change in testes weights were observed in dogs, although 
microscopic findings of degeneration/atrophy were identified. Importantly, degeneration/atrophy 
in the testes was reduced during the recovery period in both rats and dogs, providing evidence 
that these changes are reversible. 
13.1.1.2 Clinical Toxicity 
VX-970 (M6620) was being evaluated by Vertex in Study VX12-970-001 (Study 001). This is a 
first-in-human (FIH) study, evaluating the safety, tolerability, and PK of VX-970 (M6620) as a 


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single agent and in combination with gemcitabine, cisplatin and gemcitabine, cisplatin, and 
cisplatin and etoposide. Preliminary safety data from Study 001 (data cut-off date: 19 June 2013) 
are available for 6 subjects in the first 2 dose cohorts in Part A. All 6 subjects in Study 001 
Cohorts 1 and 2 of Part A had at least 1 adverse event (AE) which was considered related or 
possibly related to the study drug (VX-970 (M6620) or gemcitabine) by the investigator. The 
most common related or possibly drug-related AEs by system organ class were associated with 
gastrointestinal disorders, followed by general disorders and administration site conditions, 
nervous system disorders, and skin and subcutaneous tissue disorders. The most common drug-
related or possibly drug-related AEs by preferred term were nausea (5 subjects), vomiting (4 
subjects), fatigue (3 subjects), and rash (3 subjects). 
In addition to the detailed data on AEs through 19 June 2013, data on SAEs are available through 
18 September 2014. A total of 30 SAEs occurred in 16 subjects in Study 001 and a second study, 
Study 002, which is testing the safety, tolerability, and pharmacokinetic/pharmacodynamic 
profile of VX-970 (M6620) as a single agent and in combination with carboplatin in subjects 
with advanced solid tumors. Three of these SAEs, all of which were unrelated to study drug, 
were fatal. The most common SAEs (>1 subject) were pyrexia (4 subjects) and disease 
progression (2 subjects). A total of 12 SAEs in 7 subjects were considered related to the study 
drug by the investigator. Acute hypersensitivity, observed in a single subject receiving 140 
mg/m2 VX-970 (M6620), has been identified as an adverse drug reaction (ADR) for VX-970 
(M6620). 
Target organs for VX-970 (M6620) toxicity were considered the liver, testes, and peripheral 
blood cell populations. Importantly, liver and peripheral blood toxicities were reversed within 4 
weeks of discontinuation of VX-970 (M6620), and both toxicities are readily monitored by 
peripheral blood count and liver function tests in the first-in-human study. Testicular 
degeneration is not an infrequent complication of cytotoxic chemotherapy, and sperm counts are 
not routinely followed in subjects receiving chemotherapy. Importantly, testicular findings 
showed evidence of reversibility in both rats and dogs. Finally, subjects will be required to use 
contraception while on study drug and for 6 months afterwards [6].  
13.1.2 
VX-970 (M6620) (NSC 780162) Other Names  
VRT-0768079, VE-822 
13.1.3 
Classification 
ATR inhibitor 
13.1.4 
Molecular Formula: C24H26ClN5O3S M.W.: 500.01 Da  
13.1.5 
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. VX-970 (M6620) disrupts ATR-mediated DNA damage response signaling 
and leads to sustained accumulation of DNA damage in cancer cells co-treated with DNA-
damaging agents.  


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13.1.6 
Description  
The drug substance for VX-970 (M6620) is the HCl salt.  
13.1.7 
How Supplied  
VX-970 (M6620) is supplied by  EMD Serono as single-use 200 mg vials containing a sterile 
solution (20 mg/mL). VX-970 (M6620) 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.  
13.1.8 
Preparation  
VX-970 (M6620) 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 VX-970 
(M6620). To prepare the infusion solution add the dose volume of VX-970 (M6620) 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. 
Details of dose preparation for VX-970 (M6620) are provided in  (Dose Preparation of VX-970 
(M6620) IV Solution). 
13.1.9 
Storage  
Store intact vials protected from light inside cardboard boxes at room temperature, 25°C (77°F), 
with excursions allowed between 15° and 30°C (59° and 86°F).  
If a storage temperature excursion is identified, promptly return VX-970 (M6620) to between 
15° and 30°C and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
OSROSafety@mail.nih.gov for determination of suitability.  
13.1.10 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).  
13.1.11 Route of Administration  
Intravenous (IV) infusion 
13.1.12 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. VX-970 (M6620) 
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 


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58 
 
infusion exceeds 600 mL. To minimize the possibility of phlebitis, VX-970 (M6620) should be 
administered through a large bore catheter into a large caliber peripheral vein or central venous 
access.  
13.1.13 Patient Care Implications  
Monitor for infusion site reactions, irritation, and phlebitis. VX-970 (M6620) absorbs in the UV-
visible radiation spectrum and is widely distributed including skin, so patients receiving VX-970 
(M6620) should take protective measures to minimize sun exposure.  
13.1.14 Potential Drug Interactions  
VX-970 (M6620) is primarily metabolized by CYP3A4. VX-970 (M6620) has a low potential to 
inhibit CYP1A2, 2C9, 2C19, 2D6, and 3A4, and a moderate potential to reversibly inhibit 
CYP2E1. The potential for VX-970 (M6620) to induce CYP450 enzymes is low. Concomitant 
administration with strong inhibitors or inducers of CYP3A4 should be avoided. 
13.1.15 Incompatibilities   
In vitro drug metabolism studies suggest that VX-970 (M6620) is a substrate of CYP3A and its 
systemic exposure may be affected by concomitant medications that are strong CYP3A inhibitors 
and inducers. Prior and concomitant medication and food restrictions are provided in Table 4. 
Based upon in vitro data, VX-970 (M6620) is not a potent inhibitor or inducer of human CYP 
enzymes in isolated enzyme systems, therefore the probability of VX-970 (M6620) interaction 
with other medications that are substrates of CYP metabolism is expected to be low.  
13.2 TOPOTECAN 
For pharmaceutical information, see the Topotecan Package Insert.  
13.2.1 
Administration Procedures 
Please refer to section 3.1.2. 


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14 REFERENCES  
1. 
van Meerbeeck, J.P., D.A. Fennell, and D.K. De Ruysscher, Small-cell lung cancer. 
Lancet, 2011. 378(9804): p. 1741-55. 
2. 
Di Micco, R., et al., Interplay between oncogene-induced DNA damage response and 
heterochromatin in senescence and cancer. Nat Cell Biol, 2011. 13(3): p. 292-302. 
3. 
Peifer, M., et al., Integrative genome analyses identify key somatic driver mutations of 
small-cell lung cancer. Nat Genet, 2012. 44(10): p. 1104-10. 
4. 
Al-Ahmadie, H., et al., Synthetic lethality in ATM-deficient RAD50-mutant tumors 
underlies outlier response to cancer therapy. Cancer Discov, 2014. 4(9): p. 1014-21. 
5. 
Fokas, E., et al., Targeting ATR in vivo using the novel inhibitor VE-822 results in 
selective sensitization of pancreatic tumors to radiation. Cell Death Dis, 2012. 3: p. e441. 
6. 
Vertex, Investigator's Brochure: VX-970. 2014. 
7. 
Hall, A.B., et al., Potentiation of tumor responses to DNA damaging therapy by the 
selective ATR inhibitor VX-970. Oncotarget, 2014. 5(14): p. 5674-85. 
8. 
Josse, R., et al., The ATR inhibitors VE-821 and VX-970 sensitize cancer cells to 
topoisomerase I inhibitors by disabling DNA replication initiation and fork elongation 
responses. Cancer Res, 2014. 
9. 
Ramlau, R., et al., Phase III study comparing oral topotecan to intravenous docetaxel in 
patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol, 2006. 
24(18): p. 2800-7. 
10. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
11. 
Rustin, G.J.S., et al., Re: New guidelines to evaluate the response to treatment in solid 
tumors (ovarian cancer). Journal of the National Cancer Institute, 2004. 96(6): p. 487-
488. 
12. 
Bubley, G.J., et al., Eligibility and response guidelines for phase II clinical trials in 
androgen-independent prostate cancer: Recommendations from the prostate-specific 
antigen working group. Journal of Clinical Oncology, 1999. 17(11): p. 3461-3467. 
13. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
14. 
Vergote, I., et al., Re: New guidelines to evaluate the response to treatment in solid 
tumors [ovarian cancer]. Journal of the National Cancer Institute, 2000. 92(18): p. 1534-
1535. 


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15 APPENDICES 
15.1 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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15.2 APPENDIX B- STRONG INHIBITORS AND INDUCERS OF CYP3A 
Strong Inhibitors 
Strong Inducers 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice (1)  
indinavir 
itraconazole  
ketoconazole 
lopinavir/ritonavir 
mibefradil (2) 
nefazodone  
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
 
avasimibe (4) 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort (3) 
 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#cla
ssInhibit 
1. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
2. Withdrawn from the United States market because of safety reasons. 
3. The effect of St. John’s wort varies widely and is preparation-dependent. 
4. Not a marketed drug. 


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ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
Page 1 of 17
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Anish Thomas, M.D
STUDY TITLE:
A Phase I/II Trial of Topotecan with VX-970 (M6620), an 
ATR Kinase Inhibitor in Small Cell Cancers
STUDY SITE: 
NIH Clinical Center
Cohort: 
Affected Patient
Consent Version:  
06/12/2020 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Thomas Anish, MD
Phone: 240-760-7343
Email: anish.thomas@nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research. 
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
Patients with cancer may stop responding to chemotherapy over time. Most patients who stop 
responding to their initial chemotherapy are then treated with a different type of chemotherapy. 
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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Most chemotherapies work by damaging the DNA in the cancer cells, causing those cells to die 
and the tumor to shrink.
However, chemotherapy alone may not be effective at causing cancer cell death. Research shows 
that some tumor cells can be less affected by chemotherapy because they have ways to repair the 
damaged DNA. One of the pathways to repair DNA involves a protein called ataxia telangiectasia 
and Rad3-related (ATR). Our research in the laboratory suggests that giving chemotherapy along 
with another drug which restricts ATR will block that DNA repair process, causing the tumor cells 
to die. 
The purpose of this study is to examine whether using chemotherapy together with a drug which 
inhibits ATR will lead to an increase in the death of cancer cells, and therefore a better response 
to treatment in cancer patients. For this trial, we are using the chemotherapy drug, topotecan, with 
a drug called M6620 which inhibits ATR. M6620 is an investigational agent, meaning that it has 
not been approved by the US FDA for the treatment of your cancer. Topotecan is approved by the 
FDA for use in small cell lung cancer, ovarian cancer and in cancers of the cervix. Although not 
approved for the treatment of any other types of cancer, small studies have shown that topotecan 
may have antitumor effect in a number of other cancers, including neuroendocrine tumors and 
non-small cell lung cancer. 
This study is divided into two parts, Phase I and Phase II.  The Phase I portion of the study is being 
done to test the safety of the combination of M6620 and topotecan, and to determine the highest 
doses of these two drugs that can be given in combination safely in patients with a variety of 
cancers. During Phase II, this study will analyze how effective this drug combination is in treating 
small cell cancers. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You have been asked to take part in this study because you have been diagnosed with SCLC or an 
extra-pulmonary small cell carcinoma. Small cell cancers can arise in the lungs and less commonly 
in other parts of the body. These tumors share many similarities including their fast growth and 
limited response to treatment when it comes back after initial chemotherapy. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 70 people will take part in this study; this includes Phase I and II.
DESCRIPTION OF RESEARCH STUDY
Before you begin the study
Before you begin this study, you will have several exams and tests to make sure you are eligible 
for this study. Most of the tests needed would be part of your routine medical care for your cancer 
and are performed under a separate consent. They include blood tests, physical examination, an 
EKG and CT scans. If you are a woman who can become pregnant, you will also have a pregnancy 
test.
If it is determined that you are eligible for the study and you chose to sign the consent, you will be 
enrolled onto the study.
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PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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During the study
You will receive topotecan on days 1 to 5 and M6620 on day 5 or days 2 and 5 (depending on the 
drug dose, see paragraph below and study chart) of each 21-day cycle. You will continue to receive 
treatment until your disease no longer responds or you are no longer able to tolerate the drug. You 
will receive both medications intravenously (IV). Topotecan will be administered for 
approximately 30 minutes and M6620 for approximately 60 minutes.
Subjects will initially be enrolled on the study in groups of 3 or 6. The first group will take 
topotecan and M6620 at the starting pre-planned dose. If none or only one of the subject 
experiences intolerable side effects, the next group will be enrolled at the next highest dose. This 
will continue until more than one person in a group has intolerable side effects or until the highest 
pre-planned dose has been reached.  The maximum safe dose is set at the highest dose in which no 
more than one of six participants experienced an intolerable side effect. 
Once the maximum safe dose is determined, in the second part of the study (phase 2), up to 25 
subjects will be enrolled at that dose to evaluate the anti-cancer activity of topotecan with M6620 
in small cell lung cancer. 
If you experience side effects (described later in this consent) when taking topotecan and/or 
M6620, the dosage of these drugs may be adjusted to reduce the severity of your side effects.   
Also, subsequent doses may be delayed until you have time to recover. If the side effects are too 
severe, the doctor may decide to stop all further doses of topotecan and/or M6620. 
During the first cycle, the health care provider will monitor you weekly. After the first cycle, these 
check-ups will be performed every three weeks. If your doctor believes that it is necessary, based 
on your symptoms, the physical exam will be performed more often than indicated. Please see the 
study chart for the schedule of the tests.
Research Studies
An important part of the research is to determine how your body and tumor responds to the 
combination of drugs. To understand this, we will collect your blood, hair samples and tumor at 
different time points. Single hairs will be plucked from the scalp with forceps. Plucked hairs from 
eyebrows will be collected only if we cannot get hair from your scalp.
Biopsies will be optional. If you agree to have the biopsies, these will be performed before you 
start treatment, on day 3 of cycle one, and if you stop responding to the drug or your disease 
worsens. If you are participating in Phase I and are receiving the lowest dose of topotecan and 
M6620, you will have only one biopsy performed (on day 3 of treatment). You will be asked to 
sign a separate consent for the biopsy at the time of the procedure. 
We will be using the biopsies and blood samples to look at the genes (pieces of DNA) that are 
present in tumor cells and in blood cells.  This information may help us understand why some 
patients respond to certain treatments better than the others.  In the course of examining your DNA, 
it is possible that we could identify possible changes in genes that are not the target of our 
investigation, but which are associated with diseases.  These are called incidental or secondary 
findings.   The analyses that we perform in our laboratory are for research purposes only; they are 
not nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid.  
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Therefore, we do not plan to inform you of the results of testing on your specimens that is 
performed in our research lab.  However, in the unlikely event that we discover a finding that is 
believed to be clinically important based on medical standards at the time we first analyze your 
results, we will contact you.  This could be many years in the future. We will ask you to have an 
additional tube of blood drawn to verify the findings we have seen in our lab. If the results are 
verified, you will be re-contacted and offered a referral to a genetic healthcare provider to discuss 
the results.
Please see the section discussing the risks that you might experience other than the drug side effects 
for the implications of receiving genetic information.
We may also collect your blood on the first two days of the first cycle in order to see how quickly 
study medications are metabolized in your blood. These are called pharmacokinetic studies. If you 
are scheduled to participate in these research studies, on day 1 of cycle 1, we will collect your 
blood before you start topotecan infusion, at the end of infusion, 30 minutes after the end of 
infusion and then 1, 2, 4, 8 and 24 hours after the end of infusion. On day 2 of cycle 1, we will 
collect your blood before you start M6620 infusion, at the end of infusion, 30 minutes after the 
end of infusion and then 1, 4, 8, 24 and 48 hours after the end of infusion. On both of those days, 
you will have to be admitted to a hospital overnight.
When you are finished taking the drugs (treatment)
In the case that you have to stop receiving treatment, you will have a clinic visit approximately 4 
weeks after you discontinue taking the study drugs, in which the health care provider will perform 
a physical exam and blood will be drawn. You will then receive follow-up phone calls from the 
study team every three months.
STUDY CHART
Day
What to do and what will happen to you
Before 
starting
The research team’s health care provider will go over your medical history 
and will perform a physical exam.
Blood samples will be collected.
An echocardiogram and CT scan will be performed.
You will have a pregnancy test if you are a woman who can become pregnant. 
An optional tumor biopsy will be performed, depending on to which group 
you are assigned, and if you agree.
Cycle 1
Day 1
The research team’s health care provider will perform a physical exam.
* Blood samples will be collected.
You will have a pregnancy test if you are a woman who can become pregnant. 
Hair samples will be collected.
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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You will receive the first dose of topotecan IV.
Day 2
You will receive the second dose of topotecan and the first dose of M6620 
(depending on to which group you have been assigned) IV.
If you are receiving the first dose of M6620, you will undergo an ECG before 
and after the M6620 infusion.
* Blood and hair samples will be taken. 
Day 3
You will receive third dose of topotecan IV.
Blood and hair samples will be taken. 
An optional biopsy will be performed if you agree. 
Day 4
You will receive the fourth dose of topotecan IV.
Day 5
The research team’s health care provider will perform a physical exam.
You will receive the fifth dose of topotecan and the first or second dose of 
M6620, depending on to which group you have been assigned, IV.
If you are receiving the first dose of M6620, you will undergo an ECG before 
and after the M6620 infusion.
Blood samples may be collected.
Day 8
Blood samples will be collected for assessing blood counts, liver and kidney 
functions 
Day 15
Blood samples will be collected for assessing blood counts, liver and kidney 
functions
* If you are scheduled to participate in these research studies, you will have to be admitted to a 
hospital overnight on this day in order to collect blood for pharmacokinetic studies.
Cycle 2 and beyond
Day 1
The research team’s health care provider will perform a physical exam.
Blood samples will be collected.
You will have a pregnancy test if you are a woman who can become pregnant.
You will receive topotecan IV.
Day 2
You will receive topotecan IV. You will receive M6620 depending on the dose 
group to which you were assigned.
Day 3
You will receive topotecan IV.
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
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Day 4
You will receive topotecan IV.
Day 5
The research team’s health care provider will perform a physical exam.
You will receive topotecan and M6620 IV.
Day 8
Blood samples will be collected for assessing blood counts, liver and kidney 
functions (Cycle 2 only)
Day 15
Blood samples will be collected for assessing blood counts, liver and kidney 
functions (Cycle 2 only)
Day 21
A CT scan will be performed after every 2 cycles
Off Treatment
The research team’s health care provider will go over your medical history and 
will perform a physical exam.
Blood samples will be collected.
 An optional tumor biopsy will be performed, depending on to which group 
you are assigned, and if you agree.
You will receive follow-up phone calls every 3 months
Note: At each study visit, you will be able to report any side effects that you have experienced to 
the research team.
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will need 
to practice an effective form of birth control before starting study treatment and during study 
treatment, and for 6 months after you finish study treatment. If you think that you or your partner 
is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include: 
• abstinence 
intrauterine device (IUD)
• hormonal [birth control pills, injections, or implants]
• tubal ligation
• vasectomy
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


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RISKS OR DISCOMFORTS OF PARTICIPATION
From M6620
M6620 has been studied in multiple doses either by itself or in combination with a 
chemotherapeutic agent in subjects with advanced cancer. M6620, by itself or with a 
chemotherapeutic agent, can have some unwanted effects. 
M6620 may cause an infusion reaction. In some subjects, this is a reaction limited to the body site 
where the drug is being infused, for example swelling, itching, and/or redness around the site. In 
some subjects, the reaction is a whole-body reaction, for example flushing and/or redness 
everywhere, and/or nausea, headache or other symptoms.
M6620 infrequently (<5% of subjects) causes a serious infusion reaction, with symptoms including 
flushing, shortness of breath, low blood pressure, feeling of faintness, sweating and abdominal 
discomfort. These symptoms have resolved after stopping the infusion and treating the reaction 
with other intravenous (IV) medications. The Study doctor may treat this with medications, and 
try to decrease the chances of these side effects occurring in the future by giving you medication 
to avoid these symptoms in advance of the infusion or by slowing down the rate of infusion. 
Intravenous (IV) infusion of M6620 may cause local irritation, redness, tenderness, or rash at the 
injection site. Many of these local side effects go away after the infusion is stopped or standard 
measures are applied to treat the symptoms including removing and replacing the catheter or 
slowing the rate of infusion. 
Risks due to M6620 alone:

Nausea 32%

Vomiting 12%

Infusion site reactions (occur at the body site where the drug is infused) 9%

Systemic infusion reactions (affect the whole body) 17%
Risks when M6620 is given with chemotherapy:

Nausea 54%

Vomiting 33%

Infusion site reactions (occur at the body site where the drug is being infused) 10%

Systemic infusion reactions (affect the whole body) 15%
Additional risks of M6620 given in combination with carboplatin:

Anemia 52%

Low neutrophils (a type of immune cells that are involved in fighting infections) 45%

Low platelets (cells that play a role in stopping bleeding) 38%
In addition, the following very common adverse events were observed in at least 15% of subjects 
receiving M6620 monotherapy. There is not enough experience in M6620 whether these truly are 
side effects.

Diarrhea 15%

Fatigue (feeling tired) 20%
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
There is a possibility that M6620 may make you more sensitive to sunlight. You should limit your 
exposure to the sun, including exposure to sunlamps and tanning beds. Use of sun block and 
wearing long sleeved clothing and sunglasses is recommended. 
There may be other side effects that we cannot predict, but your Study doctors have taken steps to 
minimize the risks. During this Study, your doctor will ask you about any symptoms you may 
experience.  In addition, you will be monitored for side effects that you may not have symptoms 
from but are seen through lab testing, including, abnormal liver tests and abnormal blood counts 
including platelets, white blood cells, and red blood cells.  Many side effects go away on their own 
with time or after using other medications to treat them.
There may be risks and side effects from the M6620 that are not yet known. You should call your 
study doctor if you think you are having any of the problems listed above or even if you are having 
problems that are not on the list.
In addition, as with any medication including over-the-counter medications, there is a small but 
significant risk of allergic reactions that, if severe, can be fatal. These types of reactions can start 
shortly after taking a medication and may appear in the form of itching or redness of the skin, 
swelling of the face, lips, tongue, throat, or difficulty breathing which may be severe in some cases. 
If you experience any of these reactions, you must let the Study doctor know immediately, and, if 
you are not in the hospital at the time you are having the reaction, you should call 911 or go to the 
closest Emergency Department for treatment. If this happens, you should tell the treating physician 
that you are in a Study. You will be given a wallet card to carry with you which will have 
information about the Study you are in. 
From topotecan
Likely, some may be serious (experienced by more than 20% of persons taking the drug)

Anemia which may require a blood transfusion

Low white blood cell counts

Constipation, diarrhea, nausea, vomiting

Fever

Pain

Bruising, bleeding

Infection, especially when white blood cell count is low

Tiredness

Shortness of breath
Less likely, some may be serious (experienced by between 3 and up to 20% of persons taking 
the drug)

Sores in mouth which may cause difficulty swallowing

Headache

Cough

Scarring of the lungs
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Rare but Serious (experienced by 3% of fewer of persons taking the drug)

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat

Low white blood cell counts which may result in life-threatening infections
Note: Some of the side effects associated with these drugs could potentially lead to death.
Risks you might experience other than the drug side effects 
Biopsy Risk
Risks associated with the biopsies are pain and bleeding at the biopsy site. Sometimes a CT scan 
may be needed to identify the right tumor to biopsy.
Radiation Risk
During your participation in this research study, you will be exposed to radiation from 3 CT guided 
biopsies and 9 CT scans.  The amount of radiation exposure you will receive from these procedures 
is equal to approximately 12.3 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans that you get in this study will expose you to roughly the same amount of radiation 
as 41 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 1.2 out of 100 (1%) and of getting a fatal cancer is 0.6 out 
of 100 (0.5%).
Radiation Exposure in People Capable of Becoming Pregnant
You may not participate in this study if you are pregnant. If you are able to become pregnant, we 
will perform a pregnancy test before exposing you to radiation. You must tell us if you may have 
become pregnant within the previous 14 days because the pregnancy test is unreliable during that 
time.
CT contrast risk
Itching, hives (small bumps on the skin) or headaches are possible risks associated with contrast 
agents that may be used during CT imaging. Symptoms of a more serious allergic reaction include 
shortness of breath and swelling of the throat or other parts of the body. Very rarely, the contrast 
agents used in CT can cause kidney problems for certain patients, such as those with impaired 
kidney function.
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Blood Draw Risk
Risks associated with blood draw include pain and bruising, lightheadedness, and rarely, fainting
Hair Sample Collection Risk
You may experience pain associated with hair collection.
Psychological or Social Risks Associated with Loss of Privacy in Genetic Research
As part of the research study, it is possible that you could learn that you have genetic risks for 
another disease or disability. This may be upsetting and, depending on what you learn, might create 
a need to make challenging decisions about how to respond. 
Although your genomic information is unique to you, you share some genomic similarities with 
your children, parents, brothers, sisters, and other blood relatives. Therefore, learning your 
research results could mean something about your family members and might cause you or your 
family distress. Before joining the study, it may be beneficial to talk with your family members 
about whether and how they want you to share your results with them. 
Privacy Risks Associated with Return of Incidental or Secondary Findings
Although your genetic information is unique to you, you do share some genetic information with 
your children, parents, brothers, sisters, and other blood relatives. Consequently, it may be possible 
that genetic information from them could be used to help identify you.  Similarly, it may be 
possible that genetic information from you could be used to help identify them.  Patterns of genetic 
variation also can be used by law enforcement agencies to identify a person or his/her blood 
relatives.  
Protections against misuse of genetic information 
This study involves genetic testing on samples.  Some genetic information can help predict future 
health problems of you and your family and this information might be of interest to your employers 
or insurers. The Genetic Information Nondiscrimination Act (GINA) is a federal law that prohibits 
plans and health insurers from requesting genetic information or using genetic information. It also 
prohibits employment discrimination based on your health information. However, GINA does not 
address discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
condition or disease that has a genetic component.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
The aim of this study is to see if this experimental combination treatment will cause your tumors 
to shrink.  We do not know if you will receive personal, medical benefit from taking part in this 
study.  These potential benefits could include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.  Because there is not much information 
about the effect of this drug combination on your cancer, we do not know if you will benefit from 
taking part in this study, although the knowledge gained from this study may help others in the 
future who have cancer.  
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
ALTERNATIVE APPROACHES OR TREATMENTS
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease is no longer responding to treatment.  Your study doctor will discuss 
this in detail with you.

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the sponsor of the 
pharmaceutical company providing the drug and their designated representatives. If you withdraw 
your consent and leave the trial, any samples of yours that have been obtained for the study and 
stored at the NCI can be destroyed upon request. However, any samples and data generated from 
the samples that have already been distributed to other researchers or placed in the research 
databases cannot be recalled and destroyed.
CERTIFICATE OF CONFIDENTIALITY 
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The researchers 
can use this Certificate to legally refuse to disclose information that may identify you in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, 
if there is a court subpoena. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below.
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information: 
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

will be used for auditing or program evaluation internally by the NIH; or 

must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA). 

is necessary for your medical treatment and you have consented to this disclosure; 

is for other research. 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent. 
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information.
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible threat 
of harm to self or others.
CONFLICT OF INTEREST 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest. 
The National Institutes of Health and the research team for this study are using a drug (M6620) 
developed by EMD Serono through a joint study with your researchers and the company. The 
company also provides financial support for this study. 
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH 
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.
We would like to keep some of your specimens and data that we collect for future research and 
share them with other researchers.  We will not contact you to ask about each of these future uses. 
These specimens and data will be stripped of identifiers such as name, address or account number, 
so that they may be used for future research on any topic and shared broadly for research purposes.  
Your specimens and data will be for research purposes only and will not benefit you.  It is also 
possible that the stored specimens and data may never be used.  Results of research done on your 
specimens and data will not be available to you or your doctor.  It might help people who have 
cancer and other diseases in the future.  
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
Genomic Data Sharing
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex.  If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that  researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we cannot 
offer you a choice of whether your data will be shared.  If you do not wish to have your data placed 
in a repository, you should not enroll in this study. 
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you. 
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor (Center for Cancer Research) or their agent(s) 

Qualified representatives from EMD Serono, the pharmaceutical company who produces 
M6620.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
Page 16 of 17
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Anish Thomas 
MD, anish.thomas@nih.gov, 240-760-7343. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 06/12/2020
Page 17 of 17
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 15C0150
IRB APPROVAL DATE: 06/22/2020