DNA Damage Repair (DDR) Inhibitor-Based Basket of Baskets Phase I/II Trial in Patients With Advanced Solid Tumors Harboring Aberrations in DDR Genes (D-BoB)
Phase: PHASE1
Conditions: Metastatic Malignant Solid Neoplasm, Refractory Malignant Solid Neoplasm, Unresectable Malignant Solid Neoplasm
Sponsor: M.D. Anderson Cancer Center



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DNA DAMAGE REPAIR (DDR) INHIBITOR-BASED BASKET OF BASKETS PHASE I/II TRIAL 
IN PATIENTS WITH ADVANCED SOLID TUMORS HARBORING ABERRATIONS IN DDR 
GENES (D-BOB) 
 
Principal Investigator: 
 
 
Sponsor: The University of Texas MD Anderson Cancer Center (MDACC) 
 
Supporter: EMD Serono 
 
Study Drug(s): Avelumab, M6620 (formerly VX-970) 
 
Clinical Phase: Phase I/II 
 
Indications: Patients with advanced cancers with aberrations in genes involved in DNA Damage 
Response (DDR) 
 
IND #: 146604 
 
 

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TABLE OF CONTENTS 
STUDY SYNOPSIS ................................................................................................................................... 6 
STUDY CALENDAR ................................................................................................................................. 9 
1. INTRODUCTION ................................................................................................................................. 16 
1.1 Mechanisms of Action/Indication ............................................................................................ 16 
1.2 Rationale for the combination of DDR and immune checkpoint inhibitors ................. 17 
2. STUDY OBJECTIVES AND ENDPOINTS ...................................................................................... 18 
2.1 Primary, Secondary, and Exploratory Objectives............................................................... 18 
2.1.1 Arm A: M6620 + Avelumab ................................................................................................... 18 
2.2 Primary, Secondary, and Exploratory Endpoints ............................................................... 19 
2.2.1 Arm A – M6620 + Avelumab................................................................................................. 19 
3. STUDY DESIGN .................................................................................................................................. 19 
3.1 Study Overview ............................................................................................................................ 19 
3.2 Study Treatment Arms ............................................................................................................... 20 
3.2.1 Arm A: M6620 + Avelumab ................................................................................................... 21 
3.3 Dose Limiting Toxicity (DLT) Definition ................................................................................ 22 
3.4 Maximum Tolerated Dose (MTD) Definition .......................................................................... 24 
3.5 Dose Escalation and Stopping Rules .................................................................................... 24 
4. PATIENT ELIGIBILITY CRITERIA ................................................................................................... 25 
4.1 Inclusion Criteria ......................................................................................................................... 25 
4.2 Exclusion Criteria ........................................................................................................................ 28 
5. STUDY TREATMENTS ...................................................................................................................... 30 
5.1 Allocation to Treatment ............................................................................................................. 30 
5.2 Investigational Product Supplies ............................................................................................ 30 
5.2.1 Formulation and Packaging .................................................................................................. 30 
5.2.2 Preparation and Dispensing ................................................................................................. 31 
5.2.3 Administration, Pre-medications, and Infusion Reactions ............................................... 32 
5.2.4 Patient Compliance ................................................................................................................ 34 
5.2.5 Recommended Dose Modifications ..................................................................................... 34 
5.3 Drug Storage and Accountability ............................................................................................ 47 
5.3.1 M6620 Storage ....................................................................................................................... 48 
5.3.2 Avelumab Storage .................................................................................................................. 48 

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5.4 Concomitant Treatment ............................................................................................................. 48 
5.4.1 Other Anticancer or Experimental Drugs ............................................................................ 48 
5.4.2 Supportive Care ...................................................................................................................... 49 
5.4.3 Hematopoietic Growth Factors ............................................................................................. 49 
5.4.4 Anti-Diarrheal, Anti-Emetic Therapy .................................................................................... 49 
5.4.5 Anti-inflammatory Therapy .................................................................................................... 49 
5.4.6 Corticosteroids ........................................................................................................................ 50 
5.4.7 Surgery ..................................................................................................................................... 50 
5.4.8 Radiation Therapy .................................................................................................................. 50 
5.4.9 Bisphosphonates or Denosumab ......................................................................................... 50 
5.4.10 Androgen Deprivation Therapy for Patients with CRPC ................................................ 50 
5.4.11 Prohibited Concomitant Medications and Therapies ...................................................... 51 
6. STUDY PROCEDURES ..................................................................................................................... 51 
6.1 Screening Period ......................................................................................................................... 52 
6.2 Study Treatment Period ............................................................................................................. 52 
6.3 End of Treatment Visit ............................................................................................................... 52 
6.4 Follow up Phase .......................................................................................................................... 52 
6.5 Patient Withdrawal ...................................................................................................................... 53 
7. ASSESSMENTS .................................................................................................................................. 54 
7.1 Safety Assessments ................................................................................................................... 54 
7.2 Pharmacokinetic Assessments ............................................................................................... 58 
7.3 Tumor Response Assessments .............................................................................................. 60 
7.4 Tumor Biopsies and Blood Samples ...................................................................................... 61 
7.5 Correlative Studies ..................................................................................................................... 61 
8. ADVERSE EVENT REPORTING...................................................................................................... 67 
8.1 Adverse Events ............................................................................................................................ 67 
8.2 Definition of Adverse Event ...................................................................................................... 67 
8.3 Definition of Serious Adverse Event (SAE) .......................................................................... 67 
8.4 Reporting to the Federal Drug Administration (FDA) ........................................................ 68 
8.5 Investigator Communications with EMD Serono ................................................................ 69 
8.6 Recording of Adverse Events .................................................................................................. 70 
8.6.1 Laboratory Test Abnormalities ............................................................................................. 71 

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8.6.2 Pregnancy ............................................................................................................................... 71 
8.6.3 Adverse Drug Reactions with Concomitant Medications ................................................. 71 
9. DATA ANALYSIS/STATISTICAL METHODS ................................................................................ 72 
9.1 Analysis Sets ................................................................................................................................ 72 
9.2 Statistical Methods and Properties ........................................................................................ 72 
9.4 General Statistical Considerations ......................................................................................... 72 
9.3 Sample Size Determination ....................................................................................................... 73 
9.4 General Statistical Considerations ......................................................................................... 73 
9.5 Efficacy Analysis ......................................................................................................................... 74 
9.6 Safety Monitoring ........................................................................................................................ 74 
9.7 Pharmacokinetic Analysis ........................................................................................................ 76 
9.8 Biomarker Analysis ..................................................................................................................... 76 
9.9 Analysis of Other Endpoints .................................................................................................... 76 
9.10 Final Analysis ............................................................................................................................. 77 
9.11 Data Safety Monitoring Committee ...................................................................................... 77 
10. QUALITY CONTROL AND QUALITY ASSURANCE ................................................................. 77 
11. DATA HANDLING AND RECORD KEEPING ............................................................................. 77 
11.1 Case Report Form/Electronic Data Record ........................................................................ 77 
11.2 Record Retention ...................................................................................................................... 77 
12. ETHICS ............................................................................................................................................... 78 
12.1 Ethical Conduct of the Study ................................................................................................. 78 
12.2 Patient Information, Consent and Sample Storage .......................................................... 78 
12.3 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ...... 79 
13. DEFINITION OF END OF TRIAL .................................................................................................... 79 
14. SPONSOR DISCONTINUATION CRITERIA ................................................................................ 79 
Appendix A: ECOG Performance Status ......................................................................................... 80 
Appendix B: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines ................................................................................................................................................ 81 
Appendix C: Immune-related RECIST (irRECIST) ......................................................................... 85 
Appendix D: Assessment of Radiographic Response and Progression in Patients with 
CRPC ......................................................................................................................................................... 87 
Appendix E: Abbreviations and Definitions .................................................................................... 89 
Appendix F: List of Prohibited Medications and Therapies ....................................................... 92 

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STUDY SYNOPSIS 
 
MDACC Protocol 
Number 
2018-1059 
Protocol Version 
(Date) 
 November 18, 2022 
Trial 
Center/Country 
Single Institution Trial (MDACC)/USA 
Planned 
Trial 
Period 
(First 
Subject 
In/Last 
Subject Out) 
January 2020/January 2025 
Trial Registry 
February 12, 2020 clinicaltrials.gov 
Study Population Patients with advanced solid tumors with DNA Damage Response 
aberrations 
 
Study Design 
This is an open label, single center Phase I/II dose escalation and 
expansion study that will evaluate the safety and clinical benefit of the 
following combinations: 
• 
IV ATR inhibitor (M6620) in combination with avelumab. 
Note: Additional arms involving agents, such as an oral ATR inhibitor, 
DNA-PK inhibitor, a PARP inhibitor, an ATM inhibitor, and other 
agents will be added following a substantial amendment to the current 
protocol. 
Objectives 
 
Primary Objectives  
1. To determine the safety and tolerability of the combination of M6620 
and avelumab in patients with DDR deficient advanced solid tumors. 
 
2. To establish the maximum tolerated dose (MTD) and recommended 
phase 2 dose (RP2D) of the combination of M6620 and avelumab 
in patients with DDR deficient advanced solid tumors. 
Secondary Objectives  
1. To determine the clinical benefit of the combination of M6620 and 
avelumab, as defined by clinical benefit rate (CBR) - complete 
response [CR] + partial response [PR] + stable disease [SD] > 6 
months (CR + PR + SD > 6 months). 
 
2. To assess clinical benefit of the combination as defined by objective 
response rate (ORR = CR + PR), overall survival (OS), and 
progression free survival (PFS). 
Exploratory Objectives  
1. To evaluate clinical benefit of the combination of M6620 and 
avelumab based on specific DDR aberrations. 
 

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2. To evaluate clinical benefit of the combination of M6620 and 
avelumab based on DDR gene expression signatures. 
 
3. To evaluate the impact of treatment on PD-L1 expression and 
immune cell populations. 
 
4. To assess potential mechanisms of resistance by comparing pre- 
and on-treatment biopsies in responders and non-responders. 
 
5. To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) 
profile of M6620 in combination with avelumab in patients with DDR 
deficient advanced solid tumors. 
Endpoints 
 
Primary Endpoints  
1. Incidence and severity of adverse events (AEs) and serious adverse 
events (sAEs) (as graded by NCI CTCAE version 5.0), including 
significant changes in laboratory parameters, ECGs, and vital signs. 
 
2. Incidence of dose-limiting toxicities (DLTs) (see Section 3.3). 
Secondary Endpoints  
1. Clinical benefit will be assessed radiographically per Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and 
immune-related RECIST (irRECIST). Post-baseline imaging will 
occur every 2 cycles or 8 weeks (± 7 days) for the first year of 
treatment. Thereafter, tumor assessments will be performed every 
3 cycles or 12 weeks (± 7 days), independent of cycle delays.  
 
2. ORR, OS, and PFS by radiographic disease assessments per 
RECIST v1.1 and irRECIST. Post-baseline imaging will commence 
after 2 cycles (8 weeks) of therapy. 
Exploratory Endpoints  
1. Correlation between clinical benefit (CBR, ORR, PFS, or OS) and 
ATM mutations and/or protein loss. 
 
2. Assessment of homologous recombination deficiency (HRD) score 
and replication stress response defect (RSRD) score. 
 
3. Immunohistochemistry, immunofluorescence, and flow cytometry 
analysis of immune cell subsets and markers, including PD-L1. 
 
4. Whole exome sequencing, RNA-sequencing, and Reverse Phase 
Protein Array (RPPA) analysis of pre-, on-treatment, and optional 
at-progression tumor biopsies. 
 
5. PK summary statistics, concentration-time profiles and parameters 
(e.g. CL, AUC, Cmax, Tmax, half-life if estimable).  

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Study 
Considerations 
• 
Actionable variant(s) in the following DDR genes, based on next 
generation sequencing (NGS), will be considered in this trial: 
ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BRCA1/2, BRIP1, 
CDK12, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, 
FANCM, MRE11A, MSH2, NBN (NBS1), PALB2, RAD51, RAD51C, 
RAD51D, SMARCB1, and VHL. Other appropriate aberrations may 
be considered for patient selection at the discretion of the PI 
depending on emerging data. 
 
• 
CLIA-approved immunohistochemistry analysis of ATM protein loss 
may also be considered. 
 
• 
Interim analysis of toxicity will be performed in cohorts of 10 
patients. 
 
• 
Interim analysis for futility will be performed in cohorts of 10 patients. 
Planned Sample 
Size 
3-6 patients for dose escalation. 
30 patients for dose expansion. 
The accrual may be up to 36 patients 

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STUDY CALENDAR 
 
Assessments 
 
Treatment Period 
Post-Treatment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Short-
term 
Follow-
Up 
Long-
term 
Follow-
up 
Day 
 
Visit Window 
in days 
≤ 28 days 
prior to 
1st dosing 
of study 
drug 
D1  
 
± 
3 
D2-
4 
D8  
 
± 
2 
D15  
 
± 2 
D16-
18 
D22 
 
± 2 
D1  
 
± 
2 
D8 
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
D1  
 
± 
2 
D8  
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
 
+ 7 
Day 
30, 60, 
and 90 
after 
last 
dose  
 
± 7 
Every 
12 
weeks  
 
± 14 
Informed 
Consent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verify 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum or 
urine Beta-
hCG3 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Day 30 
and 60 
only 
 
Protocol/Safety Evaluations 
Physical 
Exam and 
ECOG4 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital Signs5 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Weight5 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG6 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGA7 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 

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Assessments 
 
Treatment Period 
Post-Treatment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Short-
term 
Follow-
Up 
Long-
term 
Follow-
up 
Day 
 
Visit Window 
in days 
≤ 28 days 
prior to 
1st dosing 
of study 
drug 
D1  
 
± 
3 
D2-
4 
D8  
 
± 
2 
D15  
 
± 2 
D16-
18 
D22 
 
± 2 
D1  
 
± 
2 
D8 
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
D1  
 
± 
2 
D8  
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
 
+ 7 
Day 
30, 60, 
and 90 
after 
last 
dose  
 
± 7 
Every 
12 
weeks  
 
± 14 
AE/SAE 
Assessment8 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Concomitant 
Medications 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Survival 
Status9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Evaluation 
Hematology10 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Chemistry11 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Thyroid 
Function12 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Urinalysis13 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Coagulation 
Test14 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Hepatitis B 
and C 
(Hepatitis B 
surface 
antigen and 
core antibody; 
anti-hepatitis 
C antibody) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Assessments 
 
Treatment Period 
Post-Treatment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Short-
term 
Follow-
Up 
Long-
term 
Follow-
up 
Day 
 
Visit Window 
in days 
≤ 28 days 
prior to 
1st dosing 
of study 
drug 
D1  
 
± 
3 
D2-
4 
D8  
 
± 
2 
D15  
 
± 2 
D16-
18 
D22 
 
± 2 
D1  
 
± 
2 
D8 
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
D1  
 
± 
2 
D8  
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
 
+ 7 
Day 
30, 60, 
and 90 
after 
last 
dose  
 
± 7 
Every 
12 
weeks  
 
± 14 
Study Treatment 
Avelumab15 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
M662016,17 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Tumor Measurement 
CT, MRI, or 
PET-CT18 
X 
 
 
Every 8 weeks for 
up to 1 year, then 
every 12 weeks 
thereafter. 
Confirmation ≥ 4 
weeks following 
initial OR PD. 
X 
 
X 
Relevant 
Tumor 
Markers19 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Research Studies (PK/PD) 
Tumor 
biopsy20 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Liquid 
biopsy21 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
PK Blood 
Samples 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 

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Assessments 
 
Treatment Period 
Post-Treatment 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 and 
Beyond 
End of 
Treatment 
(EOT) 
Short-
term 
Follow-
Up 
Long-
term 
Follow-
up 
Day 
 
Visit Window 
in days 
≤ 28 days 
prior to 
1st dosing 
of study 
drug 
D1  
 
± 
3 
D2-
4 
D8  
 
± 
2 
D15  
 
± 2 
D16-
18 
D22 
 
± 2 
D1  
 
± 
2 
D8 
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
D1  
 
± 
2 
D8  
 
± 
2 
D15  
 
± 2 
D22  
 
± 2 
 
+ 7 
Day 
30, 60, 
and 90 
after 
last 
dose  
 
± 7 
Every 
12 
weeks  
 
± 14 
-Avelumab22 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
-M662023 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnotes: 
1. Informed consent must be obtained prior to undergoing any study specific procedure and may occur prior to the 28-day screening 
period. The use of remote consenting to obtain informed consent from clinical trial participants using paper or electronic consent 
forms is allowed in this study 
 
2. Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, 
disease progression during or after therapy, as well as discontinuations due to intolerability or any other serious illness. 
 
3. For female patients of childbearing potential, who do not fit the definition of ‘female patients who are not of childbearing potential’ 
in the inclusion criterion, a serum or urine pregnancy test, will be performed on 2 occasions prior to starting study therapy: once at 
the start of screening (within 28 days of first dose of study treatment), and once at the baseline visit (Cycle 1 Day 1), immediately 
before administration of investigational agent. Pregnancy tests will also be routinely repeated on Day 1 of every cycle during the 
active treatment period. 
 
4. Physical examination and ECOG will be performed at screening, on Days 1 and 15 of each cycle, and at the End of Treatment 
(EOT) visit. Physical examinations during the study should be symptom directed. 
 

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5. Vital signs: temperature, pulse, respiratory rate, blood pressure, body surface area, and body weight will be measured at the start 
of each treatment cycle (up to 3 day before the start of a new cycle) and on day 15 (± 1 day) of each cycle. Weight will be used to 
calculate doses per institutional SOP. Height will be obtained from the electronic medical record. 
 
6. 12-lead ECG (single) will be performed at screening, and on Cycle 2 Day 1. Thereafter, ECGs will be performed as clinically 
indicated. 
 
7. ECHO/MUGA: will be performed at screening, and on Cycle 3 Day 1. Thereafter, ECHO/MUGA will be performed as clinically 
indicated. 
 
8. AE Assessment: AEs should be documented and recorded at each visit using NCI CTCAE version 5.0. Patients must be followed 
for AEs for 90 days after the last dose of study drug, or until all drug related toxicities have resolved, whichever is later; or earlier 
than 30 days should the patient commence another anticancer therapy in the meantime. 
 
9. Survival status: investigators will collect survival data for patients after progression of disease unless patient fully withdraws consent 
to consent to participate in the study. Approximately 1 year after the last dose of treatment, a chart review, patient visit, or telephone 
call will be conducted. The telephone call should be less than 5 minutes in duration, to obtain information regarding survival status. 
 
10. Hematology: complete blood count (CBC), differential, and platelets. 
 
11. Chemistry: sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose (non-fasting), calcium, 
phosphate, magnesium, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, bilirubin (total, 
direct, indirect), lactate dehydrogenase (LDH), total protein, albumin, uric acid, amylase, lipase, creatinine kinase, 
Adrenocorticotropic hormone (ACTH) and Testosterone (at screening only for CRPC patients), Gamma Glutamyl Transferase 
(GGT) and  C-reactive Protein (CRP). No need to assess on Cycle 1 Day 1 if baseline assessment was performed within 2 days 
prior to that date. Chemistry labs will be performed on Days 1 and 15 of every cycle. 
 
12. Thyroid Function: thyroid-stimulating hormone (TSH), free thyroxine (T4), and total triiodothyronine (T3) will be assessed at 
screening, Cycle 1 Day 1, and every 2 cycles or 8 weeks thereafter (C3D1, C5D1 etc.,) until disease progression or unacceptable 
toxicity, and also at the EOT visit. 
 
13. Urine analysis will include color, appearance, specific gravity, pH, protein, glucose, ketones, blood, bilirubin, and microscopy 
including WBC/high power field (HPF), and RBC/HPF, if clinically indicated. Dipstick is acceptable. Urine analysis will be at 
screening and Day 1 of every cycle. No need to repeat on Cycle 1 Day 1 if baseline assessment was performed within 2 days prior 
to that date. 

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14. Coagulation test includes prothrombin time (PT), international normalization ratio (INR), and activated partial thromboplastin time 
(aPTT). Coagulation tests will be performed at screening, and Day 1 of every cycle. No need to repeat on Cycle 1 Day 1 if baseline 
assessment was performed within 2 days prior to that date. 
 
15. Avelumab will be administered to patients at 800 mg, IV every 2 weeks, starting on Cycle 1 Day 1 (Days 1 and 15 of every cycle). 
 
16. M6620 may be administered to patients in the dose escalation phase at 1 of 3 doses: 240 mg/m2 (dose level 1), 480 mg/m2 (dose 
level 2), or 120 mg/m2 (dose level -1) IV weekly, starting on Cycle 1 Day 1 (Days 1, 8, 15, and 22 of every cycle). M6620 will be 
administered to patients in the dose expansion phase of at the recommended phase 2 dose (RP2D) established in the dose 
escalation phase. 
 
17. When M6620 and Avelumab are to be administered on the same day (e.g. C1D1, C1D15), avelumab will be infused first, with an 
interval of at least 1 hour before infusion of M6620.  
 
18. CT, MRI, or PET-CT scans will be performed at screening, and then every 2 cycles or 8 weeks (± 7 days) for the first year of 
treatment. Thereafter, tumor assessments will be performed every 3 cycles or 12 weeks (± 7 days) independent of cycle delays. 
Confirmatory scans will also be obtained ≥ 4 weeks following initial documentation of objective response (OR) or progression of 
disease (PD). The type of scan obtained is at the discretion of the investigator as appropriate for the disease. However, the same 
method should be used for the duration of the study. Baseline brain CT or MRI scan is required for all high risk patients (such as 
breast, melanoma and other cancer types as determined by the PI/sub I) at baseline (screening). Patients with stable brain 
metastases present at baseline (screening) will have brain CT or MRI scans performed at each tumor assessment. If bone 
metastases are present at baseline (screening), then repeat bone imaging is required every 8 weeks for the first 52 weeks of study 
treatment and every 24 weeks thereafter. Bone imaging is required at the time of confirmation of CR for patients who have bone 
metastases. 
 
19. Relevant tumor markers (e.g., CA125, PSA, and CEA) will be assessed at screening, and on Day 1 of every cycle (± 7 days) this 
will include blood draws at EOT and Long Term Follow-up.  
 
20. One tumor biopsy is mandatory (C1D15), although not mandatory all other tumor biopsies will be strongly encouraged. A core 
tissue biopsy may be required at baseline if no leftover tissue is available for screening, tissue is older than 1 year, or there is not 
enough tissue for testing. Tumor biopsies may be performed at baseline (pre-treatment), Cycle 1 Day 15, and at the time of 
progression/EOT (where feasible).  
 

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21. Blood samples, including for liquid biopsy (cfDNA), will be collected at baseline (pre-treatment), Cycle 1 Day 15, Cycle 3 Day 1, 
every other cycle thereafter (C5D1, C7D1 etc.,), and at the time of progression/EOT 
 
22. Blood draw for Avelumab PK: 3.5 mL whole blood) will be collected (in 3.5 mL SST (VPGOL35) tubes to prepare serum) at: (i) 
Pre dose and EOI: Cycle 1 Day 1 and cycle 1 Day 15, (ii)  Pre dose only: Cycle 3, 6 and (iii) End of treatment sample. 
 
23. Blood draw for M6620 PK: (2 mL whole blood in Vacutainer® tubes containing K2EDTA anticoagulant for plasma) will be 
collected at: pre dose and EOI: Cycle 1, day 1 and Day 15, (ii) Cycle 1, day 2-4 (one sample during this timeframe) and (iii) Cycle 
1 day 16-18 (one sample during this timeframe). 
 
 
 

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1. INTRODUCTION 
 
Genomic instability is a hallmark of cancer, arising from a combination of replication stress and 
errors in DNA damage response (DDR). DDR deficiency (DDR-D) enables the cancer cell’s 
acquisition of driver gene mutations but also engenders targetable vulnerabilities to treatment 
strategies that induce insurmountable DNA damage, such as platinum chemotherapies, and/or 
further suppress DDR leading to catastrophic instability1. In addition, multiple pre-clinical and 
clinical studies have shown significant cross-talk between DDR-D, tumor immune infiltrate, and 
response to immuno-oncology agents (IO) 2-5.  Thus, identifying DDR aberrations in cancers is 
extremely important for therapeutic decision making with the advent of immune checkpoint 
blockade and new classes of DDR inhibitors (DDRi), such as poly (ADP-ribose) polymerase 
(PARP) inhibitors (PARPi), ataxia telangiectasia mutated and rad3-related (ATR) inhibitors 
(ATRi). Multiple PARPi are FDA-approved for the treatment of recurrent BRCA1/2 mutant ovarian 
cancers, as well as BRCA1/2 mutant breast cancers6. However, the clinical response to PARPi 
and DNA damaging agents such as platinum-based chemotherapies, is limited by almost 
inevitable drug resistance, culminating in short-lived antitumor responses. Therefore, there 
remains a significant unmet clinical need for novel antitumor strategies beyond just PARPi and 
platinum to increase the depth and duration of response, and survival benefits for patients with 
advanced cancers harboring DDR aberrations. 
 
1.1 Mechanisms of Action/Indication 
 
1.1.1 Avelumab, PD-L1 immune checkpoint inhibitor 
 
Avelumab is an immune checkpoint-blocking antibody which targets programmed death ligand 1 
(PD-L1), thereby disrupting the interaction with and signaling through the programmed death 
receptor 1 (PD-1), resulting in activation of T cells. Clinically, avelumab is approved for patients 
with Merkel cell carcinoma and for patients with locally advanced or metastatic urothelial 
carcinoma following disease progression during or after platinum-based chemotherapy, or within 
12 months of neoadjuvant or adjuvant platinum-based chemotherapy. Ongoing clinical studies 
have demonstrated meaningful clinical activity across multiple tumor types and treatment settings, 
with ongoing responses > 1 year (NCT01772004, JAVELIN Solid Tumor). 
 
1.1.2 M6620, ATR inhibitor (formerly VX-970) 
 
M6620 is a first in class, potent inhibitor of ataxia telangiectasia mutated and Rad3-related protein 
(ATR). Supporting pre-clinical studies have demonstrated that PARPi-resistant BRCA1-deficient 
cells are exquisitely dependent on ATR for survival; ATR inhibitors (ATRi) disrupt BRCA1-
independent RAD51 loading to DNA DSBs in PARPi-resistant BRCA1-deficient cells, overcoming 
such resistance mechanisms7,8. ATRi may therefore potentially overcome PARPi-resistance in 
BRCA-deficient cancers. In addition, the ATR/CHK1 and ATM/CHK2 axes have multiple 
interconnected and overlapping functions in regards to DDR, cell cycle regulation, and mitigation 
of replication stress. Preclinical and early clinical studies of ATR inhibitors have shown functional 
loss of ATM to predict for ATR inhibitor sensitivity9. Deficiency in ARID1A, a key chromatin 
regulator, have also been shown to lead to homologous repair deficiency (HRD) and in particular 
susceptibility to ATR inhibition in preclinical models10. Other pre-clinical in vitro studies have 
demonstrated that M6620 sensitizes many cancer cell lines to the cytotoxic effects of numerous 
DNA-damaging drugs11. In vivo, M6620 has also been shown to potentiate the antitumor activity 

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of DNA-damaging agents and radiotherapy. For example, in patient-derived xenograft mouse 
models of non-small cell lung cancer (NSCLC), the combination of M6620 with cisplatin resulted 
in significantly greater tumor control in comparison to either single agent12. Additionally, in a 
xenograft mouse model of gastric cancer, treatment with the ATRi AZD6738, decreased 
proliferation (by Ki67 expression) and increased apoptosis (by TUNEL assay), resulting in greater 
tumor control13. In a recent phase I clinical trial, the combination of M6620 and Topotecan, was 
demonstrated to be active in platinum-refractory small-cell lung cancer (SCLC), which is notably 
resistant to Topotecan monotherapy. Partial response or prolonged stable disease (≥ 6 months) 
was observed in 3 of 5 SCLC patients enrolled in this study14. Additionally, phase I studies of 
M6620 led by Dr. Yap, have also demonstrated promising clinical activity in patients harboring 
BRCA1/2 mutant cancers15-17. 
 
1.2 Rationale for the combination of DDR and immune checkpoint inhibitors 
 
There is strong preclinical and clinical evidence that DDR-D and S-phase specific DNA damage 
leads to activation of innate immune pathway activity including the stimulator of interferon gamma 
(STING) axis, increased tumor immune infiltrate, increased PD-L1 expression, and improved 
response to immune therapy (IO)18-20.  Preclinical data has also shown DDRi can have similar 
effects on PD-L1, innate immune activity, and immune response as genetic deficiencies in DDR4,5. 
However, the clinical response to single-agent DDRi, including PARPi, is limited by drug 
resistance, with short-lived antitumor responses, even in tumors with DDR gene aberrations. In 
addition, single agent IO response is not uniform, even within a single tumor type, and predictive 
functional biomarkers are lacking. Therefore, there remains a significant unmet clinical need for 
novel antitumor strategies to increase the depth and duration of response to both IO and DDRi, 
and improve survival benefits for patients with advanced cancers harboring DDR aberrations.  
Recent preclinical data provide rationale to combine DDR inhibitors such as ATRi with 
immunotherapies in an effort to increase clinical outcomes for patients with cancers carrying 
mutations in DDR genes. In a study of DNA repair-deficient breast cancers, Parkes et al., 
identified a mechanism of immune response where STING-mediated chemokine production 
occurred in response to DNA damage. This resulted in an inflammatory microenvironment in 
DDR-deficient breast tumors. They also found that expression of PD-L1 was associated with 
tumors deficient in DDR, supporting the investigation of immunotherapies in tumors harboring 
DDR defects19. Other studies have demonstrated that PARPi treatment can increase the 
expression of PD-L1 on breast cancer cells, and that the combination of PARPi and anti-PD-L1 
therapy significantly increased antitumor response in mouse models of breast cancer in 
comparison to either monotherapy4. In a Phase I modular study led by Dr. Yap, the combination 
of the ATRi AZD6738 with the PD-L1-targeting antibody durvalumab, was shown to be well 
tolerated with signals of antitumor activity21. 
 
 

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2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Primary, Secondary, and Exploratory Objectives 
 
2.1.1 Arm A: M6620 + Avelumab 
 
Primary Objectives: 
 
1. To determine the safety and tolerability of the combination of M6620 and avelumab in 
patients with DDR deficient advanced solid tumors. 
 
2. To establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) 
of the combination of M6620 and avelumab in patients with DDR deficient advanced solid 
tumors. 
 
 
Secondary objectives: 
 
1. To determine the clinical benefit of the combination as defined by clinical benefit rate 
(CBR) - complete response [CR] + partial response [PR] + stable disease [SD] > 6 months 
(CR+PR+SD>6months).  
 
2. To assess clinical benefit of the combination as defined by objective response rate (ORR), 
overall survival (OS), duration of response (DoR) and progression free survival (PFS). 
Patients will be followed for 6 months after a confirmed response.  
 
Exploratory objectives: 
 
1. To evaluate clinical benefit of the combination of M6620 and avelumab based on specific 
DDR aberrations. 
 
2. To evaluate clinical benefit of the combination of M6620 and avelumab based on DDR 
gene expression signatures. 
 
3. To evaluate the impact of treatment on PD-L1 expression and immune cell populations. 
 
4. To assess potential mechanisms of resistance by comparing pre- and on-treatment 
biopsies in responders and non-responders. 
 
5. To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profile of M6620 in 
combination with avelumab in patients with DDR deficient advanced solid tumors 
 
 

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2.2 Primary, Secondary, and Exploratory Endpoints 
 
2.2.1 Arm A – M6620 + Avelumab 
 
Primary Endpoints: 
 
1. Incidence and severity of adverse events (AEs) and serious adverse events (sAEs) (as 
graded by NCI CTCAE version 5.0), including significant changes in laboratory 
parameters, ECGs, and vital signs. 
 
2. Incidence of dose-limiting toxicities (DLTs) (see Section 3.3). 
 
Secondary Endpoints: 
 
1. Clinical benefit will be assessed radiographically per Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1, and immune-related RECIST (irRECIST). 
 
2. ORR, OS, DOR and PFS by radiographic disease assessments per RECIST v1.1 and 
irRECIST. 
 
Exploratory Endpoints: 
 
1. Correlation between clinical benefit (CBR, ORR, PFS, DOR or OS), and ATM mutations 
and/or protein loss. 
 
2. Assessment of homologous recombination deficiency (HRD) score and replication stress 
response defect (RSRD) score. 
 
3. Immunohistochemistry, immunofluorescence, and flow cytometry analysis of immune cell 
subsets and markers. 
 
4. Whole exome sequencing, RNA-sequencing, and Reverse Phase Protein Array (RPPA) 
analysis of pre-, on-treatment, and optional at-progression tumor biopsies. 
 
5. PK summary statistics, concentration-time profiles and parameters (e.g. CL, AUC, Cmax, 
Tmax, half-life if estimable)  
 
 
3. STUDY DESIGN 
 
3.1 Study Overview 
 

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This is a single-center, investigator-initiated, open-label, study of M6620 in combination with 
avelumab (Arm A), in adult patients with advanced solid tumors with aberrations in DNA Damage 
Response (DDR) genes. 
 
Note: Additional arms will be developed based on evolving molecular and clinical data, 
and will be added to this protocol following a substantial amendment. 
 
This is an adaptive program of trials, which will be set up sequentially depending on the 
development and/or availability of the individual agents. In this adaptive study, patients with DDR 
deficient biomarker positive advanced solid tumors entered on study may crossover to other 
available combination baskets upon disease progression, depending on evolving molecular 
and/or immune profiling data. 
 
The number of patients in each basket may be increased depending on pre-defined signals and 
early stopping rules for futility or toxicity as described in Section 3.2 and Section 9.6. Patients will 
have pre and on-treatment tumor biopsies for correlative translational studies described in Section 
7.5. All patients will have serial testing of blood parameters for DDR aberrations (e.g. ctDNA) and 
immune profiling. 
 
3.2 Study Treatment Arms 
 
Figure 1: DNA Damage Repair (DDR) Inhibitor-based Basket of Baskets Trial (D-BoB) 
 
 
 
*Note: a 3-stage decision with 10 patients at each stage will be used for each regimen in the dose 
expansion phase of the trial. We will stop after the 1st stage if we see 0 successes in 10 patients, 

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after the 2nd stage if we see < 2 successes in 20 patients, and we will declare the treatment worthy 
of further study if we see > 3 successes in 30 patients.  
QW = weekly; Q2W = every two weeks; MTD = Maximum Tolerated Dose; RP2D = 
Recommended Phase 2 Dose 
 
3.2.1 Arm A: M6620 + Avelumab 
 
This basket study will begin with dose escalation and expansion of the combination of M6620 and 
avelumab. During the dose escalation phase, patients with advanced solid tumors who meet 
eligibility criteria may be treated at 1 of 3 doses of M6620 in combination with a fixed dose of 
avelumab, and will be evaluated for dose limiting toxicities (DLTs). Intrapatient dose escalation 
will be allowed in this trial. 
 
Intra-patient dose escalation for patients enrolled in dose level 1 may be considered in 
consultation with the Principal Investigator. Once the respective dose level has been declared 
safe, patients who have completed at least 2 Cycles of treatment at the original enrolled dose 
level may escalate to the next higher dose level that has cleared the DLT observation period of 
28 days. For the safety analysis, patients will be considered at both dose levels. 
 
All patients must have DDR aberrant advanced solid tumors to be eligible. The dose expansion 
phase will be enriched for patients with advanced solid tumors with aberrations in the following 
DDR genes: ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, 
FANCA, FANCC, FANCD2, FANCE, FANCF, FANCM, MRE11A, MSH2, NBN (NBS1), PALB2, 
RAD51, RAD51C, RAD51D, SMARCB1, and VHL. Other appropriate aberrations may be 
considered for patient selection at the discretion of the PI depending on emerging data. Variant 
interpretation for actionability will be performed by the MD Anderson Cancer Center (MDACC) 
Institute for Personalized Cancer Therapy (IPCT) Precision Oncology Decision Support (PODS) 
group. The PODS team facilitates a real-time mutation-by-mutation assessment of actionability. 
High-throughput literature retrieval from the MEDLINE database, along with natural language 
processing (NLP), is performed to identify scientific literature that potentially shed light on whether 
there is experimental evidence showing if a genomic alteration increases the cellular processes 
of tumorigenesis. The literature is then manually reviewed by expert scientists to validate and 
record the experimental assessment of each alteration. 
 
Table 1: Dose Escalation of the combination of M6620 and avelumab (Arm A) 
Dose Level 
Dose, frequency, and route of administration 
Dose Level 2 
M6620: 480 mg/m2, QW, IV; Avelumab: 800 mg, Q2W, IV 
Starting Dose Level 1 
M6620: 240 mg/m2, QW, IV; Avelumab: 800 mg, Q2W, IV 
Dose Level -1 
M6620: 120 mg/m2, QW, IV; Avelumab: 800 mg, Q2W, IV 
Note: other intermediate doses of M6620 may be considered following discussion with EMD 
Serono. 
 
When avelumab and M6620 are to be administered on the same day, avelumab will be 
administered first, with an interval of at least 1 hour between infusions. 
 
 
 

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1. Grade 4 neutropenia ≥ 7 days or febrile neutropenia will be considered dose limiting. 
2. Grade 3+ thrombocytopenia with bleeding or Grade 4 thrombocytopenia >7 days will be 
considered dose limiting. 
3. A study intervention-related TEAE that in the opinion of the Safety Monitoring Committee  
(SMC) is of potential clinical significance such that further dose escalation would expose 
participants to unacceptable risk. 
4. Delay by more than 4 weeks (28 days) in receiving the next scheduled cycle of study 
drug(s) due to persisting toxicities attributable to the study drug(s). 
5. Non-hematologic toxicities: 
a. Grade ≥ 3 nausea/vomiting or diarrhea lasting ≥ 72 hours while receiving optimal 
supportive medications, 
b. Grade ≥ 3 fatigue lasting ≥ 7 days, 
c. Grade3 pneumonitis of any duration, 
d. Grade ≥ 3 rash lasting ≥ 7 days despite treatment, 
e. Any Grade 4 immune related toxicities  
f. Any other Grade ≥ 3 non-hematological toxicity (except for electrolyte 
abnormalities that are reversible and asymptomatic or hair loss which is not dose-
limiting; as well as Grade 3 infusion-related reaction of any duration, 
g. AST or ALT >3 × ULN and concurrent total bilirubin >2 × ULN of any duration 
without initial findings of cholestasis (elevated alkaline phosphatase, e.g., 
findings consistent with Hy’s law or FDA definition of potential IP-induced liver 
injury).. For patients with hepatic metastases: AST, ALT >8X ULN; AST or ALT 
>5X ULN lasting ≥14 days. 
 
The following treatment-related AEs are exceptions to the above mentioned DLT definition and 
are not considered to be DLTs: 
1. Isolated Grade 4 lymphopenia without clinical correlate. 
2. Any Grade 4 neutropenia < 7 days duration not associated with any clinical symptoms. 
3. Other single laboratory values out of normal range that have no clinical correlate, and 
resolve to Grade ≤ 1 or to baseline within 7 days with adequate medical management. 
4. Any Grade 3 autoimmune thyroid-related toxicity that clinical resolves to Grade ≤ 2 within 
7 days of initiating therapy. 
5. Grade 3 diarrhea persisting < 72 hours after initiation of medical management. 
6. Grade 3 non-recurrent skin toxicity that resolves to Grade ≤ 1 in < 7 days after initiation of 
medical management. 
7. Transient Grade 3 fatigue, local reactions, flu-like symptoms, fever, headache, nausea, 
and emesis that resolve to Grade ≤ 1 in < 48 hours after initiation of medical management. 
8. Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor that resolve to Grade ≤ 2 within 6 days. 
9. Grade 3 infusion-related reaction resolving within 6 hours from the end of infusion and 
controlled with medical management. 
 
Elevation of amylase and/or lipase without clinical and/or radiographic evidence of pancreatitis 
are not considered DLTs, and the patient may resume treatment at any grade at the discretion of 
the treating physician in consultation with the PI. 
 

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During dose escalation, patients who receive <75% of the planned dose of the investigational 
products in the combination during Cycle 1 for reasons unrelated to study drug(s) are not 
evaluable for DLT and will be replaced. 
 
In rare instances, an event may fall within the definition of a DLT as defined above but the event 
may not be considered a DLT (e.g. not clinically meaningful or significant). If this occurs, the PI 
will thoroughly review the event and supporting data, and the reasons for not considering the 
event a DLT will be clearly documented with supporting rationale. In addition, other events may 
occur that do not meet the definition of a DLT but are concerning to the PI, may then be considered 
to be DLTs. 
 
In the event that a DLT is at least possibly related to the study drug(s), patients will halt treatment 
with the study drug(s) until symptoms resolve to the grade outlined in Section 5.2.5.2. Study 
drug(s) may be restarted as described in Section 5.2.5. 
 
3.4 Maximum Tolerated Dose (MTD) Definition 
 
In the dose escalation phase for the combination of M6620 and avelumab, patients will be 
assigned sequentially in groups of up to 6 patients at each dose level. Three to 6 patients will 
initially be enrolled at each dose level for DLT observation. A total of 6 patients will be enrolled at 
each dose level in the event that a DLT is observed in 1 of the first 3 patients and/or additional 
safety data are needed. 
 
The MTD is defined as the highest dose level with less than 2 patients with DLT out of at least 6 
patients at the dose level. Management and dose modifications associated with adverse events 
are outlined in subsequent protocol sections. 
 
The DLT assessment window is 28 days (1 cycle). In the absence of DLTs, patients may continue 
consecutive treatment. For patients who experience a DLT, they may continue treatment with 
modifications if the toxicity resolves and at the discretion of the treating physician and the PI. In 
the absence of clinical deterioration and if the investigator believes that the patient continues to 
receive benefit from the treatment, patients may continue to receive study drug(s) after the first 
indication of progressive disease until a confirmatory scan is obtained. 
 
To understand and safeguard against potential cumulative toxicities the study team will continue 
to monitor the occurrence of study drug related SAEs and AEs throughout the treatment period 
and during potential treatment extensions to allow for dose correction in the event of cumulative 
immune-mediated toxicities. 
 
Delayed onset of significant toxicities will be evaluated on a case-by-case basis at the discretion 
of the PI in consultation with the Safety Monitoring Committee (SMC). At minimum, a review and 
discussion of potential delayed onset of significant toxicity will take place at review prior to a dose 
escalation decision. 
 
3.5 Dose Escalation and Stopping Rules 
 
The decision to proceed to the next dose level will be made after the first 3 patients in a dose 
level have completed 28 days (1 cycle) of dosing. Prior to advancing/changing dose levels, a dose 

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1. Age ≥18 years. 
 
2. Subjects must have histologically confirmed malignancy that is metastatic or unresectable 
and for which standard curative measures do not exist or are no longer effective. 
 
3. Subjects will be eligible for this study based on the presence of actionable aberrations in 
one or more of the following DNA Damage Response (DDR) genes: ARID1A, ATM, ATR, 
ATRX, BAP1, BARD1, BRCA1/2, BRIP1, CDK12, CHEK2, FANCA, FANCC, FANCD2, 
FANCE, FANCF, FANCM, MRE11A, MSH2, NBN (NBS1), PALB2, RAD51, RAD51C, 
RAD51D, SMARCB1, and VHL, or other related genes at the discretion of the principal 
investigator in consultation with the MD Anderson Cancer Center Institute for Personalized 
Cancer Therapy Precision Oncology Decision Support (PODS) group. Variant 
interpretation for actionability will be performed by PODS. 
 
4. Subjects with germline defects in DDR genes are eligible for this trial. 
 
5. The collection of archival tumor tissue (within 1 year prior to study enrollment) will be 
mandatory. Tumor biopsies on Cycle 1 Day 15 will be mandatory. Subjects will not be put 
at undue risk to obtain the biopsy at C1D15. A biopsy at C1D15 will not be required if it 
poses a serious/severe complication risk greater than 2%. All other biopsy timepoints are 
not mandatory but will be strongly encouraged where feasible. These include at baseline 
and at disease progression. Archival and fresh tissue requests can be waived in 
exceptional circumstances with PI approval and only where rationale is documented. 
 
6. Subjects must have received at least 1 line of systemic therapy in the advanced/metastatic 
setting. Subjects with diseases without known effective options, and subjects who had 
declined standard of care therapy prior to study introduction are also eligible. 
 
7. Subjects enrolling in the dose escalation should have progressed on or be intolerant to all 
therapies known to confer a clinical benefit. Subjects must not have refused all available 
therapies.  
 
8. Subjects who have received prior therapy with immune checkpoint inhibitors (ICIs) are 
eligible for this trial. Subjects with a standard-of-care option for an Immune Checkpoint 
Inhibitor are eligible. 
 
9. Subjects must have measurable disease per RECIST v1.1, or patients may have bone 
metastatic disease evaluable by Prostate Cancer Working Group 3 (PCWG3) for subjects 
with metastatic castration-resistant prostate cancer (CRPC), or according to tumor 
evaluation criteria best suited and accepted for the tumor type to be evaluated. 
 
10. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status 
0-1. 
 
11. Subjects must have a life expectancy ≥12 weeks. 
 
12. Subjects must have normal organ and marrow function as defined below: 

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a. Absolute neutrophil count ≥1.5 x 109/L; 
b. Platelets ≥100 x 109/L; 
c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
d. Total bilirubin ≤1.5X the institutional upper limit of normal (ULN); 
e. AST(SGOT)/ALT(SGPT) ≤2.5X institutional ULN or ≤5X institutional ULN in the 
presence of liver metastases; 
f. Renal function defined by serum creatinine ≤ 2X ULN or estimated creatinine 
clearance ≥30 mL/min according to the Cockcroft-Gault formula. 
 
13. Female patients of childbearing potential must have a negative serum or urine pregnancy 
test at screening (and again at baseline just prior to first administration of study drugs). 
 
Female patients of non-childbearing potential must meet at least 1 of the following criteria: 
a. Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months, with no alternative pathological or physiological 
cause; 
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c. Have medically confirmed ovarian failure. 
 
All other female patients are considered to be of childbearing potential. 
 
14. Women of childbearing potential and fertile men must agree to use adequate 
contraception when sexually active from signing of the informed consent form for the 
full study until at least 6 months after the last study drug administration. Patients must 
agree to utilize 2 reliable and acceptable methods of contraception simultaneously. A 
man is considered fertile after puberty unless permanently sterile by bilateral 
orchiectomy. Men taking part in this study are advised not to father a child during and 
up to 6 months after treatment; prior to treatment, advice should be sought for 
conserving sperm due to the chance of irreversible infertility as a consequence of 
treatment. Female partners of childbearing potential from male study patients have to 
use adequate contraception / birth control between signing of the informed consent 
and 6 months after the last administration of the study drug if the male study patient is 
not sterilized. The investigator or a designated associate is requested to advise the 
patient how to achieve highly effective birth control. Highly effective (failure rate of 
less than 1% per year) contraception methods, when used consistently and correctly, 
include: 
• 
Combined (estrogen and progestin containing: oral, intravaginal, 
transdermal) and progestin-only (oral, injectable, implantable) hormonal 
contraception associated with inhibition of ovulation. 
• 
Intra-uterine device or intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion or vasectomized partner (provided that partner is 
the sole sexual partner and has received medical assessment of the surgical 
success). 
• 
Sexual abstinence (reliability to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient). 

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Male patients with a female partner of reproductive potential must use a condom and 
ensure that an additional form of contraception is also used during treatment and until 
6 months after last study drug administration. Patients must agree to utilize 2 reliable 
and acceptable methods of contraception simultaneously. 
 
15. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study. 
 
16. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other 
procedures. 
 
17. Human Immunodeficiency Virus (HIV)-infected (HIV1/2 antibody-positive) patients may 
participate IF they meet all the following eligibility requirements:   
a. They must be on an anti-retroviral regimen with evidence of at least two 
undetectable viral loads within the past 6 months on this same regimen; the most 
recent undetectable viral load must be within the past 12 weeks. 
b. They must have a CD4 count ≥250 cells/mcL over the past 6 months on this same 
anti-retroviral regimen and must not have had a CD4 count <200 cells/ mcL over 
the past 2 years, unless it was deemed related to the cancer and/or chemotherapy-
induced bone marrow suppression.  
i. For patients who have received chemotherapy in the past 6 months, a CD4 
count <250 cells/mcL during chemotherapy is permitted as long as viral 
loads were undetectable during this same chemotherapy. 
c. They must have an undetectable viral load and a CD4 count ≥250 cells/mcL within 
7 days of enrolment. 
d. They must not be currently receiving prophylactic therapy for an opportunistic 
infection and must not have had an opportunistic infection within the past 6 months.  
 
 
4.2 Exclusion Criteria 
 
Patients who meet any of the exclusion criteria listed below will not be eligible for participation in 
the study. 
 
1. Anticancer systemic therapy or radiotherapy within 4 weeks or 5 half-lives, whichever 
is shorter prior to starting the study agents. Prior palliative radiotherapy to metastatic 
lesion(s) is permitted, provided it has been completed 2 weeks prior to study 
enrollment, and no clinically significant toxicities are expected (e.g., mucositis, 
esophagitis). 
 
2. Known symptomatic brain metastases requiring steroids. Patients with previously 
treated diagnosed brain metastases are eligible if they have completed their treatment 
and have recovered from the acute effects of radiation therapy or surgery prior to study 
enrollment, have discontinued corticosteroid treatment for these metastases for at 
least 4 weeks and are neurologically stable. 
 

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3. Current use of immunosuppressive medication at the time of study enrollment, 
EXCEPT for the following permitted steroids: 
a. Intranasal, inhaled, topical steroids, eye drops, or local steroid injection (e.g., intra-
articular injection); 
b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent; 
c. Steroids as premedication for hypersensitivity reactions (e.g. CT scan 
premedication). 
 
4. Subjects who had major surgery within 4 weeks prior to study enrollment. 
 
5. Known prior severe hypersensitivity to investigational products or any component in 
their formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v5 Grade ≥ 3). 
 
6. Active infection requiring systemic therapy. 
 
7. Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, 
and pulmonary fibrosis. 
 
8. Subjects with radiographic evidence of pneumonitis on baseline imaging. 
 
9. Active or prior autoimmune disease that may deteriorate when receiving an 
immunostimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible. 
 
10. Prior organ transplantation including allogenic stem cell transplantation. 
 
11. Diagnosis of Myelodysplastic Syndrome (MDS). 
 
12. Vaccination within 4 weeks of study enrollment and while on trial is prohibited except 
for the administration of inactivated vaccines. 
 
13. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 month prior to enrollment), myocardial infarction (< 6 months prior 
to enrollment), unstable angina, congestive heart failure (≥ New York Heart 
Association Classification Class II) or a serious cardiac arrhythmia requiring 
medication. 
 
14. Other acute or chronic medical or psychiatric conditions including but not limited to 
recent (within the past year) or active suicidal ideation or behavior or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of study 
results, and in the judgement of the Investigator, would make the patient inappropriate 
for entry into this study. 
 
15. Pregnant female patients, breastfeeding female patients, fertile male patients, and 
female patients of childbearing potential who are unwilling or unable to use 2 highly 

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effective methods of contraception as outlined in this protocol for the duration of the 
study, and for at least 6 months after the last dose of study drug administration.  
 
16. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test is positive). 
 
 
17. Known additional malignancy that is active and/or progressive requiring treatment; 
exceptions include basal cell or squamous cell skin cancer, in situ bladder cancer, or 
other cancer for which the patient has been disease-free for ≥ 2 years. 
 
18. Persisting toxicity related to prior therapy (NCI CTCAE v5 Grade > 1); however, 
alopecia and sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 AEs not constituting 
a safety risk, based on the Investigator’s judgement, are acceptable. 
 
19. Subjects receiving treatment with strong inhibitors or inducers of CYP3A4 that cannot 
be discontinued before start of investigational treatment and for the duration of study. 
 
20. Subjects with ongoing toxicity (any grade) and/or resolved ICI toxicity (grade 3 or 
higher only.  
 
5. STUDY TREATMENTS 
 
The trial regimen will be administered in 28-day cycles. The investigational products to be 
administered in this trial are: M6620 and avelumab. For both dose escalation and expansion, 
treatment will continue until disease progression, unacceptable toxicity, and/or withdrawal of 
patient consent. 
 
5.1 Allocation to Treatment 
 
Eligible patients will be enrolled to receive one of the study drug combinations in an open-labeled, 
unblinded manner. Patients will be registered and successively assigned to the next available 
treatment slot at a dose level decided on after the safety evaluation and ongoing observations of 
earlier enrolled patients. Dose level allocation will be performed after patients have given their 
written informed consent and have completed the necessary baseline assessments. 
 
5.2 Investigational Product Supplies 
 
M6620 and avelumab will be supplied for the study by EMD Serono. The Investigational 
Pharmacy will receive a supply of study drug(s) prior to activation with instructions on how to 
confirm drug receipt. Resupplies will be made during the course of the study based on need. 
 
5.2.1 Formulation and Packaging 
 

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Packaging and labeling for all study drugs will be in accordance with applicable local regulatory 
requirements and applicable Good Manufacturing Practice (GMP) guidelines. The information on 
each study drug will be in accordance with approved submission documents. 
 
5.2.1.1 M6620 
 
M6620 drug product will be supplied as a 20 mg/mL solution for injection, in 10 mL clear vials in 
cardboard boxes with foam inserts, designed for single-use only. M6620 drug product is intended 
for intravenous administration, only after dilution with 5% dextrose solution in water (D5W). 
 
 
5.2.1. 2 Avelumab 
 
Avelumab is formulated as a 20.0 mg/mL solution and is supplied by EMD Serono in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum flip-off seal. Each vial 
will be packaged and labeled per all applicable regulatory requirements and Good Manufacturing 
Practice Guidelines. 
 
Avelumab will be packed in boxes each containing 8 vials. 
 
Avelumab will be supplied by EMD Serono and packaged, labeled, and distributed for clinical 
studies by a suitable service provider and finally released by an EMD Serono qualified person 
under Good Manufacturing Practice conditions. Avelumab will be shipped and must be stored 
under refrigerated conditions (2ºC to 8ºC) that are monitored with temperature control monitoring 
devices. 
 
5.2.2 Preparation and Dispensing 
 
5.2.2.1 M6620 
 
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. 
 
 
5.2.2.2 Avelumab 
 
Investigational products should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (e.g. physician, nurse, physician’s assistant, nurse 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance. 
 
Each single-use vial contains 200mg of Avelumab as a preservative-free acetate-buffered solution 
(pH 5.2) containing mannitol, and polysorbate 20 (Tween 20). For administration, avelumab drug 
concentrate must be diluted with 0.9% saline solution (sodium chloride for injection) supplied in 
an infusion bag; alternatively, a 0.45% saline solution can be used if needed. Detailed information 

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on infusion bags and medical devices to be used for the preparation of the dilutions and 
subsequent administration will be provided in the Investigational Product Manual. 
 
Any unused portion of the avelumab solution should be discarded in biohazard waste disposal 
with final disposal by accepted local and national standards of incineration. 
5.2.3 Administration, Pre-medications, and Infusion Reactions 
 
5.2.3.1 M6620 
 
All doses of M6620 will be administered at the investigator site by well-trained medical staff. The 
start and stop times of the M6620 infusion, along with the total dose and volume administered, 
will be recorded in the patients’ medical records. Additionally, the start and stop times of any 
interruptions to infusions and/or changes in rate of M6620 infusion will also need to be recorded 
in the patients’ medical records. The vials of M6620 that are assigned and prepared for patients 
will be recorded in the pharmacy records. These records will all be available for MDA IND Office 
representatives to verify compliance. 
 
To minimize the possibility of phlebitis, M6620 should be administered through a large bore 
catheter into a large caliber peripheral vein. The IV infusion site should be monitored closely for 
the development of erythema, induration, purulence, tenderness, or warmth. 
If any participant develops phlebitis, or signs or symptoms of inflammation that may progress to 
phlebitis or that the participant cannot tolerate, standard measures should be employed to 
ameliorate these symptoms (including removal of the infusion catheter and resumption of infusion 
through a different vein). If standard procedures to limit symptoms of injection site reaction, or 
pruritus or acute hypersensitivity are insufficient, then the infusion time may be extended beyond 
60 minutes, but no more than 90 minutes. 
 
If a patient remains on therapy after 6 months, then treating physician/investigator may consider 
changing M6620 dosing from every week to every 2 weeks for ease of schedule for the patient. 
The physician/investigator will maintain the same dose of M6620 when changing from every week 
to every 2 weeks scheduling. This option will be discussed with every patient remaining on therapy 
after 6 months, and the decision will be at the discretion of the patient and investigator. 
 
5.2.3.2 Avelumab 
 
All doses of avelumab will be administered at the investigator site by well-trained medical staff. 
The start and stop times of the avelumab infusion, along with the total dose and volume 
administered, will be recorded in the patients’ medical records. Additionally, the start and stop 
times of any interruptions to infusions and/or changes in rate of avelumab infusion will also need 
to be recorded in the patients’ medical records. The vials of avelumab that are assigned and 
prepared for patients will be recorded in the pharmacy records.  
 
Avelumab will be administered as a 1-hour infusion dose of 800 mg administered IV once every 
2 weeks. 
 
As a routine precaution, participants enrolled in this study must be observed for 1-hour post 
infusion for the first 4 infusions, in an area with resuscitation equipment and emergency agents. 
At all times during avelumab treatment, immediate emergency treatment of an infusion-related 
reaction or a severe hypersensitivity reaction according to institutional standards must be 

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assured. In order to treat possible hypersensitivity reactions, for instance, dexamethasone 10 mg 
and epinephrine in a 1:1000 dilution or equivalents should always be available along with 
equipment for assisted ventilation.  
 
The treatment recommendations for infusion-related reactions are outlined in Adverse Drug 
Reactions Requiring Avelumab Treatment Discontinuation or Modifications (Section 
5.2.5.3.2).  
 
Investigators should also monitor participants closely for potential irAEs, which may become 
manifest at any time during treatment. Such events include but are not limited to pneumonitis, 
hepatitis, colitis, endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency, and 
type 1 diabetes mellitus), myocarditis, myositis, and rash. See Adverse Drug Reactions Requiring 
Avelumab Treatment Discontinuation or Modifications details on the management of irAEs. 
Investigators should also monitor participants closely for potential irAEs, which may become 
manifest earliest after weeks of treatment. Such events may consist of persistent rash, diarrhea 
and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and 
other inflammatory eye conditions. The spectrum of hypothetical irAEs also includes formation of 
auto antibodies like anti-nuclear antibodies or anti-neutrophil cytoplasmic antibodies. See 
Adverse Drug Reactions Requiring Avelumab Treatment Discontinuation or Modifications 
(Section 5.2.5.3.2) for details on the management of irAEs. 
 
If a hypersensitivity reaction occurs, the participant must be treated according to the best available 
medical practice. Participants should be instructed to report any delayed reactions to the 
Investigator immediately. 
 
5.2.3.3 Pre-medications 
 
For avelumab, premedication with an antihistamine (for example, 25 to 50 mg diphenhydramine) 
and with paracetamol (acetaminophen; 500 to 650 mg) IV or oral equivalent approximately 30 to 
60 minutes prior to the first 4 doses of avelumab is mandatory, and thereafter is based upon 
clinical judgment and presence/severity of prior infusion reactions. Standard prophylactic 
premedication with corticosteroids is not recommended; however, prophylactic steroids to prevent 
recurrence of infusion-related reaction are not prohibited, based on the Investigator’s clinical 
judgment. Premedication should be administered for subsequent avelumab doses based upon 
clinical judgment and presence/severity of prior infusion reactions. 
 
Premedication with a corticosteroid and/or an antihistamine should be given to participants who 
have developed acute hypersensitivity and/or pruritus with M6620 infusion and who continue to 
receive treatment with M6620. 
 
5.2.3.4 Administration of Avelumab and M6620 on the same day 
 
On days when both avelumab and M6620 are to be administered (e.g., C1D1, C1D15), avelumab 
infusion will precede infusion of M6620, with at least 1 hour in between infusions to observe 
patients for infusion-related reactions. 
 
5.2.3.5 Food Requirements 
 
The investigational products may be administered without regard to food. 
 

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5.2.4 Patient Compliance 
 
The information related to each trial drug administration, including the date, time, and dose of 
study drug, will be recorded in the CRF. The investigator will make sure that the information 
entered into the CRF regarding drug administration is accurate for each patient. Any reason for 
non-compliance should be documented. 
 
5.2.5 Recommended Dose Modifications 
 
Every effort should be made to administer the study drugs on the planned dose and schedule. 
 
In the event of significant toxicity, dosing may be delayed and/or reduced as described below. 
Toxicity will be graded according to NCI CTCAE, version 5.0. In the event of multiple toxicities, 
dose modification should be based on the worst toxicity observed. Patients are to be instructed 
to notify Investigators at the first occurrence of any adverse symptom. 
 
Dose modifications may occur: 
• 
Within a cycle: dosing interruption until adequate recovery and dosing reduction, if 
required, during a given treatment cycle. 
• 
Between cycles: next cycle administration may be delayed due to persisting toxicity when 
a new cycle is due to start. 
 
5.2.5.1 Dose Interruptions 
 
Appropriate follow up assessments should be done until adequate recovery occurs as assessed 
by the Investigator. Criteria required before treatment can resume are described in Dose Delays 
(Section 5.2.5.2). 
 
Doses may be held as needed until toxicity resolution. Depending on when the AE resolved, a 
treatment interruption may lead to the patient missing all subsequent planned doses within that 
same cycle or even to delay the initiation of the subsequent cycle. 
 
If the AE that led to the treatment interruption recovers within the same cycle, then re-dosing in 
that cycle is allowed. Doses omitted for toxicity are not replaced within the same cycle. The need 
for a dose reduction at the time of treatment resumption should be based on the criteria defined 
in Dose Modifications (Section 5.2.5.3), unless expressly agreed otherwise following discussion 
between the Investigator and the SMC. 
 
In the event of a treatment interruption for reasons other than treatment-related toxicity (e.g. 
elective surgery) lasting >28 days, treatment resumption will be decided in consultation with the 
SMC. 
 
5.2.5.2 Dose Delays 
 

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Patients experiencing Grade 3 or 4 potentially treatment related toxicity or intolerable Grade 2 
toxicity despite supportive care should have their treatment interrupted/delayed. Appropriate 
follow-up assessments should be done until adequate recovery (or until deemed irreversible) 
occurs as assessed by the Investigator. A treatment delay of more than 4 weeks due to lack of 
recovery will result in discontinuation of the patient from the treatment, unless continuation (with 
dose reduction) upon subsequent recovery is considered in the patient’s best interest by the 
investigator (e.g. proven clinical benefit). 
 
A new cycle of treatment may begin only if: 
a. ANC ≥ 1000/μL 
b. Platelet count ≥ 100,000/μL 
c. Hemoglobin ≥ 8.5 g/dL 
d. Non-hematologic toxicities have returned to baseline or Grade ≤ 1 severity (or, at the 
investigator discretion, Grade ≤ 2 if not considered a safety risk for the patient). 
Withhold scheduled dose for liver function test related AEs (including asymptomatic) Grade ≥ 3 
until return to baseline or Grade ≤ 1 severity. In cases of potential liver injury, consultation with a 
hepatologist should be considered in the decision to initiate treatment with anti-inflammatory 
medications. 
 
If these conditions are not met, treatment must be delayed by 1 week. If, after a 1-week delay, all 
toxicities have recovered within the limits described above, treatment with study drugs, can be 
resumed. Both study drugs should be delayed simultaneously if applicable. If the patient has not 
recovered after 1 week of delay, treatment may be delayed by 1 more week. However, initiation 
of the next cycle can only be delayed by a maximum of 4 weeks (28 days). Therefore, if persisting 
toxicity does not allow for the resumption of treatment, the patient will be permanently 
discontinued. 
 
For all ≥ Grade 3 hematological or non-hematological AEs that are NOT study drug-related, after 
consultation with the Medical Monitor and at the discretion of the treating physician, study drug 
dosing may be continued. 
 
Elevation of amylase and/or lipase without clinical and/or radiographic evidence of pancreatitis 
are not considered DLT, and the patient can resume treatment at any grade at the discretion of 
the treating physician in consultation with the PI. 
 
Patients continuing on protocol after more than a 28 days delay in treatment can continue on a 
case by case basis after discussion with the Medical Monitor and at the discretion of the treating 
physician. 
 
Each dose modification or treatment delay has to be documented in the eCRF, including the 
respective reason. 
 
5.2.5.3 Dose Modifications 
 
In the event that a DLT that is at least possibly related to one of the study drugs occurs, patients 
will halt treatment with study drugs until symptoms resolve to the grade outlined in Section 5.2.5.2, 
and then treatment can be restarted. After the first two cycles reduction in the frequency of dosing 
in study drug(s) may be required based on the worst toxicity experienced in the previous cycle. 

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No specific dose adjustments are recommended for Grade 1/2 treatment-related toxicity. 
However, investigators should always manage their patients according to their medical judgment 
based on the particular clinical circumstances. 
 
During the dose escalation arm for the combination of M6620 and avelumab, patients 
experiencing recurrent and intolerable Grade 2 toxicity may resume dosing at the next lower dose 
level or at a decreased frequency once recovery to ≤ Grade 1 or baseline is achieved. Patients 
enrolled in the expansion arms may resume dosing, once recovery to ≤ Grade 1 or baseline is 
achieved after experiencing recurrent and intolerable ≥ Grade 2. If a dose or frequency reduction 
is required due to the treatment related toxicity, this may be allowed as an alternative to 
discontinuation of treatment, upon agreement with the MDACC IND Office. 
 
Once a patient has a dose reduction or reduction in the frequency in the dosing for a drug-related 
toxicity, the dose will not be re-escalated. Patient requiring more than two dose reductions will be 
withdrawn from treatment unless otherwise agreed between the investigator and the MDACC IND 
Office. 
 
Adverse events (both non-serious and serious) associated with study drug(s) exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. The immunotherapy drug avelumab must be 
withheld for drug-related toxicities and severe or life threatening AEs as per Table 3. Where 
appropriate, these guidelines include the use of oral or intravenous treatment with corticosteroids 
as well as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. The dose modification guidelines are intended 
to be applied when the physician determines the events to be related to avelumab. 
 
For subjects whose dose was withheld due to toxicity, subjects may resume immunotherapy study 
drug (avelumab) upon resolution of toxicity to Grade 0-1 or baseline. 
 
Note: The general treatment recommendations outlined in Sections 5.2.5.1, 5.2.5.2, and 5.2.5.3 
can be used unless more specific treatment guidelines are outlined in Sections 5.2.5.3.2.1 and 
5.2.5.3.2.2 below. 
 
5.2.5.3.1 Adverse Drug Reactions Requiring M6620 Treatment Discontinuation or 
Modifications 
 
In the case of occurrence of an AE attributed to M6620, treatment may be interrupted and may 
resume when all toxicities have returned to Grade 2 or less, at the discretion of the Investigator.  
Except for participants in Part A during the DLT observation period, doses of M6620 may be 
reduced after occurrence of a related AE using the following guidelines, any exceptions to this 
dose modification criterion will need to be agreed between the PI and IND Office: 
a. For Grade 4 hematologic toxicity: the dose of M6620 will be reduced by 25%. 
b. For Grade 3 non-hematologic toxicity: M6620 will be discontinued. 
c. For Grade 4 non-hematologic toxicity: M6620 will be discontinued. 
 

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Guidelines for dose modification for toxicity are provided below. The final dose reduction or delay 
for each participant may be determined by the Investigator. However, these guidelines provide 
the minimum dose reduction or delay criteria. Additionally, if a participant who is responding to 
treatment experiences toxicity even after 2 dose reductions, the participant may continue to 
receive treatment if in the judgment of the Investigator it is in the best interest of the participant. 
In this case the dose of M6620 will further be reduced by at least 25%. 
 
In case of M6620 Grade 3 or higher toxicity (excluding fatigue or nausea/vomiting/diarrhea 
adequately managed by supportive care), treatment will be interrupted and may be resumed when 
all toxicities have returned to Grade 2 or lower, at the discretion of the Investigator. 
 
For the following hematologic toxicities, once the toxicity has returned to Grade 2 or lower, dosing 
can be resumed with 1 dose level reduction. If, after 1 dose level reduction, any of the below drug-
related hematologic toxicities are subsequently observed, then dosing may be resumed with 
2 dose level reductions: 
a. Grade 4 thrombocytopenia; 
b. Febrile neutropenia (growth factor support, per site protocol, may be used in lieu of dose 
reduction) except during the DLT assessment period prior to occurrence of a DLT. Once 
a DLT has occurred, it is acceptable to use growth factor support even during the DLT 
period; 
c. Grade 4 neutropenia lasting more than 7 days. 
If any of the drug-related toxicity listed below is subsequently observed, the M6620 dose will be 
reduced by 1 dose level: 
a. Grade 3 non-hematologic toxicity (except for fatigue or nausea, vomiting, or diarrhea 
adequately controlled by medication). For infusion reactions, hypersensitivity, or allergic 
reactions related or possibly related to M6620, see below for additional guidelines for 
management; 
b. Any Grade 2 or lower non-hematologic toxicity requiring dose delay of more than 2 weeks. 
For Grade 4 non-hematologic toxicity, treatment will be interrupted and may be resumed with 
2 dose level reductions when toxicity has returned to Grade 2 or lower. 
 
If any toxicity not described above results in a delay in dosing during any part of the study and 
the participant may be benefitting from therapy, then the doses of M6620 may be reduced by 
1 dose level at the discretion of the Investigator. 
 
5.2.5.3.2 Adverse Drug Reactions Requiring Avelumab Treatment Discontinuation or 
Modifications 
 
Treatment with avelumab should be permanently discontinued, if any of the following ADRs 
occurs: 
Any Grade 4 ADRs:  
• 
Permanently discontinue avelumab except for laboratory values out of normal range that 
do not have any clinical correlate. 
Any Grade 3 ADRs:  

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• 
Withhold avelumab except for laboratory values out of normal range that do not have any 
clinical correlate; 
• 
Permanently discontinue avelumab if toxicity does not resolve to Grade ≤ 1 or Baseline 
within 12 weeks of last administration or if the same Grade 3 toxicity recurs (consider 
consult with the Medical Monitor before permanently discontinuing the treatment). 
If dosing is delayed more than 4 weeks, treatment may be resumed after consultation with the 
study Medical Monitor. Any delay in dosing in excess of 12 weeks is not permitted. 
Infusion-related reactions and irAEs should be handled according to guidelines as outlined in 
table below. 
 
5.2.5.3.2.1 Management of Infusion-Related Reactions 
 
To mitigate infusion-related reactions associated with avelumab, participants have to be pre-
medicated with an antihistamine and with paracetamol (acetaminophen) prior to the first 4 
infusions of avelumab. Premedication should be administered for subsequent avelumab doses 
based upon clinical judgment and the presence/severity of prior infusion reactions. 
 
Management of symptoms should follow the guidelines shown in Table 2. 
 
Table 2: Treatment Modification for Symptoms of Infusion-related Reactions Associated 
with Avelumab. 
NCI-CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
• 
Mild 
transient 
reaction; 
infusion 
interruption not indicated. 
 
• 
Decrease the avelumab infusion rate 
by 50% and monitor closely for any 
worsening. 
Grade 2 – moderate 
• 
Therapy 
or 
infusion 
interruption 
indicated but responds promptly to 
symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for ≤ 24 hours. 
 
• 
Temporarily 
discontinue 
avelumab 
infusion. 
• 
Resume infusion at 50% of previous 
rate once infusion-related reaction has 
resolved or decreased to at least 
Grade 1 in severity, and monitor 
closely for any worsening. 
Grade 
3 
or 
Grade 
4 
– 
severe 
or 
life-threatening 
• 
Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following 
initial 
improvement; 
hospitalization indicated for clinical 
sequelae. 
• 
Grade 
4: 
Life-threatening 
consequences; 
urgent 
intervention 
indicated. 
 
• 
Stop 
the 
avelumab 
infusion 
immediately and disconnect infusion 
tubing from the participant. 
• 
Participants have to be withdrawn 
immediately from avelumab treatment 
and must not receive any further 
avelumab treatment. 

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(i.e., hypopituitarism/hypophysiti
s) 
Grade 
3 
or 
Grade 
4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, 
adrenal 
insufficiency, type I diabetes 
mellitus) 
Withhold avelumab therapy 
Consider hospitalization 
Endocrinology consult 
 
Start 
thyroid 
hormone 
replacement 
therapy 
(for 
hypothyroidism), 
anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids 
(for 
adrenal 
insufficiency) or insulin (for type I 
diabetes 
mellitus) 
as 
appropriate. 
 
Rule 
out 
secondary 
endocrinopathies 
(i.e., hypopituitarism/hypophysiti
s) 
Resume avelumab once 
symptoms 
and/or 
laboratory tests improve to 
Grade ≤ 1 (with or without 
hormone 
replacement/suppression). 
 
Continue 
hormone 
replacement/suppression 
and 
monitoring 
of 
endocrine 
function 
as 
appropriate.  
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies) 
If 
secondary 
thyroid 
and/or 
adrenal 
insufficiency 
is 
confirmed 
(i.e., 
subnormal 
serum 
thyroxine 
with 
inappropriately 
low 
thyroid-
stimulating hormone and/or low 
serum 
cortisol 
with 
inappropriately 
low 
adrenocorticotropic hormone)  
• 
Refer to endocrinologist 
for dynamic testing as 
indicated 
and 
measurement of other 
hormones 
(FSH, 
LH, 
GH/IGF-1, 
PRL, 
testosterone 
in 
men, 
estrogens in women)  
• 
Hormone 
replacement/suppressiv
e therapy as appropriate  
• 
Perform 
pituitary 
MRI 
and 
visual 
field 
examination as indicated 
 
If hypophysitis confirmed: 
• 
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month. 
• 
Withhold 
avelumab 
if 
moderate, severe or life-
Resume avelumab once 
symptoms and hormone 
tests improve to Grade ≤ 1 
(with or without hormone 
replacement). 
 
In addition, for hypophysitis 
with 
abnormal 
MRI, 
resume 
avelumab 
only 
once shrinkage of the 
pituitary gland on MRI/CT 
scan is documented.  
 
Continue 
hormone 
replacement/suppression 
therapy as appropriate. 

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Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
ADL=activities of daily living, AHA=American Heart Association, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, BNP=B-type natriuretic peptide, CK-MB=creatine kinase MB, 
CT= computed tomography, ESC=European Society of Cardiology, FSH=follicle stimulating 
hormone, GH=growth hormone, IGF-1=insulin-like growth factor 1, irAE=immune-related adverse 
event, 
IV=intravenous, 
LH=luteinizing 
hormone, 
MRI=magnetic 
resonance 
imaging, 
NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events, 
PRL=prolactin, T4=thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of normal. 
 
5.2.5.4 Treatment beyond Progression 
 
5.2.5.4.1 Treatment beyond Initial Progression 
 
Participants will receive avelumab as outlined in the study design until PD. Avelumab may 
continue past the initial determination of PD according to RECIST v1.1, as long as the following 
criteria are met: 
a. Treatment with avelumab is ongoing. 
b. No new unacceptable treatment or disease-related toxicity. 
c. Tolerance of study interventions. 
d. Stable ECOG PS. 
e. Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (for example, central nervous system metastases). 
A radiographic assessment should be performed within 4 to 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the participant is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with avelumab. 
 
5.2.5.4.2 Treatment beyond Confirmed Progression 
 
Participants who experience PD may continue treatment with study interventions if the 
Investigator believes the participant will experience clinical benefit from the treatment and there 
is no unacceptable toxicity resulting from the treatment. The decision to continue treatment 
beyond confirmed PD should be discussed with the Medical Monitor and documented in the study 
records. 
 
If the participant continues with treatment after confirmed PD, they should remain on the study 
and continue to receive monitoring according to the Study Calendar. Participants who continue 
beyond progression will be evaluated for further tumor response as per the protocol schedule. 
 
Treatment should be discontinued permanently upon documentation of further, unequivocal PD, 
unless there are no alternative therapeutic options and the benefit-risk assessment is favorable 
in consultation between the Investigator and the Medical Monitor. In case of continuation of 
treatment beyond PD, treatment will be discontinued once any other criteria for withdrawal are 
met (See Section 6.5). 

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5.2.5.4.3 Continuation of Study Intervention after Local Treatment of Disease Progression 
 
If PD is due to brain metastasis, participants may continue study interventions after the local 
treatment of the brain lesions with respect to the criteria defined in Section 4.2, and provided that 
the above criteria are met in addition to the following: 
a. Tumor assessment showing PD has been performed and was documented according to 
RECIST v1.1, prior to the procedure. 
b. Brain metastases have been treated locally and are clinically stable for at least 2 weeks 
prior to re-initiation of study interventions. 
c. There are no ongoing neurological symptoms that are related to the brain localization of 
the disease (sequelae that are a consequence of the treatment of the brain metastases 
are acceptable). 
d. Participants must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent). 
e. Benefit-risk assessment to continue study intervention is favorable under consideration of 
any alternative treatment options as assessed by the Investigator. 
In addition, if PD is mainly due to a metastatic lesion, which in the opinion of the Investigator may 
be surgically removed, participants may continue study interventions after the local treatment of 
such a lesion provided that: 
a. Tumor assessment showing disease progression has been performed and was 
documented according to RECIST v1.1, prior to the procedure. 
b. It has been at least 2 weeks and the participant has fully recovered from the surgery. 
c. Benefit-risk assessment to continue study intervention is favorable under consideration of 
any alternative treatment options as assessed by the Investigator. 
 
5.3 Drug Storage and Accountability 
 
The investigator, or an approved representative, e.g. pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements. 
 
Investigational products should be stored in their original containers and in accordance with the 
labels. The storage conditions stated in the investigator brochure may be superseded by the label 
storage. 
 
The storage conditions and temperatures will be recorded on the Investigational Pharmacy 
temperature logs. 
The Investigator or an approved representative (e.g. pharmacist) will ensure that all 
investigational product is stored in a strictly controlled, secure area, at appropriate temperatures 
and in accordance with applicable regulatory requirements. 
 
The Investigator or designated personnel must maintain adequate records documenting the 
receipt, use, loss or other disposition of the investigational product(s). Accountability Logs will be 
maintained by the Investigational Pharmacy. The forms must identify the investigational product, 

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including batch or code numbers, and account for its disposition on a patient by patient basis, 
including specific dates and quantities. 
 
Destruction of investigational product will be performed per the MDACC policy. 
 
5.3.1 M6620 Storage 
 
Store intact vials protected from light inside cardboard boxes at room temperature, 25ºC (77ºF), 
with excursions allowed between 15 and 30ºC (59 and 86ºF). 
 
Note: If a temperature excursion is identified, promptly return M6620 to between 15 and 30ºC and 
quarantine the supplies. Provide a detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to the CMO (Fisher) for determination of 
suitability. 
 
Stability testing of the intact vials is on-going. Prepared solutions must be protected from light and 
used within 4 hours from time of preparation if stored at room temperature or 24 hours if stored 
refrigerated (2ºC-8ºC) 
 
5.3.2 Avelumab Storage 
 
Avelumab must be stored in the refrigerator at 2ºC – 8ºC (36ºF – 46ºF). Do not freeze. Protect 
from light. Do not shake vigorously.  
 
Note: If a temperature excursion is identified, promptly return Avelumab to 2ºC – 8ºC (36ºF – 
46ºF) and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to the CMO (Fisher) for 
determination of suitability. 
 
5.4 Concomitant Treatment 
 
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician.  
 
All concomitant medications and treatments, including herbal supplements, supportive care drugs 
(e.g. antiemetic treatment and prophylaxis), drugs used to treat adverse events or chronic 
diseases, blood products, and nondrug interventions (e.g. paracentesis) will be recorded from 28 
days prior to the start of study treatment (i.e. the screening period) and up to 90 days after the 
last dose of investigational product (i.e. the Short Term Follow up Day 90 Visit). If a patient begins 
a new anti-cancer therapy, reporting of concomitant medications should end at the time the new 
treatment is started. All concomitant medications will be captured in the EMR, but not the EDC. 
 
5.4.1 Other Anticancer or Experimental Drugs 
 
No additional anticancer therapy will be permitted while patients are receiving one of the study 
drug combinations. 

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Additionally, the concurrent use of vitamins or herbal supplements should be considered with 
caution. 
 
Palliative and supportive care for disease related symptoms may be administered at the 
Investigator’s discretion. 
 
5.4.2 Supportive Care 
 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical Oncology 
(ASCO) guidelines and as deemed necessary by the treating investigator. 
 
5.4.3 Hematopoietic Growth Factors 
 
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during the DLT 
period – Cycle 1 (Please See Section 5.2.5.3.1), but they may be used to treat treatment-
emergent neutropenia as indicated by the current American Society of Clinical Oncology (ASCO) 
guidelines (J Clin Oncol, 2006. 24(19):3187-3205). 
 
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the treating 
physician in line with local guidelines. Erythropoietin or darbepoetin may be used at the 
investigator’s discretion for the supportive treatment of anemia. 
 
5.4.4 Anti-Diarrheal, Anti-Emetic Therapy 
 
Primary prophylaxis of diarrhea, nausea and vomiting is permitted at the investigator’s discretion. 
The choice of the prophylactic drug, as well as the duration of treatment, is up to the investigator 
and assuming the drug is not included in Prohibited Concomitant Medications and Therapies 
(Section 5.4.11). 
• 
Diarrhea: All patients who experience diarrhea should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. 
• 
Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice. Patients should be strongly 
encouraged to maintain liberal oral fluid intake. 
 
5.4.5 Anti-inflammatory Therapy 
 
Anti-inflammatory or narcotic analgesic may be offered, as needed, assuming the drug is not 
included in Prohibited Concomitant Medications and Treatments (Section 5.4.11). 
 

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5.4.6 Corticosteroids 
 
Chronic, systemic corticosteroid use (more than 10 mg/day of prednisone equivalent) for palliative 
or supportive purpose is not permitted. Use of corticosteroids as symptomatic treatment may be 
allowed on an individual basis and upon discussion with the SMC. Steroids for replacement 
therapy (physiologic replacement) are allowed. Acute emergency administration, topical 
applications, inhaled sprays, eye drops, or local injections of corticosteroids are allowed. 
 
5.4.7 Surgery 
 
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time between surgery and the study drug(s) required to minimize the risk 
of impaired wound healing and bleeding has not been determined. Stopping study drug(s) is 
recommended at least 14 days prior to surgery. 
 
Postoperatively, the decision to reinitiate study drug(s) treatment should be based on a clinical 
assessment of satisfactory wound healing and recovery from surgery. 
 
5.4.8 Radiation Therapy 
 
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions and other 
sites of disease if considered medically necessary by the treating physician, provided that the 
bony lesions and/or other sites of disease to be irradiated were present at the time of screening 
tumor assessments and the investigator clearly indicates that the need for palliative radiotherapy 
is not indicative of disease progression. All attempts should be made to rule out disease 
progression in the event of increased localized pain. 
 
Study treatment should be suspended for at least 5 half-lives of M6620, prior to the start of 
palliative radiotherapy to exclude synergistic toxicities between DDR inhibitors and radiation 
therapy. 
 
5.4.9 Bisphosphonates or Denosumab 
 
Bisphosphonates or denosumab treatment is allowed and it will be given as per local practice. 
The need to initiate treatment with bisphosphonate or denosumab or to increase the dose of these 
therapies while on study treatment (for patients who started bisphosphonate or denosumab 
therapy > 2 weeks before study enrollment), may be considered as a symptom of disease 
progression that should be considered as a symptom of disease progression that should be 
confirmed radiologically. 
 
5.4.10 Androgen Deprivation Therapy for Patients with CRPC 
 
Patients with CRPC must receive androgen deprivation therapy with a GnRH agonist/antagonist 
or bilateral orchiectomy (medical or surgical castration). 
 

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5.4.11 Prohibited Concomitant Medications and Therapies 
 
The following treatments must not be administered during the trial: 
• 
Immunotherapy not specified in this protocol, and immunosuppressive drugs, i.e., 
chemotherapy or systemic corticosteroids except: 
a. When required for the treatment of immune-related adverse events or infusion-
related reactions/hypersensitivity. 
b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or 
equivalent. 
c. Systemic corticosteroids for the management of patients with allergy to CT IV 
Radiographic Contrast Media. 
 
• 
Administration of a live vaccine within 30 days prior to study treatment. 
 
• 
Strong inhibitors or inducers of CYP3A4 (See Appendix F).  
 
• 
Herbal remedies with immunostimulating properties (e.g., mistletoe extract), or known to 
potentially interfere with major organ function (e.g., hypericin). 
Any additional concomitant therapy that becomes necessary during the trial and any changes to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication for each drug. 
 
6. STUDY PROCEDURES 
 
For screening, treatment period, and follow up procedures see the Study Calendar. 
 
For the treatment period discussed below, where multiple procedures are scheduled at the same 
nominal time point(s) relative to dosing, the following prioritization of events should be adhered 
to, where possible, in order of the most important to the least important: 
a. Clinical safety lab tests – obtain prior to study drug administration 
b. Blood pressure/pulse rate – may be obtained prior to or after ECG collection but must be 
obtained prior to study drug administration. 
c. ECGs – obtain within 30 minutes of study drug administration 
d. Other procedures – all other procedures should be obtained as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection, unless 
sampling is determined by the study personnel to potentially impact the results. 
During the COVID-19 pandemic, alternative methods for conducting study assessments should 
be considered when compliance, feasibility, and safety can be assured. These methods may 
include:  
• 
Telemedicine visits, e.g., via telephone/video (using compliant video-conference tools as 
permitted by health authority regulations)  
• 
Use of primary care centers and local laboratories for blood draws  
 

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If alternative methods are used, local laboratory reference ranges will be documented. Local 
laboratory test results, laboratory accreditation, and reports should be retrieved and documented 
in the participant’s study records. 
 
6.1 Screening Period 
 
All screening activities must take place within 28 days prior to enrollment into the study, unless 
otherwise indicated. 
 
The required screening assessments and laboratory tests are summarized in the Study Calendar 
and Section 7 (Assessments). Following completion of the screening assessments and 
confirmation of eligibility, patients may initiate study treatment. 
 
6.2 Study Treatment Period 
 
Treatment will continue until progression of disease (PD) or unacceptable toxicity, withdrawal of 
consent by the patient, or non-compliance by the patient with protocol requirements. Safety 
assessments will be performed as illustrated in the Study Calendar. 
 
Per the physician’s discretion, a patient may continue treatment even if there is progression of 
disease as long as the patient remains clinically stable and/or pseudoprogression is assumed (in 
the case of combinations involving avelumab). 
 
Clinical and radiological examinations for disease status are performed per the study calendar. 
 
If a patient discontinues treatment due to any other reason than disease progression/death/ 
withdrawal of informed consent, the disease evaluations shall continue until disease progression. 
This includes patients who wish to discontinue treatment, but agree that further data is captured 
for the purpose of the study (partial withdrawal). 
 
6.3 End of Treatment Visit 
 
Patients that discontinue from treatment will undergo an end of treatment (EOT) visit, regardless 
of the reason of discontinuation, per the study calendar. 
 
In the event a patient is unable to return to the clinic for the follow-up visit, telephone contact with 
the patient to assess adverse events and concomitant medications and treatment is expected. If 
laboratory assessments are needed to follow-up unresolved adverse events, retrieval of 
assessments performed at an institution local to the patient is acceptable. 
 
6.4 Follow up Phase 
 
Patients who discontinue treatment for reasons other than progression of disease (and withdrawal 
of consent for participation in the trial) will continue to visit the clinic for evaluation of their disease 
by CT/MRI scan approximately every 12 weeks until progression of disease is determined or 
patient receives additional anti-neoplastic medication. 

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Of note, a patient may decide to discontinue study treatment. This is not the same as full 
withdrawal of consent to participate in the trial and these patients should be encouraged to 
continue to be followed up as for other patients until progression of disease. If a patient chooses 
to have no further interaction regarding the study (fully withdrawal of consent), the investigator 
must provide written documentation of the patient’s decision to fully withdraw from the study. 
 
Investigators will collect survival data for patients after progression of disease unless patient fully 
withdrew consent to participate in the study. Approximately one year after last dose of treatment, 
a chart review, patient visit, or telephone call will be conducted. The telephone call will be less 
than five minutes to obtain information regarding survival status. 
 
6.5 Patient Withdrawal 
 
Patients will be free to discontinue treatment or withdraw from the study at any time, for any 
reason, or they may be withdrawn/ removed if necessary in order to protect their health (see 
reasons for withdrawal below). It is understood by all concerned that an excessive rate of 
withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of subjects 
should be avoided. Patients who are withdrawn from the study outside of the DLT period will not 
be replaced. 
 
Patients will be removed from further treatment for the following reasons: 
a. Confirmed evidence of true disease progression (See Section 5.2.5.4) 
b. Non-compliance 
c. Need for treatment with medications not allowed by the study protocol (unless the 
medication is temporary and continuation of study treatment following cessation of that 
medication is reasonable at the discretion of the Investigator and Study Monitor) 
d. Patient no longer consents to participate in the study 
e. Intercurrent illness that interferes with study assessments 
f. Incidence or severity of AEs in this study indicates a potential health hazard to the patient 
g. Investigator’s discretion 
h. Pregnancy 
i. 
Termination of the study 
Reasons for withdrawal from study follow up may include: 
a. Completed study follow up 
b. Study terminated by Sponsor 
c. Lost to follow up 
d. Refusal of further follow up for survival 
e. Death 
If there is a medical reason for withdrawal of treatment, the patient will remain under the 
supervision of the investigator until the AEs have been resolved or declined to baseline values.  
 
If a patient has failed to attend scheduled assessments in the study, the investigator must 
determine the reasons and circumstances as completely and accurately as possible.  
 
In case of premature discontinuation of the study treatment, the investigations scheduled for the 
EOT and the follow-up visits should be performed, if possible. The reason for discontinuation has 

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to be documented in the eCRF in all cases. Should a patient decide to withdraw, every effort will 
be made to complete and report the observations as thoroughly as possible. The investigator 
should contact the patient to determine as completely as possible the reason for the withdrawal. 
A complete final evaluation at the time of the patient’s withdrawal should be made, with an 
explanation of why the patient is withdrawing from the study. If the reason for removal of a patient 
from the study is an adverse event or an abnormal laboratory test result, the principal specific 
event or test will be recorded on the case report form. 
 
If a patient withdraws consent for further study treatment, the patient should still be followed for 
progression and survival. If a patient withdraws consent for further participation in the study, 
follow-up assessments will be discontinued. 
 
7. ASSESSMENTS 
 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  
All procedures should be followed within the allowed flexibility windows as outlined in the Study 
Calendar. 
 
7.1 Safety Assessments 
 
7.1.1 Pregnancy Testing 
 
All pregnancy tests used in this study, either urine or serum, must be performed by a certified 
laboratory. For female patients of childbearing potential, 2 negative pregnancy tests are required 
before receiving investigational product - 1 negative pregnancy test during screening period 
(within 28 days of first dose of study drugs), and 1 at the baseline visit immediately before 
administration of investigational product. 
 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a further negative pregnancy result will then be required at the baseline visit 
before the patient receives the investigational products. Pregnancy tests will also be routinely 
repeated on Day 1 of every cycle (prior to dosing of study drugs) during the active treatment 
period, at the end of study therapy, and additionally whenever 1 menstrual cycle is missed or 
when potential pregnancy is otherwise suspected. In the case of a positive hCG test and 
confirmed pregnancy, the patient will be withdrawn from administration of investigational products 
and will be withdrawn from the study. Additional pregnancy tests may also be undertaken if 
requested by the Institutional Review Board (IRB) or if required by local regulations. 
 
7.1.2 Contraception Check 
 
Male patients who are able to father children and female patients who are of childbearing 
potential, who are, in the opinion of the investigator, sexually active and at risk of pregnancy with 
their partner(s), will need to affirm that they meet the criteria for correct use of 2 highly effective 
(<97% failure rate) methods of contraception. 
 
Adequate methods of contraception include: 

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• 
Total abstinence when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception; 
• 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment and thus 
are not considered to be of child-bearing potential. In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment; 
• 
Male sterilization (at least 6 months prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject; 
• 
Combination of any of the following two (a+b or a+c or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception; 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS); 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository. 
In case of use of oral contraception, women should have been stable on the same pill 
before taking study treatment. 
 
Note: Oral contraceptives are allowed but should be used in conjunction with a barrier 
method of contraception due to unknown effect of drug-drug interaction. Women are 
considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment is she considered not of 
child bearing potential. 
 
The investigator or his/her designee will discuss with the patient the need to use 2 contraception 
methods consistently and correctly and document such conversation in the patient’s chart. In 
addition, the investigator or his/her designee will instruct the patient to call immediately if one or 
both selected contraception methods are discontinued, or if pregnancy is known or suspected in 
the patient or the patient’s partner. 
 
7.1.3 Adverse Events 
 
An adverse event (AE) is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after signed information consent and study entry. Medical 
conditions/diseases present before starting study drug are only considered adverse events if they 
worsen after starting study drug. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, or 
require therapy. 
 
Assessment of AEs will include the type, incidence, severity (graded by the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0) timing, 
seriousness, and relatedness. 
 

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AEs that occur during the study, including baseline signs and symptoms, will be recorded in 
MOCLIA. The active reporting period begins from the time that the patient provides informed 
consent, which is obtained prior to the patient’s participation in the study, i.e., prior to undergoing 
any study-related procedure and/or receiving investigational product, through and including 90 
calendar days after the last administration of the investigational product. 
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
 
7.1.4 Laboratory Safety Assessments 
 
The required safety laboratory tests are listed in Table 4 below. Required safety laboratory tests 
including at minimum: hematology (hemoglobin, platelets, and white blood cells), and chemistry 
(ALT, AST, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, sodium, 
potassium, and glucose) must be reviewed prior to study drug administration per the study 
calendar. 
 
Table 4: Required Safety Laboratory Tests 
Hematology 
Chemistry 
Coagulation 
Urinalysis 
(Dipstick 
is 
acceptable) 
Pregnancy Test 
Hemoglobin 
ALT 
PT or INR 
Urine dipstick for 
urine protein: If 
positive (≥ 2+), 
collect 24hr 
urine or collect 
spot urine and 
microscopic 
(Reflex Testing) 
For 
female 
patients 
of 
childbearing 
potential, serum 
or urine with a 
sensitivity of ≥ 25 
mIU/mL 
Platelets 
AST 
PTT 
WBC 
Alkaline 
Phosphatase 
 
Absolute 
Neutrophils 
Sodium 
 
Urine dipstick for 
urine blood: If 
positive 
and 
clinically 
indicated collect 
a 
microscopic 
(Reflex Testing) 
Absolute 
Lymphocytes 
Potassium 
 
 
Absolute 
Monocytes 
Magnesium 
 
 
Absolute 
Eosinophils 
Chloride 
 
 
 
Absolute 
Basophils 
Total Calcium 
 
 
 
 
Total Bilirubin 
Direct Bilirubin 
Indirect Bilirubin 
 
 
 
Thyroid 
Function Tests: 
Blood 
urea 
nitrogen 
(BUN) 
or Urea 
 
 
 
TSH, Free T4 
Creatinine 
 
 
 
Total T3 
Uric Acid 
 
 
 

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Glucose 
(non-
fasted) 
 
 
 
Other Tests: 
Albumin 
 
 
 
ACTH 
Phosphorus 
or 
Phosphate 
 
 
 
HBV 
surface 
antigen 
Total Protein 
 
 
 
Anti-HCV 
antibody 
Amylase 
 
 
 
If 
Anti-HCV 
antibody 
test 
positive, 
then 
HCV RNA 
Gamma 
Glutamyl 
Transferase 
(GGT) 
 
 
 
Testosterone (at 
screening 
only 
for 
CRPC 
patients) 
Creatine Kinase 
 
 
 
 
C-reactive 
Protein (CRP) 
 
 
 
 
LDH 
 
 
 
 
Lipase 
 
 
 
 
7.1.5 Physical Examinations and Vital Signs 
 
Patients will have a physical examination (PE) per the study calendar, and will include the 
measurement of body weight, vital signs and assessment of ECOG performance status. Findings 
of all physical examinations should be recorded in the source documents, and any change from 
baseline considered by the investigator to be clinically significant should be recorded as an 
adverse event in the CRF. At screening only, height will be obtained from the electronic medical 
record. 
 
Abbreviated PEs should be performed as appropriate at each visit where complete physical 
exams are not required, with special attention to skin and mucosa, and on an as needed basis for 
assessment of adverse events. Abbreviated exams should be targeted to specific symptoms or 
complaints and be consistent with local standard of care. 
 
For treatment involving M6620, a patient’s body weight will be measured per study calendar at 
Day 1 of each dosing cycle, and it will be used to calculate the patient’s dose of M6620 for that 
cycle. 
 
Vital signs will include measurements of blood pressure, pulse rate and temperature (oral, 
tympanic, temporal or axillary). On Day 1 of each cycle, vital signs should be measured prior to 
infusion start (pre-dose) of first study drug (if more than one study drug is given) and 1 hour after 
the start of the infusion of last study drug (if more than one study drug is given). The blood 
pressure cuff, which has been properly sized and calibrated, should be used to measure blood 
pressure. The use of automated devices for measuring BP and pulse rate is acceptable. 
 
7.1.6 (12-Lead) Electrocardiograms 

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A standard 12-lead (with a 10 second rhythm strip) tracing will be used for all electrocardiogram 
(ECG) assessments. 
 
All patients require a single ECG measurement at baseline and C2D1. Thereafter, on treatment 
ECGs will be performed as clinically indicated. 
 
Clinically significant findings seen on subsequent ECGs should be recorded as adverse events. 
In case of QTc > 500 msec, a subsequent ECG should be repeated to verify the result. If ECG is 
confirmed > 500 msec, local guidelines (e.g. Repeat ECGs, review by cardiologist) should be 
followed. 
 
7.2 Pharmacokinetic Assessments 
 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to dosing. 
However, the exact time of the sample collection will always be noted on the CRF. For samples 
where nominal time coincides with end of infusion, a sample collected within 10 minutes post end 
of infusion will not be captured as a protocol deviation, as long as the exact time of the sample 
collection is noted on the source document and data collection tool (e.g., CRF). If a scheduled 
blood sample collection cannot be completed for any reason, the missed sample time may be re-
scheduled with agreement of clinical investigators, patient and sponsor. PK sampling schedule 
may be modified based on emerging PK data. Details on processes for collection, processing, 
handling, storage and shipment of these samples will be provided in the Laboratory Manual.  
 
PK samples would be stored in Institutional Tissue Bank (ITB) for ~1.5-2 years, while the clinical 
data mature and await sample analyses. 
 
7.2.1 Blood for PK Analysis of Avelumab 
 
Blood samples (3.5 ml whole blood at each time point) will be collected for serum PK analysis of 
avelumab as outlined in the Study Calendar. Pre-dose avelumab PK samples will be collected 
within 1 hour prior to avelumab infusion. The post-dose avelumab samples should be taken within 
10 minutes after the avelumab infusion ends. PK sampling for avelumab will occur as follows: (i) 
Pre dose and EOI: Cycle 1 Day 1 and cycle 1 Day 15, (ii) Pre dose only: Cycle 3, 6 and (iii) End 
of treatment sample. 
 
Storage & Processing for PK evaluation: 
1. Do not draw blood for serum as the first tube. When using a winged blood collection, a 2mL 
Red tube (optional discard tube) should be used prior to the first specimen collection. The 
discard tube is used to fill the blood collection set tubing's "dead space" with blood. The 
discard tube does not need to be filled completely and should be a non-additive or coagulation 
tube, thus SST cannot be used as discard tube. This step ensures maintenance of the proper 
blood-additive-ratio of the specimen.  
2. Collect 3.5 mL of blood in a SST tube with Silica Clot Activator and Polymer Gel.  
3. Gently invert the tube 5 times to mix the clot activator with blood. 
4. Allow blood to clot for 30 minutes at room temperature in a vertical position. 
5. After allowing clot to form, centrifuge the tube for 15 minutes at 1100-1300 x g at +25 degrees 
Celsius (if refrigerated centrifuge is available, set the temperature at 25 degrees Celsius in 

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order to prevent heating during centrifugation and to optimize flow of the barrier material; flow 
may be impeded if chilled before or during centrifugation).    
6. Carefully collect and aliquot the serum equally in 2 separate micronics tubes. 
7. Put the tubes immediately in the freezer in an upright position at -80 degrees Celsius. If not 
available, store at –20 degrees Celsius (for a maximum of one month). In case of 
temperature deviations, the affected samples, the length of deviation and maximum 
temperature reached should be tracked and promptly communicated to the CRA/CTL.  
If shipment is required: Ship the samples to the Central Lab in batches in dry ice. Material stored 
at –20 degrees Celsius must be shipped within a maximum of 1 month from blood draw to central 
laboratory 
8. Do not draw blood for serum as the first tube. When using a winged blood collection, a 2mL 
Red tube (optional discard tube) should be used prior to the first specimen collection. The 
discard tube is used to fill the blood collection set tubing's "dead space" with blood. The 
discard tube does not need to be filled completely and should be a non-additive or coagulation 
tube, thus SST cannot be used as discard tube. This step ensures maintenance of the proper 
blood-additive-ratio of the specimen. 
9. Collect 5 mL of blood in a SST tube with Silica Clot Activator and Polymer Gel.  
10. Gently invert the tube 5 times to mix the clot activator with blood. 
11. Allow blood to clot for 30 minutes at room temperature in a vertical position. 
12. After allowing clot to form, centrifuge the tube for 15 minutes at 1100-1300 x g at +25 degrees 
Celsius (if refrigerated centrifuge is available, set the temperature at 25 degrees Celsius in 
order to prevent heating during centrifugation and to optimize flow of the barrier material; flow 
may be impeded if chilled before or during centrifugation).    
13. Carefully collect and aliquot the serum equally in 3 separate micronics tubes. 
14. Put the tubes immediately in the freezer in an upright position at -80 degrees Celsius. If not 
available, store at –20 degrees Celsius (for a maximum of one month). In case of 
temperature deviations, the affected samples, the length of deviation and maximum 
temperature reached should be tracked and promptly communicated to the CRA/CTL.  
Ship the samples in batches in dry ice. Material stored at –20 degrees Celsius must be shipped 
within a maximum of 1 month from blood draw to central laboratory 
 
 
7.2.2 Blood for PK Analysis of M6620 
 
Blood samples (2 ml whole blood at each time point) will be collected for plasma PK analysis of 
M6620, as outlined in the Study Calendar. Pre-dose M6620 PK samples will be collected within 
1 hour prior to M6620 infusion. The end-of-infusion M6620 PK samples should be taken within 10 
minutes after the M6620 infusion ends and the sample taken during days 2-4 may be taken at 
any time within this visit window 
 
PK sampling for M6620 will occur as follows: I) M6620 predose and EOI: cycle 1 day 1 and day 
15; II) cycle 1 day 2-4 (one sample during this timeframe) and cycle 1 day 16-18 (one sample 
during this timeframe) to capture a sample during the terminal phase of M6620. 
 
Storage & Processing for PK evaluation: 
Blood sample: The total duration between blood sample collection at room temperature and 
final storage of the plasma sample must not exceed 60 minutes  
• 
The blood samples have to be collected into 2 mL K2 EDTA tubes 
• 
Store blood samples until centrifugation at ambient temperature  

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• 
Centrifuge blood samples at approx. 1500 g for approx. 15 minutes at room temperature  
• 
After centrifugation, split the plasma into 2 aliquots and transfer plasma into 2 labeled 
polypropylene tubes (PK M6620 primary and back-up sample) and lock them with push caps. 
The primary sample tube must contain at least 0.4 mL plasma, the other back-up sample tube 
the rest of the plasma. 
• 
Freeze the 2 plasma aliquots (tubes) immediately after centrifugation and aliquotation 
at - 20°C±5°C and store in upright position 
Plasma sample: Store samples in an upright position until shipment at –20°C±5°C in a 
temperature controlled freezer 
Analyte stability in matrix: Stability in matrix at room temperature: 1 day 
Long term frozen stability in matrix at -20oC and -75°C: 3 months (Stability for 6 and 12 months 
will be analyzed at a later timepoint) Freeze/thaw cycles: -20oC and -75°C: four times. 
 
7.3 Tumor Response Assessments 
 
The tumor assessment for inclusion must be recorded and measured within 28 days prior to 
treatment start. Clinical benefit rate will be evaluated based on RECIST v 1.1 and irRECIST using 
CT scan or MRI scan or PET-CT scan. For patients with multiple measurable lesions, up to 5 
lesions in total and 2 lesions per organ should be identified. 
 
Tumor assessments will include all known or suspected disease sites. Imaging may include chest, 
abdomen, and pelvis CT or MRI scans. Baseline Brain CT or MRI scan is required for all high risk 
patients (such as breast, melanoma and other cancer types as determined by the PI/sub I) at 
baseline (screening). Patients with stable brain metastases present at baseline (screening) will 
continue to have brain CT or MRI scans performed at each tumor assessment. Otherwise, brain 
CT or MRI scan is required only when clinically indicated if new brain metastases are suspected. 
 
Whole body bone scintigraphy (bone scans) should be performed at screening and at regular 
imaging intervals as defined in the study calendar for all patients with prostate cancer.  If clinically 
indicated per investigators’ discretion, participants with other tumor types may undergo bone 
scan at baseline to assess the presence of bone lesions. If bone metastases are present at 
baseline (screening), then repeat bone imaging is required at regular intervals with other imaging 
as defined in the study calendar thereafter. Otherwise, bone imaging is required only if new bone 
metastases are suspected. Bone imaging is also required at the time of confirmation of CR for 
patients who have bone metastases. 
 
The exact technique used for measurement of lesions (i.e., CT, MRI, or PET/CT scan) will be left 
to the discretion of the investigator, however, for each patient the same technique must be used 
throughout the study, assessed whenever possible by the same individual. The CT/ MRI abdomen 
must include the pelvis. A PET/CT is allowed, but ultrasound and x-ray of thorax is not allowed. 
 
In cases where there is suspicion of progression before the next scheduled assessment, an 
unscheduled tumor assessment should be performed. In case a detected increase in tumor size 
is below the resolution limit of the CT/ MRI scanner, it is acceptable to continue with treatment 
until a second assessment at a later time point unequivocally confirms progressive disease. 
Partial response requires confirmation with a follow-up scan at least 4 weeks apart. 
 

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If the increase in tumor burden is ≥ 20% relative to nadir, then in the absence of rapid clinical 
deterioration, confirmation by a repeat, consecutive assessment no less than 4 weeks from the 
date first documented is recommended. Patients will continue with study drug until confirmation 
scan is obtained. 
 
The following are defined as non-target lesions: bone lesions, leptomeningeal disease, 
pleural/pericardial effusion, ascites, inflammatory breast disease, lymphangitis, cystic lesions and 
lesions not measurable by CT or MRI. All non-target lesions are described over time and need 
not be measured. 
 
The first evaluation of disease status by imaging will be done after 2 cycles or 8 weeks (± 7 days) 
of treatment and every 2 cycles or 8 weeks (± 7 days) thereafter at the physician’s discretion. 
After completion of 1 year of treatment, tumor assessments will be performed every 3 cycles or 
12 weeks (± 7 days) independent of cycle delays. 
 
Patients will also be eligible for the study if their disease is evaluable outside irradiated field on 
CT/ MRI. 
 
In case palliative radiation becomes necessary during the treatment within the study, there must 
be at least two target lesions left outside the irradiated filed for continuous assessment for 
response. 
 
 
7.4 Tumor Biopsies and Blood Samples 
 
Archival tumor tissue samples, tissue from biopsies performed at baseline, while on treatment, 
and at disease progression, will be used to analyze candidate DNA, RNA, or protein markers, or 
immune changes, which may contribute to the response or resistance to the combinations being 
tested in this study. Archival tissue available from a biopsy or surgery that was performed within 
1 year prior to study enrollment, will be acceptable. While not mandatory, tumor biopsies will be 
strongly encouraged. Patients may have pre-treatment (baseline), and on-treatment (Cycle 1 Day 
15) tumor biopsies for correlative studies. In the event that clinical benefit is not observed or is 
transient, an understanding of the mechanisms of resistance may help guide optimal patient 
selection for future development of the combination. Therefore, an optional tumor biopsy will also 
be performed at disease progression, unless clinically contraindicated. Target lesions may be 
used for tumor biopsies as long as there are other target lesions that are accessible for RECIST 
measurement. 
 
Given the limited ability to assess tumor tissue-based biomarkers longitudinally, a number of 
biomarkers will also be measured in peripheral blood at a number of time points. Blood samples 
will be obtained at baseline, Cycle 1 Day 15, Cycle 3 Day 1, every other cycle thereafter, and at 
disease progression. 
 
7.5 Correlative Studies 
 
To allow for the correlative studies detailed below to be performed, a subset of patients will 
undergo pre-treatment, on-treatment, and where feasible at-progression tumor biopsies. Serial 
blood sampling will also be undertaken to longitudinally assess pharmacodynamic and/or 

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mechanistic biomarkers for the combination of M6620 and avelumab. Correlative studies to be 
undertaken are outlined below. 
7.5.1 To determine baseline molecular markers (DNA, RNA, and protein) or other markers 
(e.g. HRD or RSRD score, somatic mutation burden, immune profiling) that may predict 
clinical benefit. 
 
We will undertake DNA whole exome sequencing (WES), RNA sequencing (RNA-seq), and 
reverse phase protein array (RPPA) studies, as well as immune profiling on tumor biopsies 
obtained from patients at baseline to assess if baseline markers are correlated with clinical 
benefit. We will use ROC curve analysis with Wilcoxon rank sum testing. With 30 patients, if the 
clinical benefit rate is 33%, and we assume a 10% alpha level, then we have 90% power to detect 
a ROC area of 0.83 as different from the null value of 0.5. 
 
7.5.1.1 Genomic Sequencing Plan 
 
Whole exome sequencing will be performed to an average depth of 100x. Normal samples (blood 
will be collected when possible) will be sequenced to a similar depth to distinguish germline and 
somatic aberrations. All samples will be assessed using a Nimblegen pull down SeqCap EZ 
human Exome Library and sequenced with four samples per lane on the Illumina HiSeq 2000 in 
our CCSG sequencing core. This approach provides an average 100-fold depth across the human 
exome. All computational analysis will use shared resources within the Research Information 
Systems and Technology Services (RISTS) at MDACC. RISTS provides a high performance 
computing environment that consists of an 8064 processor computer cluster (336 nodes) with 794 
TB data storage capacity for CPU-intensive large-scale computing. Similar to our previous studies 
and participation by Ken Chen in the TCGA analysis platform at the WashU Genome Center, 
sequence analysis will consist of 4 major steps: 1) read alignment, 2) variant calling, 3) variant 
stratification, and 4) report (Figure 5). We will align reads in the FASTQ format to several different 
versions of reference sequences using BWA. We will use Samtools, VarScan and MuTect to call 
somatic SNVs and indels and GATK to detect germline SNVs and indels. We will use Pyclone 
and ABSOLUTE to estimate tumor purity and clonal architecture. We will perform variant 
annotation using the variant effect predictor (VEP), AnnoVar, InterVar, CanDrA, CHASM, 
MutationAssessor, SIFT and PolyPhen and OncoKB. The Institute for Personalized Cancer 
Therapy (IPCT) precision oncology decision support (PODS) team will further review these 
annotations and identify additional preclinical evidences in the literature. 
 
7.5.1.2 Homologous Recombination Deficiency (HRD) Score 
 
We will focus on HRD scores that we have previously defined22-24. An HRD score was defined as 
an unweighted summation of the 1) loss of heterozygosity (LOH) scores, defined as the number 
of LOH regions >15 Mb, but less than a whole chromosome in length, within a tumor genome, 2) 
telomeric allelic imbalance (TAI) score, defined as the number of allelic imbalances (DNA 
segments having unequal maternal and paternal copies) extending to the telomeric end of the 
chromosome and 3) large-scale state transition (LST) score, defined as the number of 
chromosomal breaks between adjacent regions of at least 10 Mb. The accuracy of these scores 
is critically dependent on accurate estimation of allele specific copy numbers (ASCNs). We will 
use ASCAT, FACET, Sequenza and TITAN to perform ASCN analysis from heterogeneous tumor 
samples and calculate HRD scores. 
 
7.5.1.3 Replication Stress Response (RSR) Defect Score 
 

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Using isogenic cell line models, we recently developed a gene expression signature to predict 
defects in replication stress response (RSR)24. We functionally validated this gene signature in a 
panel of 16 breast cancer cell lines, with 8 of 9 signature high cell lines exhibiting defects in RSR 
(Figure 2A). As the ATR/CHK1 signaling cascade plays a critical role in replication stress 
response, we hypothesized that high RSR 
defect 
scores 
would 
correspond 
to 
increased sensitivity to inhibitors of this 
pathway, which was validated by the strong 
negative correlation with IC50 values for the 
CHK1 inhibitor AZD7762 (Figure 2B). 
Emerging evidence also suggests that 
PARP is activated at stalled replication forks 
during replication stress and this function 
may largely contribute to PARP sensitivity. 
Upon analyzing the correlation between 
RSR defect score and olaparib sensitivity, 
we found that they were likewise negatively 
correlated (Figure 2C). 
 
To investigate if these findings are 
conserved in colorectal cancer cell lines, we 
tested the ability of our RSR defect 
signature to predict response to CHK1 
inhibition (AZD7762, Figure 2D), PARP 
inhibition (olaparib, Figure 2E), and dual 
inhibition of CHK1 and PARP (Figure 2F). 
We found that while the gene signature 
independently predicted activity of either CHK1 or PARP inhibition alone, the signature was best 
at predicting dual drug sensitivity. Based on this, we hypothesize that this RSR defect gene 
signature may be predictive of response to DDR inhibitor-based combinations. To test this, RNA-
sequencing data obtained from the analysis of pre-treatment tumor biopsies will be analyzed and 
used to assess the predictive power of the RSR defect signature with respect to the clinical benefit 
of each DDR inhibitor-based combination treatment. These preliminary results may be used as 
the basis to refine the signature for adaptation to large-scale clinical translation. 
 
7.5.1.4 RNA-seq Analysis 
 
We maintain a RNA Seq data analysis workflow that makes use of the high performance 
computing facilities, including several cluster systems at the MD Anderson Cancer Center to 
analyze next generation sequencing data from RNA extracted from human or animal tissues. 
Fresh frozen or FFPE samples are prepared by the IPCT genomics lab and sequenced by the 
Sequencing Core Facility. The workflow makes use of proven software and best practices to 
analyze single or paired-end data. The workflow completes in 2 to 5 days depending on size of 
data and status of clusters. Results from this workflow are deposited to a centralized location and 
are used for second-stage analysis to answer specific questions. 
 
7.5.1.5 Reverse Phase Protein Array (RPPA) 
 
We will perform an RPPA-based proteomic analysis using 181 high-quality antibodies that target 
total (n=128), cleaved (n=1), acetylated (n=1) and phosphorylated forms (n=51) of proteins in 
patient samples. The function space covered by the antibodies used in the RPPA analysis 

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7.5.1.6.3 Flow Cytometry Analysis 
 
High order flow cytometry panels will be designed to assess lymphocyte subsets and phenotype 
in peripheral blood. Flow cytometry panels will focus on effector and regulatory T cells by 
analyzing the expression of markers such as: CD3, CD4, CD8, ICOS, Ki67, CD25, FOXP3, 
Perforin, IFN-γ, TIM3, Granzyme B, and PD-1. 
 
7.5.1.6.4 Cytokine Analysis (MSD) 
 
The Meso Scale Discovery (MSD) platform will be used for the detection of soluble factors (e.g. 
from serum or plasma). This technology allows for the detection of up to 40 analytes per well and 
uses a very low sample volume. This method has a sensitivity of up to 1000X higher than 
traditional ELISA assays with a large linear range of 3-4 logs. The instrument performs 
immunoassays utilizing electrochemiluminescense to detect the signal in a 96 well plate format. 
This technology can be utilized for either single agent detection or in multiplex format. A wide 
menu of validated single or multiplex kits for the detection of 1 to 40 analytes are available from 
the manufacturer and can be customized. Cytokines available for testing include: IFN-γ, IL-1α, IL-
2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, and TNF-α. 
 
7.5.1.6.5 HTG EdgeSeq Immuno-Oncology Panel Analysis (IOP) 
 
HTG has developed a novel technology known as quantitative nuclease protection assay 
(qNPATM), or HTG Edge Chemistry that enables extraction and amplification-free quantification of 
mRNA or miRNA. This process does not require RNA extraction from FFPE, and is amenable to 
small clinical specimens, as it requires very little sample input (~ 1-2 mm2 FFPE tissue or 1.56 ng 
RNA). We will obtain the gene expression profile of 549 genes implicated in the host immune 
response to tumors, allowing us to profile tumor infiltrating lymphocytes, immune response in 
tumors, and potential prognostic drug signatures. 
 
7.5.1.6.6 HTG EdgeSeq Oncology Biomarker Panel Analysis (OBP) 
 
HTG has developed a novel technology known as quantitative nuclease protection assay 
(qNPATM), or HTG Edge Chemistry that enables extraction and amplification-free quantification of 
mRNA or miRNA. This process does not require RNA extraction from FFPE, and is amenable to 
small clinical specimens, as it requires very little sample input (~ 1-2 mm2 FFPE tissue or 1.56 ng 
RNA). We will obtain the gene expression profile of 2568 oncology-related biomarkers (distributed 
across 24 pathways) from FFPE tumor samples by using next generation sequencing detection 
technology. Profiling tumor tissues will allow us to identify new biomarkers and analyze tumor cell 
signaling pathways. The demonstrated performance of the assay in breast, lung, colon, and 
prostate cancers, and melanoma FFPE samples enables multiplex oncology biomarker profiling 
of these and other malignant neoplasms with a simple workflow using next generation sequencing 
detection technology (no RNA extraction, rapid sequencing library preparation). Please see Table 
6 below. 
 
Table 6: HTG EdgeSeq Oncology Biomarker Panel Pathways 
 
AMPK Pathway 
Angiogenesis 
FGFR Pathway 
Cell Cycle 
Cluster 
of 
Differentiation 
JAK/STAT Pathway 

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EGF/PDGF Pathway 
EGFR/HER Pathway 
PI3K/AKT Pathway 
Hypoxia 
Stress Toxicity 
Cardio Toxicity 
NF-ΚB Pathway 
Apoptosis 
DNA Repair 
Stem Cells 
DMPK 
Hedgehog Pathway 
MAPK Pathway 
Wnt Pathway 
 
 
7.5.2 To evaluate underlying mechanisms of action of the combinations by assessing 
pharmacodynamic (PD) biomarkers in serial tumor and blood samples. 
 
We will use RNA-seq, RPPA and other assays as well as immune profiling to assess changes in 
PD biomarkers with treatment. Immuno-profiling will include multiplex immunofluorescence (mIF) 
and immunohistochemistry (IHC) to characterize immune cell infiltrates and immune checkpoint 
proteins (e.g. PD-1, PD-L1) on serial tumor samples. Flow cytometry analysis will also be 
conducted on serial blood samples to analyze circulating T cell populations. Cytokine analysis will 
also be performed on blood specimens. We will compare post-baseline values to baseline values 
using t-tests or Wilcoxon signed rank test if the data are clearly not Gaussian. With 30 patients, 
we will have 90% power to detect a mean difference of 0.55*s (where “s” is the standard deviation 
of the paired differences) assuming a two-sided 10% alpha. Dot plots of marker values over time 
will be produced to visualize changes. 
 
7.5.3 To assess response and resistance in circulating tumor DNA (ctDNA), and 
concordance of genomic alterations between serial tumor biopsies and ctDNA. 
 
We will undertake targeted NGS studies using serially collected ctDNA samples (at baseline, 
different timepoints on treatment, and at progression), and plot levels of target DNA anomalies 
over time in patients and correlate these with levels of tumor burden over time. In particular, we 
will assess ctDNA levels in responding patients and identify new resistance mechanisms in 
samples from progressing patients. NGS will also be used to assess ctDNA changes on 
treatment, and also to assess the correlation between serially collected biopsies and ctDNA 
samples. 
 
7.5.4 To evaluate potential mechanisms of drug resistance through profiling of tumor 
progression biopsies. 
 
By comparing molecular profiles of tumors collected at disease progression with baseline profiles 
through the use of WES, RNA-seq, and RPPA studies as well as immune profiling, we will attempt 
to identify new DNA anomalies, as well as changes in gene and protein expression levels. 
 
7.5.5 To develop response biomarkers for the assessment of ATR  and PD-L1 inhibition. 
 
We will attempt to identify signatures of response and resistance by comparing biomarker profiles 
of tumor biopsies collected on-treatment to baseline profiles, and correlating these with tumor 
response. 
 
7.5.6 To develop and characterize patient-derived xenografts (PDXs) to determine 
mechanisms of antitumor response and resistance. 
 
Patient-derived xenografts will be established in mice using tumor biopsies obtained from patients 
at baseline and at time of drug resistance. Molecular profiling will be undertaken with whole exome 

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sequencing, RNA-seq and RPPA studies to assess mechanisms of antitumor response and 
resistance. By comparing profiles in PDX tumors from responding and progressing patients, we 
will attempt to identify signatures of response and progression. 
 
8. ADVERSE EVENT REPORTING 
 
8.1 Adverse Events 
 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational product(s) will be reported as described in the following sections. 
 
For all AEs, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a serious 
adverse event (SAE) requiring immediate notification to the Safety Project Manager (MDACC IND 
Office). For all AEs, sufficient information should be obtained by the investigator to determine the 
causality of the AE. The investigator is required to assess causality. Follow up by the investigator 
may be required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and the MDACC IND Office concurs with that assessment. 
 
As part of ongoing safety reviews conducted by the MDACC IND Office, any non-serious AE that 
is determined by the MDACC IND Office to be serious will be reported by the MDACC IRB as an 
SAE per MDACC institutional policy. To assist in the determination of case severity, further 
information may be requested from the investigator to provide clarity and understanding of the 
event in the context of the clinical study. 
 
The active reporting period begins from the time that the patient provides informed consent 
through 90 calendar days after the last administration of the investigational product(s) unless 
other anti-cancer therapy is commenced, at which time toxicity follow up will cease at the 
discretion of the treating physician . 
 
8.2 Definition of Adverse Event 
 
An adverse event is defined in the International Conference on Harmonization (ICH) Guideline for 
Good Clinical Practice (GCP) as ‘any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have 
a causal relationship with this treatment,’ (ICH E6:1.2). 
 
An adverse event cab therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
medicinal product, whether or not it is considered related to the medicinal product. 
 
8.3 Definition of Serious Adverse Event (SAE) 
 
An adverse event or suspected adverse reaction is considered ‘serious’ if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 

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a. Death. 
b. A life threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, may have caused death. 
c. Inpatient hospitalization or prolongation of existing hospitalization. 
d. A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
e. A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgement, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the PI or the IND Sponsor (IND Office). 
• 
All events occurring during the conduct of a protocol and meeting the definition of an SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in ‘The University of Texas MD Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices.’ 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be 
reported to the IND Office, regardless of attribution (within 5 working days of knowledge 
of the event). 
• 
All life threatening or fatal events, that are unexpected, and related to the study drug(s), 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
• 
Serious adverse events will be captured from the time of the first protocol specific 
intervention, until 90 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
• 
Additionally, any serious adverse events that occur after the 90 day time period, which are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 
SAEs in screening will only be captured if they are related to a protocol procedure. 
Hospitalizations clearly documented as disease progression will not be captured as SAEs unless 
the patient continues on study. 
 
8.4 Reporting to the Federal Drug Administration (FDA) 
 
Serious adverse events will be forwarded to the FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 

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It is the responsibility of the PI and the research team to ensure that SAEs are reported according 
to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
Sponsor’s guidelines, and the IRB policy. 
 
8.5 Investigator Communications with EMD Serono 
 
For SAEs, the active reporting period to EMD Serono or its designated representative begins from 
the time that the patient provides informed consent through 90 calendar days after the last 
administration of the investigational product. SAEs occurring in a patient after the active reporting 
period has ended, should be reported to EMD Serono if the investigator becomes aware of them; 
at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of 
being related to investigational product(s) are to be reported to EMD Serono. 
 
AEs (serious and non-serious) should be reported on the case report form (CRF) from the time 
the patient has taken at least one dose of investigational product through the patient’s last visit. 
 
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at 
the time the new treatment is started. Death must be reported if it occurs during the SAE reporting 
period after the last dose of investigational product, irrespective of any intervening treatment. 
 
The investigator’s primary responsibilities in safety reporting are to identify and follow up on SAEs 
experienced by participants in the study, and to forward the information to the IRB, IND Office, 
and EMD Serono, as required by local regulations (for regulatory reporting) and Investigator-
Initiated Research (IIR) agreement (for reporting to EMD Serono). 
 
The following reportable events must be submitted to EMD Serono within 24 hours (or 
immediately for death or life threatening events) using the MDACC SAE form with the EMD 
Serono Reportable Events Fax Cover Sheet with each SAE submission: 
a. SAEs, 
b. Exposure during pregnancy or breastfeeding (even if not associated with an AE), 
c. Occupational exposure (even if not associated with an AE), 
d. Potential drug-induced liver injury (Hy’s Law cases): these events are considered 
important medical events and should be reported as SAEs. 
 
Contact information for submission of reportable events to EMD Serono: 
 
 
OR 
Email: i
 
 
Specifying: 
• 
PROTOCOL NUMBER and/or Title 
• 
EMD Serono assigned Study Number 
• 
SUBJECT Number 
• 
SITE Number/PI Name 

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The MDACC SAE form will be submitted to EMD Serono. The following details must be recorded 
for each SAE in the SAE report form: 
a. A description of the AE in medical terms according to NCI CTCAE v5.0, not as reported 
by the subject, 
b. The severity grade as assessed by the investigator according to the definitions in NCI 
CTCAE v5.0, 
c. The date of becoming serious and the date of becoming known (if different), 
d. The reason for seriousness, 
e. The outcome of the SAE at the time of the report, 
f. Information on administration of the study drug(s), 
g. Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history. 
 
If in any one subject the same SAE occurs on several occasions, then the SAE in question must 
be documented and assessed anew each time. The investigator is required to submit SAE Follow 
up reports until the SAE has resolved or stabilized, and all queries have been answered. 
 
8.6 Recording of Adverse Events 
 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the study participants, are properly recorded in the participant’s medical records 
and the electronic case report form. 
 
The following adverse event attributes must be assigned by the investigator: 
a. Adverse event term according to NCI CTCAE v5.0 
b. Severity grade according to NCI CTCAE v5.0 
c. Start date and stop date (or date of last assessment) 
d. Outcome 
e. Causality to study drug(s) (assessed as either related or unrelated) 
f. Any action taken. 
Adverse events will be followed until they resolve to baseline or are considered stable. It will be 
left to the investigator’s clinical judgement to determine whether an AE is related and of sufficient 
severity to require the subject’s removal from treatment or from the study. A subject may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse 
event. If either of these situations arises, the subject should be strongly encouraged to undergo 
an end-of-study assessment and be under medical supervision until symptoms resolve or the 
condition becomes stable. 
Pre-existing diseases, when worsening during study therapy, have to be considered as AEs. They 
can lead to SAEs, if they meet the criteria described in Section 8.3. 
Intensity of AEs will be graded using the National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE), version 5.0. If an adverse event occurs which is not described in 
the CTCAE version 5.0, the four-point scale below will be used: 
• 
Mild: discomfort noticed but no disruption of normal daily activity. 
• 
Moderate: discomfort sufficient to reduce or affect daily activity. 
• 
Severe: inability to work or perform normal daily activity. 

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• 
Life threatening: represent an immediate threat to life. 
 
8.6.1 Laboratory Test Abnormalities 
 
Laboratory test results will be recorded on the laboratory results pages of the eCRF. In the event 
of unexplained abnormal laboratory test values, the tests should be repeated immediately and 
followed up until they have returned to the normal range and/or an adequate explanation of the 
abnormality is found. 
 
Laboratory test value abnormalities as such should not be reported on the AE page of the eCRF 
as adverse events unless they are treatment-emergent and they satisfy one or more of the 
following conditions for clinical significance: 
a. Accompanied by clinical symptoms. 
b. Lead to a change in study medication (e.g. dose modification, interruption or permanent 
discontinuation). 
c. Require a change in concomitant therapy (e.g. addition, interruption, discontinuation of, or 
any other change in a concomitant medication, therapy or treatment). 
Please note: any laboratory result abnormality fulfilling the criteria for a serious adverse event 
should be reported as such, in addition to being recorded as an adverse event in the eCRF. 
 
8.6.2 Pregnancy 
 
Pregnancy per se is not considered an AE. A medical occurrence observed in the mother or 
fetus/newborn would be considered an AE. 
 
Female patients must be instructed to immediately inform the investigator if they become pregnant 
during the study. The study treatment must immediately be stopped and the patient withdrawn 
from the study. Pregnancies occurring up to 6 months after completion of the last treatment cycle 
must also be reported to the investigator. The investigator must report all pregnancies within 24 
hours of knowledge to EMD Serono. The investigator should counsel the patient, discuss the risks 
of continuing the pregnancy, and the possible effects on the fetus. The patient should be 
monitored until the conclusion of the pregnancy. 
 
Pregnancy occurring in the partner of a patient participating in the study should also be reported 
to the investigator, MDACC IND Office, and EMD Serono. The partner should be counseled and 
followed as described above. 
 
8.6.3 Adverse Drug Reactions with Concomitant Medications 
 
The investigators must be aware that for all concomitant medications, the regulations of post-
marketing reporting for suspected adverse drug reactions apply, i.e. reporting to the marketing 
authorization holder or the local regulatory bodies. 
 

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9. DATA ANALYSIS/STATISTICAL METHODS 
 
Ying Yuan, Ph.D. (Professor, Department of Biostatistics, MDACC) will perform all statistical 
analyses. Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented as outlined below. 
 
9.1 Analysis Sets 
 
9.1.1 Safety Analysis Set 
 
The safety analysis set includes all enrolled patients who receive at least one (1) dose of study 
medication. 
 
9.1.2 DLT Analysis Set 
 
The DLT analysis set is a subset of the safety analysis set and includes all enrolled patients in 
the dose escalation phase, receive at least one dose of the combination treatment, and either 
experience DLT during the first cycle (28 days) of treatment, or complete the DLT observation 
period for the first cycle of treatment. 
 
Patients without DLTs who withdraw from study treatment before receiving at least 75% of the 
planned dose of each of the investigational products in the combination in Cycle 1 for reasons 
other than toxicity, which are attributable to the investigational products are not evaluable for DLT. 
Additional patients will be enrolled in the specific cohort to replace patients who are not considered 
DLT evaluable. 
 
9.1.3 Response Analysis Set 
 
All enrolled patients who receive at least one (1) dose of study medication with baseline 
assessment and have at least one post-baseline tumor assessment will be considered evaluable 
for response. 
 
9.2 Statistical Methods and Properties 
 
The study will be monitored for futility and excessive toxicity in cohorts of 10 as described below. 
If the trial does not stop early, we will estimate the clinical benefit rate and the response rate 
separately with appropriate 95% confidence intervals. We will also estimate the progression free 
survival (PFS) and overall survival (OS) using Kaplan-Meier methods. 
 
9.4 General Statistical Considerations 
 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 
presented, as well as two-sided 95% confidence intervals, unless otherwise stated. For 
continuous variables, the number of subjects, mean, median, standard deviation (SD), minimum, 

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and maximum values will be presented. Time-to-event data will be summarized using Kaplan-
Meier methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 95% 
confidence intervals, as well as percentage of censored observations. 
 
No imputation of missing efficacy data is planned. For time-to-event analyses, patients who have 
no efficacy evaluations for disease recurrence will be considered censored at time 0. 
 
For AEs, missing dates will not be imputed, however, if partial dates are available, they will be 
used to assess if the AE occurred during the treatment period. Missing severities of AEs will not 
be imputed and will be considered missing in any tabulations of AE severity. If an AE is missing 
a response to the question regarding relationship to treatment, the event will be considered to be 
related. 
 
Evaluations will be performed separately for each trial arm. 
 
9.4.1 Demographics and Baseline Characteristics 
 
The demographic characteristics to be summarized will include gender, race, ethnicity (Hispanic 
origin), and age at time of consent. For gender, race and Hispanic origin, the summary statistics 
will be the number and percentage of patients within each group or the total sample. The 
categories for race will be those recorded in the database. For age at time of consent, the mean, 
median, minimum, maximum, and standard deviation will be provided for each group and the total 
sample. 
 
Baseline characteristics include: Performance status, duration from initial diagnosis, response to 
previous therapy (Y/N). 
 
9.3 Sample Size Determination 
 
There will be 3-6 patients enrolled per dose level in the dose escalation phase of the combination 
of M6620 and avelumab. 
 
Each dose expansion arm may have up to 30 patients each. A 3-stage design with 10 patients in 
each stage will be utilized. We will stop after the 1st stage if we see 0 successes in 10 evaluable 
patients on RP2D, after the 2nd stage if we see < 2 successes in 20 evaluable patients, and we 
will declare the treatment worthy of further study if we see > 3 successes in 30 evaluable patients. 
If we set p0 (highest success rate for unacceptable treatment) = 5% and p1 (lowest success rate 
for acceptable treatment) = 20%, this design has alpha = 5%, 80% power and probability of early 
termination under p0 of 60% after 1st stage and 79% after either 1st or 2nd stage. 
 
9.4 General Statistical Considerations 
 
Tabulations will be produced for appropriate demographic, baseline, efficacy and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
subjects within each category (with a category for missing data) of the parameter will be 
presented, as well as two-sided 95% confidence intervals, unless otherwise stated. For 
continuous variables, the number of subjects, mean, median, standard deviation (SD), minimum, 

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and maximum values will be presented. Time-to-event data will be summarized using Kaplan-
Meier methodology using 25th, 50th (median), and 75th percentiles with associated 2-sided 95% 
confidence intervals, as well as percentage of censored observations. 
 
No imputation of missing efficacy data is planned. For time-to-event analyses, patients who have 
no efficacy evaluations for disease recurrence will be considered censored at time 0. 
 
For AEs, missing dates will not be imputed, however, if partial dates are available, they will be 
used to assess if the AE occurred during the treatment period. Missing severities of AEs will not 
be imputed and will be considered missing in any tabulations of AE severity. If an AE is missing 
a response to the question regarding relationship to treatment, the event will be considered to be 
related. 
 
All evaluations will be performed separately for each trial arm. 
 
9.4.1 Demographics and Baseline Characteristics 
 
The demographic characteristics to be summarized will include gender, race, ethnicity (Hispanic 
origin), and age at time of consent. For gender, race and Hispanic origin, the summary statistics 
will be the number and percentage of patients within each group or the total sample. The 
categories for race will be those recorded in the database. For age at time of consent, the mean, 
median, minimum, maximum, and standard deviation will be provided for each group and the total 
sample. 
 
Baseline characteristics include: Performance status, duration from initial diagnosis, response to 
previous therapy (Y/N). 
9.5 Efficacy Analysis 
 
The efficacy population will consist of all patients who receive at least one dose of study 
medication with baseline assessment and have at least one (1) post-baseline tumor assessment. 
This population will be used for primary analyses of efficacy. 
 
9.5.1 Efficacy Evaluation 
 
Clinical efficacy will be measured by clinical benefit rate (CBR) per RECIST v1.1 and irRECIST. 
CBR is defined as complete response (CR) + partial response (PR) + stable disease (SD) > 6 
months. Overall response rate (ORR) will be measured using RECIST 1.1 criteria. Secondary 
efficacy endpoints include objective response (CR+PR), progression free survival (PFS), Duration 
of Response (DoR), overall survival (OS) and ORR. A 95% CI of response rate will be estimated 
based on the binomial distribution. 
 
9.6 Safety Monitoring 
 
The safety population will consist of all patients who have received any amount of study 
medications. We will employ Thall and Simon methods (1994) to perform interim safety monitoring 
every 10 patients for up to 30 patients. Formally, denote qT as the probability of toxicity and 
assuming a non-informative beta(0.3,0.7) prior for qT, we will stop the study if we determine that 

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there is more than an 80% chance that the posterior probability of toxicity is more than 30%. 
Specifically, our interim monitoring rule for toxicity is: Pr [qT >30% | data] >0.8. The stopping 
boundaries corresponding to the above monitoring rule are to terminate study if (# patients with 
DLT) / (# patients evaluated) >=5/10, 8/20. The calculations were performed using MultcLean 
Desktop v 2.0.1. We will compare the proportion of patients with CTCAE grade 3 or higher 
treatment-related toxicities between treatments using chi-squared test or Fisher exact test as 
appropriate for the data. 
 
Table 7: Expected early stopping probability 
True toxicity probability 
Early stopping probability 
Expected number of patients 
enrolled before stopping 
0.2 
0.05 
29.1 
0.3 
0.28 
25.7 
0.4 
0.63 
19.9 
0.5 
0.89 
14.9 
0.6 
0.98 
11.8 
 
 
9.6.1 Safety Evaluation 
 
Safety analyses will be conducted using the safety population. For the objective of describing the 
toxicity profile, descriptive statistics will be provided on the grade and type of toxicity by dose 
level. 
 
9.6.2 Adverse Events 
 
Adverse Events (AEs) will be coded using the NCI CTCAE v5.0 (or MedDRA if code is not 
available in CTCAE) and displayed separately for patients. Analyses of AEs will be performed for 
those events that are considered treatment emergent, where treatment-emergent is defined as 
any AE with onset or worsening of a pre-existing condition on or after the first administration of 
study medication through 90 days following last dose or any event considered drug-related by the 
investigator through the end of the study. AEs with partial dates will be assessed using the 
available date information to determine if treatment-emergent; AEs with completely missing dates 
will be assumed to be treatment-emergent. 
 
AEs will be summarized by patient incidence rates, therefore, in any tabulation, a patient 
contributes only once to the count for a given AE preferred term. The number and percentage of 
patients with any treatment-emergent AE will be summarized separately for patients in the trial. 
The number and percentage of patients with treatment-emergent AEs assessed by the 
Investigator as at least possibly related to treatment will also be tabulated. The number and 
percentage of patients with any grade ≥ 3 treatment-emergent AE will be tabulated in the same 
manner. In the event a patient experiences repeated episodes of the same AE, then the event 
with the highest severity and/or strongest causal relationship to study treatment will be used for 
purposes of tabulations. 
 
Serious AEs will also be tabulated. No formal hypothesis-testing analysis of AE incidence rates 
will be performed. All AEs (treatment emergent and post-treatment) will be listed in patient data 
listings. By-patient listings will be provided for the following: patient deaths; serious AEs; and AEs 
leading to withdrawal. 

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9.6.3 Laboratory Data 
 
The actual value and change from baseline to each on study evaluation will be summarized for 
each clinical laboratory parameter, including hematology and clinical chemistry, separately for all 
study patients. In the event of repeat values, the last non-missing value per study day/time will be 
used. 
 
Severity of select clinical lab measures will be determined using CTCAE criteria (e.g. those 
measures that have a corresponding CTCAE grade classification). Labs with CTCAE grades 
greater than or equal to 3 will be presented in a data listing. Shift tables that present changes 
from baseline to worst on-study values relative to CTCAE classification ranges will be produced. 
 
9.6.4 Vital Signs and Physical Examinations 
 
The actual value and change from baseline to each on study evaluation will be summarized for 
vital signs for all study patients combined. By-patient listings of vital sign measurements will be 
presented in data listings. 
 
Physical examination results at screening will be summarized; all other abnormal physical 
examination data were to be recorded on the AE eCRF. All examination findings will be presented 
in a data listing. 
 
9.6.5 Concomitant Medications 
 
The use of concomitant medications will be included in by-patient data listings. 
 
9.7 Pharmacokinetic Analysis 
 
Pharmacokinetic analyses for avelumab and M6620 will consist of summary statistics and plots 
of concentration-time data. Additionally the pharmacokinetic data may be utilized in a population 
pharmacokinetic analysis to determine typical and individual PK parameters (e.g. CL, Vss, AUC, 
Cmax, Tmax, half-life if estimable). 
 
9.8 Biomarker Analysis 
 
Biomarker studies outlined in Section 7.5 will be mostly exploratory in nature and considered 
hypothesis-generating. Statistical methods employed will depend on the extent and nature of the 
data obtained. 
 
9.9 Analysis of Other Endpoints 
 
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameter, and biomarkers. Data will also be displayed 
graphically where appropriate. 
 

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9.10 Final Analysis 
 
The final analysis will take place after the MTD expansion has been completed. Additional data 
summarization may take place after all available survival data are collected, or after investigator 
decision, as appropriate. 
 
9.11 Data Safety Monitoring Committee 
 
Routine safety monitoring will be performed by the Medical Monitor. Safety monitoring, including 
analysis of PK, will be performed by a Safety Monitoring Committee, consisting of the Principal 
Investigator (and co-investigators as needed), Sponsor representatives (e.g., designee from the 
IND Office), the study-specific Medical Monitor, and EMD Serono. Additional investigators and 
study team members will participate in reviews as needed. An Independent Data Monitoring 
Board will not be utilized for this open-label study. 
 
10. QUALITY CONTROL AND QUALITY ASSURANCE 
 
This study will be monitored by the MD Anderson IND Office and a protocol-specific monitoring 
plan will be followed. 
 
11. DATA HANDLING AND RECORD KEEPING 
 
11.1 Case Report Form/Electronic Data Record 
 
All patients who meet eligibility criteria and are enrolled in this trial will be registered in Clinical 
Oncology Research Database (CORe) at the University of Texas MD Anderson Cancer Center at 
Houston. Data will be collected and stored in the Investigational Cancer Therapeutics database, 
Molecular and Clinical Data Integrated Portal (MOCLIA). 
 
11.2 Record Retention 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories: investigator’s study file and subject/ patient data. 
 
The 
investigator’s 
study 
file 
will 
contain 
all 
essential 
documents 
such 
as 
the 
protocol/amendments, case report and query forms, patient information and informed consent 
form, institutional review board and regulatory authority approval, notification of the federal 
regulatory authority and competent regional authorities (if applicable), drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents/correspondence, etc. 
 
Patient data includes patient hospital/clinic records (e.g. medical reports, surgery reports 
appointment book, medical records, pathology and laboratory reports, ECG, etc.), signed 
informed consent forms and patient screening and eligibility screening forms. 

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The investigator must keep these two categories of documents on file for at least 15 years (or 
longer, as legally required) after completion or discontinuation of the study. The documents must 
be archived in a secure place and treated as confidential material. 
 
12. ETHICS 
 
12.1 Ethical Conduct of the Study 
 
The study will be conducted in accordance with the protocol, legal and regulatory requirements, 
and the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), 
ICH Guideline for Good Clinical Practice, and the Declaration of Helsinki. 
 
12.2 Patient Information, Consent and Sample Storage 
 
All parties will ensure protection of patient personal data and will not include patient names or 
other identifiable data in any samples collected, reports, publications, or other disclosures, except 
where required by law. 
 
When study data are compiled for transfer to EMD Serono and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by EMD Serono in order to de-identify study patients. The investigator 
site will maintain a confidential list of patients who participated in the study, linking each patient’s 
numerical code to his or her actual identity. In case of data transfer, EMD Serono will maintain 
high standards of confidentiality and protection of patients’ personal data consistent with 
applicable privacy laws. 
 
The investigator site will store any patient samples in a secure storage space with adequate 
measures to protect confidentiality. 
 
The informed consent document and any patient recruitment materials must be in compliance 
with ICH GCP, local regulatory requirements, and legal requirements, including applicable privacy 
laws. 
 
The informed consent document used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by the IRB, and EMD Serono, and be 
available for inspection. 
 
The investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
 
The investigator, or a person designated by the investigator, will obtain written informed consent 
from each patient before any study-specific activity is performed. The investigator will retain the 
original of each patient's signed consent document. 
 

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The consent discussion can occur in person, over the phone, during a telemedicine visit, or over 
a videocall. Alternatively, prospective participants may be provided an informed consent form via 
email or MyChart message, which they review independently.  
 
Subjects can electronically sign the consent via iConsent (when in clinic) or KLIC-Sign (when 
remote consenting), which are both 21 CFR Part 11 compliant. Alternatively, subjects can sign a 
hard copy of the consent form while in clinic, which will be scanned into their electronic medical 
record. 
 
12.3 Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
 
In the event of any prohibition or restriction imposed (i.e. clinical hold) by an applicable regulatory 
authority in any area of the world, or if the investigator is aware of any new information that may 
influence the evaluation of the benefits and risks of the investigational product, the IRB should be 
informed immediately. 
 
In addition, the investigator will inform the IRB immediately of any urgent safety measures taken 
by the investigator to protect the study patients against any immediate hazard, and of any serious 
breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
 
13. DEFINITION OF END OF TRIAL 
 
End of trial is defined as last subject last visit (LSLV). 
 
14. SPONSOR DISCONTINUATION CRITERIA 
 
Premature termination of this study may occur because of a regulatory authority decision, change 
in the opinion of the IRB, drug safety problems, or at the discretion of the MDACC IND Office. In 
addition, EMD Serono retains the right to discontinue the development of the involved study drugs 
at any time. 
 
If a study is prematurely terminated or discontinued, EMD Serono or the MDACC IND Office will 
promptly notify the investigator. As directed by EMD Serono, all study materials must be collected 
and all CRFs completed to the greatest extent possible. 
 

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Appendix A: ECOG Performance Status 
 
Grade 
Performance 
0 
Fully active, able to carry out all pre-disease performance without 
restriction. 
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. 
2 
Ambulatory and capable of all self-care, but unable to carry out work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
4 
Completely disabled. Cannot carry out any self-care. Totally confined 
to bed or chair. 
5 
Dead 
 
 
 

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Appendix B: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines 
 
Adapted from E.A. Eisenhauer et al. New response evaluation criteria in solid tumors: Revised 
RECIST guideline (version 1.1)25. 
 
CATEGORIZING LESIONS AT BASELINE 
 
Measurable Lesions 
• 
Lesions that can be accurately measured in at least one dimension. 
• 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when 
assessed by CT or MRI (slice thickness 5-8 mm). 
• 
Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 
• 
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 
• 
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other measurable lesions. 
 
Non-measurable disease 
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and <15 mm) and truly non-measurable disease such as pleural 
or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured with 
calipers, abdominal masses identified by physical exam that are not measurable by reproducible 
imaging techniques. 
• 
Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability 
at baseline. 
• 
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment. 
 
Normal sites 
• 
Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease. Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above. If 
non-cystic lesions are also present, these are preferred as target lesions. 
• 
Normal nodes: Nodes with short axis <10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease. 
 
RECORDING TUMOR ASSESSMENTS 
 
All sites of disease must be assessed at baseline. Baseline assessments should be done as close 
as possible prior to study start. For an adequate baseline assessment, all required scans must be 
done within 28 days prior to start of study treatment and all disease must be documented 
appropriately. If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
 
Target Lesions 
 

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All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative 
of all involved organs, should be identified as target lesions at baseline. Target lesions should be 
selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. 
Record the longest diameter for each lesion, except in the case of pathological lymph nodes for 
which the short axis should be recorded. The sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to 
assessments performed post-baseline. 
• 
If two target lesions coalesce the measurement of the coalesced mass is used. If a large 
target lesion splits, the sum of the parts is used. 
• 
Measurements for target lesions that become small should continue to be recorded. If the 
lesion is considered to have disappeared, 0 mm should be recorded; otherwise if a lesion 
is determined to be present but too small to measure, the lesion status will indicate “too 
small to measure and judged to be less than 10 mm” and 5 mm will be used in the 
calculation of the sum of the diameters. 
 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement should 
still be recorded. 
 
Non-target Disease 
All non-measurable disease is non-target. All measurable lesions not identified as target lesions 
are also included as non-target disease. Measurements are not required but rather assessments 
will be expressed as ABSENT, INDETERMINATE (i.e., Not Evaluable), PRESENT/NOT 
INCREASED, INCREASED. Multiple non-target lesions in one organ may be recorded as a single 
item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning. If a change needs to be made the case should 
be discussed with the radiologist and the Principal Investigator to determine if substitution is 
possible. If not, subsequent objective statuses are not evaluable. 
 
Target Disease 
 
• 
Complete Response (CR): Complete disappearance of all target lesions with the exception 
of nodal disease. All target nodes must decrease to normal size (short axis <10 mm). All 
target lesions must be assessed. 
• 
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions. All target lesions must be assessed. 
• 
Stable Disease (SD): Does not qualify for CR, PR or Progression. All target lesions must 
be assessed. Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir (smallest sum of diameters consider baseline and all 
assessments prior to the time point under evaluation), but enough that a previously 
documented 30% decrease no longer holds. 
• 
Objective Progression (PD): 20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm. 

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• 
Not evaluable (NE): Progression has not been documented, and one or more target 
lesions have not been assessed; or 
• 
Assessment methods used were inconsistent with those used at baseline; or 
• 
One or more target lesions cannot be measured accurately (e.g., poorly visible unless due 
to being too small to measure); or 
• 
One or more target lesions were excised or irradiated and have not reappeared or 
increased. 
 
Non-target Disease 
• 
CR: Disappearance of all non-target lesions and normalization of tumor marker levels (if 
being followed). All lymph nodes must be ‘normal’ in size (<10 mm short axis). 
• 
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level (if being 
followed) above the normal limits. 
• 
PD: Unequivocal progression of pre-existing lesions. Generally the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy. In the presence of SD or PR 
in target disease, progression due to unequivocal increase in non-target disease should 
be rare. 
• 
Not evaluable (NE): Progression has not been determined and one or more non-target 
lesion sites have not been assessed or assessment methods used were inconsistent with 
those used at baseline or one or more non-target lesions cannot be assessed (e.g., poorly 
visible or unclear images) or one or more non-target lesions were excised or irradiated 
and have not reappeared or increased. 
 
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology. If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment. A lesion identified in an area not previously scanned will be considered a new 
lesion. 
 
Supplemental Investigations 
 
• 
If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with biopsy 
or fine needle aspirate. If no disease is identified, objective status is CR. 
• 
If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
 
Subjective Progression 
Patients requiring discontinuation of treatment without objective evidence of disease progression 
should not be reported as PD on tumor assessment CRFs. This should be indicated on the end 
of treatment CRF as off treatment due to Global Deterioration of Health Status. Every effort should 
be made to document PD even after discontinuation of study treatment. 
 
Determination of Tumor Response by RECIST 

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When both target and non-target lesions are present, individual assessments will be recorded 
separately. New lesions will also be recorded separately. Determination of tumor response at 
each assessment based on target, non-target and new lesions is summarized in the following 
table. 
 
Objective Response Status at Each Assessment for Patients with Measurable 
Disease at Baseline 
 
 
Determination 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 sum on 
study). For CR and PR, the patient’s best response assignment will depend on the achievement 
of both measurement and confirmation criteria. CR and PR must be confirmed by 2 
measurements at least 4 weeks apart. In the case of SD, follow up measurements must have met 
the SD criteria at least once after start of the treatment at a minimum interval of 6 weeks. 

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Appendix C: Immune-related RECIST (irRECIST) 
 
Increasing clinical experience indicates that traditional response criteria may not be sufficient to 
fully characterize activity in this new era of targeted therapies and/or biologics. 
This is particularly true for immunotherapeutic agents such as anti-CTLA4 and anti-PD-1\anti PD-
L1 antibodies which exert the antitumor activity by augmenting activation and proliferation of T-
cells, thus leading to tumor infiltration by T-cells and tumor regression rather than direct cytotoxic 
effects. Clinical observations of patients with advanced melanoma treated with ipilimumab, for 
example, suggested that conventional response assessment criteria such as Response 
Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria are 
not sufficient to fully characterize patterns of tumor response to immunotherapy because tumors 
treated with immunotherapeutic agents may show additional response patterns that are not 
described in these conventional criteria. 
Furthermore, the conventional tumor assessment criteria (RECIST and WHO criteria) have been 
reported as not capturing the existence of a subset of patients who have an OS similar to those 
who have experienced CR or PR but were flagged as PD by WHO criteria. 
On these grounds, a tumor assessment system has been developed that incorporates these 
delayed or flare-type responses into the RECIST v1.1 (irRECIST). For irRECIST, with the 
exception of a CR assessment, only target and new measurable lesions are taken into account. 
In contrast to RECIST v1.1, the irRECIST: 
• 
Requires confirmation of both progression and response by imaging at least 4 weeks from 
the date first documented, and  
• 
Does not necessarily score the appearance of new lesions as progressive disease if the 
sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 
target lesions, maximum of 2 per organ) and measurable new lesions does not increase 
by >20%. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline and throughout the study. 
 
irRECIST responses are defined as follows: 
• 
Overall immune-related complete response (irCR): Complete disappearance of all 
lesions (whether measurable or not) and no new lesions. All measurable lymph nodes 
also must have a reduction in short axis to <10 mm.  
• 
Overall immune-related partial response (irPR): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions decreases 
≥30%. 
• 
Overall immune-related stable disease (irSD): Sum of the diameters (longest for non-
nodal lesions, shortest for nodal lesions) of target and new measurable lesions does not 
meet criteria for irCR or irPR (compared to baseline), or immune-related progressive 
disease (irPD, compared to nadir). 
• 
Overall immune-related progressive disease (irPD): Sum of the diameters (longest for 
non-nodal lesions, shortest for nodal lesions) of target and new measurable lesions 
increases ≥20% (compared to nadir), confirmed by a repeat, consecutive observation at 
least 4 weeks from the date first documented. 
New measurable lesions: Incorporated into tumor burden (i.e., added to the target lesion 
measurements). A lymph node has to be ≥15 mm in short axis to be a measurable new lesion 
and its short axis measurement is included in the sum. Up to 2 new lesions per organ and up 

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to 5 new lesions in total can be added to the measurements. New non-measurable lesions: 
Do not define progression but preclude irCR. 
 
Measurable disease 
Non-measurable disease 
Target and New 
Measurable 
Lesions (Tumor 
Burden)a 
Non-Target Lesions 
New, non- 
measurable 
Lesions 
Overall 
response 
using 
irRECISTb 
Decrease 100% 
Absent 
Absent 
irCR 
Decrease 100% 
Stable 
Any 
irPR 
Decrease 100% 
Unequivocal 
progression 
Any 
irPR 
Decrease ≥30% 
Absent/stable 
Any 
irPR 
Decrease ≥30% 
Unequivocal 
progression 
Any 
irPR 
Decrease <30% and 
increase 
<20% 
Absent/stable 
Any 
irSD 
Decrease <30% and 
increase 
<20% 
Unequivocal 
progression 
Any 
irSD 
Increase ≥20% 
Any 
Any 
irPD 
a Decreases assessed relative to baseline. 
b Response (irCR and irPR) and progression (irPD) must be confirmed by a second, 
consecutive assessment at least 4 weeks apart. 
 
 
 

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Appendix D: Assessment of Radiographic Response and Progression in Patients with 
CRPC 
 
Radiographic imaging for patients with CRPC is categorized as soft tissue or bone. Soft tissue 
imaging may include CT scans of the chest, abdomen and pelvis or MRIs of the abdomen and 
pelvis). Bone imaging including a whole body radionuclide bone scan (scintigraphy) is required at 
baseline and at regular image screening intervals in all patients with prostate cancer enrolling on 
trial. 
The investigator will assess response of soft tissue disease by RECIST v1.1 (see Appendix 16.2). 
However, bone disease will not be considered as non-target lesions assessed by RECIST v1.1. 
An objective response is defined as a best overall response of CR or PR per RECIST v1.1 and 
must be confirmed on repeated imaging at least 4 weeks after initial documentation. 
Bone disease will be assessed for progressive disease only by PCWG3.64. The documentation 
required for the determination of radiographic progression is shown in the table below. 
 
Date 
Progression 
Detecteda 
Criteria for 
Progression 
Criteria to 
Confirm 
Progression 
Criteria to Document 
Disease 
Progression on 
Confirmatory Scan 
Week 8 
Bone lesions: 2 
or more new 
lesions 
compared to 
screening bone 
scan by 
PCWG3 
Timing: At least 6 
weeks after 
progression identified 
or at Week 16 visitb 
2 or more new bone 
lesions on bone scan 
compared to Week 8 scan 
Soft tissue 
lesions: 
Progressive 
disease on CT 
or MRI by RECIST 
v1.1 
No confirmatory scan 
required for soft tissue 
disease progression 
No confirmatory scan 
required for soft tissue 
disease 
progression 
Week 16 or 
later 
Bone lesions: 2 or 
more new lesions 
on bone scan 
compared to 
Week 8 bone 
scan 
Timing: At least 6 
weeks after 
progression identified 
or at next imaging 
time pointb 
Persistent or increase in 
number of bone lesions 
on 
bone scan compared 
to prior scanc 
Soft tissue lesions: 
Progressive 
disease on CT or 
MRI by RECIST 
v1.1 
No confirmatory scan 
required for soft 
tissue disease 
progression 
No confirmatory scan 
required 
for soft tissue 
disease 
progression 
• Progression detected by bone scan at an unscheduled visit either before Week 8 
or between scheduled visits will require a confirmatory scan at least 6 weeks later 
and should follow confirmation criteria outlined in the table for the next scheduled 
scan. 
• Confirmation must occur at the next available scan. 

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• For confirmation, at least 2 of the lesions first identified as new must be present at 
the next available scan (confirmation scan). 
 
Disease progression in bone disease must be confirmed at least 6 weeks later, as per PCWG3. 
See table below for the timing of confirmatory imaging requirements. 
 
Confirmatory Imaging Requirements for Patients with mCRPC Based on RECIST v1.1 and 
PCWG3 
 
Disease Site 
Response 
Progressiona 
Soft tissue 
Must be confirmed at least 
4 weeks later 
No confirmation required 
Bone 
Not applicable 
Must be confirmed at least 6 
weeks later 
a To inform permanent treatment discontinuation. 
 
Radiographic PFS is defined as the time from the start of treatment to documentation of 
radiographic progression in soft tissue by investigator’ assessment according to RECIST v1.1, in 
bone by investigator’s assessment according to PCWG3, or death if within 2 tumor assessments 
after last completed tumor assessment, whichever occurs first. 
 
 

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Appendix E: Abbreviations and Definitions 
 
Abbreviation Definition 
ADL 
Activities of daily living 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AHA 
American Heart Association 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT 
Alanine Aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ASCO 
American Society of Clinical Oncology 
ATM 
Ataxia telangiectasia mutated 
ATR 
Ataxia telangiectasia mutated and Rad3-related 
AUC 
Area under the curve 
BNP 
B-type natriuretic peptide  
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CBR 
Clinical benefit rate 
CFR 
Code of Federal Regulations 
CK-MB 
Creatinine kinase MB 
Cmax 
Maximum plasma drug concentration 
CMO 
Contract Manufacturing Organization 
CNB 
Core needle biopsy 
CPK 
Creatinine phosphokinase 
CR 
Complete response(s) 
CRF 
Case report form 
CRP 
C-reactive protein 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DDR 
DNA Damage Response 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
DSB 
Double strand break 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture (system) 
EOI 
End of Infusion 
EOT 
End of treatment 
ESC 
European Society of Cardiology 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 

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GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GnRH 
Gonadotropin-releasing hormone 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B virus surface antigen 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HGSOC 
High grade serous ovarian cancer 
HIV 
Human immunodeficiency virus 
HPF 
High power field 
HR 
Heart rate 
HRD 
homologous recombination deficiency 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IGF-1 
Insulin-like growth factor 1 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IO 
Immuno-oncology 
IPCT 
Institute for Personalized Cancer Therapy 
IRB 
Institutional review board 
irAE 
Immune-related adverse event 
irRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
ITB 
Institutional Tissue Bank 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
LLN 
Lower limit of normal 
LSLV 
Last subject last visit 
LVEF 
Left ventricular ejection fraction 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MDACC 
The University of Texas MD Anderson Cancer Center 
MRI 
Magnetic resonance imaging 
MUGA 
Multi-gated acquisition scan 
NCI 
National Cancer Institute 
NSAID 
Non-steroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PARP 
Poly(ADP-ribose) polymerase 
PCWG3 
Prostate Cancer Working Group 3 
PD 
Pharmacodynamic or progressive disease 
PD-L1 
Programmed death ligand 1 
PDX 
Patient-derived xenograft 
PET 
Positron emission tomography 

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PFS 
Progression free survival 
PK 
Pharmacokinetic 
PODS 
Precision Oncology Decision Support 
PR 
Partial response 
PRL 
Prolactin 
PS 
Performance status 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose 
RPPA 
Reverse phase protein array 
RSRD 
Replication stress response defect 
SAE 
Serious adverse event 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
STING 
Stimulator of interferon gamma 
T4 
Thyroxine 
TBD 
To be determined 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time of maximum plasma concentration following drug administration 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix F: List of Prohibited Medications and Therapies 
 
The following medications should not be administered while participating in this trial.  
 
 
 
 
 
 
 
 
CYP3A4 and CYP3A5 Inhibitors CYP3A4 and CYP3A5 Inducers
 indinavir
efavirenz
 nelfinavir
nevirapine
 ritonavir
barbiturates
 clarithromycin
carbamazepine
 itraconazole1
enzalutamide
 ketoconazole
glucocorticoids
 nefazodone
modafinil
 saquinavir
oxcarbazepine
 telithromycin
phenobarbital2
 aprepitant
phenytoin2
 erythromycin
pioglitazone
 fluconazole
rifabutin
 grapefruit juice
rifampin1
 verapamil2
St. John's Wort
 diltiazem
troglitazone1
 cimetidine
amiodarone
NOT azithromycin
chloramphenicol
boceprevir
ciprofloxacin
delaviridine
diethyl-dithiocarbamate
fluvoxamine
gestodene
imatinib
m befradil
mifepristone
norfloxacin
norfluoxetine
starfruit
telaprevir
voriconazole

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