Conditions: Solid Tumor Leiomyosarcoma Osteosarcoma
Keywords: Solid Tumor leiomyosarcoma Osteosarcoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This research study is studying a drug called M6620 as a possible treatment for advanced solid tumor.

Detailed description:
This study is made up of two phases: a Translational Lead-In Phase and a Phase II. These two phases serve different functions. The translational lead-in phase is designed to test the drug on a small number of patients in efforts to gain information on two research questions:

* If M6620 has an anti-cancer effect on participants
* If M6620 research findings that were discovered in laboratory studies are also found in human research studies.

Phase II is a much larger study to determine if M6620 has an anti-cancer effect in different groups of patients.

The FDA (the U.S. Food and Drug Administration) has not approved M6620 as a treatment for any disease.

ATR is an enzyme in cells that is responsible for multiple functions including repairing damaged DNA, helping cells that are stressed during the DNA copying process, and working to maintain the ends of chromosomes. In cancer cells, active ATR enzymes protect the cancer by helping the cells repair damage, stay alive, and maintain health. M6620 is a drug designed to inhibit the ATR enzyme. Inhibiting ATR may block how cancers repair their naturally damaged DNA, handle cancer cell stress, and maintain cancer cell life and health. Administration of M6620 may therefore assist in the slowing of growth or destruction of some cancers.

In this research study, the investigators are...

* Gathering initial data on the anti-cancer activity of M6620 when given alone to participants within selected cancer populations
* Determining if there are changes in the biological components in the participant's body that may be associated with damaged DNA repair

Arms:
arm 1: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 2: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 3: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 4: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 5: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 6: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 7: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 8: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 9: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 10: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 11: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle. arm 12: M6620 will administered intravenously on days 1,4, 8, 11, 15, 18, 22, 25 on a 28-day cycle.

Interventions: intervention 1: M6620
Intervention descriptions: intervention 1: M6620 is a drug designed to inhibit the ATR enzyme. Inhibiting ATR may block how cancers repair their naturally damaged DNA, handle cancer cell stress, and maintain cancer cell life and health.

Protocol document:
Prot_SAP_000.pdf: 
 
Page 1
NCI Protocol #: N/A 
 
DF/HCC Protocol #: 18-274 
 
TITLE:  A Phase II Study of M6620 (VX-970) in Selected Solid Tumors 
 
Coordinating Center: 
 
 
Massachusetts General Hospital 
 
Principal Investigator (PI): 
Gregory M. Cote MD, PhD 
 
Massachusetts General Hospital 
 
gcote@mgh.harvard.edu 
 
Other Investigators: 
Geoffrey Shapiro MD, PhD 
 
Dana-Farber Cancer Institute 
 
geoffrey_shapiro@dfci.harvard.edu 
 
 
Keith Flaherty MD 
 
Massachusetts General Hospital 
 
KFLAHERTY@mgh.harvard.edu 
 
 
 
George Demetri MD 
 
Dana-Farber Cancer Institute 
 
george_demetri@dfci.harvard.edu 
 
 
Katherine Janeway MD 
 
Dana-Farber Cancer Institute 
 
kjaneway@partners.org 
 
 
 
Andrea Bullock MD, MPH 
 
Beth Israel Deaconess Medical Center 
 
abullock@bidmc.harvard.edu 
 
 
 
Statistician: 
 
 
  
Alona Muzikansky 
 
 
Massachusetts General Hospital 
 
 
AMUZIKANSKY@mgh.harvard.edu      
 
 
 
 
 
 
 
 
NCI-Supplied Agent: N/A 
Other Agent: M6620 (VX-970) / Merck KGaA, Darmstadt, Germany (EMD Serono) 
 
IND #: 140881 
IND Sponsor: DF/HCC Investigator, Gregory Cote MD, PhD 
 
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SCHEMA 
 
Translational Lead-in Study: 
 
 
 
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Phase II Study: 
Cohorts 1A and 2-5 will enroll 15 patients in stage 1.  
Cohorts 1A and 2-5: If >3/15 patients meet the primary endpoint an additional 10 
patients will be accrued (25 total) 
Cohorts 1B: will enroll 30 patients in a single stage 
 
Cohorts 2-5 will include all solid tumors with genetic alterations identified by next-
generation sequencing (NGS) 
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TABLE OF CONTENTS 
 
SCHEMA ................................................................................................................................... 2 
1. 
OBJECTIVES ................................................................................................................. 7 
1.1 
Study Design........................................................................................................ 7 
1.2 
Primary Objective – Translational Lead-In ........................................................... 8 
1.3 
Primary Objective – Phase II ................................................................................ 8 
1.4 
Secondary Objectives ........................................................................................... 8 
2. 
BACKGROUND ............................................................................................................. 8 
2.1 
Study Diseases and Rationale ............................................................................... 8 
2.2 
M6620 (VX-970) ............................................................................................... 12 
2.3 
Correlative Studies Background ......................................................................... 17 
3. 
PARTICIPANT SELECTION ....................................................................................... 19 
3.1 
Eligibility Criteria .............................................................................................. 19 
3.2 
Exclusion Criteria (All Participants) ................................................................... 22 
3.3 
Inclusion of Women and Minorities ................................................................... 23 
4. 
REGISTRATION PROCEDURES ................................................................................ 23 
4.1 
General Guidelines for DF/HCC Institutions ...................................................... 23 
4.2 
Registration Process for DF/HCC Institutions .................................................... 24 
5. 
TREATMENT PLAN .................................................................................................... 24 
5.1 
Treatment Regimen ............................................................................................ 24 
5.2 
Pre-Treatment Criteria ....................................................................................... 25 
5.3 
Agent Administration ......................................................................................... 25 
5.4 
General Concomitant Medication and Supportive Care Guidelines ..................... 27 
5.5 
Criteria for Taking a Participant Off Protocol Therapy ....................................... 28 
5.6 
Duration of Follow Up ....................................................................................... 28 
5.7 
Criteria for Taking a Participant Off Study ......................................................... 28 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................. 29 
6.1 
Dose Delays ....................................................................................................... 29 
6.2 
Dose Modifications ............................................................................................ 29 
6.3 
Toxicity Management Guidelines ....................................................................... 30 
6.4 
Overdose ............................................................................................................ 32 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ........................... 32 
7.1 
Definitions ......................................................................................................... 32 
7.1.3    Serious Adverse Events (“SAE” or “SAEs”) ...................................................... 33 
7.2 
Expected Toxicities ............................................................................................ 34 
7.3 
Adverse Event Characteristics ............................................................................ 35 
7.4 
Expedited Reporting Requirements .................................................................... 35 
7.4.4    Expedited Reporting to the Food and Drug Administration (FDA) ..................... 36 
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7.4.5    Expedited Reporting to Hospital Risk Management ........................................... 36 
7.5 
Routine Adverse Event Reporting ...................................................................... 36 
7.6 
Routine Reporting to the Funder (Merck KGaA, Darmstadt, Germany 
(EMD Serono) ................................................................................................... 36 
8. 
PHARMACEUTICAL INFORMATION....................................................................... 38 
8.1 
M6620 (VX-970) ............................................................................................... 38 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ....................................... 40 
9.1 
Archival Tissue Collection (All Participants) ..................................................... 40 
9.2 
Fresh Tumor Tissue Biopsies (Translational Lead-in Cohorts T1, T2, T3 
Only; Optional for T4) ....................................................................................... 40 
9.3 
Pharmacokinetic Sampling (Translational Lead-in Study Only).......................... 42 
9.4 
ATM Mutation Status and Immunohistochemistry ............................................. 42 
10. 
STUDY CALENDAR ................................................................................................... 43 
11. 
MEASUREMENT OF EFFECT .................................................................................... 46 
11.1 
Antitumor Effect – Solid Tumors ....................................................................... 46 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ......................................... 53 
12.1 
Data Reporting ................................................................................................... 53 
12.2 
Data Safety Monitoring ...................................................................................... 53 
13. 
STATISTICAL CONSIDERATIONS ........................................................................... 54 
13.1 
Study Design/Endpoints ..................................................................................... 54 
13.2 
Sample Size and Study Duration ........................................................................ 55 
13.3 
Reporting and Exclusions ................................................................................... 56 
14. 
PUBLICATION PLAN ................................................................................................. 56 
REFERENCES ......................................................................................................................... 57 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................ 59 
 
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LIST OF TABLES 
 
Table 1: Translational Lead-in Study Design ...............................................................................7 
Table 2: Phase II Study Design....................................................................................................7 
Table 3: Adverse Events That Occurred in At Least 15% of Subjects and At Least 2 Subjects in 
Any Single-agent Study Part by SOC and PT for Subjects Receiving M6620 Single-agent 
Therapy, Safety Set ................................................................................................................... 15 
Table 4: Regimen Description ................................................................................................... 25 
Table 5: M6620 Dose Reductions (Twice Weekly Dosing) ....................................................... 29 
Table 6: M6620 Dose Reductions (Once Weekly Dosing) ......................................................... 30 
Table 7: Management of Non-Hematological Toxicity .............................................................. 30 
Table 8: Management of Hematological Toxicity ...................................................................... 31 
Table 9: Hydrochloride Drug Substance .................................................................................... 38 
Table 10: Free Base Drug Substance ......................................................................................... 38 
Table 11: PK Sample Collection ............................................................................................... 42 
Table 12: Study Calendar ........................................................................................................... 44 
Table 13: For Participants with Measurable Disease (i.e., Target Disease) ................................. 52 
Table 14: For Participants with Non-Measurable Disease (i.e., Non-Target Disease) ................. 52 
 
 
 
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1. OBJECTIVES 
 
1.1 
Study Design 
 
This is an open label, phase II basket trial of M6620 with a translational lead-in study in 
participants with select advanced solid tumors. Participants with tumors harboring the alterations 
listed in the tables below will be enrolled to the appropriate corresponding cohort. Enrollment to 
the translational study will initiate first. Following an analysis of the results from the lead-in 
study, enrollment to the phase II trial will commence. The single T3 patient with SDH-GIST will 
be moved to cohort T4 with the Amendment dated April 30, 2019. This will be counted towards 
T4 accrual numbers and not T3 accrual numbers. 
 
Table 1: Translational Lead-in Study Design 
Translational Cohort 1 (T1): 
ATRX-mutant leiomyosarcoma (LMS) 
Translational Cohort 2 (T2): 
Truncating ATM mutations (any solid tumor) 
 
Translational Cohort 3 (T3): 
Germline BRCA1/2 mutations, other homologous repair (HR) alterations (e.g. somatic 
BRCA1/2, BARD1, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCE, FANCF, FANCM, 
MRE11A, NBN, PALB2, RAD51B, RAD51C and RAD51D), MYC amplification, FBXW7 
truncating or missense mutations, CCNE1 amplification, ARID1A mutations (any solid tumor) 
Translational Cohort 4 (T4): 
SDH-deficient Gastrointestinal Stromal Tumor (GIST) 
*other ATM mutations may be considered see section 9.4 
 
 
Table 2: Phase II Study Design 
Cohort 1 
 
1A
Osteosarcoma
1B
Leiomyosarcoma (LMS)
Cohort 2 
 
2
Truncating ATM mutations
Cohort 3 
 
3A
Germline BRCA1/2 mutations
3B 
Other homologous repair (HR) alterations (e.g. somatic BRCA1/2, 
BARD1, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCE, 
FANCF, FANCM, MRE11A, NBN, PALB2, RAD51B, RAD51C and 
RAD51D)
Cohort 4 
 
4A 
MYC amplification, FBXW7 truncating or missense mutations 
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4B
CCNE1 amplification
Cohort 5 
 
5
ARID1A mutations
*other ATM mutations may be considered see section 9.4 
 
 
 
1.2 
Primary Objective – Translational Lead-In 
 
 To determine the preliminary anti-cancer activity of M6620 monotherapy in 
selected cancer populations including ATRX-mutated LMS, ATM-mutated solid 
tumors, BRCA1/2 and other HR-mutated cancers, malignancies with replicative 
stress, ARID1A-mutated cancers, and SDH-deficient GIST. 
 To determine changes in the pharmacodynamic endpoints of phospho-Chk1 and 
H2AX in biopsy specimens of patients treated with M6620 monotherapy. 
 
1.3 
Primary Objective – Phase II 
 
 To determine the anti-cancer activity of M6620 monotherapy in selected cancer 
populations including osteosarcoma, LMS, ATM-mutated solid tumors, BRCA1/2 
and other HR-mutated cancers, malignancies with replicative stress, and ARID1A-
mutated cancers. 
 
1.4 
Secondary Objectives 
 
 To determine correlations between selected biomarkers and M6620 monotherapy 
anti-cancer activity, including mutations detected in targeted NextGen 
Sequencing (NGS), ALT status (telomeric repeat-containing RNA [TERRA] in 
situ hybridization [ISH], C-circle assay), ATM, RAD51, MYC, Cyclin E and 
ARID1A immunohistochemistry (IHC). 
 To confirm the safety and overall tolerability of M6620 in these patient 
populations. 
 
2. BACKGROUND 
 
2.1 
Study Diseases and Rationale 
 
2.1.1 
Cohorts T1, 1A and 1B: Sarcoma 
  
The sarcomas represent a complex and heterogeneous group of orphan mesenchymal 
malignancies arising from bone or soft tissue. In metastatic soft tissue sarcomas, chemotherapy 
has led to a median survival of only 12 months across histologies1,2. In metastatic osteosarcoma 
5-year survival rates are only in the range of 15-30%3.  
 
Cancers rely on either telomerase or the ALT pathway to extend telomeres and bypass 
senescence. ALT is a recombination-mediated mechanism that extends telomeres. Depending on 
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which assay is used, ALT is estimated to be activated in 10-15% of cancers4. Interestingly, the 
sarcomas have a high prevalence for ALT. For example, it has been reported that up to 50-60% 
of osteosarcomas and LMS are ALT+. ATRX-DAXX is a chromatin-remodeling complex that 
functions at genomic loci including telomeres. Loss of ATRX has been linked to activation of the 
ALT pathway in cancer cells. In work from the Zou laboratory5, it was found that ATRX is a cell 
cycle-regulated repressor of the telomere non-coding RNA TERRA and ATRX loss 
compromises the cell-cycle regulation of TERRA leading to overexpression/persistent 
association throughout the cell cycle. This dysregulation ultimately generates a recombinogenic 
nucleoprotein structure (RPA-coated single-stranded DNA) at telomeres, which activates the 
ATR checkpoint kinase and promotes telomere recombination. Importantly, it was determined 
that ATR is a key regulator of ALT where ATR inhibitors disrupt the ALT pathway and 
selectively kill ALT+ cancer cells in a panel of osteosarcoma and glioblastoma cell lines. 
 
In our clinical experience ATRX is mutated in ~39% of LMS6. In unpublished work, there is 
near 100% correlation with ATRX alterations and ALT+ status in LMS. However, we have also 
noted that there are sarcomas, including LMS, with intact ATRX that activate ALT through other 
pathways. To enrich for ALT in this translational aspect of the study we will focus on those with 
ATRX mutations and loss of expression by IHC. In the larger study, we will include all LMS or 
osteosarcomas, regardless of ATRX status, and retrospectively determine ALT status.   
 
2.1.2 
Cohort 2:  Mutations in ATM  
 
Complementation of an ATM patient derived cell line with wild-type ATM rescues M6620 
hypersensitivity while cells complemented with a kinase-dead version of ATM remains 
hypersensitive (unpublished data, Center for DNA Damage and Repair, DFCI).  These results are 
consistent with enhanced sensitivity of a variety of cell lines to ATR inhibitors after knock-down 
of ATM.  Therefore, tumors with genomic deletion of ATM or lack of ATM expression due to 
epigenetic silencing are expected to respond to M6620.  Since the kinase domain of ATM is 
located at the C-terminus of the protein, all truncating mutations resulting in deletion of the 
kinase domain would result in a non-functional protein.  Among missense mutations, 23 are 
annotated as pathogenic in the ClinVar database, a freely accessible archive of the relationships 
among human variations and phenotypes supported by the National Center for Biotechnology 
Information (NCBI).  Therefore, patients whose tumors harbor truncating mutations or one of the 
23 missense mutations are likely to respond to M6620.  Furthermore, the mutant allele may 
encode an unstable protein or may have a dominant-negative effect if the wild-type allele is 
retained.  Both these scenarios are likely to result in enhanced sensitivity to M6620.   
 
2.1.3 
Cohort 3T, 3A, 3B, 4A, 4B, 5: Mutations in BRCA1/2 and other genes implicated in HR, tumors with 
replication stress, and ARID1A alterations  
 
Tumors with deficiencies in HR due to loss or deleterious mutations in HR pathway genes are 
expected to succumb to ATR inhibition.  ATR is activated early in response to DNA double-
strand breaks where ATR phosphorylates and activates multiple proteins that participate in HR 
and activation of cell cycle checkpoint7,8.  Carriers of germline or somatic known deleterious 
mutations in BRCA1 or BRCA2 will be recruited to cohort 3A while cohort 3B will constitute 
patients whose tumors harbor somatic mutations in BRCA genes or mutations in other HR 
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pathway genes.  Of specific interest are known deleterious mutations in BARD1, BRIP1, CDK12, 
CHEK2, FANCA, FANCC, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, RAD51B, 
RAD51C and RAD51D.  Of note, among patients with BRCA mutations who have been treated 
with PARP inhibitors, reversal of PARP inhibitor resistance may be achieved by ATR inhibition.  
In cancer cells that have become PARP inhibitor-resistant via restoration of HR, ATR inhibition 
is expected to restore an HR-deficient state.  In cancer cells that have become PARP inhibitor-
resistant by stabilization of replication forks, ATR inhibition is expected to destabilize 
replication forks.  Therefore, PARP inhibitor-resistant cancers may respond to ATR inhibitor 
monotherapy9.  
 
2.1.4 
Cohort 4A and 4B: Tumors with replication stress  
 
Unlicensed replication origin firing and compromised replication fork stability results in 
replication stress (RS).  Single- and double-stranded DNA breaks and presence of extensive 
single-strand DNA are manifestations of RS.  These conditions result in the activation of the 
ATR pathway, so that tumors with RS are dependent on ATR for survival10.  In this cohort, we 
will test the efficacy of M6620 in tumors with amplifications in MYC (Cohort 4A) and CCNE1 
(Cohort 4B).  In addition to patient tumors with MYC amplification, cohort 4A will also include 
subjects with truncating or missense mutations designated as deleterious (cBioPortal) in FBXW7.  
FBXW7 is a component of the SCF-like E3 ubiquitin ligase complex, of which, MYC is a major 
substrate.   
 
The eligibility criteria for CCNE1 amplification will be greater than 8-fold and that of MYC will 
be 6-fold.  The Brigham and Women’s Center for Advanced Molecular Diagnostics (CAMD) has 
performed preliminary analyses indicating that amplification identified by targeted NGS 
accurately reflects tumors in which these amplifications are identified by fluorescence in situ 
hybridization (FISH).  
 
Although increased CCNE1 copy number can lead to increased cyclin E protein expression, this 
is not a universal finding. Based on work done with our collaborators, it is expected that 50% of 
tumors will have high cyclin E protein levels in the presence of any degree of CCNE1 
amplification.  Our collaborators have further evaluated the CCNE1-amplified group to see if a 
certain degree of gene amplification correlates with high cyclin E protein expression.  This work 
is illustrated below. A minimum 6-fold CCNE1 amplification will give the highest probability of 
treating tumors with high cyclin E protein expression. 
 
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2.1.5 
Cohort 5: ARID1A  
 
ARID1A is among the most highly-mutated genes across various tumor types. Mutations are most 
prevalent in endometrial, colorectal, gastric and bladder cancer.  The majority of mutations 
identified in the cancer genome atlas (TCGA) are truncating, and none of the missense mutations 
have been classified as deleterious by Mutation Assessor or annotated pathogenic in the ClinVar 
database.  Although bi-allelic truncation mutations are less common, tumors with mono-allelic 
truncation mutation tend to have low levels of protein expression, and in vitro studies in cell 
lines suggest that ARID1A is a haplo-insufficient tumor suppressor.  Lack of ARID1A protein 
determined by IHC is associated with poor prognosis in multiple tumor types.  ARID1A is a 
large protein with a DNA binding domain while the C-terminus encodes multiple LXXLL 
protein interaction motifs.  ARID1A interacts with several proteins to form the BAF complexes, 
a subfamily of mammalian SWI/SNF chromatin remodelers.  ATM and ARID1A were the two 
top hits in an siRNA screen using HCC1143, a triple negative breast cancer cell line, to identify 
genes that exhibit a synthetic-lethal interaction with ATR inhibitor11.  In an expanded set of 
tumor cell lines, ones with mutant ARID1A were found to be more sensitive to ATR inhibition 
compared to cells with wild-type ARID1A.  ARID1A mutant/deficient cells are defective in 
TOPO2A and the G2/M checkpoint regulated by ATR.  When ATR is inhibited, the cells enter 
mitosis without resolving replication defects resulting in genomic instability and apoptosis.  
 
2.1.6 
Cohort T4: SDH-deficient GIST 
 
GIST are a subtype of sarcoma derived from the Interstitial Cells of Cajal in the GI tract.  In 
nearly all GIST either the oncogene c-KIT or PDGFRA undergo activating mutations that drive 
cancer growth. In a subset of GIST, which lack KIT/PDGFRA mutations, there is deficiency in 
one of the SDHX gene subunits. Tyrosine kinase inhibitors have minimal activity in this subtype 
of GIST and there are no FDA-approved therapies for these patients. Notably, SDH-GIST also 
tend to be associated with the pediatric and adult population, while KIT/PDGFRA-GIST 
typically occurs in adults only.    
 
Figure: 6-fold CCNE1 amplification is associated with high cyclin E 
expression within tumor cells.  The graph above shows the degree of 
cyclin E protein expression for non-amplified, moderately amplified 
and highly amplified CCNE1.  80% of tumors with 6-fold or greater 
CCNE1 gene amplification were highly expressed cyclin E protein, 
compared with 25% and 50% of tumors with low or moderate 
amplification respectively. 
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It was recently recognized that tumors with mutations in Krebs-cycle proteins (e.g. SDH-
deficient paraganglioma/pheochromocytoma) are deficient in HR dsDNA break repair.12 The 
proposed mechanism is as follows. SDH deficiency in the tumor Kreb cycle leads to elevated 
fumarate and succinate. These in turn suppress HR activity through KDM4A/B, known 
regulators of DNA repair.  Thus, there is a therapeutic potential for synthetic lethality in tumors 
with this alteration.   
 
In the initial experience of this trial an adult with known SDH-deficient GIST refractory to 
sunitinib and regorafenib was treated with M6620. After 16 days of dosing the patient was 
observed to have a minor radiologic response with shrinkage of -13.84% and a marked 
improvement in clinical symptoms.  
 
2.2 
M6620 (VX-970) 
 
M6620 is a potent inhibitor of ataxia telangiectasia mutated and Rad3-related kinase (ATR, 
inhibition constant [Ki] <300 pM) that blocks ATR activity in cells, with a concentration 
associated with 50% inhibition (IC50) of 20 nM. Complete compound background information is 
available in the investigator’s brochure (IB). 
 
2.2.1 
Pre-Clinical Summary 
 
2.2.1.1 
Pharmacology 
 
M6620 (VX-970) is a potent inhibitor of ATR kinase (inhibition constant [Ki] <300 pM) with 
excellent selectivity over other kinases (>50-fold selectivity over 290/291 kinases tested). In 
vitro, M6620 sensitized many cancer cell lines and primary human tumor cells, but not normal 
cell lines, to the cytotoxic effects of a range of DNA-damaging drugs and ionizing radiation (IR). 
The reliance of many cancer cells on ATR for survival following treatment with DNA-damaging 
agents can be driven by a number of mechanisms including disruption of alternative DNA 
damage repair pathways in these cells. One such example is disruption of the signaling pathway 
mediated by ataxia telangiectasia mutated (ATM) kinase. This pathway is defective in many 
cancer cells. In contrast, normal cell tolerance to inhibition of ATR is attributed to the presence 
of alternative, compensatory DNA damage response (DDR) pathways. 
 
In mouse xenograft models derived from human cancer cell lines and primary human tumors, 
M6620 dose-dependently enhanced the anti-tumor effects of multiple DNA-damaging drugs and 
IR. In many cases, marked regression was observed for combinations with M6620. Furthermore, 
the combination of M6620 and a DNA-damaging drug has been shown to be more effective than 
the DNA-damaging drug alone at its maximum tolerated dose (MTD). As a single agent, M6620 
had no significant impact on tumor growth in the experimental models examined.  
 
Dose schedule optimization studies in mouse models have demonstrated that administration of 
M6620 by IV injection at a dose of 20 mg/kg/week (either as a single injection or as two 10-
mg/kg injections 3 days apart) was highly effective in combination with cisplatin or gemcitabine. 
Furthermore, timing of M6620 administration is critical, with maximal activity observed when 
M6620 was given 12 to 24 hours after cisplatin or gemcitabine treatment. 
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Therapeutic dose estimations were based on achieving an area under the concentration versus 
time curve (AUC) of 4080 ng∙h/mL/week in whole blood (achieved with an IV dose of 20 
mg/kg/week in mouse). Allometry predicts that a human dose of 2.5 mg/kg (corresponding to 
100 mg/m2) will be sufficient to achieve this exposure. In murine models, M6620 was generally 
well tolerated at efficacious doses in combination with DNA-damaging agents. In some 
instances, some body weight loss was observed, and from intensive and sustained dosing of 
M6620 in combination with cisplatin, enhanced changes in specific peripheral blood cell 
population was observed versus cisplatin treatment alone. This enhanced effect was attributed to 
a synergistic increase in growth arrest in normal cells. In vitro studies have demonstrated that the 
enhanced growth arrest seen when ATR inhibitors are added to cisplatin treatment is reversed 
after ATR activity is restored. 
 
2.2.1.2 
Pharmacokinetics 
 
In rats, mice, dogs, and monkeys, M6620 had a high volume of distribution; tissue exposure, 
including tumor, was high. In rats, no accumulation or retention was observed in tissues and the 
elimination half-lives were similar across all tissues and whole blood. Whole blood half-lives 
after IV administration in rats and dogs were 11.6 and 9.8 hours, respectively. M6620 had high 
plasma protein binding and the free fraction in human blood was 2.1%. A low potential for drug-
drug interactions was predicted, based on minimal inhibition or induction of CYP isozymes by 
M6620; however, strong inducers or inhibitors of CYP3A4 may alter M6620 kinetics and blood 
levels. M6620 was primarily eliminated by oxidative metabolism, with CYP3A4 as the principle 
isozyme responsible. Metabolites were excreted in the urine and bile. All metabolites observed in 
human hepatocyte incubations were also observed in either rat or dog hepatocyte incubations and 
in the blood, bile, or urine from rats or dogs. Accordingly, rat and dog were recommended as the 
appropriate species for toxicology assessment. The systemic clearance values of M6620 
following IV administration were determined to be 26 and 13 mL/min/kg in the rat and dog, 
respectively. 
 
2.2.1.3 
Safety Pharmacology 
 
A battery of in vitro and in vivo safety pharmacology studies designed to evaluate effects of 
M6620 against multiple protein targets, and the cardiovascular system did not demonstrate any 
toxicologically significant effects at exposures or concentrations that exceed the clinically 
relevant exposures of M6620. 
 
2.2.1.4 
Toxicology 
 
The M6620 toxicology studies in rats and dogs identified the liver, testes, and peripheral blood 
cell populations as target organs following oral or IV administration. Importantly, liver and 
peripheral blood toxicities were reversed within 4 weeks of discontinuation of M6620. Following 
oral exposure, the MTD in rats was 150 mg/kg and M6620 was not tolerated at doses ≥30 mg/kg 
in dogs. IV administration in a regimen that more closely reflects the clinical regimen was 
tolerated in animals and allowed the determination of a severely toxic dose to 10% of animals 
(STD10) in rats and a highest non-severely toxic dose (HNSTD) in dogs. The animal to human 
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exposure ratio on a weekly AUC basis at the rat STD10 following IV administration (30 mg/kg) 
was 5.3-fold the weekly human exposure at 210 mg/m2. The animal to human exposure ratio on 
a weekly AUC basis at the dog HNSTD following IV administration (20 mg/kg) was 7.7-fold the 
weekly human exposure at 210 mg/m2. 
 
M6620 had no cardiovascular liabilities, was not genotoxic in a GLP mutagenicity assay, had no 
hemolytic potential in human blood or compatibility issues in human plasma, and was well 
tolerated in an acute rabbit parenteral injection study. M6620 absorbs in the UV-visible spectrum 
and has high tissue distribution in rats; therefore, appropriate precautions to safeguard patients 
from excessive UV-visible radiation should be taken in the clinic pending results from 
nonclinical phototoxicity assessment. 
 
2.2.2 
Clinical Summary 
 
2.2.2.1 
Pharmacokinetics 
 
Noncompartmental analyses were conducted on preliminary clinical pharmacokinetic (PK) data 
obtained from Parts A and B of Study VX12-970-001 (Study 001) and Study VX13-970-002 
(Study 002) for both whole blood and plasma matrices. The mean M6620 plasma concentrations 
versus time profiles were similar in shape to those of the corresponding whole blood profiles. 
Overall, the Cmax were approximately 1.3-fold greater in whole blood than in the plasma matrix, 
suggesting that plasma is an appropriate matrix to characterize the PK of M6620. PK exposures 
tended to increase dose proportionally with increasing dose based upon Cmax and AUC0-∞ after 
administration of M6620 as a single agent. The mean terminal elimination half-life was 
approximately 17 hours across all dose groups. Collectively, the data suggest that co-
administration of gemcitabine, cisplatin, or carboplatin 24 hours before M6620 administration 
did not appear to affect the PK of M6620. 
 
2.2.2.2 
Single Agent Safety 
 
M6620 was administered as a single agent in the lead-in periods of the phase 1 first-in-human 
study 001 Parts A and B (doses of 18 mg/m2 to 210 mg/m2, lead-in periods of 7 to 21 days); 
during the phase 1 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).  
 
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 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 only 
AEs that occurred in the single-agent phases of all 4 study parts were nausea and ALT increased. 
 
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 
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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. 
 
Table 3: Adverse Events That Occurred in At Least 15% of Subjects and At Least 2 
Subjects in Any Single-agent Study Part by SOC and PT for Subjects Receiving M6620 
Single-agent Therapy, Safety Set 
 
Study 001 
Study 002 
 
Part A 
Part B 
Part A 
Part B 
System Organ Class 
Preferred Term 
(All Doses) Lead-
in Phase Lead-in 
Safety Set  
N=30  
n (%) 
140 mg/m2 
Lead-in 
Safety Set  
N = 4  
n (%) 
(All Doses) 
Safety Set  
N = 17  
n (%) 
240 mg/m2 
Single-agent 
Safety Set  
N = 15  
n (%) 
Subjects with any 
AEs 
18 (60.0) 
3 (75.0) 
17 (100.0) 
14 (93.3) 
Gastrointestinal Disorders 
Nausea 
6 (20.0) 
1 (25.0) 
6 (35.3) 
8 (53.3) 
Diarrhea 
2 (6.7) 
0 
4 (23.5) 
4 (26.7)
Vomiting 
2 (6.7)  
0  
4 (23.5)  
2 (13.3)  
General Disorders and Administration Site Conditions 
Fatigue 
3 (10.0) 
0 
6 (35.3) 
4 (26.7) 
Infections and Infestations 
Urinary tract 
infection 
1 (3.3)  
0  
4 (23.5)  
1 (6.7)  
Investigations 
ALT increased 
1 (3.3) 
1 (25.0) 
3 (17.6) 
1 (6.7) 
Blood creatinine 
increased 
0 
0 
3 (17.6) 
1 (6.7) 
Metabolism and Nutrition Disorders 
Hyperglycemia 
0  
1 (25.0)  
3 (17.6)  
0  
Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps) 
Cancer pain 
0  
0  
3 (17.6)  
0  
Malignant neoplasm 
progression 
0  
0  
3 (17.6)  
1 (6.7)  
Blood and Lymphatic System Disorders 
Anemia 
0 
0 
5 (29.4) 
3 (20.0) 
Vascular Disorders 
Flushing 
0  
0  
4 (23.5)  
2 (13.3)  
Nervous System Disorders 
Headache 
2 (6.7) 
0 
3 (17.6) 
2 (13.3) 
Dizziness 
2 (6.7)  
0  
0  
3 (20.0)  
Injury, Poisoning and Procedural Complications 
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Table 3: Adverse Events That Occurred in At Least 15% of Subjects and At Least 2 
Subjects in Any Single-agent Study Part by SOC and PT for Subjects Receiving M6620 
Single-agent Therapy, Safety Set 
 
Study 001 
Study 002 
 
Part A 
Part B 
Part A 
Part B 
Infusion-related 
reaction 
0  
0  
2 (11.8)  
5 (33.3)  
Abbreviations: AE: adverse event; ALT: alanine aminotransferase; N: number of 
subjects in each treatment group; n: number of subjects in category; PT: preferred 
term; SOC: system organ class 
Notes: Every subject is counted once for each applicable specific AE category within 
same treatment group when the AE occurred.
 
 
2.2.2.3 
Adverse Drug Reactions 
 
After careful assessment, infusion-related reactions, nausea, and vomiting are considered adverse 
drug reactions (ADRs) for M6620, and myelosuppression events are considered ADRs for 
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 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 M6620 have been 
serious, including those described as acute hypersensitivity reactions. Local infusion-related 
reactions to M6620, sometimes described as infusion site reactions, may include signs or 
symptoms such as infusion site erythema, swelling, or pain. 
 
Nausea and vomiting have occurred commonly in patients receiving M6620 monotherapy. Many 
of the affected subjects experienced these events on the same day M6620 was administered, and 
there was some suggestion of a dose response. 
 
Myelosuppression AEs for subjects who received M6620 in combination with carboplatin have 
included neutropenia, thrombocytopenia, platelet count decreased, and febrile neutropenia. 
 
2.2.2.4 
Pharmacodynamics 
 
Paired M6620 tumor biopsies were obtained pre- and post-M6620 administration from a subset 
of subjects in study 002 Part B, and pS345 Chk1 levels assessed by IHC. A preliminary analysis 
of the data showed decreased Chk1 phosphorylation in 2/2 paired tumor biopsies (74% at M6620 
90 mg/m2 + carboplatin AUC5; 94% at M6620 120 mg/m2 + carboplatin AUC5). 
 
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2.2.2.5 
Single Agent Efficacy 
 
Subjects in phase I study 002 Part A received single-agent M6620 therapy. One subject with 
colorectal cancer had a complete response (CR). The subject’s tumor lesion diameter decreased 
from 18 mm at Screening to “too small to measure” at Cycle 31. This subject has completed 44 
cycles of M6620 therapy and continues to be on treatment at the time of the data cut-off. Five of 
17 subjects had stable disease (SD) as the best overall response. 
 
2.2.2.6 
Rationale for Translational Lead-in Study 
 
The development of M6620 has largely been focused on optimizing dosing for chemotherapy 
combination studies (see Section 2.2.2.1 VX12-970-001 and Study VX13-970-002). Patients 
included in the above studies were not pre-selected for biomarkers predicted to be sensitive to 
ATR inhibition. Moreover, it is unknown whether current dosing strategies (twice per week) are 
adequate to durably inhibit ATR without the stressor of concurrent chemotherapy.  Interestingly, 
of note, the patient with a complete response described in Section 2.2.2.5 was an ATM-mutant 
colorectal cancer patient treated at the first dose level (60 mg/m2 once per week)13. With this 
background, we designed a Translational Lead-in Study to confirm target engagement, and 
potentially to observe clinical responses, in the indications where we anticipate the highest 
likelihood for response. This strategy will be critical for dosing confirmation prior to embarking 
on a larger basket-type study.    
 
2.2.2.7 
Rationale for ctDNA Sample Collection  
 
C-circle assay (an assay of telomeric repeats, which proportionally reflects the average length of 
telomeres, is measured by quantitative PCR [qPCR])19) on T1 fresh biopsy samples and 
circulating tumor DNA (ctDNA), only. 
 
 
2.3 
Correlative Studies Background 
 
It is anticipated that at the time of enrollment most participants on this study will have had their 
tumor genomically characterized by either the OncoPanel test at DFCI/BWH (a custom hybrid 
capture panel which via NGS will identify mutations and copy-number alterations in over 400 
cancer associated genes) or via another CLIA-certified method (e.g. SNaPshot at MGH or 
Foundation Medicine). Gene expression profiling has been demonstrated to predict disease-free 
and overall survival in multiple cancers and guide future treatment decisions and biologic 
discovery14-16.  
 
Current methods for identifying ALT positive tumors by direct measurement of telomere length 
are best suited to testing cell lines or frozen tissue rather than paraffin embedded clinical 
samples. DNA testing for ATRX can be performed on clinical samples but this only identifies a 
subset of ALT cases associated with mutations in this gene17. The same limitation applies to tests 
based on the loss of ATRX staining by IHC. Though ATRX sequencing will be used for 
Translational Lead-in study entry, given the strong correlation to ALT status, we recognize that 
there are other ALT positive tumors that will be missed with this assay. Thus, there is interest in 
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developing other methods to detect ALT status. The laboratory of Miguel Rivera MD, PhD at 
MGH has extensive experience using RNA-ISH via a branched-DNA amplification to detect 
novel biomarkers in paraffin embedded clinical samples18,19. Moreover, as noted above, TERRA 
expression persists throughout the cell cycle in ALT positive cells.  To this end, the Rivera 
laboratory is developing a RNA-ISH assay to detect high levels of TERRA and thereby identify 
ALT positive malignancies. For all T1, 1A  and 1B FFPE samples on study, ALT status will be 
determined by TERRA ISH, with confirmatory testing by the C-circle assay (an assay of 
telomeric repeats, which proportionally reflects the average length of telomeres, is measured by 
quantitative PCR [qPCR])20) on T1 fresh biopsy samples, only. 
 
To explore the determinants of response and resistance to M6620, biopsy tissue will be collected 
from all participants enrolling to the translational lead-in study at baseline and on treatment. IHC 
will be performed for selected biomarkers including H2AX (a marker of dsDNA breaks), 
phosph-CHK1 (downstream of ATR), and possibly also ATM, RAD51, MYC, Cyclin E, and 
ARID1A as well as others as determined appropriate at the time of analysis. Results from tissue 
analysis will be used to confirm downstream target engagement (increased H2AX), altered 
expression of proteins of interest by IHC and to confirm amplifications by FISH. 
 
An optional biopsy at the time of disease progression will also be offered to all participants 
enrolling to the translational lead-in study.  
 
The baseline fresh tissue obtained from participants will also undergo whole exome sequencing 
(WES) at an outside facility. WES enables a comprehensive analysis of DNA mutation in human 
tumor samples. Gene expression profiling has been demonstrated to predict disease-free and 
overall survival in multiple cancers and guide future treatment decisions and biologic 
discovery14-16. The analyses will involve up to 100 genes of interest in DNA repair. This will 
allow identification of further genomic variations that may occur outside of the pre-set 
enrollment genetic alterations of these patients. RNA-sequencing will also be performed on 
selected biopsy specimens based on the results of the WES and clinical outcome on trial. RNA-
sequencing allows for monitoring of gene expression and transcriptome changes, giving the 
complete HR state of the tumor. WES will be performed again on any time of progression 
samples to assess genomic determinants of resistance. The data obtained via WES and RNA-
sequencing will enable us to identify secondary alterations that may impact clinical response. 
 
Additional specimens collected for clinical reasons (e.g. biopsies, effusion/ascites fluid) may be 
collected for correlative studies, if available. 
 
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3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
Participants Enrolling to the Translational Lead-in Study: 
 
3.1.1 For enrollment to cohort T1: participants must have metastatic or progressive LMS with 
a) treatment with at least one prior systemic therapy b) ATRX mutation by NGS. 
 
3.1.2 For enrollment to cohorts T2 or T3: participants must have a histologically or 
cytologically confirmed advanced solid tumor for which no standard curative therapy is 
available.  
 
3.1.3 For enrollment to cohort T2: participants must have a truncating ATM mutation. Other 
ATM mutations with sufficient evidence of gene inactivation may be considered eligible 
after review (see section 9.4). Testing may be completed via the DFCI/BWH OncoPanel, 
MGH SNaPshot, or any other CLIA-certified method. 
 
3.1.4 For enrollment to cohort T3, participants must have one of the following (testing may be 
completed via the DFCI/BWH OncoPanel, MGH SNaPshot, or any CLIA-certified 
laboratory): 
 
a) Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or 
suspected deleterious (known or predicted to be detrimental/lead to loss of function). 
b) A somatic mutation in BRCA1 or BRCA2, or another mutation within a known HR 
gene including BARD1, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCE, 
FANCF, FANCM, MRE11A, NBN, PALB2, RAD51B, RAD51C, or RAD51D. 
c) A MYC amplification of greater than 6-fold. 
d) FBXW7 truncating, missense, or other inactivating mutation designated as deleterious. 
Other deleterious mutations may be considered after discussion with the overall PI. 
e) CCNE1 amplification of greater than 8-fold. 
f) An ARID1A mutation as determined by the DFCI/BWH OncoPanel or any other 
CLIA-certified method. 
g) Other (unlisted) mutations within known HR genes may be considered with approval 
from the site principal investigator. 
 
3.1.5 For enrollment to cohort T4: participants must have GIST with known mutation in SDHX 
genes or loss of expression of SDHX protein(s), as determined by standard pathology 
assays. Prior therapy is not required.  
  
3.1.6 Age ≥ 18 years for T1, T2, and T3; Age ≥ 12 years for T4 
 
3.1.7 ECOG performance status ≤ 2 (Karnofsky [KPS] ≥ 60%; KPS of 50 is not permitted) 
(See Appendix A) 
 
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3.1.8 For T1, T2, and T3, participants must have tumor amenable to biopsy, and be a candidate 
for tumor biopsy according to the treating investigator. The patient must be willing to 
undergo a fresh tumor biopsy for this study. If the biopsy is deemed unsafe, the patient 
may enroll with the permission of the overall PI (though the patient will not count 
towards accrual numbers, see section 9.2) 
 
3.1.9 Participants must have archival tissue available for analysis. Participants without 
available archival tissue enrolling to the translational lead-in study may instead use tissue 
from the fresh pre-treatment biopsy. 
 
 
Participants Enrolling to the Phase II: 
 
3.1.10 For enrollment to cohort 1A: participants must have metastatic or progressive 
osteosarcoma treated with at least one prior systemic therapy. 
 
3.1.11 For enrollment to cohort 1B: participants must have metastatic or progressive 
leiomyosarcoma treated with at least one prior systemic therapy. 
 
3.1.12 For enrollment to cohorts 2 – 5: participants must have a histologically or cytologically 
confirmed advanced solid tumor for which no standard curative therapy is available.  
 
3.1.13 For enrollment to cohort 2: participants must have a truncating ATM mutation. Other 
ATM mutations with sufficient evidence of gene inactivation may be considered eligible 
(see section 9.4). Testing may be completed via the DFCI/BWH OncoPanel, MGH 
SNaPshot, or any other CLIA-certified method. 
 
3.1.14 For enrollment to cohort 3A: participants must have a germline mutation in BRCA1 or 
BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to 
be detrimental/lead to loss of function). Testing may be completed via the DFCI/BWH 
OncoPanel, MGH SNaPshot, or any CLIA-certified laboratory. 
 
3.1.15 For enrollment to cohort 3B: participants must have a somatic mutation in BRCA1 or 
BRCA2, or another mutation within a known HR gene including BARD1, BRIP1, CDK12, 
CHEK2, FANCA, FANCC, FANCE, FANCF, FANCM, MRE11A, NBN, PALB2, 
RAD51B, RAD51C, or RAD51D. Other (unlisted) mutations within known HR genes may 
be considered with approval from the site principal investigator. 
 
3.1.16 For enrollment to cohort 4A: participants must have a MYC amplification of greater than 
6-fold or an FBXW7 truncating or missense mutation designated as deleterious, as 
determined by the DFCI/BWH OncoPanel, MGH SNaPshot, or any other CLIA-certified 
method. 
 
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3.1.17 For enrollment to cohort 4B: participants must have a CCNE1 amplification of greater 
than 8-fold as determined by the DFCI/BWH OncoPanel, MGH SNaPshot, or any other 
CLIA-certified method. 
 
3.1.18 For enrollment to cohort 5: participants must have an ARID1A mutation as determined by 
the DFCI/BWH OncoPanel, MGH SNaPshot, or any other CLIA-certified method. 
 
3.1.19 For enrollment to cohort 1A: Age > 12 
 
3.1.20 For enrollment to cohorts 1B – 5: Age ≥ 18 
 
3.1.21 ECOG performance status ≤ 2 (Karnofsky ≥ 60%; KPS of 50 is not permitted) for 
participants ≥ 16 years of age, Lansky ≥ 50% for participants < 16 years of age (see 
Appendix A) 
 
3.1.22 Participants must have archival tissue available for analysis. 
 
 
All Participants: 
 
3.1.23 If any participant could enroll to more than one cohort based on mutational status, the 
cohort enrollment decision will be discussed with the overall principal investigator. For 
example, if a participant has both an ATM mutation and an FBXW7 mutation and thus 
could enroll to either Cohort 2 or Cohort 4A, the decision of which cohort to enroll to 
will be made in conjunction with the overall principal investigator. The decision as to 
which cohort the participant should be enrolled on must be made prior to the initiation of 
study treatment. 
 
3.1.24 Participants must have RECIST 1.1 measurable disease.  See Section 11 for the 
evaluation of measurable disease. 
 
3.1.25 Participants must have normal organ and marrow function as defined below: 
 
All Participants: 
 
Absolute neutrophil count 
≥ 1,500/mcL 
 
Platelets 
≥ 100,000/mcL 
 
Total bilirubin 
≤ 1.5 × institutional upper limit of normal (ULN) for  
 
 
 
 
age 
 
Adult Participants (Age ≥ 18 years): 
 
AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional ULN; OR 
 
 
 
 
 
 
 
≤ 5 × institutional ULN if liver metastases are present 
 
Serum or plasma creatinine ≤ 1.5 × institutional ULN, OR 
 
Creatinine clearance 
≥ 60 mL/min by Cockcroft-Gault equation for 
participants with creatinine levels above 1.5 × 
institutional ULN 
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Pediatric Participants (Age < 18 years): 
 
ALT (SGPT)  
 
 
≤ 3 × institutional (ULN) 
Note: for the purposes of this study, the ULN for SGPT 
will be defined as 45 U/L. 
 
Serum or plasma creatinine Participants 13 – 15 years: males ≤ 1.5 mg/dL, females  
 
 
≤ 1.4 mg/dL, participants 16 – 17 years: males ≤ 1.7 
 
mg/dL, females ≤ 1.4 mg/dL; OR 
 
Creatinine clearance 
≥ 60 mL/min/1.73 m2 by Schwartz formula for 
participants with creatinine levels above the limits 
described above 
 
3.1.26 The effects of M6620 on the developing human fetus are unknown.  For this reason and 
because anti-cancer agents are known to be teratogenic, women of child-bearing potential 
and men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) prior to study entry and for the duration of study participation.  
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.  Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior to 
the study, for the duration of study participation, and 6 months after completion of 
M6620 administration. 
 
3.1.27 Ability to understand and the willingness to sign a written informed consent document 
(or parent or legally authorized representative, if minor). 
 
 
3.2 
Exclusion Criteria (All Participants) 
 
3.2.1 Participants who have had chemotherapy, immune therapy, other investigational therapy, 
or major surgery within 3 weeks (2 weeks for radiotherapy; 6 weeks for nitrosoureas or 
mitomycin C) prior to entering the study, or participants who have not recovered to ≤ 
Grade 1 or baseline from therapies administered more than 3 weeks prior (with the 
exceptions of 1. Alopecia and peripheral neuropathies which may be ≤ Grade 2 at study 
entry and 2. Laboratory abnormalities that are not listed in 3.1 and that are not considered 
clinically meaningful [e.g. decreased lymphocyte count, electrolyte abnormalities)] 
 
3.2.2 Participants who have received oral tyrosine kinase inhibitors (TKIs) within 5 half-lives 
of study entry. 
 
3.2.3 Participants who have previously received treatment with an ATR inhibitor, including but 
not limited to M6620 (VX-970). 
 
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3.2.4 Participants with known untreated brain metastases should be excluded from this clinical 
trial because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. Participants with a history of brain metastases that have been treated, no 
longer require corticosteroids, and have been stable on imaging for at least one month 
following the end of treatment are permitted. 
 
3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to M6620. 
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.7 Pregnant women are excluded from this study because M6620 is an agent with the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with M6620, breastfeeding should be discontinued if the mother is treated with M6620. 
 
3.2.8 Known HIV-positive participants are ineligible because of the increased risk of lethal 
infections when treated with potentially marrow-suppressive therapy. 
 
3.2.9 Patients with a history of another malignancy are excluded with the exception of 1. 
patients who remain disease-free for 3 years and 2. adequately treated cervical carcinoma 
in situ, non-melanoma skin cancer (e.g. basal cell, squamous cell carcinomas), low-risk 
thyroid cancer.  
 
3.2.10 Patients with Li Fraumeni syndrome or ataxia telangiectasia syndrome  
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
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Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
5. TREATMENT PLAN 
 
Enrollment will begin with the translational lead-in study (cohorts T1, T2, T3, and T4, please 
refer to Table 1). Participants may be enrolled to any of the cohorts in parallel with no 
observation period or delay between the initiation of treatment for any of the patients. When 
enrollment to the translational study cohorts has been completed, a review of available safety, 
efficacy, pharmacodynamic, and pharmacokinetic data will occur prior to the initiation of the 
phase II trial. The review will involve the overall principal investigator in conjunction with the 
site principal investigators, any applicable study team members, as well as consultation with 
Merck KGaA (EMD Serono) as appropriate. 
 
5.1 
Treatment Regimen 
 
M6620 will be administered to all participants twice weekly on cycle days 1, 4, 8, 11, 15, 18, 22 
and 25 via intravenous (IV) infusion at a dose of 240 mg/m2, with 28 consecutive days defined as 
a treatment cycle. Treatment will be administered on an outpatient basis.  Reported adverse 
events and potential risks are described in Section 7.  Appropriate dose modifications are 
described in Section 6.  
  
 
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Table 4: Regimen Description 
Agent 
Precautions 
Dose1 
Route 
Schedule2 
Cycle 
Length
M6620 
(VX-
970) 
To be administered through a 
large bore catheter into a large 
caliber peripheral vein. Monitor 
for phlebitis or signs of 
inflammation. 
 
Alternatively, may be infused via 
a central line or implanted venous 
access system (i.e. Port-a-Cath®).
 
M6620 should not come in 
contact with sodium chloride due 
to incompatability; 5% dextrose 
in water must be used for IV line 
priming and flushing.
240 
mg/m2 
IV over 60 
minutes (± 
10-minute 
infusion 
window)  
Days 1,4, 8, 
11, 15, 18, 
22, 25 
28 days 
(4 
weeks) 
 
 
 
1. Body surface area (BSA) to be calculated per institutional standards of practice. In the 
event of changes in participant weight, institutional standards of practice should be 
followed for dose re-calculations. 
2. After 16 weeks participants may consider a weekly dosing schedule on cycle days 1, 
8, 15, and 22 after discussion with the site principal investigator.
 
 
5.2 
Pre-Treatment Criteria 
 
 
5.2.1 
Cycle 1, Day 1 
 
If screening assessments were completed ≤ 72 hours prior to cycle 1 day 1, laboratory tests do 
not need to be repeated on cycle 1 day 1 and the screening laboratory values can be used as the 
cycle 1 day 1 values. If cycle 1 day 1 laboratories are performed, the values must re-meet 
eligibility criteria. 
 
5.2.2 
Subsequent Cycles  
 
Please refer to Section 6 for toxicity management guidelines. 
 
5.3 
Agent Administration 
 
5.3.1 
M6620 (VX-970) 
 
M6620 will be infused IV twice weekly on cycle days 1, 4, 8, 11, 15, 18, 22, and 25 via a large 
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bore catheter into a large caliber peripheral vein. Alternatively, M6620 may be infused via a 
central line or implanted venous access system (i.e. Port-a-Cath®). After 16 weeks participants 
may consider a weekly dosing schedule on cycle days 1, 8, 15, and 22 after discussion with the 
site principal investigator. The infusion should be delivered over 60 minutes, there is an 
allowable ± 10 minute infusion window. When the total volume of infusion exceeds 600 mL, the 
infusion time maybe be extended beyond 60 minutes (as tolerated), but no more than 90 minutes. 
Infuse using an infusion set containing low-sorption or non-PVC, DEHP-free tubing and an in-
line 0.2 micron filter. M6620 should not come in contact with sodium chloride, 5% dextrose in 
water must be used for IV line priming and flushing.  
 
Body surface area (BSA) to be calculated per institutional standards of practice. In the event of 
changes in participant weight, institutional standards of practice should be followed for dose re-
calculations. 
 
5.3.2 
Infusion-Related Reactions 
 
M6620 is associated with infusion-related reactions. Systemic infusion-related reactions to 
M6620 may include signs or symptoms such as pruritus, flushing, chills/rigors, urticaria/rash, 
headache, bronchospasm/dyspnea, hypotension or hypertension, and mental status changes, 
among others. Some systemic infusion-related reactions to M6620 have been serious. In almost 
all cases, these reactions occurred within minutes of the second exposure to M6620. All subjects 
have fully recovered with standard treatment for the reactions, including immediate 
discontinuation of the inciting infusion and administration of IV corticosteroid and antihistamine, 
as well as IV fluids and oxygen when clinically indicated. 
 
If any subject develops pruritus, flushing, or any other symptom suggestive of a systemic 
infusion reaction, standard measures may be employed to manage these symptoms (e.g., 
antihistamines and/or steroids). 
 
In the event of the occurrence of any Grade 2 or greater infusion-related reaction, the M6620 
infusion should be immediately stopped. Participants should be treated in accordance with 
institutional standards of practice. In the event of a Grade 2 infusion-related reaction, the 
infusion may be resumed at the treating investigator’s discretion upon resolution of symptoms to 
baseline. If symptoms recur following re-initiation, the infusion should be discontinued. In the 
event of any Grade 3 or greater infusion-related reaction, protocol therapy should be permanently 
discontinued. 
 
If a participant experienced a prior Grade 1 or Grade 2 infusion-related reaction, at the treating 
investigator’s discretion the participant may be pre-medicated prior to subsequent infusions. 
Standard desensitizing measures should be followed (e.g. premedication with 200 mg 
hydrocortisone or equivalent approximately 60 minutes prior to the infusion, and 25-50 mg of 
diphenhydramine hydrochloride or equivalent approximately 30 minutes prior to the infusion). 
At the treating investigator’s discretion, the rate of the infusion may be extended beyond 60 
minutes, but may not exceed 90 minutes.  
 
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5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
No investigational or commercial agents or therapies other than M6620 may be administered 
with the intent to treat the participant's malignancy, with the exception of palliative radiation 
therapy with the site principal investigator’s agreement. M6620 should be held during palliative 
radiation therapy. Bisphosphonate or denosumab use is permitted. Participants with prostate 
cancer may continue androgen deprivation therapy, including luteinizing hormone-releasing 
hormone LHRH-analogues, as long as the therapy was initiated prior to study entry. 
 
Patients should be monitored during M6620 (VX-970) infusion for acute hypersensitivity or 
severe infusion reactions, which may include loss of consciousness and/or hemodynamic 
instability, including hypotension. In the event of one of these reactions, the infusion should be 
stopped immediately, and standard supportive measures should be applied according to the 
presentation. This may include administration of fluids and epinephrine. 
 
Investigators should use appropriate supportive medications to address toxicities that arise 
during the study, including but not limited to anti-emetics, anti-diarrheals, and blood product 
transfusion. Use of colony-stimulating factors (CSFs) should be avoided when possible. 
Investigators may use CSFs as medically necessary to address a current episode of neutropenia. 
Primary prophylactic use of CSFs is prohibited. Secondary prophylactic use of CSFs per ASCO 
guidelines following an instance of a neutropenic episode experienced while on trial will be 
allowed at the treating investigator’s discretion. 
 
M6620 absorbs in the UV-visible radiation spectrum and is widely distributed to tissues, 
including the skin, so subjects should be cautioned to minimize exposure to the sun and other 
sources of visible and UV radiation when possible. Participants should be advised to take 
protective measures when necessary, including wearing a broad-spectrum sunscreen with high 
SPF and protective clothing.  
 
5.4.1 
Drug-Drug Interactions 
 
The potential for M6620 to induce CYP450 enzymes is low. M6620 is not anticipated to elicit 
clinically significant drug-drug interactions from reversible or time-dependent inhibition or 
induction pathways, however the drug interaction profile of M6620 has not been fully 
characterized. Caution should be used when co-administering medications with M6620. As 
M6620 is primarily metabolized by CYP3A4, concomitant administration with potent inhibitors 
or inducers of CYP3A4 should be avoided when medically feasible. 
 
The following list of potent CYP3A4 inhibitors and inducers is not exhaustive: 
 Potent CYP3A4 inhibitors: clarithromycin, itraconazole, ketoconazole, hepatitis C virus 
and human immunodeficiency virus protease inhibitors, nefazodone, posaconazole, 
telithromycin, voriconazole 
 Potent CYP3A4 inducers: carbamazepine, rifampin, phenobarbital, phenytoin, St. John’s 
wort 
 
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5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
 
Disease progression, unless the participant is exhibiting clinical benefit as determined 
by the treating investigator 
 
 
Intercurrent illness that prevents further administration of treatment 
 
 
Unacceptable adverse event(s) 
 
 
Participant decides to withdraw from the protocol therapy 
 
 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
The research team will update the relevant Off Treatment information in OnCore.  
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Gregory M. Cote MD, PhD at 617-724-4000.  
 
5.6 
Duration of Follow Up 
 
Participants will be followed for 30 days after removal from protocol therapy or until death, 
whichever occurs first.  Participants removed from protocol therapy for unacceptable adverse 
event(s) will be followed until resolution or stabilization of the adverse event. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 Lost to follow-up 
 Withdrawal of consent for data submission 
 Death 
 Completion of the 30 day follow up period after study drug discontinuation, or resolution 
or stabilization of any unacceptable adverse events (whichever is longer) 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
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The research team will update the relevant Off Study information in OnCore.  
 
Patients who require replacement and otherwise do not meet 5.5  Criteria for Taking a Participant 
Off Protocol Therapy and/or 5.7 Criteria for Taking a Participant Off Study may continue on 
study protocol. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
6.1 
Dose Delays 
 
The study agent may be held for a maximum of 28 days to allow for recovery of toxicity. 
Participants requiring a longer delay should be removed from protocol therapy. Participants who 
are deriving clinical benefit who require a longer hold may be allowed to continue treatment 
following discussion and agreement with the overall principal investigator. 
 
If a participant’s dosing is held, the counting of cycle days and assessment schedule will 
continue without interruption. For example, a participant who does not receive their Cycle 1 Day 
8 infusion due to toxicity may restart dosing on Cycle 1 Day 11 and proceed with their next 
scheduled visit as previously planned (Cycle 1 Day 11). Interim clinic visits may be conducted as 
clinically necessary to manage toxicity; however, the cycle will not restart due to adverse events 
and held infusions will not be administered or “made up” following toxicity resolution. 
Assessments during drug holds (laboratory values, vitals signs, exam, etc.) are only required as 
clinically indicated and will not be counted as protocol violations if not performed.    
 
6.2 
Dose Modifications 
 
Dose reductions may be made in accordance with the tables below. Dose reductions below 120 
mg/m2 will not be permitted. Participants requiring dose reductions below 120 mg/m2 should be 
discontinued from protocol therapy. Once a participant’s dose has been reduced it may be re-
escalated to a previous dose level after discussion with the site principal investigator. 
 
Table 5: M6620 Dose Reductions (Twice Weekly Dosing) 
Dose Level 
M6620 Dose (IV on days 1, 4, 8, 11, 15, 18, 
22, and 25) 
-1
210 mg/m2
-2
165 mg/m2
-3 
120 mg/m2 
 
Participants who have transitioned to a weekly dosing schedule will dose reduce based on the 
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table below: 
 
Table 6: M6620 Dose Reductions (Once Weekly Dosing) 
Dose Level 
M6620 Dose (IV on days 1, 8, 15, and 22) 
-1
210 mg/m2
-2 
165 mg/m2 
-3
120 mg/m2
 
 
6.3 
Toxicity Management Guidelines 
 
Management of toxicity considered at least possibly related to the study agent is detailed in the 
tables below. 
 
Table 7: Management of Non-Hematological Toxicity 
Event Term 
CTCAE 
Grade 
Management Guidelines 
Infusion 
Related 
Reaction 
Grade 1 
Monitor participant for worsening signs or symptoms. If 
symptoms worsen, follow the guidelines for the appropriate 
higher grade reaction. At the treating investigator’s discretion, 
the infusion may be paused or discontinued. 
 
Consider pre-medication and/or slowing of the infusion rate for 
subsequent infusions if clinically appropriate as determined by 
the treating investigator (see Section 5.3.2). 
Infusion 
Related 
Reaction 
Grade 2 
Stop infusion. Administer appropriate supportive care as per 
local standards of practice. At the treating investigator’s 
discretion, the infusion may be re-started when symptoms 
resolve to baseline, or the infusion may be discontinued. If 
symptoms recur following restart, the infusion should be 
discontinued. 
 
Consider pre-medication and/or slowing of the infusion rate for 
subsequent infusions if clinically appropriate as determined by 
the treating investigator (see Section 5.3.2). At the treating 
investigator’s discretion, study agent dose may be reduced for 
subsequent infusions by one dose level. 
Infusion 
Related 
Reaction
≥ Grade 3 
Permanently discontinue protocol therapy. Administer 
appropriate supportive care as per local standards of practice. 
Any Other 
Non-
Hematologic 
Toxicity
≥ 3A 
Hold study medication dosing. Upon resolution to ≤ Grade 2 or 
baseline, resume dosing with one dose level reduction. 
 
Exceptions:
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Table 7: Management of Non-Hematological Toxicity 
Event Term 
CTCAE 
Grade 
Management Guidelines 
 Grade 3 nausea, vomiting, diarrhea, or constipation that 
was not optimally managed. In this instance, hold study 
medication dosing and initiate appropriate medical 
management (e.g. anti-emetics, anti-diarrheals, 
laxatives). If symptoms resolve to ≤ Grade 1 or baseline 
within 48 hours of instituting appropriate care, 
participants may resume dosing at the same dose level 
or may be dose reduced by one dose level at the treating 
investigator’s discretion. 
 Laboratory abnormalities that are judged by the treating 
investigator to be not clinically significant. Participants 
may continue dosing at the same dose level as judged 
appropriate by the treating investigator. 
 Asymptomatic laboratory abnormalities that resolve to ≤ 
Grade 1 or baseline within 48 hours of repletion. Study 
medication should be held until abnormalities resolve to 
≤ Grade 1 or baseline and may be resumed at the same 
dose level as judged appropriate by the treating 
investigator. Repletion and resumption of study 
treatment may occur on the same day. 
A. Participants experiencing intolerable Grade 2 events may have their study medication 
held and/or dose reduced at the treating investigator’s discretion. 
 
 
Table 8: Management of Hematological Toxicity 
Event 
Term 
CTCAE 
Grade 
Management Guidelines 
Neutrophil 
Count 
Decreased 
≥ Grade 3 (not 
associated with 
fever/infection)
1st Occurrence: Hold study medication dosing until resolution 
to ≤ Grade 2 or baseline. Upon resolution, may resume at the 
same dose level at the treating investigator’s discretion, or 
may reduce dose by one dose level. 
 
Repeat Occurrence: Hold study medication dosing until 
resolution to ≤ Grade 2. Upon resolution, reduce dose by one 
dose level.
Febrile 
Neutropenia
≥ Grade 3 
Hold study medication dosing until resolution. Upon 
resolution, reduce dose by one dose level.
Platelet 
Count 
Decreased 
Grade 3 (not 
associated with 
clinically 
significant 
Hold study medication dosing until resolution to ≤ Grade 2 or 
baseline. Upon resolution, may resume at the same dose level 
at the treating investigator’s discretion, or may reduce by one 
dose level.
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Table 8: Management of Hematological Toxicity 
Event 
Term 
CTCAE 
Grade 
Management Guidelines 
bleeding)
Platelet 
Count 
Decreased 
Grade 4;  
Grade 3 
(associated 
with clinically 
significant 
bleeding)
Hold study medication dosing until resolution to ≤ Grade 2 or 
baseline. Upon resolution, reduce dose by one dose level. 
Anemia 
Grade 4A 
Hold study medication dosing until resolution to ≤ Grade 2 or 
baseline. Upon resolution, reduce dose by one dose level. 
A. Participants experiencing Grade 3 anemia may have their study medication dosing held 
and/or dose reduced at the treating investigator’s discretion. 
 
6.4 
Overdose 
 
There is currently no specific treatment in the event of overdose with M6620 and possible 
symptoms of overdose are not established. Adverse reactions associated with overdose should be 
treated symptomatically and should be managed appropriately. 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event monitoring and reporting is a routine part of every clinical trial.  The list of 
Expected Toxicities (Section 7.2)  and the definitions and characteristics of an observed AE 
(Section 7.1 and Section 7.3) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
7.1 
Definitions  
 
7.1.1 
Adverse Event (“AE”) 
 
An AE is any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An 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 product, whether or not considered related to the 
medicinal product. 
 
7.1.2    Special Considerations 
 
 Use of a medicinal product during pregnancy or breastfeeding: reports where embryo, 
fetus or child may have been exposed to medicinal products (either through maternal 
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exposure or transmission of a medicinal product via semen following paternal 
exposure), 
 Reports of medication errors, uses outside what is foreseen in the protocol, including 
misuse and abuse of the product. 
 
Special Considerations will be described in the Final Study Report or any interim reports, 
as applicable. 
 
7.1.3    Serious Adverse Events (“SAE” or “SAEs”) 
 
A SAE is any AE as defined above, which also fulfills at least one of the seriousness 
criteria below: 
 results in death, 
 is life-threatening1), 
 requires in-patient hospitalization or prolongation of existing hospitalization, 
 results in persistent or significant disability/ incapacity, 
 is a congenital anomaly/ birth defect, or 
 is otherwise considered as medically important2). 
1) Life-threatening in this context refers to a reaction in which the patient was at risk 
of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if more severe.  
2) Medical and scientific judgement should be exercised in deciding whether other 
situations should be considered serious reactions, such as important medical 
events that might not be immediately life threatening or result in death or 
hospitalization but might jeopardize the patient or might require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse.  
7.1.4    Safety Issues/Concerns 
 
A safety issue/concern is defined as an important identified risk or important potential 
risk. Safety issues/concerns are events which may occur during the Study, not falling 
under the definition of SUSARs and consequently not being subject of the reporting 
requirements for SUSARs. Examples are events related to the conduct of the Study or the 
development of an investigational medicinal product likely to affect the safety of 
subjects, such as (but not limited to): 
 a major safety finding from a newly completed animal study (such as carcinogenicity), 
 recommendations of the DSMB, if any, where relevant for the safety of subjects, 
 
 
 
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7.1.5    Events not to be considered AEs 
 
Medical conditions present in a patient and documented at the time of Study enrolment, 
and that do not worsen in severity or frequency during the Study and are defined as   
baseline medical conditions; are NOT to be considered AEs. 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
 
7.1.6    Events not to be considered SAEs 
 
Previously planned (prior to signing the informed consent form) surgeries, and non-
disease related elective surgeries planned during the course of the study, should not be 
reported as SAEs unless the underlying medical condition has worsened or appeared 
during the course of the study. 
 
Preplanned hospitalizations or procedures for preexisting conditions that are already 
recorded in the patient’s medical history at the time of study enrollment should not be 
considered SAEs. Hospitalization or prolongation of hospitalization without a 
precipitating clinical AE (e.g., for the administration of study therapy or other protocol-
required procedure) should not be considered SAEs. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
Death due to disease progression should not be reported as an SAE unless the investigator 
deems it to be related to the use of study drug. 
 
7.2 
Expected Toxicities  
 
For this protocol only, the AEs/grades listed below do not require expedited reporting to the 
Overall PI, Funder or the DFCI IRB.  However, they still must be reported through the routine 
reporting mechanism (i.e. case report form). All the adverse drug reactions (ADRs) described in 
this section are assessed as expected events for regulatory reporting purposes. Please refer to the 
investigator’s brochure for M6620 for the most up-to-date information. 
 
 Infusion related reactions (including flushing, pruritus, rash, rash erythematous, rash 
macular, rash pruritic, rhinitis allergic, erythema, eyelid edema, facial edema, and 
hypersensitivity) 
 Infusion site reactions (including infusion site erythema, catheter site pruritus, catheter 
site related reaction, infusion site extravasation, catheter site pain, catheter site rash, 
infusion site discomfort, infusion site pruritus, infusion site rash, injection site rash, and 
injection site reaction, catheter site inflammation, infusion site swelling) 
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 Nausea 
 Vomiting 
 
AEs for M6620 that are listed above should be reported only if the adverse event varies in nature, 
intensity or frequency from the expected toxicity information which is provided above or in 
 the current Investigator’s Drug Brochure. 
 
7.3 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Attribution of the AE for Reporting Purposes: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.4 
Expedited Reporting Requirements  
 
7.4.1    Expedited Reporting Guidelines to the Overall Principal Investigator (PI) 
 
Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form. All events meeting  SAE definition 
as defined in section 7.1.3 should be reported, regardless of attribution.  
 
7.4.2 
DF/HCC Expedited Reporting Guidelines to the DFCI IRB 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.4.3    Expedited Reporting to the Funder (Merck KGaA, Darmstadt, Germany (EMD Serono) 
 
Institution shall ensure that information on any AE is recorded comprehensively and 
maintain high quality at all times. Institution shall perform a causality assessment of each 
recorded AE. For recording in the safety database, all SAEs (related and non-related, 
including all fatal outcomes), Special Considerations and Safety Issues/Concerns shall be 
sent to Funder in English language. 
 
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Participating Investigators must report SAE’s that meet the SAE definition as defined in 
section 7.1.3 to the Funder.  Only SAE’s occurring after the initial dose of study 
treatment will be reported. The information shall be sent via facsimile or the email listed 
below within one (1) business day or three (3) calendar days, whatever comes first, after 
becoming aware of the event using Medwatch form 3500 A.  
 
 
Fax No.: +49-6151-72 6914 
Email address:ICSR_CT_GPS@merckgroup.com 
 
A copy of this report must also be submitted to the Overall PI.  
 
7.4.4    Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the 
FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following the 
reporting requirements and timelines set by the FDA.  
 
7.4.5    Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any 
participant safety reports or sentinel events that require reporting according to 
institutional policy.  
 
7.4.6    Expedited Reporting of Pregnancies 
 
Investigators must report to the Overall PI any pregnancy occurring in a subject exposed 
to the Investigational Product (either through maternal exposure or transmission of the 
Product via semen following paternal exposure to the Product) during the course of the 
Study.   
 
The Overall PI will inform the Funder of all reported pregnancies and will ensure that the 
case is followed up to the end of the pregnancy and provide all relevant documentation  
and a final report on the outcome to Funder. 
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI 
on the toxicity case report forms.  AEs reported through expedited processes (e.g., 
reported to the IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
7.6 
Routine Reporting to the Funder (Merck KGaA, Darmstadt, Germany (EMD Serono) 
 
7.6.1 
Global Patient Safety Reporting  
 
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The Overall PI shall provide Funder’s Global Patient Safety department on a quarterly basis with 
information on AEs, safety laboratory data, vital signs and any efficacy data necessary to assess 
and monitor the safety of the Investigational Product 
 
7.6.2 
Reconciliation 
 
To ensure completeness and accuracy of the transfer of safety events to Funder, Overall PI shall 
perform a reconciliation of all safety events occurred during the Study versus Funder’s Global 
Safety Database prior to closing the Study database. Funder shall provide the excerpt of its 
Global Safety Database to Institution in a timely manner. 
 
7.6.3 
Periodic Reports 
 
The Overall PI shall provide Funder in a timely manner with a copy of any periodic report sent to 
health authorities or Ethics Committees. 
 
7.6.4 
Coding of Safety Data 
 
Overall PI shall use accepted international standard definitions for severity, seriousness,  the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology (last version) for coding 
purposes. Furthermore, the related MedDRA coding conventions ‘Points to Consider’ published 
by the Maintenance and Support Services Organization shall be applied by Institution for coding 
of event data. 
 
7.6.5 
Safety Data Monitoring Committee 
 
Overall PI shall evaluate the set-up of a safety data monitoring committee to ensure the  safety of 
the participants and the validity and integrity of safety data generated from the  study according 
to applicable Guidelines on Data Monitoring Committees. 
 
7.6.6 
SUSARS 
 
Institution is responsible for assessment of Suspected Unexpected Serious Adverse Reactions 
(“SUSARs”). For expedited reporting only Institution’s assessment of SUSARs shall be used. 
 
7.6.7 
Signal Detection 
 
Funder will perform regular signal detection on the Investigational Product in its global safety 
database. In case of any action arising from such signal detection activities which is relevant for 
the conduct of the Study, Funder will inform the Overall PI in a timely manner. 
 
Funder will perform a medical assessment for the purpose of signal detection and cumulative 
reporting of safety information and will also request follow-up information from the Overall 
Principal Investigator as needed. In case of any action arising from such signal detection 
activities which is relevant for the conduct of the Study, Funder will inform the Overall Principal 
Investigator in a timely manner. 
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7.6.8 
Study Report 
 
Complete data on AEs (including Special Considerations) shall be collected and provided to 
Funder at the end of the Study in the Final Study Report, and on special request from Funder 
during the course of the Study. The safety data sets shall be provided in an internationally 
accepted format which allows integration into the Global Safety Database of Funder. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational product 
administered in this study can be found in Section 7.2. 
 
8.1 
M6620 (VX-970) 
 
8.1.1 
Description 
 
The active drug substance can be supplied as the hydrochloride salt or as the free base 
form. 
 
Table 99: Hydrochloride Drug Substance 
Code Name 
M6620, VRT-0768079, VX-970
Molecular Formula
C24H26ClN5O3S 
Molecular Weight 
500.01 Da
Appearance 
Yellow powder 
Melting Point 
295˚C
Solubility in Water 
3.2 mg/mL @ pH 6.22 
pKa 
9.15 (base), 1.07 (base)
 
Table 1010: Free Base Drug Substance 
Code Name 
M6620, VRT-0768079, VX-970
Molecular Formula 
C24H25N5O3S 
Molecular Weight 
463.55 Da
Appearance 
Yellow powder 
Melting Point 
211˚C
Solubility in Water 
0.1 mg/mL @ pH 6.71 
Solubility in 1-butanol 
0.01 mg/mL
Solubility in water saturated 1-butanol
2.0 mg/mL 
pKa 
9.15 (base), 1.07 (base)
 
 
8.1.2 
Form 
 
M6620 is a sterile solution intended for IV administration. It is presented at a 
concentration of 20mg/mL in a 10mL single use glass vial.  
 
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8.1.3 
Storage and Stability 
 
Single-use, sterile, light-protected vials of M6620 should be stored at room temperature 
(15°C to 30°C). 
 
Diluted IV solution (IV bags) should be covered to protect from light and stored in the 
dark for a maximum of 24 hours at refrigerated conditions (2°C to 8ºC). Diluted solution 
is stable at ambient and refrigerated conditions for 24 hours. 
 
8.1.4 
Compatibility 
 
No other medications should be administered via the same IV infusion line. M6620 is not 
compatible with sodium chloride, 5% dextrose in water (D5W) should be used to prime 
and flush the IV infusion line. 
 
8.1.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment.  
 
8.1.6 
Availability 
 
M6620 is an investigational product that will be supplied by Merck KGaA, Darmstadt, 
Germany (EMD Serono). 
 
8.1.7 
Preparation 
 
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 
M6620. 
 
To prepare the infusion solution add the dose volume of 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. 
 
8.1.8 
Administration 
 
M6620 will be infused IV twice weekly on cycle days 1, 4, 8, 11, 15, 18, 22, and 25 via a 
large bore catheter into a large caliber peripheral vein. Alternatively, M6620 may be 
infused via a central line or implanted venous access system (i.e. Port-a-Cath®). The 
infusion should be delivered over 60 minutes, there is an allowable ± 10 minute infusion 
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window. When the total volume of infusion exceeds 600 mL, the infusion time maybe be 
extended beyond 60 minutes (as tolerated), but no more than 90 minutes. Infuse using an 
infusion set containing low-sorption or non-PVC, DEHP-free tubing and an in-line 0.2 
micron filter. M6620 should not come in contact with sodium chloride, 5% dextrose in 
water must be used for IV line priming and flushing. 
 
Of note, after 16 weeks participants may consider a weekly dosing schedule on cycle 
days 1, 8, 15, and 22 after discussion with the site principal investigator.  
 
8.1.9 
Ordering 
 
M6620 will be ordered by site pharmacy personnel via contacting Merck KGaA, 
Darmstadt, Germany (EMD Serono) at: Lori Magnelli (lori.magnelli@emdserono.com; 
Ph 781-490-8556). 
 
8.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.1.11 Destruction and Return 
 
Expired or unused supplies of M6620 should be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
9.1 
Archival Tissue Collection (All Participants) 
 
Archival tissue is required for enrollment to the trial. Archival tissue may be either a formalin-
fixed paraffin-embedded (FFPE) block or unstained slides. Participants undergoing a baseline 
fresh tumor biopsy who do not have sufficient archival tissue at study entry may be allowed to 
use tissue from the fresh biopsy in lieu of archival tissue. Pediatric participants without sufficient 
archival tissue at study entry are not required to undergo fresh tumor biopsy.   
 
Please refer to the protocol laboratory manual for specific handling and shipping instructions. 
 
 
9.2 
Fresh Tumor Tissue Biopsies (Translational Lead-in Cohorts T1, T2, T3 Only; Optional for T4) 
 
Core needle, incisional, or excisional biopsies should be obtained for analysis. Please refer to the 
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protocol laboratory manual for specific handling and shipping instructions. 
 
 Biopsy #1: Fresh tumor tissue biopsies will be obtained at baseline from all T1, T2, and 
T3 patients enrolling to the translational lead-in study. Biopsy is optional for T4.  
o The baseline fresh tumor biopsy may be obtained any time before the participant’s 
Cycle 1 Day 1. 
o At the time the baseline biopsy sample is obtained, a germline blood sample 
should also be collected. 
o For cohorts T2 and T3, fresh biopsy is not required for patients with adequate 
archival biopsy available (15 slides; lower numbers may be allowed with 
permission from the overall PI)  provided that the samples are not older than 6 
months and the patient has not received systemic therapy between the time of 
biopsy and consent for study 18-274 
 Biopsy #2: On-treatment biopsy will be obtained from all T1, T2, and T3 participants if 
medically feasible (optional for T4).  
o The biopsy should be scheduled to occur within 30 hours of the end of the 
infusion of the fifth (5th) dose of study drug. Following agreement with the site 
principle investigator, the biopsy may alternately be obtained within 30 hours 
following the completion of the seventh (7th) dose of study drug.   
o PT and PTT should be collected before Biopsy #2 
o The biopsy should not be performed if the patient did not receive the study drug 
infusion. If a participant does not receive their planned study drug infusion due to 
toxicity, every effort should be made to re-schedule the biopsy to occur within 30 
hours of when they actually receive their fifth (or seventh) dose of study drug. In 
the event re-scheduling of the biopsy is not feasible it will not be considered a 
protocol violation, however the toxicity necessitating the dose hold and the reason 
the biopsy was not obtained must be clearly documented and discussed with the 
site principal investigator. 
 Biopsy #3: An additional optional biopsy at the time of disease progression will be 
offered to all participants.  
o The time of progression biopsy should be obtained prior to the initiation of 
another anti-cancer therapy when possible. In the event this is not feasible, the 
time of progression biopsy may be obtained up to 30 days after the date that 
disease progression was determined. The date of progression may be considered 
either the date the radiological scan was performed, or the date the treating 
investigator judged the participant to have progressed. 
 On the same day as the collection of any of the biopsies, a single PK sample will be 
obtained. Please refer to Section 9.3 and the protocol laboratory manual for specific 
collection, handling, and shipping instructions. 
 Any participant who is unable to complete both the baseline and on-treatment biopsies 
will be replaced to allow sufficient collection of pharmacodynamic data to evaluate the 
primary objective of the translational lead-in study. 
 If the biopsy is deemed unsafe, the patient may enroll with the permission of the overall 
PI 
 
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9.3 
 Pharmacokinetic Sampling (Translational Lead-in Study Only) 
 
Limited PK sampling will be collected on participants in the translational lead-in study at the 
time points indicated in the table below. Please refer to the protocol laboratory handbook for 
specific PK collection, handling, and shipping instructions. 
 
 
Table 1111: PK Sample Collection 
Visit Day 
Time of Collection 
Sample Number 
Cycle 1 Day 15 
 
Pre-dose (0 – 5 minutes prior to the 
initiation of the infusion) 
PK-1 
Cycle 1 Day 15 
End of infusion (0-5 minutes after 
infusion is complete) 
PK-2 
Biopsy #1 
On the same day as the biopsy 
collection 
PK-B1 
Biopsy #2 
On the same day as the biopsy 
collection, within 30 hours of the end 
of the infusion of the 5th dose of 
study drug (or 7th if the biopsy is 
collected following the 7th infusion 
per Section 9.2); every effort should 
be made to obtain PK-B2 as close to 
the time of biopsy as is feasible (e.g. 
within 2 hours).
PK-B2 
Biopsy #3 
On the same day as the biopsy 
collection. Every effort should be 
made to obtain PK-B3 as close to the 
time of biopsy as is feasible (e.g. 
within 2 hours). 
 
If the participant does not undergo a 
time of progression biopsy, this PK 
sample will not be collected. 
PK-B3 
  
9.4 
ATM Mutation Status and Immunohistochemistry 
 
 For all ATM patients (T2 and Cohort 2) mutation status will be reviewed for eligibility 
by the overall PI (Cote), and if necessary, the DFCI site PI (Shapiro), other site PIs, and 
laboratory collaborators.  
 For non-truncating ATM mutations, the NGS data will be evaluated for probability of 
ATM protein inactivation by the overall PI (Cote), the DFCI site PI (Shapiro), other site 
PI’s, and laboratory collaborators. If the mutation is suggestive of ATM inactivation the 
eligibility will be confirmed by the overall PI (Cote), the DFCI site PI (Shapiro), and 
laboratory collaborators.  
 If the patient and ATM mutation meet eligibility, the patient may be enrolled on study in 
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T2 and Cohort 2 and initiate study treatment as per protocol. In parallel, archival or fresh 
biopsy tumor will be analyzed for ATM status by IHC via a CLIA-approved assay at 
BWH.  
o If ATM is expressed by IHC, the patient will be allowed to continue on treatment 
if clinically indicated; however, this patient will be replaced and not count 
towards accrual limits.   
o If ATM is not expressed by IHC, the patient will continue study as procedures per 
protocol and the patient will count towards accrual limits.     
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy, with 
the exception of the informed consent and baseline imaging which must be done < 28 days prior 
to the start of therapy.  
 
Assessments must be performed prior to administration of any study agent.  
 
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Page 44
Table 12: Study Calendar 
 
Pre-
Study 
Cycle 1 
Day 1 
Cycle 
1 Day 
4a 
Cycle 
1 Day 
8a 
Cycle 
1 Day 
11a 
Cycle 
1 Day 
15a 
Cycle 
1 Day 
18a 
Cycle 
1 Day 
22a 
Cycle 
1 Day 
25a 
Cycle 
2+ 
Day 1b
Cycle 
2+ 
Day 
4a, c 
Cycle 
2+ 
Day 8a
Cycle 
2+ 
Day 
11a, c 
Cycle 
2+ 
Day 
15a 
Cycle 
2+ 
Day 
18a, c 
Cycle 
2+ 
Day 
22a 
Cycle 
2+ 
Day 
25a, c 
Off 
Treatmentd 
Informed consent
X
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history
X
Physical exam
X
X
X
X
X
X
X
X
Vital signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height
X
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status
X
X
X
X
X
CBC w/diff, plts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistryf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
β-HCGg
X
ECGh 
X 
As clinically indicated 
 
Adverse event 
evaluation
 
X-------------------------------X 
X 
Radiologic 
evaluation
X 
CT or MRI imaging of any disease-involved site. Imaging to be conducted every 8 weeks (± 7 day scheduling window). 
X 
Archival tissue 
collectioni
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh Tumor 
Biopsy, Germline 
Blood Sample 
Collectionj
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
M6620 
administrationk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK Collectionl
X
X
X
cfDNA 
Collectionm
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                               
 
 
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Table 12: Study Calendar 
 
Pre-
Study 
Cycle 1 
Day 1 
Cycle 
1 Day 
4a 
Cycle 
1 Day 
8a 
Cycle 
1 Day 
11a 
Cycle 
1 Day 
15a 
Cycle 
1 Day 
18a 
Cycle 
1 Day 
22a 
Cycle 
1 Day 
25a 
Cycle 
2+ 
Day 1b
Cycle 
2+ 
Day 
4a, c 
Cycle 
2+ 
Day 8a
Cycle 
2+ 
Day 
11a, c 
Cycle 
2+ 
Day 
15a 
Cycle 
2+ 
Day 
18a, c 
Cycle 
2+ 
Day 
22a 
Cycle 
2+ 
Day 
25a, c 
Off 
Treatmentd 
a. 
A ± 3 day scheduling window to accommodate for adverse weather, vacations, holidays, or other scheduling issues may be permitted after discussion with the overall PI. There is a required 
minimum of 72 hours between doses in Cycle 1. After Cycle 1, if the patient is tolerating therapy without clinically significant AE’s or SAE’s, the investigator may shorten this window to 
up to 60 hours to allow for scheduling flexibility. 
b. 
A -1 / +7 day scheduling window is allowable to accommodate adverse weather, vacations, holidays, or other scheduling issues.  
c. 
Visit only required in participants receiving twice weekly infusions, not required in participants receiving once weekly infusions. 
d. 
Off-treatment evaluation to occur 30 days following the end of study treatment, +/- 2 weeks. Note: for IND trials, follow up visits or other contact are required in order to identify SAEs 
during the 30 days following the last dose of study drug. 
e. 
Heart rate, blood pressure, respiratory rate, and temperature. Assessments to be collected prior to study agent dosing when applicable. 
f. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
g. 
Serum pregnancy test for women of childbearing potential. Childbearing potential defined as any female who has not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy) or is not post-menopausal (defined as amenorrhea >12 consecutive months; or women with a documented plasma follicle-stimulating hormone 
level >35µlU/mL). 
h. 
Single ECG to be collected, QTc to be calculated per institutional standards. 
i. 
Archival tumor tissue must be available for analysis for enrollment on the trial. Please refer to Section 9.1 for details. 
j. 
Translational lead-in study T1, T2, and T3 participants only, optional for T4, not applicable for phase II participants. Tumor tissue biopsy collection is required at baseline and again on-
treatment, and optional at the time of disease progression as detailed in Section 9.2. A germline blood sample will be collected with the baseline tumor tissue biopsy. If the patient is not 
having a pre-treatment biopsy, the germline blood sample should still be collected during screening. 
k. 
M6620 will be infused IV twice weekly on cycle days 1, 4, 8, 11, 15, 18, 22, and 25. After 16 weeks, participants may consider a weekly dosing schedule on cycle days 1, 8, 15, and 22 
after discussion with the site principal investigator. Please refer to Section 5.1 for more detail. Labs must result before dosing. 
l. 
Translational lead-in study participants only, not applicable for phase II participants. PK to be collected as detailed in Section 9.3. Effort should be made to obtain the PK sample as close 
to the time as biopsy as feasible (e.g. within 2 hours) 
m. 
20 mL of peripheral blood will be collected in two 10 mL Streck cfDNA tubes at any time during screening before c1d1 for cohort T1 only. 
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Page 46
 
11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks (± 
7-day scheduling window).  In addition to a baseline scan, confirmatory scans should also be 
obtained not less than 4 weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants 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 target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area will not be 
considered measurable unless there has been demonstrated growth in the lesion following 
completion of the radiation treatment. 
 
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 
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(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, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  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.  
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Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in 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 thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT  scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both approaches 
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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. 
 
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.   
MIBG (meta-iodobenzylguanidine).The following is recommended, to assure high 
quality images are obtained.  
Patient preparation: Iodides, usually SSKI (saturated solution of potassium iodide), 
are administered to reduce thyroidal accumulation of free radioiodine, preferably 
beginning the day prior to injection and continuing for 3 additional days (4 days 
total). For infants and children, one drop t.i.d. is sufficient, for adolescents 2 drops 
t.i.d., and for adults 3 drops t.i.d. Participants and/or parents are asked about exposure 
to potential interfering agents. If none is noted, an indwelling intravenous line is 
established. The dose of MIBG is administered by slow intravenous injection over 90 
seconds.  
Images from the head to the distal lower extremities should be obtained.  
I-123MIBG scintigraphy is performed to obtain both planar and tomographic images.  
Planar: Anterior and posterior views from the top of the head to the proximal lower 
extremities are obtained for 10 minutes at 24 hours and occasionally at 48 hours 
following injection of 10 mCi/1.7 square meters of body surface area (~150 μCi/kg, 
maximum 10 mCi). Anterior views of the distal lower extremities are adequate. A 
large field of view dual head gamma camera with low energy collimators is preferred.  
 
SPECT: Most participants receiving I-123 MIBG also undergo SPECT at 24 hours, 
using a single or multi-headed camera with a low energy collimator. The camera is 
rotated through 360 degrees, 120 projections at 25 seconds per stop. Data are 
reconstructed using filtered back projections with a Butterworth filter and a cut off 
frequency of 0.2-0.5. SPECT/CT may be performed at institutions with this capacity. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
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as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later data 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 
from 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 participant to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
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. 
 
11.1.3.1 
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 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 
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increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.3.2 
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 patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.3.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.3.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 
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Table 13: For Participants 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 disease progression. 
 
Note:  Participants 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 14: For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR
No
CR
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.4 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, or 
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death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 
Duration of overall complete response: 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, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.5 Response Review 
 
Evaluation of scans will be done centrally using the Tumor Imaging Metrics Core 
(TIMC). 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality in accordance with DF/HCC SOPs. 
 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
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participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
13.1.1 Translational Lead-in Study 
 
A small translational lead-in study will be conducted prior to the initiation of the phase II trial. 
The translational lead-in will serve to determine changes in the pharmacodynamic endpoints of 
phospho-Chk1 and H2AX in biopsy specimens of patients treated with M6620 monotherapy, 
and to evaluate the preliminary anti-cancer activity of M6620 monotherapy in selected cancer 
populations, including:  
 
 Cohort T1: ATRX-mutated LMS 
 Cohort T2: ATM-mutated solid tumors 
 Cohort T3: BRCA1/2 and other HR-mutated cancers, malignancies with replicative stress, 
and ARID1A-mutated cancers. 
 Cohort T4: SDH-deficient  GIST 
 
Each cohort will enroll 6 participants. Mandatory baseline and on-treatment biopsies will be 
collected from all T1, T2, and T3 participants, and an optional time-of-progression biopsy will 
be offered to all participants. Biopsies are optional for T4. Any T1/T2/T3 patient unable to 
complete both the baseline and on-treatment biopsies will be replaced to allow for sufficient 
collection of pharmacodynamic data. Non-parametric paired analysis will be conducted to assess 
the significance of changes between baseline and on-treatment pharmacodynamics parameters. 
With 6 samples the study will be powered (80%) to detect an effect size of 1.067 in mean of 
paired difference between baseline and on-treatment phospho-Chk1 and H2AX with a 
significance level of 0.05 using a two-sided Wilcoxon test and assuming that the actual 
distribution is double exponential. 
 
The probability of rejecting the treatment in the lead-in phase for a true but unknown rate of 60% 
reduction in baseline phospho-CHK1 and a 50% increase in γH2AX of 50% is 0.65. If this rate is 
20% the probability of rejection is 0.98 and if the rate is 80% the probability of rejection is 0.098 
 
Following the completion of enrollment to the translational lead-in study, a review of all 
available safety, efficacy, pharmacodynamic, and pharmacokinetic data will occur prior to the 
initiation of the phase II trial. Review will be conducted by the overall principal investigator, site 
principal investigators, any applicable study team members, as well as consultation with Merck 
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KGaA (EMD Serono) as appropriate. Alteration of the phase II design based on findings from 
the translational lead-in study may occur with a protocol amendment following the review. 
 
 
13.1.2 Phase II 
 
After completion of the review of the initial translational lead-in study, a phase II, five-cohort 
basket trial with the primary endpoint of disease control rate at 16 weeks will open. The disease 
control rate is defined as achievement of confirmed objective response (complete or partial 
response), or stable disease that is confirmed at 16 weeks from the baseline disease evaluation.  
We will enroll 25 patients in cohorts 1A, 2-5 following a two-stage approach. We will enroll 30 
patients in a single stage for cohort 1B.  
 
Assuming the null and alternative hypothesis (null: 15%, alternative: 35%) is the same among 
cohorts 1A and 2-5, at the first stage analysis, we will need to observe at least 3 patients with 
controlled disease out of 15 patients to continue through the second stage.  At the second stage, 
we will assess disease control rate again, and we will need to observe at least 7 instances of 
patients with controlled disease out of 25 patients to reject the null hypothesis and accept the 
treatment as having value for further study.  The overall power for disease control rate at 16 
weeks is 81%.  The overall type I error, the chance of incorrectly rejecting the null hypothesis is 
7%.  The probability of stopping at the first stage under the null hypothesis is 60%.  The 
operating characteristics of this design are based on the two-stage Minimax design. While cohort 
1B is conducted as a single cohort, the hypothesis tested are identical to the ones in the other 
cohorts. With one-sided type 1 error of 7% (as in the other cohort) this arm will have 87% power 
to differentiate between the null of 15% and alternative of 35%. The null will be rejected if at 
least 8 patients have controlled disease. 
 
It is estimated that ~50% of LMS are ALT+. Thus, for cohort 1B, study characteristics favor 
enrollment to a single stage of 30 patients. ALT status will be determined retrospectively after 
study completion and sub group analysis will be conducted on these patients. We expect 
approximately 15 patients to be included in this analysis. With 15 patients, the study will be 
sufficiently powered (at least 80%) to detect an increase of at least 25% from the null of poor 
disease control rate of 15% with one-sided significance level of 0.07. if at least 5 patients in this 
cohort are observed with controlled disease, the drug will be considered for further investigation 
in this study population.  
 
Toxicity is an important secondary endpoint.  With 25 patients in each cohort, there is at least 
72% probability of observing one or more toxicities with a true rate as low as 5%.  With 25-30 
treated patients in each cohort, the maximum width of a 90% two-sided confidence interval for 
any estimated adverse event proportion ± 18%. 
 
  
13.2 
Sample Size and Study Duration 
 
A total of 24 participants will be enrolled to the translational lead-in study among the three 
cohorts, and a maximum of 205 participants will be enrolled to the phase II trial among the five 
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cohorts. Total study duration (translational lead-in and phase II) is estimated to be approximately 
60 months. 
 
13.3 
Reporting and Exclusions 
 
13.3.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
13.3.2 Evaluation of the Primary Efficacy Endpoint 
 
All eligible participants included in the study who receive at least one dose of study 
medication will be assessed for response, even if there are major protocol therapy 
deviations. Each participant should be assigned one of the following categories: 1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because of 
other cause, or 9) unknown (not assessable, insufficient data). By arbitrary convention, 
category 9 usually designates the "unknown" status of any type of data in a clinical 
database. 
 
13.3.3 Evaluation of the Primary Pharmacodynamic Endpoint (Translational Lead-in Study Only) 
 
All eligible participants who successfully underwent both the baseline and the on-
treatment biopsies will be assessed for pharmacodynamic response as measured by 
changes in phospho-CHK1 and H2AX. Any participant who was unable to undergo both 
the baseline and on-treatment biopsy will be replaced. In the event the biopsy tissue 
obtained from either the baseline or on-treatment biopsy was not sufficient for analysis, 
the participant will be replaced. 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
 
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van 't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical 
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Ting DT, Lipson D, Paul S, et al. Aberrant overexpression of satellite repeats in 
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pancreatic and other epithelial cancers. Science. 2011;331(6017):593-596. 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
Performance Status Criteria  
Karnofsky and Lansky performance scores are intended to be multiples of 10  
 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description  
Score  
Description  
Score 
Description  
0  
Fully active, able to carry on all 
pre-disease performance 
without restriction.  
100  
Normal, no complaints, no 
evidence of disease 
100  
Fully active, normal.  
90  
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90  
Minor restrictions in physically 
strenuous activity.  
1  
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. 
80  
Active, but tires more quickly  
70  
Cares for self, unable to carry 
on normal activity or do active 
work. 
70  
Both greater restriction of and less 
time spent in play activity.  
2  
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  
Required occasional assistance, 
but is able to care for most of 
his/her needs. 
60  
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50  
Requires considerable 
assistance and frequent 
medical care.  
50  
Gets dressed, but lies around 
much of the day; no active play, 
able to participate in all quiet play 
and activities. 
3  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours.  
40  
Disabled, requires special care 
and assistance. 
40  
Mostly in bed; participates in 
quiet activities. 
30  
Severely disabled, 
hospitalization indicated. 
Death not imminent.  
30  
In bed; needs assistance even for 
quiet play.  
4  
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair.  
20  
Very sick, hospitalization 
indicated. Death not imminent. 
20  
Often sleeping; play entirely 
limited to very passive activities. 
10  
Moribund, fatal processes 
progressing rapidly. 
10  
No play; does not get out of bed.  
 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 
 
 
 
 
 
 
 
 
 
 
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/271-

/443806- 	 

ICF_001.pdf: 
  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 1 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
Protocol Title:  A Phase II Study of M6620 (VX-970) in Selected Solid Tumors 
DF/HCC Principal Research Doctor / Institution:   
Gregory Cote, MD, PhD / Massachusetts General Hospital 
DF/HCC Site-Responsible Research Doctor / Institution:   
Geoffrey Shapiro, MD, PhD / Dana Farber Cancer Institute 
 
Andrea Bullock, MD MPH / Beth Israel Deaconess Medical Center 
 
Katherine Janeway, MD / Dana-Farber Cancer Institute/Boston Children’s 
Hospital 
Translational Lead-In Informed Consent Form 
 
A. INTRODUCTION 
 
You are invited to take part in a clinical trial, a type of research study, because 
you have an advanced solid tumor. This research study is studying a drug called 
M6620 as a possible treatment for this diagnosis.   
 
For purposes of this research, you will be referred to as a “participant”.   
 
It is expected that about 223 people will take part in this research study.  
 
EMD Serono, a pharmaceutical company, is supporting this study by providing 
the study drug and funding for the study procedures.  
 
This research consent form explains why this research study is being done, what 
is involved in participating in the research study, the possible risks and benefits 
of participation, alternatives to participation, and your rights as a research 
participant.  The decision to participate is yours.  If you decide to participate, 
please sign and date at the end of this form. We will give you a copy so that you 
can refer to it while you are involved in this research study. If you choose not to 
participate in this research study, the research doctors will discuss other 
treatment options with you and/or refer you back to your primary doctor.  
 
We encourage you to take some time to think this over, to discuss it with other 
people and your primary doctor, and to ask questions now and at any time in the 
future. 
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 2 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
B. WHY IS THIS RESEARCH STUDY BEING DONE?  
 
This study is made up of two phases: a Translational Lead-In Phase and a Phase 
II.  These two phases serve different functions. The translational lead-in phase is 
designed to test the drug on a small number of patients in efforts to gain 
information on two research questions:  
• 
If M6620 has an anti-cancer effect on participants  
• 
If M6620 research findings that were discovered in laboratory studies are 
also found in human research studies.  
 
Phase II is a much larger study to determine if M6620 has an anti-cancer effect in 
different groups of patients.  
 
You are being invited to participate in the translational lead-in phase of study. 
   
The FDA (the U.S. Food and Drug Administration) has not approved M6620 as a 
treatment for any disease. 
 
ATR is an enzyme in cells that is responsible for multiple functions including 
repairing damaged DNA, helping cells that are stressed during the DNA copying 
process, and working to maintain the ends of chromosomes. In cancer cells, 
active ATR enzymes protect the cancer by helping the cells repair damage, stay 
alive, and maintain health. M6620 is a drug designed to inhibit the ATR enzyme. 
Inhibiting ATR may block how cancers repair their naturally damaged DNA, 
handle cancer cell stress, and maintain cancer cell life and health.  
Administration of M6620 may therefore assist in the slowing of growth or 
destruction of some cancers. 
 
In this research study, we are... 
• Gathering initial data on the anti-cancer activity of M6620 when given 
alone to participants within selected cancer populations 
• Determining if there are changes in the biological components in your 
body that may be associated with damaged DNA repair. 
 
 
 
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 3 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
C. WHAT OTHER OPTIONS ARE THERE? 
 
Taking part in this research study is voluntary. Instead of being in this research 
study, you have other options which may include the following: 
 
• Receive standard treatment including chemotherapy and/or 
immunotherapy, depending on your disease. 
• Take part in another research study.  
• Receive no therapy specific to your cancer. 
• Comfort care, also called palliative care.  This type of care may help to 
reduce pain, tiredness, appetite problems and other problems caused 
by the cancer.  It does not treat the cancer directly, but instead tries to 
treat the symptoms.   
 
Please talk to the research doctor about your options before you decide whether 
you will take part in this research study. 
 
D. WHAT IS INVOLVED IN THE RESEARCH STUDY? 
 
Sometimes it is hard to keep track of all of the details and procedures that are 
part of a research study.  We will describe them in this consent form and you can 
refer to this at any time during the research study. 
 
Before the research starts (screening):   
After signing this consent form, you will be asked to undergo some screening 
tests or procedures to find out if you can be in the research study.  Many of these 
tests and procedures are likely to be part of regular cancer care and may be 
done even if it turns out that you do not take part in the research study.  If you 
have had some of these tests or procedures recently, they may or may not have 
to be repeated.   
 
• A medical history, which includes questions about your demographics, 
health, current medications, and any allergies.  At future visits, this will be 
abbreviated and you will be asked about any changes in your health or 
symptoms you may have recently experienced. 
• A physical exam, which examines the health of your various body 
systems.  
• Your vital signs will be measured, which may include your pulse, 
oxygen level, respiratory rate, temperature, and blood pressure. This may 
include measuring your height and/or weight as well. 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 4 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
• Performance status, which evaluates how you are able to carry on with 
your usual activities.  
• Blood tests, totaling up to approximately 5 tablespoons at any one visit, 
to: 
• Measure your chemistry results, which provide information the health 
of various body systems 
• Assess your pregnancy status if you are a woman who is able to 
become pregnant 
• Take a baseline germline sample for analysis. Germline samples are 
used to look for genetic mutations that are inherited and may increase 
the risk and likelihood of the cancer you have.  
• To try to detect circulating free tumor DNA, for Cohort T1 only 
(approximately 1 tablespoon) 
• An electrocardiogram (ECG), which measures the electrical activity of 
your heart 
• An assessment of your tumor by one or more of the following standard 
assessment tools: CT (Computerized Tomography) scan, or MRI 
(Magnetic Resonance Imaging) scans.  
• If clinically necessary, your doctor may also request additional scans 
as medically appropriate:  
• x-ray  
• FDG-PET (fluorodeoxyglucose-positron emission tomography 
• PET-CT (Positron emission tomography–computed tomography) 
• MIBG(Metaiodobenzylguanidine). 
• Review of your tissue to determine your eligibility to participate in this 
study: 
• Your previously collected and stored tissue (archival tissue) will 
be obtained for tests. Reviewing your archival tissue is mandatory for 
entering into this study. 
• A new biopsy will be performed to collect a sample of your tumor 
tissue. Performing a new biopsy is mandatory for entering into this 
study. This biopsy serves an important function in this study, as it will 
help researchers assess the anti-tumor effects of the treatment. This is 
required for Cohorts T1-T3 and optional for T4.  
 
If these tests show that you are eligible to participate in the research study, you 
may begin the study treatment.  If you do not meet the eligibility criteria, you will 
not be able to participate in this research study. 
 
Study Treatment Overview: 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 5 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
• Infused Study Drug: One treatment cycle is 28 days long. You will be 
given M6620 twice weekly into your vein (by intravenous infusion) over 
about 60 minutes. After 16 weeks (4 Cycles) of treatment, your doctor may 
give you the option of switching to a once weekly infusion schedule if it is 
medically appropriate for you. Either way, study drug administration will 
continue as long as you do not have any unmanageable side effects and 
your disease doesn’t get worse.   
 
Study Visit: On treatment 
 
You will have regularly scheduled appointments to infuse the study drug. While 
you are receiving the infusion twice weekly, those infusions will occur on Cycle 
Days 1, 4, 8, 11, 15, 18, 22, and 25.  If you are able and decide to switch to the 
once weekly treatment (after 4 Cycles), that will occur on Cycle Days 1, 8, 15, 
and 22. 
 
The study visits may involve any of the procedures described in the 
screening section above, as well as the following: 
• Infused Study Drug 
• Blood tests: 
• 
Take a pharmacokinetic (PK) sample for analysis. PK samples are 
used to analyze the various components in your blood and body. 
Sometimes this sample will be drawn after your dose of the study 
drug has been administered, to see how your body absorbs and 
metabolizes the drug. 
 
 
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 6 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
Research Study Plan: 
 
 
Screening 
Cycle 1 
Cycles 2 and Beyonda 
Off 
Treatment 
 
Days 1 
and 15 
Day 4, 
11, 18, 
and 25 
Day 8 
and 22 Day 1 
Days 4, 
11, 18, 
25 
Day 8 
and 22 Day 15 
Medical History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
 
X 
X 
 
 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
 
 
X 
 
 
 
X 
Blood Test 
X 
X 
X 
X 
X 
 
X 
X 
X 
ECG 
X 
Only if clinically indicated 
 
Tumor Assessment 
Scan(s) 
X 
Every 8 Weeks 
X 
Archival Tissue Review 
X 
 
 
 
 
 
 
 
 
Tumor Biopsy 
Xb 
Xc 
 
 
 
 
 
 
Xd 
M6620 Administration  
 
X 
X 
X 
X 
X 
X 
X 
 
a If you switch to a once weekly infusion schedule, you will only have visits on 
Cycle Days 1, 8, 15, and 22 
b  Screening biopsy required for Cohorts T1-3. Optional for T4.  
c On treatment tumor biopsy on Cycle 1 Day 15. This is optional for T4 
d There is an optional biopsy for participants whose disease progresses 
 
Study Visit: Off Treatment 
You will have one visit when you go off treatment. Procedures and tests for this 
visit are described above in the Research Study Plan. 
Planned Follow-up:  
We would like to keep track of your medical condition. We would like to do this by 
following your condition for 30 days after you stop taking the study drug. This is 
to assess if you have any side effects after the treatment.  
 
When you leave the study, information from your chart will be collected about 
your cancer and wellbeing. The study team may also call you on the telephone if 
they have any questions or need to speak to you to hear about how you are 
doing. If the study team finds you have remaining side effects from the treatment, 
your condition will be followed until the side effects resolve, and the doctor may 
ask you to come in for a visit as well 
 
Keeping in touch with you and checking your condition helps us look at the long-
term effects of the research study.   
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 7 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
E. HOW LONG WILL I BE IN THIS RESEARCH STUDY? 
 
You will be in this research study as long as you do not have any unmanageable 
side effects and your disease does not get worse. 
 
You may be taken off the research study drug for many reasons including if: 
• It is considered to be in your best interest 
• The study treatment or procedures are found to be unsafe or ineffective 
• There is any problem with following study treatments and procedures 
• You are a female and become pregnant or plan to become pregnant 
• Your condition worsens 
• A decision is made to close the study 
• Or for other unforeseen reasons that make it necessary to stop your 
participation in the research study 
 
If you are removed from the research study, the research doctor will explain to 
you why you were removed.   
 
There may be an opportunity for you to continue on the study treatment even if 
you are removed from the study. Your doctor will discuss this with you if that is 
the case. 
 
In addition, you can stop participating in the research study at any time, however, 
the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study.  If you decide to stop participating in this 
research study, we encourage you to talk to the research doctor and your 
primary doctor first. 
 
F. WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY? 
 
There are risks to taking part in any research study. One risk is that you may get 
a study drug that does not help treat your disease or that makes your condition or 
disease worse.  Another risk is that there may be side effects.   
 
All cancer treatments can have side effects, which can range from mild and 
reversible to severe, long lasting and possibly life-threatening.  There is a great 
deal of variability among side effects of different cancer treatments and between 
individuals.  In a research study, all of the risks or side effects may not be known 
before you start the study. You need to tell your doctor or a member of the 
study team immediately if you experience any side effects.  
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 8 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
 
Everyone in the research study will be watched carefully for side effects.  You will 
be monitored during the administration of study drugs to keep track of your blood 
counts and organ function, particularly your kidney and liver function.  If you 
experience side effects, they may go away after you stop taking the study drug.  
Some side effects can be mild; but others can be long lasting and may never go 
away.  Some may be life-threatening or fatal.  
 
Since the effect of the study drug(s) taken with other medications may not be 
known, it is important that you tell the research doctor about all prescription and 
non-prescription drugs, herbal preparations and nutritional supplements that you 
are taking or planning to take. There may also be some foods that you should 
avoid while on this research study and your research doctor will review this 
information with you. 
 
During the research study, you will be notified of newly discovered side effects or 
significant findings, which may affect your health or willingness to participate.  
You may be asked to sign a new consent form that shows that you have been 
informed of new information relating to this research study. 
 
Risks Associated with M6620: 
Likely (At least a 15% chance that this will happen) 
• Nausea 
• Vomiting 
• Diarrhea 
• Fatigue 
• Urinary Tract Infection 
• Changes in liver tests that may indicate liver inflammation.  
• Changes in blood tests (creatinine) that may indicate kidney 
dysfunction. Kidney dysfunction may mean your body can’t filter out 
waste properly, leading to waste build up in your blood that causes 
swelling in the arms and legs, tiredness, and weakness. 
• Hyperglycemia, or high blood sugar.  This may cause increased thirst, 
headaches, trouble concentrating, blurred vision, frequent need to 
urinate, fatigue, and weight loss. 
• Worsening of cancer pain 
• Anemia, or low red blood cell count. This may cause tiredness and 
shortness of breath. 
• Flushing or redness of the skin 
• Headache 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 9 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
• Dizziness 
• Infusion related reaction where your body has a negative reaction to 
the drugs being administered. Symptoms may include dizziness, 
fainting, flushing of the skin, fever, shortness of breath, nausea, 
vomiting, or pain at the site of the infusion. 
 
An episode of delayed allergic reaction has occurred, which was possibly related 
to M6620. Delayed allergic reaction may include a rash, hives, fever, difficulty 
breathing, and low blood pressure. Although usually reversible with treatment, it 
can be severe or life threatening. 
 
An episode of febrile neutropenia has occurred, which was probably related to 
M6620. Symptoms of this condition include fever and an abnormally low level of 
a type of white blood cell called neutrophils. 
 
During an infusion, one episode of moderate phlebitis, or inflammation of the 
veins causing discomfort, pain, and swelling, occurred once for a patient that did 
not have a port. The patient had a port placement completed and the event has 
not recurred. 
 
Cancer research often includes biopsies, scans, x-rays that are also provided as 
routine care.  The following describes the side effects of procedures done only 
for the purposes of research.  
 
Risks Associated with Biopsies: 
Biopsies are normally performed under the guidance of an imaging technique. 
Each procedure requires a separate consent prior to the biopsy. The risks may 
include: 
• Pain and discomfort. The amount of pain and discomfort will vary, 
depending on the location of the biopsy site. These risks can be discussed 
with the study doctor. 
• Minor bleeding at the biopsy site. 
• Tenderness at the biopsy site. 
• Scarring at the biopsy site. 
• Rarely, an infection at the biopsy site. 
 
Uncommonly, complications from biopsies can be life threatening. As with any 
interventional procedure, other potentially serious complications from bleeding or 
organ damage may occur. These might require additional surgical intervention. 
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 10 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
Risks Associated with MRI Scans:  
When having an MRI (Magnetic Resonance Imaging) scan, you will lie still on a 
table that slides into a tunnel slightly wider than your body. People who feel 
uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the 
narrow cylinder. If you feel uncomfortable in confined spaces, please tell your 
research doctor. Your doctor may give you a medication to make you feel more 
comfortable. As images are taken, a loud banging noise will be produced.  
Earplugs or headphones will be available if needed. The MRI can be stopped at 
any time at your request, but the scan may not be complete. 
Reproductive Risks:  
The drug used in this research study may affect a fetus. While participating in this 
research study, you should not become pregnant or father a baby, and should 
not nurse a baby. We can provide counseling about preventing pregnancy for 
either male or female study participants. Let your doctor know immediately if you 
become pregnant or find out that you are going to be the father of a child. 
 
Non-Physical Risks:  
Because of side effects or the time required for tests and clinic visits while you 
are on this research study, you may be unable to keep up with your normal daily 
activities.  
 
G. WHAT ARE THE BENEFITS OF THE RESEARCH STUDY? 
 
We do not know if taking part in this study will help you. This study may help 
researchers learn information that could help people in the future. 
 
 
H. CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS? 
 
You have the right to choose not to sign this form.  If you decide not to sign this 
form, you cannot participate in this research study.  
 
You can stop being in the research study at any time.  Tell the research doctor if 
you are thinking about stopping or decide to stop.  He or she will tell you how to 
stop.  Leaving the research study will not affect your medical care outside of the 
research study.   
 
If you choose not to participate, are not eligible to participate, or withdraw from 
this research study, this will not affect your present or future care and will not 
cause any penalty or loss of benefits to which you are otherwise entitled.  
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 11 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
It is important to tell the research doctor if you are thinking about stopping so 
your research doctor can evaluate the risks from stopping the drug. In some 
cases, the abrupt stopping of a drug can have risks in itself. Another reason to 
tell your research doctor that you are thinking about stopping is to discuss what 
follow-up care and testing could be most helpful for you. 
 
 
I. WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY? 
 
You will not be paid for participating in this study.  
 
We may use your samples and information to develop a new product or medical 
test to be sold.  The sponsor and hospital may benefit if this happens. There are 
no plans to pay you if your samples are used for this purpose.  
 
J. WHAT ARE THE COSTS? 
 
Taking part in this research study might lead to added costs to you or your 
insurance company. 
 
You will not be charged for M6620. 
 
You or your insurance company will be charged for portions of your care during 
this research study that are considered standard care. You may be responsible 
for co-payments and deductibles that are typical for your insurance coverage. 
 
If you have questions about your insurance coverage, or the items you might be 
required to pay for, please call financial services for information.  The contact 
information for financial services are:   
 
• Beth Israel Deaconess Medical Center: (617) 667-5661 
• Boston Children’s Hospital: (617) 355-7188 
• Brigham and Women’s Hospital: (617) 732-5524 or (617) 732-7485 
• Dana-Farber Cancer Institute: (617) 632-3455 
• Massachusetts General Hospital: (617) 726-2191 
 
 
 
 
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 12 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
The National Cancer Institute provides an online resource to help people 
participating in cancer clinical trials understand which services their insurance 
company is required by law to pay.  This can be found at the website below or 
can be provided by the study team: 
 
www.cancer.gov or 1-800-4-CANCER (1-800-422-6237) 
 
K. WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN 
THIS RESEARCH STUDY? 
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of this research study as soon as possible.  The 
research doctor’s name and phone number are listed in this consent form. 
 
The treating hospital will offer you the care needed to treat injuries directly 
resulting from taking part in this research.  These treatments will be billed to your 
insurance company. You will be responsible for deductibles and co-payments. 
There are no plans to pay you or give you other compensation for the injury. You 
do not give up your legal rights by signing this form.  
 
We will need to collect certain personal information about you for insurance or 
payment reporting purposes, such as your name, date of birth, gender, social 
security number or Medicare identification number and information related to this 
research study. We may be required to report this information to the Centers for 
Medicare & Medicaid Services. We will not use this information for any other 
purpose. 
 
L. WHAT ABOUT CONFIDENTIALITY? 
 
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  
 
Medical information created by this research study may become part of your 
hospital medical record and may be forwarded to your primary doctor. 
Information that does not become part of your medical record will be stored in 
your study file.  It may also become part of a DF/HCC research database.   
 
As part of the research, your deidentified samples may be shared with outside 
laboratories or institutions for analysis. 
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 13 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
The study team plans to publish the results of this research study and when we 
do, we may be asked to make the data we collect available to other researchers. 
We will not include information that identifies you in any publications or to the 
researchers who request the data to do additional research. 
      
The Genetic Information Nondiscrimination Act of 2008 (GINA) is a federal law 
that protects Americans from being treated unfairly because of differences in 
their DNA that may affect their health, and may prevent discrimination by health 
insurers and employers based on genetic information.   GINA is intended to ease 
concerns about discrimination that might keep some people from getting genetic 
tests that could benefit their health, and enable people to take part in research 
studies such as this without fear that their DNA information might be used 
against them by health insurers or their workplace.  This protection does not 
extend to disability or life insurance. Additional information can be found at 
http://www.genome.gov/10002328. 
 
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. 
 
M. WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY? 
 
If you have questions about the study, please contact the research doctor or 
study staff as listed below: 
 
Massachusetts General Hospital 
• Gregory Cote, MD, PhD: (617) 724-4000 
 
Dana-Farber Cancer Institute 
• Geoffrey Shapiro, MD, PhD: (617) 632-3000 
 
Beth Israel Deaconess Medical Center 
• Andrea Bullock, MD MPH: (617) 667-2100 
 
Dana-Farber Cancer Institute(DFCI)/Boston Children’s Hospital(BCH) 
• Katherine Janeway, MD (617) 632-4994 
 
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 14 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
24-hour contact at Massachusetts General Hospital, Dana-Farber, and Beth 
Israel: Please call the number of your facility above and ask to speak to your 
study doctor, or for your study doctor to be paged. 
 
24-hour contact at DFCI/BCH: please page the Pediatric Oncology Fellow on 
call by calling the page operator at (617) 632-3352. 
 
For questions about your rights as a research participant, please contact a 
representative of the Office for Human Research Studies at Dana-Farber Cancer 
Institute (617) 632-3029. This can include questions about your participation in 
the study, concerns about the study, a research related injury, or if you feel/felt 
under pressure to enroll in this research study or to continue to participate in this 
research study.  
 
N. FUTURE USE OF DATA AND SPECIMENS 
 
Your personal information and/or biospecimens collected during this study may 
be stored and used for future research.  If so, any personal identifiers will be 
removed so that the information or samples cannot be linked back to you. As a 
result, we will no longer be able to identify and destroy them. 
 
Investigators, including investigators from collaborating institutions, can request 
this data and samples for new research.  Samples and data may also be shared 
with outside non-profit academic investigators as well as with for-profit 
pharmaceutical investigators or commercial entities, with whom we collaborate. 
 
You will not be asked to provide additional informed consent for the use of your 
de-identified information or samples in future research. 
 
O. PRIVACY OF PROTECTED HEALTH INFORMATION 
 
Federal law requires Dana-Farber/Harvard Cancer Center (DF/HCC) and its 
affiliated research doctors, health care providers, and physician network to 
protect the privacy of information that identifies you and relates to your past, 
present, and future physical and mental health conditions (“protected health 
information”).  If you enroll in this research study, your “protected health 
information” will be used and shared with others as explained below. 
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 15 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
1. What protected health information about me will be used or shared with 
others during this research? 
 
• Existing medical records, including mental health records. 
• New health information created from study-related tests, procedures, 
visits, and/or questionnaires 
 
2. Why will protected information about me be used or shared with others? 
 
The main reasons include the following: 
• To conduct and oversee the research described earlier in this form; 
• To ensure the research meets legal, institutional, and accreditation 
requirements;  
• To conduct public health activities (including reporting of adverse events 
or situations where you or others may be at risk of harm); and 
• To provide the study sponsor with information arising from an adverse 
event or other event that relates to the safety or toxicity of the drug(s) 
used in the study and for the purpose of this or other research relating the 
study drug(s) and their use in cancer;  
• To better understand the diseases being studied and to improve the 
design of future studies; and, 
• Other reasons may include for treatment, payment, or health care 
operations.  For example, some medical information produced by this 
research study may become part of your hospital medical record because 
the information may be necessary for your medical care. (You will also be 
given a notice for use and sharing of protected health information.) 
 
3. Who will use or share protected health information about me? 
 
• DF/HCC and its affiliated research doctors and entities participating in the 
research will use and share your protected health information.  In addition, 
other DF/HCC offices that deal with research oversight, billing or quality 
assurance will be able to use and share your protected health information. 
 
4/15/2023 7:28 am


  
Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 16 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
4. With whom outside of DF/HCC may my protected health information be 
shared? 
 
While all reasonable efforts will be made to protect the confidentiality of your 
protected health information, it may also be shared with the following entities: 
 
• Outside individuals or entities that have a need to access this information 
to perform functions relating to the conduct of this research such as 
analysis by outside laboratories on behalf of DF/HCC and its affiliates (for 
example, data storage companies, insurers, or legal advisors). 
• The sponsor of the study, its subcontractors, representatives, business 
partners, and its agents: DF/HCC 
• The supporting pharmaceutical company of the study, its subcontractors, 
representatives, business partners, and its agents: EMD Serono. The 
support company may send study data outside of the U.S. 
• Other research doctors and medical centers participating in this research, 
if applicable 
• Federal and state agencies (for example, the Department of Health and 
Human Services, the Food and Drug Administration, the National 
Institutes of Health, and/or the Office for Human Research Protections), or 
other domestic or foreign government bodies if required by law and/or 
necessary for oversight purposes. A qualified representative of the FDA 
and the National Cancer Institute may review your medical records. 
• Hospital accrediting agencies 
• A data safety monitoring board organized to oversee this research, if 
applicable 
 
Some who may receive your protected health information may not have to 
satisfy the privacy rules and requirements.  They, in fact, may share your 
information with others without your permission.  
 
5. For how long will protected health information about me be used or 
shared with others? 
 
• There is no scheduled date at which your protected health information that 
is being used or shared for this research will be destroyed, because 
research is an ongoing process.   
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 17 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
6. Statement of privacy rights: 
 
• You have the right to withdraw your permission for the research doctors 
and participating DF/HCC entities to use or share your protected health 
information.  We will not be able to withdraw all the information that 
already has been used or shared with others to carry out related activities 
such as oversight, or that is needed to ensure quality of the study. To 
withdraw your permission, you must do so in writing by contacting the 
researcher listed above in the section: “Whom do I contact if I have 
questions about the research study?” 
• You have the right to request access to your protected health information 
that is used or shared during this research and that is related to your 
treatment or payment for your treatment, but you may access this 
information only after the study is completed.  To request this information, 
please contact the researcher listed above in the section: “Whom do I 
contact if I have questions about the research study?” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 18 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
P. OPTIONAL RESEARCH STUDIES:  
 
You are being asked to participate in some optional studies.  If you decide not to 
participate in any of the optional studies, you can still participate in the main 
research study.  Please take your time to make your decision and discuss it with 
others and your primary care physician.   
 
Your participation in this optional research study is voluntary, and you will not be 
penalized or lose any benefits if you refuse to participate or decide to stop.   
  
 
 
Optional Study #1: Optional Biopsy upon Disease Progression 
 
 
The study team would like perform an additional tumor biopsy if your disease 
progresses while you are on the study treatment. The purpose of this optional 
biopsy is to look at your tumor tissue and research how it may or may not have 
responded to the study drug. 
Please indicate whether or not you want to take part in this optional research 
study. 
 Yes       
 
 
 
 
 Initials                       Date 
 No        
 
 
 
 
 Initials                       Date 
  
 
 
Optional Study #2: Optional Research on Collected Samples 
 
If you undergo an additional procedure, for clinical (non-research) reasons, that 
results in the collection of tumor tissue (e.g. biopsy, surgery, fluid collection) the 
study team would like to take a sample for research. The purpose of this optional 
collection is to look at your tumor tissue and research how it may or may not 
have responded to the study drug. 
 
Please indicate whether or not you want to take part in this optional research 
study. 
 Yes       
 
 
 
 
 Initials                       Date 
 No        
 
 
 
 
 Initials                       Date 
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 19 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
Optional Study #3: Optional Screening Biopsy (For T4 Only) 
 
The study team would like to perform an additional biopsy during screening. The 
purpose of this optional biopsy is to look at your tumor tissue and research how it 
may or may not have responded to the study drug. 
  
Please indicate whether or not you want to take part in this optional research 
study. 
 Yes       
 
 
 
 
 Initials                       Date 
 No        
 
 
 
 
 Initials                       Date 
 
 
 
 
 
Optional Study #4: Optional On-Treatment Biopsy (For T4 Only) 
 
The study team would like to perform a biopsy on Cycle 1 Day 15. The purpose 
of this optional biopsy is to look at your tumor tissue and research how it may or 
may not have responded to the study drug. 
 
Please indicate whether or not you want to take part in this optional research 
study. 
 Yes       
 
 
 
 
 Initials                       Date 
 No        
 
 
 
 
 Initials                       Date 
 
 
  
 
 
 
 
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 20 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
Q. DOCUMENTATION OF ASSENT 
 
Signature of participant between age of 10 and 18: The person doing this 
research study has explained what will happen to me if I take part in this 
research study.  My signature below means that I want to be in this research 
study.  I can decide not to take part in this research study if I do not want to and 
nothing will happen to me if I decide I do not want to participate.   
 
 
____________________________________ __________________ 
Signature of Participant 
 
 
 
Date 
 
To be completed by person obtaining assent: 
 
The assent discussion was initiated on   
 (date).  
 The information was presented in age-appropriate terms.  The minor: 
 
 Agreed to take part in the study 
 
 Did not agree to take part in the study 
 
 An assent discussion was not initiated with the minor for the following reason(s): 
 
 Minor is incapacitated 
 
 Minor is under 10 years of age 
 
 Other 
 
 
 
 
 
Signature of Individual obtaining assent:  
 
 
Printed name of above:  
 
 
Date:  
 
 
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 21 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
R. DOCUMENTATION OF CONSENT 
 
My signature below indicates: 
• I have had enough time to read the consent and think about 
participating in this study; 
• I have had all of my questions answered to my satisfaction; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary and I can withdraw at 
any time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
Date 
or Legally Authorized Representative   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Participant   
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 22 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
To be completed by person obtaining consent: 
Adult Participant 
 
 
The consent discussion was initiated on   
 (date). 
 
Signature of individual obtaining consent:  
 
 
Printed name of above:  
 
 
 
Date:  
 
 
 A copy of this signed consent form will be given to the participant or legally authorized representative. 
 1)  The participant is an adult and provided consent to participate. 
 
 1a)  Participant (or legally authorized representative) is a non-English speaker and 
 
signed the translated Short Form in lieu of English consent document: 
 
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation of the 
English consent form.  The participant was given the opportunity to ask questions.  
Signature of Interpreter/Witness:  
 
Printed Name of Interpreter/Witness:  
 
Date:  
 
 
 
 1b)  Participant is physically unable to sign the consent form because:  
 
 
 
 The participant is illiterate. 
 
 
 
 The participant has a physical disability. 
 
 
 
 Other (please describe): _________________________________________ 
 
The consent form was presented to the participant who was given the opportunity  
 
to ask questions and who communicated agreement to participate in the research.  
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:  
 
 2)  The participant is an adult who lacks capacity to provide consent and his/her legally authorized 
representative: 
 2a) gave permission for the adult participant to participate  
 2b) did not give permission for the adult participant to participate  
 
 
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 23 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
To be completed by person obtaining consent: 
 
Minor Participant 
 
 
The consent discussion was initiated on   
 (date). 
 
Signature of individual obtaining consent:  
 
 
Printed name of above:   
 
 
Date:  
 
 
 A copy of this signed consent form will be given to the participant or legally authorized 
representative, or, where the participant is a minor, the participant’s parent or legal guardian. 
 
 1) The parent or legally authorized representative gave permission for the minor to 
participate. 
 
 1a) Parent or legally authorized representative is a non-English speaker and signed 
 
 
the translated Short Form in lieu of English consent document 
 
As someone who understands both English and the language spoken by the participant, I 
interpreted and/or witnessed, in the participant’s language, the researcher’s presentation 
of the English consent form.  The participant was given the opportunity to ask questions.  
Signature of Interpreter/Witness:  
 
Printed name of Interpreter/Witness:  
 
Date:  
 
 
 
 1b) Parent or legally authorized representative is physically unable to sign the consent 
form because:  
 
 
 
 The participant is illiterate. 
 
 
 
 The participant has a physical disability. 
 
 
 
 Other (please describe): _________________________________________ 
 
 
 
The consent form was presented to the parent or legally authorized representative 
 
who was given the opportunity to ask questions and who communicated agreement for 
the minor to participate in the research.  
Signature of Witness:  
 
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Research Consent Form          
for Biomedical Research 
Dana-Farber/ Harvard Cancer Center 
BIDMC/BCH/BWH/DFCI/MGH/Partners Network Affiliates  
OHRS 10.02.2017b 
 
Page 24 of 24 
DFCI Protocol Number:  
         18-274 
Approved Date (DFCI IRB Approval):  
03/16/2020 
Date Posted for Use:  
03/19/2020 
 
 
 
Printed Name of Witness:  
 
Date:  
 
 
 1c) The parent or legally authorized representative did not give permission for the minor to 
participate 
 
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