A Phase 2, Open-label, Study of Vobramitamab Duocarmazine in Participants With Metastatic Castration-resistant Prostate Cancer and Other Solid Tumors
Phase: PHASE2
Conditions: Castration-Resistant Prostatic Cancer, Androgen-Independent Prostatic Cancer, Androgen-Insensitive Prostatic Cancer, Androgen-Resistant Prostatic Cancer, Hormone Refractory Prostatic Cancer, Anal Cancer, Anal Neoplasm, Carcinoma, Squamous Cell of Head and Neck, Head and Neck Squamous Cell Carcinoma, Laryngeal Squamous Cell Carcinoma, Oral Squamous Cell Carcinoma, Malignant Melanoma, Melanoma, Non-small Cell Lung Cancer, Non-small Cell Carcinoma, Small-cell Lung Cancer, Small Cell Carcinoma
Sponsor: MacroGenics

Vobramitamab Duocarmazine 
MacroGenics, Inc. 
Clinical Study Protocol: CP-MGC018-03 
Protocol Amendment 5, 19 August 2024 
 
CLINICAL STUDY PROTOCOL: CP-MGC018-03 
PROTOCOL AMENDMENT 5  
Study Title: 
A Phase 2, Open-Label Study of Vobramitamab Duocarmazine in 
Participants with Metastatic Castration-Resistant Prostate Cancer and 
Other Solid Tumors (TAMARACK) 
Study Number: 
CP-MGC018-03 
Study Phase: 
Phase 2 
Product Name: 
Vobramitamab duocarmazine (also known as MGC018) 
NCT Number: 
NCT05551117 
EU CT Number: 
2022-501078-20 
Indication: 
Advanced solid tumors 
Coordinating 
Principal 
Investigator: 
To be determined 
Sponsor: 
MacroGenics, Inc. 
9704 Medical Center Drive 
Rockville, MD 20850 
USA 
+1 (301) 251-5172 
Sponsor’s Study 
Physician: 
Refer to study contact list for current details 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of MacroGenics, Inc. that 
can only be used for the purpose of reviewing or performing this study. Any use, viewing or 
disclosure of such information that is not authorized in writing by the sponsor is strictly 
prohibited. 
 
 
 
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Protocol Amendment 5, 19 August 2024 
 
 
 
 
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Vobramitamab Duocarmazine 
MacroGenics, Inc. 
Clinical Study Protocol: CP-MGC018-03 
Protocol Amendment 5, 19 August 2024 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURES ........................................................................................................... 10 
 
LIST OF ABBREVIATIONS ....................................................................................................... 12 
1 
SYNOPSIS ........................................................................................................................ 15 
2 
BACKGROUND INFORMATION .................................................................................. 22 
2.1 
Disease Background................................................................................................. 22 
2.1.1 
Prostate Cancer .............................................................................................. 22 
2.1.1.1 
Standard of Care in Metastatic Castration-Resistant 
Prostate Cancer ..................................................................................... 22 
2.1.2 
Anal Carcinoma ............................................................................................. 24 
2.1.3 
HNSCC .......................................................................................................... 24 
2.1.4 
Melanoma ...................................................................................................... 25 
2.1.5 
NSCLC ........................................................................................................... 25 
2.1.6 
SCLC .............................................................................................................. 25 
2.2 
Rationale for Study .................................................................................................. 26 
2.2.1 
Rationale for Vobramitamab Duocarmazine in Metastatic 
Castration-resistant Prostate Cancer (Part 1) ................................................. 26 
2.2.2 
Rationale for Vobramitamab Duocarmazine in Other Advanced 
Solid Tumors (Part 2) ..................................................................................... 26 
2.3 
Background on Vobramitamab Duocarmazine ........................................................ 27 
2.4 
Dose Selection ......................................................................................................... 27 
2.4.1 
Dose Selection for Part 1 ............................................................................... 27 
2.4.2 
Dose Selection for Part 2 ............................................................................... 29 
2.5 
Risk Benefit Assessment .......................................................................................... 29 
2.5.1 
Risk Assessment ............................................................................................. 29 
2.5.1.1 
SARS-CoV-2 (COVID-19) Guidance .................................................. 30 
2.5.2 
Benefit Assessment ........................................................................................ 30 
2.5.3 
Overall Assessment ........................................................................................ 30 
3 
STUDY PURPOSE AND OBJECTIVES ......................................................................... 32 
3.1 
Primary Objective .................................................................................................... 32 
3.2 
Secondary Objectives............................................................................................... 32 
3.3 
Exploratory Objectives ............................................................................................ 33 
4 
STUDY DESIGN .............................................................................................................. 34 
4.1 
Overall Study Design ............................................................................................... 34 
4.1.1 
Part 1 Study Design ....................................................................................... 35 
4.1.2 
Part 2 Study Design ....................................................................................... 36 
4.2 
Study Treatment Discontinuation ............................................................................ 37 
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Protocol Amendment 5, 19 August 2024 
 
4.2.1 
Lost to Follow Up .......................................................................................... 38 
4.3 
Participant Study Discontinuation ........................................................................... 38 
4.4 
Definition of End of Study ....................................................................................... 38 
5 
ELIGIBILITY CRITERIA ................................................................................................ 39 
5.1 
Inclusion Criteria ..................................................................................................... 39 
5.2 
Exclusion Criteria .................................................................................................... 41 
6 
STUDY TREATMENTS .................................................................................................. 45 
6.1 
Description of Dosing Regimens ............................................................................. 45 
6.1.1 
Vobramitamab Duocarmazine Dosing Regimen ............................................ 45 
6.1.2 
Comparator Product Dosing Regimen(s) (Part 1) .......................................... 45 
6.2 
Method of Assigning Participants to Treatment Groups .......................................... 46 
6.3 
Blinding.................................................................................................................... 46 
6.4 
Emergency Unblinding ............................................................................................ 46 
6.5 
Study Drugs and Supplies ........................................................................................ 47 
6.5.1 
Vobramitamab Duocarmazine ........................................................................ 47 
6.5.2 
Comparator Products ..................................................................................... 47 
6.6 
Preparation and Administration ............................................................................... 47 
6.7 
Packaging and Labeling ........................................................................................... 47 
6.8 
Treatment Compliance ............................................................................................. 48 
6.9 
Accountability .......................................................................................................... 48 
6.10 
Study Drug Disposition at End of Study ................................................................. 48 
7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES ..................................................................................................................... 49 
7.1 
Premedication and Prophylaxis for Vobramitamab Duocarmazine ......................... 49 
7.2 
Dose Modification and Dose Delay ......................................................................... 49 
7.2.1 
Vobramitamab Duocarmazine Dose Delay and Interruption ......................... 49 
7.2.2 
Vobramitamab Duocarmazine Dose Reduction ............................................. 50 
7.3 
Management of Potential Adverse Events Related to Vobramitamab 
Duocarmazine .......................................................................................................... 50 
7.3.1 
Guidelines for Management of Adverse Events Related to 
Vobramitamab Duocarmazine ........................................................................ 50 
7.3.2 
Infusion Related Reaction .............................................................................. 51 
7.3.3 
Diarrhea .......................................................................................................... 52 
7.3.4 
Pneumonitis .................................................................................................... 53 
7.3.5 
Palmar-Plantar Erythrodysesthesia ................................................................ 55 
7.3.6 
Ocular Adverse Events ................................................................................... 56 
7.3.7 
Hematologic Adverse Events ......................................................................... 57 
7.3.7.1 
Neutropenia .......................................................................................... 57 
7.3.7.2 
Thrombocytopenia ............................................................................... 58 
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Protocol Amendment 5, 19 August 2024 
 
7.3.7.3 
Anemia ................................................................................................. 58 
7.3.8 
Effusions ........................................................................................................ 59 
7.3.8.1 
Pleural Effusion .................................................................................... 60 
7.3.8.2 
Pericardial Effusion .............................................................................. 60 
7.3.9 
Cardiac Adverse Events ................................................................................. 60 
7.4 
Management of Potential Adverse Events Related to Comparator 
Products (Part 1) ...................................................................................................... 61 
8 
CONCOMITANT THERAPY AND RESTRICTIONS ................................................... 62 
8.1 
Concomitant Therapy ............................................................................................... 62 
8.1.1 
Prohibited Therapy ......................................................................................... 62 
8.1.2 
Permitted Therapy .......................................................................................... 63 
8.1.3 
Contraception ................................................................................................. 63 
8.2 
Restrictions .............................................................................................................. 64 
8.2.1 
Fluid and Food Intake .................................................................................... 64 
8.2.2 
Participant Activity Restrictions .................................................................... 64 
9 
STUDY PROCEDURES .................................................................................................. 65 
9.1 
Informed Consent..................................................................................................... 65 
9.2 
Screening Period ...................................................................................................... 65 
9.3 
Registration and Enrollment .................................................................................... 65 
9.4 
Medical History ....................................................................................................... 66 
9.4.1 
Prostate Cancer History (Part 1) .................................................................... 66 
9.4.2 
Other Cancer History (Part 2) ........................................................................ 67 
9.5 
Prior and Concomitant Medications and Procedures ............................................... 67 
9.6 
Physical Examination............................................................................................... 67 
9.6.1 
Vital Signs ...................................................................................................... 67 
9.6.2 
Height and Weight.......................................................................................... 67 
9.7 
Performance Status .................................................................................................. 68 
9.8 
Laboratory Tests ....................................................................................................... 68 
9.8.1 
Clinical Laboratory Tests ............................................................................... 68 
9.8.2 
Central Laboratory Tests ................................................................................ 69 
9.8.2.1 
Blood Samples...................................................................................... 70 
9.8.2.2 
Tumor Biopsy Specimens .................................................................... 70 
9.9 
Tumor Assessments .................................................................................................. 70 
9.10 
Electrocardiography ................................................................................................. 71 
9.11 
Echocardiography .................................................................................................... 71 
9.12 
Ophthalmic Examination ......................................................................................... 71 
9.13 
Symptomatic Skeletal Events (Part 1 Only) ............................................................ 72 
9.14 
End of Treatment Visit ............................................................................................. 72 
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Protocol Amendment 5, 19 August 2024 
 
9.15 
Post-Treatment Follow-Up Period ........................................................................... 72 
10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS............................................................................................... 74 
10.1 
Pharmacokinetic Assessments ................................................................................. 74 
10.2 
Immunogenicity Assessments .................................................................................. 74 
10.3 
Biomarker Assessments ........................................................................................... 74 
11 
ASSESSMENT OF EFFICACY ....................................................................................... 75 
11.1 
Efficacy Assessments ............................................................................................... 75 
11.1.1 
Tumor Response Assessments ....................................................................... 75 
11.1.2 
Survival Assessments ..................................................................................... 76 
12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY ......................... 77 
12.1 
Definitions................................................................................................................ 77 
12.1.1 
Adverse Event ................................................................................................ 77 
12.1.2 
Adverse Drug Reaction .................................................................................. 77 
12.1.3 
Adverse Event of Special Interest .................................................................. 77 
12.1.4 
Serious Adverse Event ................................................................................... 77 
12.1.5 
Assessment of Causality ................................................................................ 78 
12.1.6 
Severity Criteria ............................................................................................. 79 
12.2 
Adverse Event Collection and Documentation ........................................................ 79 
12.2.1 
All Adverse Events ........................................................................................ 79 
12.2.2 
Serious Adverse Events .................................................................................. 80 
12.2.3 
Pregnancy ....................................................................................................... 81 
12.2.4 
Special Reporting Situations .......................................................................... 82 
12.2.4.1 
Sponsor Notification of Adverse Events of Special Interest ................ 82 
12.2.4.2 
Overdose............................................................................................... 83 
12.2.4.3 
Product Quality Issues .......................................................................... 83 
12.2.4.4 
Discontinuation of Study Treatment Due to an Adverse 
Event..................................................................................................... 83 
13 
PRODUCT QUALITY COMPLAINT HANDLING ....................................................... 84 
13.1 
Procedures ................................................................................................................ 84 
13.2 
Contacting Sponsor Regarding Product Quality ...................................................... 84 
14 
STATISTICAL ANALYSIS .............................................................................................. 85 
14.1 
Determination of Sample Size ................................................................................. 85 
14.2 
Independent Data Monitoring Committee ............................................................... 88 
14.3 
Analysis Populations ................................................................................................ 88 
14.4 
Demographics and Baseline Characteristics ............................................................ 89 
14.5 
Study Treatment Exposures and Concomitant Medications .................................... 89 
14.6 
Pharmacokinetic, Exposure-Response, Immunogenicity, and Biomarker 
Analyses ................................................................................................................... 89 
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Protocol Amendment 5, 19 August 2024 
 
14.6.1 
Pharmacokinetic Analysis .............................................................................. 89 
14.6.2 
Exposure-Response Analyses ........................................................................ 89 
14.6.3 
Immunogenicity Analysis .............................................................................. 90 
14.6.4 
Biomarker Analysis ........................................................................................ 90 
14.7 
Efficacy Endpoints and Analyses ............................................................................. 90 
14.7.1 
Primary Efficacy Endpoints and Analysis ..................................................... 90 
14.7.1.1 
Radiographic Progression-Free Survival per PCWG3 
(Part 1) .................................................................................................. 90 
14.7.1.2 
Objective Response Rate per RECIST v1.1 (Part 2) ............................ 91 
14.7.2 
Secondary Efficacy Endpoints and Analyses ................................................. 92 
14.7.2.1 
Prostate-Specific Antigen Response (Part 1) ....................................... 92 
14.7.2.2 
Time to Prostate-Specific Antigen Progression (Part 1) ...................... 92 
14.7.2.3 
Progression-Free Survival per RECIST v1.1 (Part 2) .......................... 92 
14.7.2.4 
Objective Response Rate per PCWG3 (Part 1) .................................... 93 
14.7.2.5 
Duration of Response (Part 1 and Part 2) ............................................. 93 
14.7.2.6 
Tumor Size Change Over Time (Part 1 and Part 2) ............................. 93 
14.7.2.7 
Time to First Symptomatic Skeletal Event (Part 1) ............................. 93 
14.7.3 
Exploratory Efficacy Endpoints and Analyses............................................... 94 
14.7.3.1 
Overall Survival (Part 1 and Part 2) ..................................................... 94 
14.8 
Safety Endpoints and Analyses ................................................................................ 94 
14.8.1 
Adverse Events .............................................................................................. 94 
14.8.2 
Laboratory Values .......................................................................................... 95 
14.8.3 
Other Safety Endpoints .................................................................................. 95 
14.9 
Interim Analyses ...................................................................................................... 95 
14.10 
Other Assessments or Analyses ............................................................................... 95 
15 
QUALITY CONTROL AND ASSURANCE ................................................................... 96 
15.1 
Monitoring, Auditing, and Inspections .................................................................... 96 
15.2 
Data Collection and Management ............................................................................ 97 
16 
ADMINISTRATIVE CONSIDERATIONS...................................................................... 98 
16.1 
Institutional Review Board or Independent Ethics Committee Approval ............... 98 
16.2 
Ethical Conduct of the Study ................................................................................... 98 
16.3 
Participant Information and Consent ....................................................................... 98 
16.4 
Participant Confidentiality ....................................................................................... 99 
16.5 
Source Documents ................................................................................................... 99 
16.6 
Retention of Data ..................................................................................................... 99 
16.7 
Sample Retention and Secondary Research ............................................................. 99 
16.8 
Financial Disclosure............................................................................................... 100 
16.9 
Publication and Disclosure Policy ......................................................................... 100 
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Protocol Amendment 5, 19 August 2024 
 
16.10 
Discontinuation of the Study or Study Sites .......................................................... 100 
16.11 
Summary of Results (European Union Member States) ........................................ 101 
16.12 
Identification of the Coordinating Principal Investigator ...................................... 101 
17 
REFERENCE LIST ........................................................................................................ 102 
 
LIST OF TABLES  
Table 1 
Part 2 Cohort Enrollment (Closed to Enrollment) .............................................. 36 
Table 2 
Overview of Study Treatments ........................................................................... 45 
Table 3 
Vobramitamab Duocarmazine Dose Reduction Algorithm ................................ 50 
Table 4 
Guidelines for Vobramitamab Duocarmazine-Related Adverse 
Events Not Specified in the Protocol .................................................................. 51 
Table 5 
Management of Infusion Related Reaction ........................................................ 52 
Table 6 
Dose Modification for Diarrhea ......................................................................... 53 
Table 7 
Management of Noninfectious Pneumonitis ...................................................... 54 
Table 8 
Dose Modification for Palmar-Plantar Erythrodysesthesia ................................ 56 
Table 9 
Management of Ocular Symptoms ..................................................................... 57 
Table 10 
Management of Neutropenia .............................................................................. 58 
Table 11 
Management of Thrombocytopenia.................................................................... 58 
Table 12 
Management of Anemia ..................................................................................... 59 
Table 13 
Management of Pleural Effusion ........................................................................ 60 
Table 14 
Management of Pericardial Effusion .................................................................. 60 
Table 15 
Management of Cardiac Adverse Events ........................................................... 60 
Table 16 
Eastern Cooperative Oncology Group Performance Status ............................... 68 
Table 17 
Clinical Laboratory Tests .................................................................................... 69 
Table 18 
Radiographic Progressive Disease per Prostate Cancer Working 
Group 3 ............................................................................................................... 76 
Table 19 
Adverse Events of Special Interest ..................................................................... 82 
Table 20 
Simon’s Two-Stage Design Parameters .............................................................. 87 
Table 21 
Censoring Rules for Primary Analysis of Radiographic Progression-
Free Survival ...................................................................................................... 91 
Table 22 
Schedule of Events (Every 4 Week Cycle) ....................................................... 109 
Table 23 
Schedule of Events - Post-Treatment Follow-up Period ...................................112 
Table 24 
Pharmacokinetic Sample Collection Schedule ..................................................113 
 
LIST OF FIGURES  
Figure 1 
Study Schema ..................................................................................................... 35 
 
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MacroGenics, Inc. 
Clinical Study Protocol: CP-MGC018-03 
Protocol Amendment 5, 19 August 2024 
 
LIST OF APPENDICES  
APPENDIX 1 
TIME AND EVENTS SCHEDULE 
APPENDIX 2 
PHARMACOKINETICS AND IMMUNOGENICITY 
COLLECTION SCHEDULES 
APPENDIX 3 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
 
 
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Clinical Study Protocol: CP-MGC018-03 
Protocol Amendment 5, 19 August 2024 
 
SPONSOR SIGNATURES  
Study Title: 
A Phase 2, Open-Label Study of Vobramitamab Duocarmazine in 
Participants with Metastatic Castration-Resistant Prostate Cancer and 
Other Solid Tumors (TAMARACK) 
Study Number: 
CP-MGC018-03 
 
This clinical study protocol has been approved by the sponsor: 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Study Physician 
MacroGenics, Inc. 
 
 
 
Signed: 
See Appended Electronic Signature Page 
Date: 
 
 
 
Study Biostatistician 
MacroGenics, Inc. 
 
 
 
 
 
 
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Protocol Amendment 5, 19 August 2024 
 
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Clinical Study Protocol: CP-MGC018-03 
Protocol Amendment 5, 19 August 2024 
 
LIST OF ABBREVIATIONS  
The list of abbreviations of specialist terms does not include general scientific abbreviations of 
temperature, weight, and volume. 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
ADT 
androgen deprivation therapy 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ARAT 
androgen receptor axis-targeted therapy 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUCt 
area under the concentration-time curve until time t 
AUCtau 
area under the concentration-time curve for a dosing interval 
BID 
twice daily 
BOR 
best overall response 
CBC 
complete blood count 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease-2019 
CR 
complete response 
CRPC 
castration-resistant prostate cancer 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
DCR 
disease control rate 
DoR 
duration of response 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
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Clinical Study Protocol: CP-MGC018-03 
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EOTV 
end of treatment visit 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GnRH 
gonadotropin-releasing hormone 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HFS 
hand-foot syndrome 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form  
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
IRB 
Institutional Review Board 
IRR 
infusion related reaction 
IRT 
interactive response technology 
ITT 
intention to treat 
IV 
intravenous(ly) 
LTFU 
lost to follow up 
LVEF 
left ventricular ejection fraction 
mCRPC 
metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition (scan) 
NCI 
National Cancer Institute 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly (ADP-ribose) polymerase 
PCWG3 
Prostate Cancer Working Group 3 
PD 
progressive disease 
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Clinical Study Protocol: CP-MGC018-03 
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PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
per os (oral) 
PPE 
palmar-plantar erythrodysesthesia 
PPK 
population pharmacokinetic(s) 
PQC 
product quality complaint 
PR 
partial response 
PSA 
prostate-specific antigen 
PT 
preferred term 
Q3W 
once every 3 weeks 
Q4W 
once every 4 weeks 
Q8W 
once every 8 weeks 
Q12W 
once every 12 weeks 
RANK-L 
receptor activator of nuclear factor kappa-B ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome-coronavirus-2 
SD 
stable disease 
SOC 
system organ class 
SPP 
statistical programming plan 
SSE 
symptomatic skeletal event 
SUSAR 
suspected unexpected serious adverse reaction 
TBSE 
total body skin examination 
Tmax 
time to maximal concentration 
ULN 
upper limit of normal 
US 
United States 
v 
version 
vc-seco-DUBA 
valine-citrulline-seco-DUocarmycin hydroxyBenzamide-Azaindole (SYD980) 
 
 
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1 
SYNOPSIS  
Sponsor: MacroGenics, Inc. 
EU CT Number: 2022-501078-20 
Name of Product: Vobramitamab duocarmazine (MGC018) 
Study Title: A Phase 2, Open-Label Study of Vobramitamab Duocarmazine in Participants with Metastatic 
Castration-Resistant Prostate Cancer and Other Solid Tumors (TAMARACK) 
Study Number: CP-MGC018-03 
Study Phase: Phase 2 
Investigator(s)/Centers: 
The study will be conducted at approximately 70 centers in approximately 9 countries. 
Primary Objectives:  
Part 1: To evaluate the efficacy of vobramitamab duocarmazine in metastatic castration-resistant prostate cancer 
(mCRPC) at two dose levels as measured by radiographic progression-free survival (rPFS) by investigator 
assessment using Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. 
Part 2: To evaluate the efficacy of vobramitamab duocarmazine in select solid tumors as measured by 
investigator assessment of objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 
Secondary Objectives:  
Both Parts: 
• 
To characterize the frequency and severity of adverse events (AE) and overall tolerability observed with 
vobramitamab duocarmazine. 
Part 1 Only: 
• 
To evaluate the efficacy of vobramitamab duocarmazine as measured by prostate-specific antigen (PSA). 
• 
To evaluate the efficacy of vobramitamab duocarmazine in participants with RECIST-evaluable disease 
as measured by ORR and duration of response (DoR) by investigator assessment using PCWG3 criteria. 
• 
To evaluate the effect of vobramitamab duocarmazine on symptomatic skeletal events (SSEs). 
Part 2 Only: 
• 
To evaluate the efficacy of vobramitamab duocarmazine in participants with select solid tumors as 
measured by DoR and progression-free survival (PFS) by investigator assessment using RECIST v1.1. 
Study Treatments: 
Part 1:  
Experimental Arm A 
• 
Vobramitamab duocarmazine 2.0 mg/kg IV every 4 weeks (Q4W) 
Experimental Arm B 
• 
Vobramitamab duocarmazine 2.7 mg/kg IV Q4W 
 
Part 2: Vobramitamab duocarmazine 2.7 mg/kg IV Q4W (before 22Jul2024); now 2.0 mg/kg IV Q4W for 6 cycles 
I 
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Study Design: 
Study CP-MGC018-03 is an open-label, two-part, Phase 2 study assessing the efficacy, safety, and tolerability of 
vobramitamab duocarmazine.  
In Part 1 of the study, approximately 100 participants will be randomized 1:1 to one of two dose levels of 
vobramitamab duocarmazine (2.0 mg/kg Q4W and 2.7 mg/kg Q4W). Part 1 will enroll participants with 
metastatic castration-resistant prostate cancer (mCRPC) previously treated with one prior ARAT (abiraterone, 
enzalutamide, or apalutamide) for prostate cancer in either the metastatic or non-metastatic, castration-sensitive 
or castration-resistant setting. Participants may also have received up to one prior docetaxel-containing regimen 
for prostate cancer, and up to 3 total prior lines of therapy for mCRPC. Enrollment will use a central 
randomization scheme with stratified permuted blocks. Randomization will be stratified based on 1) presence of 
visceral disease (yes vs no), 2) prior taxane (yes vs no) and 3) region (United States/Canada vs other).  
Per the Dear Investigator Letter, dated 22 July 2024, participants on treatment in Part 1 will discontinue 
vobramitamab duocarmazine, complete an EOTV, and enter the follow-up period. 
Part 2 of the study consists of participants with unresectable, locally advanced or metastatic squamous carcinoma 
of the anal canal (anal SCC), head and neck squamous cell carcinoma (HNSCC), melanoma, squamous non-small 
cell lung cancer (NSCLC) or small cell lung cancer (SCLC) whose disease has progressed following at least one 
prior line of standard systemic therapy for advanced or metastatic disease. Participants initially received 
vobramitamab duocarmazine 2.7 mg/kg Q4W. Per the Dear Investigator Letter, dated 22 July 2024, participants 
in Part 2 who were receiving 2.7 mg/kg must lower their dose to 2.0 mg/kg Q4W and will receive a maximum of 
6 cycles of treatment. Each disease-specific cohort planned to use a Simon’s 2-stage design and enroll up to 
approximately 40 participants if both stages were conducted (see schema below). Part 2 of the study was closed 
to enrollment prior to reaching the Stage 1 enrollment target(s). 
An Independent Data Monitoring Committee (IDMC) will provide study oversight and evaluate cumulative 
clinical data at regular intervals.  
The study treatment schema is presented below. 
Arm A
2.0 mg/kg Q4W
Arm B
2.7 mg/kg Q4W
mCRPC
N=100
R 1:1
Part 1
Part 2
Stage 1
Stage 2
ENROLLMENT COMPLETED
ENROLLMENT CLOSED EARLY
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Number of Participants Enrolled: 
In Part 1, the study planned to enroll up to approximately 50 participants on each arm. Total enrollment in Part 1 
was planned to be up to approximately 120 participants to account for participants originally enrolled on the 
control arm under Amendment 1 (see full protocol for details). Due to unexpected rapid enrollment in Part 1, this 
part of the study enrolled a total of 182 participants.  
Part 2 planned to enroll up to approximately 40 participants in each of 5 disease-specific cohorts for a total 
enrollment in Part 2 of up to approximately 200 participants. Part 2 of the study was closed to enrollment prior to 
reaching the Stage 1 enrollment target(s) due to feasibility reasons. 
Planned total enrollment on the study was to be up to approximately 382 participants. 
Study Population: 
The study population consists of adult participants with confirmed, relapsed or refractory, unresectable, locally 
advanced or metastatic solid tumors. 
Part 1: participants with mCRPC who progressed during or after receiving one prior ARAT (enzalutamide, 
abiraterone, or apalutamide) for prostate cancer in either metastatic or non-metastatic, castration-sensitive or 
castration-resistant setting. Participants may also have received up to one prior docetaxel regimen, but no other 
prior chemotherapy agents. 
In Part 1, prior treatment with first generation anti-androgens (e.g., nilutamide, bicalutamide), oral ketoconazole, 
PARP inhibitor, immunotherapy (e.g., checkpoint inhibitor, sipuleucel-T), or radiopharmaceutical (e.g., 
radium-223 dichloride, lutetium-177 vipivotide tetraxetan) is permitted but not required. Participants with a 
known history of documented BRCA mutation (germline or somatic) are not eligible unless they received prior 
treatment with a PARP inhibitor where such treatment is available, indicated, and tolerated. Participants must 
have received ≤ 3 total prior lines of therapy for mCRPC. 
Part 2: participants with locally advanced or metastatic anal SCC, HNSCC, melanoma, squamous NSCLC, or 
SCLC who have been intolerant to or progressed after at least one prior line of systemic therapy for advanced or 
metastatic disease. 
Participants must have good performance status, adequate organ function, and no underlying medical or 
psychiatric condition impairing the participant’s ability to receive, tolerate, or comply with planned study 
treatment dosing or study procedures. 
Duration of Treatment and Study Duration:  
Duration of Treatment 
Study treatment will continue until protocol-specified progressive disease (PD), adverse event (AE) requiring 
discontinuation, physician decision, withdrawal of consent, allowed treatment duration is reached, or other 
treatment discontinuation criteria are met per protocol. 
Per the Dear Investigator Letter, dated 22 July 2024, study treatment will not be administered for more than 
6 cycles. Previously, study treatment was generally not to be administered for more than 26 cycles or longer than 
2 years.  
Study Duration and End of Study Definition 
Study accrual was anticipated to occur over approximately 3 years. Due to unexpected rapid enrollment in Part 1 
and closure of Part 2 to further enrollment, study accrual was less than 2 years. With a 6-month treatment 
duration and post-treatment follow up of approximately 6 months, the overall study duration is estimated to be 
approximately 3 years. 
The end of the overall study is defined as date of last participant last visit. 
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Criteria for Evaluation:  
Safety Assessments: 
The safety assessment is based on AEs occurring from the first administration of study treatment until 30 days 
after the last dose of study treatment or until initiation of another anticancer therapy, whichever comes first. 
Events that occur during the follow-up period will be captured and followed if they are considered by the 
investigator to be treatment related. The safety assessment is based on signs, symptoms, physical examination 
findings, and laboratory test results.  
PD or events related to PD are considered efficacy endpoints, and not reported as AEs or SAEs. AEs and SAEs 
will be reported if it is unclear whether the event is due to PD.  
Tumor Response Assessments: 
Tumor response assessments will be determined using computed tomography (CT) and/or magnetic resonance 
imaging (MRI). Bone scans will be obtained, in addition to CT and/or MRI, to evaluate bone metastasis. 
Target and non-target lesions will be designated per PCWG3 criteria (Part 1) or RECIST v1.1 (Part 2) at 
screening and evaluated approximately every 8 weeks for the first 24 weeks and every 12 weeks thereafter (or as 
clinically indicated) until PD, death, initiation of another anticancer therapy, withdrawal of consent, lost to follow 
up (LTFU), or end of study, whichever occurs first. After receipt of the last dose of study treatment, participants 
will enter a post-treatment follow-up period. 
At each tumor response assessment time point, the overall tumor response status will be determined by 
investigators based on assessment of target and non-target lesions as well as appearance of any new lesions per 
PCWG3 criteria (Part 1) or RECIST v1.1 (Part 2). 
Survival Assessments: 
Survival status is assessed approximately every 12 weeks (± 14 days) for up to 6 months from last dose of study 
treatment or until withdrawal of consent, LTFU, death, or end of the study, whichever occurs first. Updated 
survival status may be requested by the sponsor at any time during the study. 
PSA Assessment (Part 1 only): 
PSA is assessed at baseline and Day 1 of each cycle (Q4W) while on study treatment. During the follow-up 
period, PSA is assessed approximately every 12 weeks (± 14 days) from the last tumor response assessment for 
up to 6 months from last dose of study treatment until PD, death, initiation of another anticancer therapy, 
withdrawal of consent, LTFU, or end of study, whichever occurs first. 
Pharmacokinetic Assessments: 
Serum concentrations of vobramitamab duocarmazine (conjugated and total antibody) will be measured using 
validated bioanalytical methods. Plasma concentrations of the payload, SYD986, will be measured using a liquid 
chromatography-tandem mass spectrometry assay. Analysis of concentration data will be used to estimate PK 
parameters for vobramitamab duocarmazine (conjugated and total antibody) and SYD986 (and metabolites if 
appropriate) in participants with sufficient concentration data to calculate PK parameters. 
Immunogenicity Assessments: 
Anti-drug antibodies (ADAs) against vobramitamab duocarmazine will be detected using validated assay 
methods. Samples positive for ADA will be saved for future evaluation of neutralizing antibody activity. 
Biomarker Assessments: 
Exploratory biomarker assessments are described in the protocol. 
Statistical Methods:  
A separate statistical analysis plan (SAP) and statistical programming plan (SPP) will further describe the details 
regarding statistical methods and govern the statistical analysis. 
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Sample Size Determination: 
In Part 1, approximately 100 participants as planned per Amendment 2 will be randomized in a 1:1 ratio to each 
of the two vobramitamab duocarmazine arms. Randomization will be stratified by 3 stratification factors: 1) 
visceral disease (yes vs no), 2) prior taxane (yes vs no), and 3) region (United States/Canada vs other). The 
historic benchmarks for each vobramitamab duocarmazine arm to compare with are 25% PSA response rate and 
8 months median rPFS.  
Since the goal of Part 1 is to select one of two vobramitamab duocarmazine doses for further study in mCRPC, 
Simon’s randomized Phase 2 selection design was used to determine the sample size for each treatment arm. The 
planned sample size of 50 per arm would provide 76% probability of correctly selecting the best dose assuming 
66% and 59% rPFS rates at 6 months (equivalent to 10 vs 8 months median rPFS) for the two vobramitamab 
duocarmazine arms, respectively. For PSA response rate, the planned sample size of 50 per arm would provide 
84% power to reject 25% null rate at 1-sided 0.1 alpha level for each vobramitamab duocarmazine arm at an 
alternative rate of 40%.  
Part 2 of the study was closed to enrollment prior to completing the Stage 1 enrollment target(s). Part 2 originally 
planned to enroll approximately 200 response-evaluable participants, consisting of approximately 40 participants 
for each of 5 tumor-specific cohorts. For each cohort, Simon’s 2-stage design is used to test null hypothesis H0: 
p ≤ p0 vs alternative hypothesis H1: p = p1 at 1-sided significance level ≤ 0.1 (alpha) with the power of 
approximately 80%, where p0 is the benchmark response rate representing a lack of tumor response and p1 is the 
target response rate representing evidence of sufficient tumor response worthy of further development. Simon’s 
2-stage design parameters for each tumor-specific cohort are provided herein.  
Analysis Populations: 
Study analyses will be performed on the following populations: 
• 
Safety Population: All participants who received any dose of study treatment. This population will be 
used to summarize safety data. Participants will be analyzed according to the actual study treatment 
received. This population will also be used to summarize baseline data for biomarker and 
immunogenicity analyses and for supplementary analyses of rPFS, PFS, and OS. 
• 
Intent-to-Treat (ITT) Population: All participants*. Participants will be analyzed according to the 
study treatment assigned. This population will be used for summary of baseline data and analyses of 
rPFS, OS, and other efficacy endpoints where applicable.  
• 
Tumor Response Evaluable Population: All participants* who received at least one dose of study 
treatment and had RECIST-evaluable disease per PCWG3 (Part 1) or RECIST v1.1 (Part 2) at baseline 
(i.e., participants with bone-only disease are excluded from this population). This population will be 
used for efficacy analyses related to tumor response and will be analyzed according to the study 
treatment assigned.  
• 
PSA Response Evaluable Population: All participants in Part 1* who received at least one dose of 
study treatment, with a baseline PSA ≥ 2 ng/mL and at least one post-baseline PSA measurement. This 
population will be used to calculate and summarize PSA response rates according to the study treatment 
assigned. 
• 
PK Evaluable Population: All participants who received at least one dose of study treatment, date and 
time of dose administration and relative PK sample collection are known, and have sufficient 
concentration data to derive at least one PK parameter. Participant data may be excluded from PK 
analysis at the discretion of the pharmacokineticist. 
• 
ADA Evaluable Population: All participants who received at least one dose of vobramitamab 
duocarmazine and have at least one ADA sample. 
* Note: participants in Part 1 who were assigned to the control arm prior to its removal in Amendment 2 and who 
were re-randomized to a vobramitamab duocarmazine arm will be analyzed as a separate cohort for safety and 
efficacy endpoints. 
 
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Efficacy: 
Primary Efficacy Endpoint and Analysis 
Part 1: 
The primary efficacy endpoint of Part 1 is rPFS determined by the investigator. The rPFS is defined as the time 
from the date of randomization to the date of first documented PD per PCWG3 or death from any cause, 
whichever occurs first. For participants without an event of PD or death at the time of data cutoff for rPFS 
analysis, the rPFS will be censored at the date of the last tumor assessment. 
The Kaplan-Meier method will be used to generate rPFS curves and estimate the median rPFS along with 95% 
confidence intervals (CIs) for each study treatment arm. The method of Brookmeyer and Crowley will be used to 
construct 95% CI for median rPFS. The 95% CIs for rPFS rates at 6, 8, and 12 months will be calculated by 
normal approximation after log(-log) transformation. A sensitivity analysis will be performed that includes 
documented PD or death as a rPFS event regardless of when it occurs during the study. 
The analysis of rPFS will occur when all participants on Part 1 have been followed for rPFS for at least 6 months. 
The 2.0 mg/kg Q4W dose of vobramitamab duocarmazine will be selected for further study in mCRPC if it 
demonstrates promising efficacy, unless there is compelling additional activity at the higher dose and it has an 
acceptable safety and tolerability profile. Efficacy, safety, and exposure-response variables will inform the 
selection decision. 
Part 2: 
The primary efficacy endpoint of Part 2 is ORR as determined by the investigator per RECIST v1.1. ORR is 
estimated as the proportion of participants in the Tumor Response Evaluable Population who achieve a best 
overall response (BOR) of confirmed complete response (CR) or partial response (PR). ORR and the 2-sided 95% 
exact binomial CI will be calculated for each disease-specific cohort. 
Secondary Efficacy Endpoints and Analyses 
Part 1: 
PSA response is defined as a ≥ 50% decline in PSA from baseline with PSA confirmation ≥ 3 weeks after the first 
documented reduction in PSA of ≥ 50%. The PSA response rate will be calculated as the proportion of 
participants with a PSA response in the PSA response-evaluable population. PSA response rates at 8 weeks, 
12 weeks, and at any time will be summarized. The 2-sided 95% exact binomial CI for PSA response rate will be 
calculated. The best PSA percent change from baseline will be presented by waterfall plot. 
Number and percent of participants with their best overall response (BOR) will be summarized. ORR is estimated 
as the proportion of participants in the Tumor Response Evaluable Population who achieve a best overall 
response (BOR) of confirmed complete response (CR) or partial response (PR) without prior confirmed bone 
progression per PCWG3. ORR and the 2-sided 95% exact binomial CI will be calculated for each treatment arm. 
DoR will be estimated using the Kaplan-Meier method.  
Part 2:  
DoR will be estimated using the Kaplan-Meier method. PFS is defined as the time from first dose date to the date 
of first documented PD per RECIST v1.1 or death from any cause, whichever occurs first. For participants 
without an event of PD or death at the time of data cutoff for PFS analysis, PFS will be censored at the date of the 
last tumor assessment. The Kaplan-Meier method will be used to generate PFS curves and estimate the median 
PFS, and PFS rates at 6, 8 and 12 months. The method of Brookmeyer and Crowley will be used to construct 95% 
CI for median PFS. The 95% CIs for PFS rate will be calculated by normal approximation after log(-log) 
transformation. 
Safety:  
Treatment-emergent AEs will be summarized in tables and listings. Tables will display the number and percent of 
participants that experience the given AE. AEs prior to the first dose of study treatment (e.g., due to study-related 
procedures) will be presented in listings only. AEs will be graded according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and coded to the Medical Dictionary for 
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Regulatory Activities (MedDRA) dictionary. AEs will be summarized by system organ class (SOC) and preferred 
term (PT), relationship to study treatment, and highest severity.  
Interim Analysis: 
In Part 1, one futility analysis will be performed on each vobramitamab duocarmazine arm based on PSA 
response rate at 8 weeks on the first 20 PSA evaluable participants in each vobramitamab duocarmazine arm. At 
the futility analysis, if the probability of true PSA response rate for a vobramitamab duocarmazine arm greater 
than or equal to 40% is <10%, that is, if ≤ 25% (5/20) PSA response rate is observed, enrollment to that arm may 
stop unless other data warrant continuing enrollment. 
 
 
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2 
BACKGROUND INFORMATION  
2.1 
Disease Background  
2.1.1 
Prostate Cancer  
With an estimated almost 1.4 million new cases and 375,000 deaths worldwide, prostate cancer 
is the second most frequent cancer and the fifth leading cause of cancer death among men in 
2020 (1). Incidence rates are 3-fold higher in developed than in developing countries (37.5 and 
11.3 per 100,000, respectively), whereas mortality rates are less variable (8.1 and 5.9 per 
100,000, respectively). The highest incidence rates are observed in Northern and Western 
Europe, the Caribbean, Australia/New Zealand, Northern America, and Southern Africa, with the 
lowest incidence rates in Asia and Northern Africa (1). 
In the United States (US), prostate cancer is the most commonly diagnosed cancer in men and 
the second-leading cause of cancer-related death (2). An estimated 288,300 men will be 
diagnosed with prostate cancer in 2023, and 34,700 deaths will occur secondary to prostate 
cancer in the US. Among 3.1 million new cases of prostate cancer in the US during 2003–2017, 
localized, regional, distant, and unknown stage prostate cancer accounted for 77%, 11%, 5%, and 
7% of cases, respectively (3). 
Advanced prostate cancer is commonly treated with androgen deprivation therapy (ADT) to 
achieve castrate levels of testosterone (4). Treatment with ADT can cause remission of metastatic 
prostate cancer, as evidenced by PSA suppression in about 90% of patients. After a mean time of 
2–3 years on ADT, however, the disease progresses despite continuous ADT. Metastatic prostate 
cancer has a 5-year survival rate of 29.3% (5). 
2.1.1.1 
Standard of Care in Metastatic Castration-Resistant Prostate 
Cancer   
The therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has 
shifted toward use of newer approved treatments with life-extending therapies during earlier 
stages of advanced castration-sensitive prostate cancer. These newer approved therapies include 
abiraterone acetate (hereinafter referred to as abiraterone), enzalutamide, apalutamide, and 
darolutamide, which block androgen synthesis or block the androgen receptor, in combination 
with ADT, e.g., gonadotropin-releasing hormone (GnRH) receptor modulators. Despite the 
efficacy of these therapies, tumors progress to castration-resistant prostate cancer (CRPC). 
The CRPC state is defined as disease progression despite castrate testosterone levels (serum 
testosterone ≤ 50 ng/dL or 1.7 nmol/L). Despite castrate levels of androgens, the androgen 
receptor remains active and other biologic pathways drive progression in CRPC. Progression of 
CRPC can present as either a continuous rise in serum PSA levels, progression of pre-existing 
disease, and/or the appearance of new metastases as defined by Prostate Cancer Working 
Group 3 (PCWG3) criteria. The median overall survival (OS) of CRPC from first line therapy is 
approximately 3 years (6). 
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This limited OS has led to the development of agents aimed at tumor reduction through 
cytotoxicity or further decreasing androgen production or blocking androgen receptor function. 
NCCN (Prostate Cancer Version 3.2022) preferred options for management of mCRPC include 
the FDA-approved taxanes (docetaxel and cabazitaxel), mitoxantrone, androgen receptor axis-
targeted therapy (ARAT; abiraterone and enzalutamide), immunotherapy (sipuleucel-T), and a 
radioligand (radium-223 dichloride). Additional FDA-approved products for specific targeted 
indications that occur in a small percentage of patients include pembrolizumab for microsatellite 
instability-high (MSI-H), deficient mismatch repair (dMMR), or tumor mutational burden 
(TMB) ≥ 10 mutations per megabase, olaparib for homologous recombination repair (HRR) 
mutation, and rucaparib for BRCA mutation (7, 8). The FDA also recently approved lutetium-
177 vipivotide tetraxetan, a targeted radioligand, for treatment of patients with prostate-specific 
membrane antigen (PSMA)-positive mCRPC. 
Although patients with mCRPC have treatment options, none of these options are curative. In the 
first-line setting, 15% receive docetaxel and 65% receive ARAT. There is no agreement on the 
optimal sequencing for these therapies with 54% of patients receiving an ARAT in the second 
line and 15% in the third line setting (9). Abiraterone and enzalutamide are commonly used 
back-to-back (e.g., abiraterone followed by enzalutamide, or enzalutamide followed by 
abiraterone). However, this approach is typically reserved for patients with few treatment 
options, given reported cross-resistance and limited clinical benefit with short duration of 
response (9). Median progression-free survival (PFS) and OS for mCRPC after approved first-
line therapy ranges from only 2.8–8.0 and 11–15 months, respectively (10). 
In the randomized, open-label, Phase 3 study of cabazitaxel versus ARAT (abiraterone or 
enzalutamide) in mCRPC patients previously treated with docetaxel and the alternative ARAT, 
median PFS was 4.4 months with cabazitaxel and 2.7 months with ARAT therapy [CARD study; 
NCT02485691; (11)]. Median OS was 13.6 months with cabazitaxel and 11.0 months with 
ARAT. Cabazitaxel is approved only after failure of a docetaxel-containing treatment regimen, 
and only 1–11% of patients receive cabazitaxel during the course of their disease (9), as many 
patients with mCRPC prefer to avoid additional chemotherapy. 
Sipuleucel-T and radium-223 are alternative available therapies for patients with mCRPC, but 
have low real-world usage (9). Use of sipuleucel-T and radium-223 is either limited regionally 
(sipuleucel-T in the US) and/or restricted to certain indications such as patients with 
asymptomatic/minimally symptomatic disease (sipuleucel-T) or those with bone-only disease 
and symptoms (radium-223). Lutetium-177 vipivotide tetraxetan, a targeted radioligand therapy, 
plus best standard of care demonstrated significant improvement in OS compared to that of 
standard of care alone in patients with progressive PSMA-positive mCRPC who had received 
prior ARAT and taxane-based chemotherapy regimens (see PLUVICTO™ US prescribing 
information). Prior use of any of these agents is permitted in participants on this study. 
Published retrospective studies indicate a median PFS of 2.7–4.6 months and median OS of 4.8–
15.8 months for patients who received third-line therapy (12). With this limited impact on tumor 
outcomes there continues to be an unmet need for the treatment of advanced mCRPC. 
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2.1.2 
Anal Carcinoma  
Cancers of the anus, anal canal, and anorectum are relatively uncommon, accounting for < 1% of 
all new cancer diagnoses in the US and globally (1, 2). An estimated 9760 new cases of anal 
cancer occurred in the USA in 2023, with 1870 deaths due to the disease (2). Incidence of these 
cancers has increased in recent years, with a 2.7% increase per year from 2001 to 2015 according 
to the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) 
database (13). Similar trends have been observed in Western Europe, Australia, and South 
America (14). Approximately 90% of anal cancer cases are associated with HPV infection, with 
rising HPV infection rates contributing to the increased incidence of anal cancer (14). 
Metastatic anal cancer is an incurable malignancy that has limited therapeutic options. NCCN 
guidelines recommend carboplatin and paclitaxel or other platinum-based chemotherapy 
regimens as first-line therapy. Nivolumab or pembrolizumab are recommended as second-line 
therapy, although neither has FDA approval for this indication (National Comprehensive Cancer 
Network [NCCN] Guidelines Anal Carcinoma version 3.203). NCCN guidelines make no 
recommendations for subsequent lines of therapy as no other regimens have been shown to be 
effective. Thus, there is a significant unmet medical need in this population. 
2.1.3 
HNSCC  
Squamous cell carcinoma of the head and neck accounts for about 4% of cancers in the US. In 
2023, an estimated 66,920 patients will be diagnosed annually in the US with approximately 
15,400 deaths secondary to head and neck cancer (2). Globally, over 500,000 patients are 
diagnosed with this disease annually (15). Head and neck cancers are predominately of squamous 
histology (> 90%) (16). Infection with human papillomavirus (HPV), specifically HPV-16, is a 
risk factor for certain head and neck cancers, particularly oropharyngeal cancers involving the 
tonsils or base of the tongue (17, 18). 
Treatment for patients with locally advanced HNSCC remains unsatisfactory. Less than 40% of 
patients are cured with primary treatment with combination of radiation therapy and cisplatin-
based chemotherapy. Survival is less than 20% at 2 years in patients with recurrent disease 
following treatment with radiochemotherapy. The combination of the EGFR inhibitor cetuximab 
with radiotherapy showed significant improvement in outcomes for patients with locally 
advanced disease when compared with radiotherapy alone. However, it failed to change the rate 
of distant metastasis. The combination of cetuximab with radiochemotherapy failed to improve 
progression-free survival (PFS) and overall survival (OS) in patients with advanced stage disease 
(19). In addition, there is evidence to suggest the role of immune checkpoints that limit T cell 
responses to tumors in HNSCC. Pembrolizumab is approved as a single agent or in combination 
with chemotherapy for patients with metastatic or unresectable, recurrent HNSCC and for 
patients with recurrent or metastatic HNSCC with disease progression on or after 
platinum-containing chemotherapy (20). However, there remains a need to identify new 
therapeutic options for patients with HNSCC. 
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2.1.4 
Melanoma  
In 2020, an estimated 324,635 new cases of melanoma of the skin were diagnosed globally, with 
57,043 deaths due to the disease (1). In the US, estimates for 2023 were 97,610 new cases and 
7,990 deaths attributable to melanoma of the skin (2). Among patients with advanced melanoma, 
sustained long-term overall survival (OS) at 5 years was observed in a greater percentage of 
patients who received nivolumab plus ipilimumab or nivolumab alone than in those who 
received ipilimumab alone (21). Even with recent advancements in treatment, the median 
progression-free survival (PFS) for patients with advanced melanoma on pembrolizumab is 
limited (22). Other approved targeted therapies for advanced melanoma have limited duration of 
disease control and include agents targeting BRAF V600-activating mutations, e.g., 
dabrafenib/trametinib (23). Although current treatment options provide a survival benefit in 
advanced disease, a need remains for improved treatment in advanced cases. 
2.1.5 
NSCLC  
Lung cancer accounts for approximately 12% of all cancers in adults. In 2023, approximately 
238,340 patients in the US are expected to be diagnosed with lung cancer, and an estimated 
127,070 will die from this disease (2). NSCLC represents approximately 80% to 85% of all lung 
cancers and can be subclassified as squamous (~30%) or non-squamous (~70%). 
Although novel therapies have become available for a proportion of patients with NSCLC, the 
mortality related to this disease remains high. A vast majority of patients with NSCLC have 
advanced stage or metastatic disease (Stage IIIB/IV) at time of initial diagnosis. Systemic 
therapy is required for treatment of these patients. First-line systemic treatment options for 
Stage IIIB/IV NSCLC patients are limited, with cisplatin-based doublet chemotherapy being the 
basis for most first-line treatment. Patients whose tumors harbor oncogenic mutations including 
EGFR, KRAS, ALK, ROS1, and BRAF are treated with the respective targeted agents (24). 
Pembrolizumab has been shown to significantly improve overall and progression-free survival 
(PFS) compared with chemotherapy and is FDA approved for use in patients with previously 
untreated NSCLC and a PD-L1 tumor proportion score (TPS) of 50% or greater (25). 
Approximately 30% of patients with NSCLC have a PD-L1 TPS of 50% or higher (26). 
Pembrolizumab is also approved for the treatment of previously treated patients with advanced 
NSCLC with TPS ≥ 1%. Nivolumab is approved for the treatment of previously treated patients 
with advanced NSCLC, irrespective of their TPS (27–29). Despite these approaches, therapy for 
patients with advanced disease remains largely non-curative. This study will limit enrollment to 
participants with squamous NSCLC due to the lack of availability of other targeted therapies in 
this patient population compared to non-squamous NSCLC, as well as the observed activity of 
other B7-H3 directed ADCs (e.g., DS-7300) in this subset of patients with lung cancer.  
2.1.6 
SCLC  
Lung cancer is the most common cancer in the world, with an estimated 2.2 million new cases in 
2020 (1). Lung cancer is also the most common cause of death from cancer in 2020 with 
1.8 million deaths globally (1). Similarly, lung cancer is the most lethal cancer in the US, 
responsible for an estimated 127,070 deaths in 2023 (2).  
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Approximately 15% of all lung cancer cases are SCLC. It is a highly aggressive neoplasm that is 
strongly associated with cigarette smoking. Eighty percent of patients have extensive stage 
disease at diagnosis and a vast majority of patients with SCLC die of their disease, despite being 
initially responsive to chemotherapy. Standard frontline treatment for SCLC includes platinum-
etoposide doublet chemotherapy in combination with a PD-1/PD-L1 monoclonal antibody (30). 
The majority of patients will progress, and the median survival for patients with extensive stage 
disease is 9.5 months (31). New therapeutic strategies are needed to improve the prognosis. 
2.2 
Rationale for Study  
2.2.1 
Rationale for Vobramitamab Duocarmazine in Metastatic 
Castration-resistant Prostate Cancer (Part 1)  
Antibody-drug conjugates (ADCs) have demonstrated activity and received FDA approval for 
several solid tumors. However, ADCs are not yet approved for management of mCRPC. 
Alkylating agents (e.g., estramustine) have received FDA approval for treatment of prostate 
cancer; thus, targeted delivery of duocarmycin, an alkylating agent, by vobramitamab 
duocarmazine may offer a potential therapy for patients with mCRPC. 
Efficacy of ADCs is derived from the targeting of proteins expressed by tumor cells with limited 
expression of these target proteins in normal tissues. Vobramitamab duocarmazine is an ADC 
that leverages the high level of B7-H3 expression in mCRPC to control tumor growth (see 
Section 2.3). Tumor responses and disease stabilization have been observed in participants 
treated with vobramitamab duocarmazine in the Phase 1 cohort expansion of CP-MGC018-01 
study. Vobramitamab duocarmazine is designed to maximize the therapeutic index of the 
cytotoxic duocarmycin and has the potential to address the unmet need and provide a novel 
mechanism for treatment of mCRPC with a non-overlapping toxicity profile of other available 
therapies.  
2.2.2 
Rationale for Vobramitamab Duocarmazine in Other Advanced 
Solid Tumors (Part 2)  
B7-H3 is a member of the B7-family of immunomodulatory molecules and is overexpressed in a 
wide range of solid tumors, with limited expression in normal human tissues (32, 33). Tumor 
types on which B7-H3 expression has been observed include bladder cancer (34, 35), breast 
cancer (33, 36, 37), cervical cancer (38), colorectal cancer (39–42), endometrial cancer (43), 
esophageal cancer (44, 45), gastric cancer (33, 46), liver cancer (47, 48), melanoma (33, 49, 50), 
osteosarcoma (51), ovarian cancer (33, 52–54), pancreatic cancer (33, 55–58), prostate cancer 
(33, 59–61), renal cell carcinoma (RCC) (33, 62, 63), NSCLC (33, 64–66), SCLC (67, 68), and 
HNSCC (69–72). In the majority of cancers, overexpression of B7-H3 associates with adverse 
clinical and pathological features of disease, increased risk of recurrence, and reduced survival. 
The study population for Part 2 includes participants with advanced solid tumors known to 
express B7-H3 and who have been intolerant of or experienced disease progression on or 
following standard therapy. The tumor types selected for investigation have consistent B7-H3 
expression and are considered likely to be responsive to the cytotoxic payload. Objective tumor 
responses were observed in participants with melanoma, NSCLC, and HNSCC following 
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administration of vobramitamab duocarmazine in Study CP-MGC018-01 (see MGC018 
Investigator Brochure [IB]), and other B7-H3 targeting agents have seen encouraging and 
durable response rates of response in SCLC (73). 
2.3 
Background on Vobramitamab Duocarmazine  
Vobramitamab duocarmazine (also known as MGC018) is an ADC targeted against B7-H3. 
Vobramitamab duocarmazine is comprised of the cleavable linker-duocarmycin payload, valine-
citrulline-seco-DUocarmycin hydroxyBenzamide-Azaindole (vc-seco-DUBA; SYD980), 
conjugated through reduced interchain disulfides to the anti-B7-H3 humanized immunoglobulin 
G1 (IgG1) kappa monoclonal antibody MGA017 (74). Vobramitamab duocarmazine has an 
average drug-to-antibody ratio of ~2.7, and an average molecular weight of ~150 kDa. 
Vobramitamab duocarmazine is designed to bind to cell-surface B7-H3, internalize into cells, and 
release the cytotoxic duocarmycin. Duocarmycins represent a group of antitumor antibiotics 
produced by Streptomyces that bind to the minor groove of DNA. Following binding to 
cell-surface B7-H3 and internalization of vobramitamab duocarmazine through endocytosis, the 
peptide linker is cleaved by lysosomal proteases, such as cathepsin B. Subsequently, 
2 self-elimination reactions occur on the duocarmycin moiety to generate seco-DUBA, which 
then spontaneously rearranges to form the activated duocarmycin drug (also known as DUBA or 
SYD986) that binds and alkylates DNA. The irreversible alkylation of DNA disrupts the nucleic 
acid architecture, ultimately leading to cell death. Due to the nature of the “cleavable” 
linker/payload, the protease-cleaved, activated DUBA is membrane permeable, and when 
released by dying cells, can cause death of neighboring tumor cells, irrespective of B7-H3 
expression (75). Importantly, the bystander cytotoxic effect of the vc-seco-DUBA linker/payload 
may afford vobramitamab duocarmazine therapeutic benefit toward tumors with heterogeneous 
overexpression of B7-H3. 
Nonclinical studies necessary to support clinical studies have been performed and are 
summarized in the MGC018 IB. 
The clinical development program for vobramitamab duocarmazine includes two ongoing 
MacroGenics-sponsored clinical studies (Study CP-MGC018-01 and Study CP-MGC018-02). 
Study CP-MGC018-01 is a Phase 1/2, first-in-human, open-label, dose escalation and cohort 
expansion study of vobramitamab duocarmazine monotherapy in participants with advanced 
solid tumors. Study CP-MGC018-02 is a Phase 1/1b, open-label, dose escalation and cohort 
expansion study of vobramitamab duocarmazine in combination with lorigerlimab in participants 
with advanced solid tumors. Please refer to the MGC018 IB for further details on the clinical 
experience with vobramitamab duocarmazine. 
2.4 
Dose Selection  
2.4.1 
Dose Selection for Part 1  
Clinical pharmacokinetics (PK) of vobramitamab duocarmazine were evaluated after single and 
multiple dose administration at doses ranging from 0.5 mg/kg to 4.0 mg/kg in Study 
CP-MGC018-01. The PK of vobramitamab duocarmazine and its primary metabolite, SYD986, 
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were estimated using noncompartmental and population pharmacokinetic (PPK) methods. Dose 
proportionality and steady state PK were characterized based on data from Study 
CP-MGC018-01. A preliminary PPK model was developed and used for preliminary exposure-
response analyses to support doses selected for evaluation in Study CP-MGC018-03. 
As of 06-Dec-2021, safety data in Study CP-MGC018-01 Phase 1 dose escalation did not 
demonstrate significant differences in the incidence or severity of adverse events (AEs) across 
doses ranging from 2.0 mg/kg to 4.0 mg/kg. No maximum tolerated dose (MTD) was defined. As 
no dose level met the per protocol criteria for MTD, i.e., ≥ 2 dose-limiting toxicities, the 
maximum administered dose was 4.0 mg/kg, and 3.0 mg/kg was determined as the recommended 
Phase 2 dose (RP2D). The RP2D was evaluated in 5 different tumor types in the Study 
CP-MGC018-01 cohort expansion. On average, the incidence of AEs was higher for mCRPC 
than the other 4 tumor types enrolled in cohort expansion. 
Antitumor activity was observed at vobramitamab duocarmazine doses ranging from 2.0 mg/kg 
to 4.0 mg/kg. As of 06-Dec-2021, two participants, one with non-small cell lung cancer and one 
with mCRPC, had a reduction in target lesion sum of over 20% at the 2.0 mg/kg dose level. At 
the 3.0 mg/kg dose level, there were ≥ 50% PSA reductions and stabilization of disease in 
mCRPC. One participant with melanoma had a partial response (PR) at the 4.0 mg/kg dose level. 
Efficacy, safety, and PK data supported the RP2D of 3.0 mg/kg administered intravenously (IV) 
once every 3 weeks (Q3W) in cohort expansion of Study CP-MGC018-01. 
While efficacy was demonstrated between 2.0 mg/kg to 4.0 mg/kg vobramitamab duocarmazine 
administered Q3W, the safety assessment in mCRPC participants demonstrated a higher 
incidence and severity of AEs at the RP2D resulting in 73.2% of mCRPC participants having had 
at least one dose reduction and the actual mean dose administered was 2.5 mg/kg every 4 weeks 
(Q4W) during cohort expansion. The probability of dose modification increased with increased 
vobramitamab duocarmazine exposure, although there was considerable overlap in exposure 
between participants who did not and did have a dose modification. The incidence of toxicities, 
particularly palmar-plantar erythrodysesthesia (PPE)/hand-foot syndrome (HFS), may have a 
significant impact in participants with mCRPC due to the effect of PPE/HFS on activities of 
daily living (ADL). The probability of a participant experiencing PPE/HFS as well as severity of 
PPE/HFS at exposures corresponding to 2.0 mg/kg Q4W and 2.7 mg/kg Q4W are markedly 
reduced. Collectively, these data suggest the number of dose modifications will decrease along 
with a lower incidence and severity of toxicity at the predicted area under the concentration-time 
curve (AUC) corresponding to 2.0 mg/kg Q4W (approximately 100 µg/mL*day) and 2.7 mg/kg 
Q4W (approximately 140 µg/mL*day), which are in the range of target exposure (AUC = 62–
188 µg/mL*day) associated with antitumor activity in tumor-bearing mice. Increasing the dosing 
interval from 3 weeks to 4 weeks should allow participants sufficient time to recover from 
toxicities. In summary, lower doses of vobramitamab duocarmazine and an increased dosing 
interval may delay the onset, incidence, and severity of AEs while maintaining antitumor activity 
with fewer dose modifications.  
The vobramitamab duocarmazine doses and schedule selected, 2.0 and 2.7 mg/kg Q4W, are 
based on the observed safety and efficacy profile of vobramitamab duocarmazine at all doses 
tested to date and the predictable PK characteristics in the ongoing Phase 1 study. 
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2.4.2 
Dose Selection for Part 2  
Part 1 of this study is ongoing, and the optimal dose for participants with mCRPC has not yet 
been selected. However, preliminary data suggest that both 2.0 and 2.7 mg/kg Q4W are better 
tolerated than the 3.0 mg/kg Q3W regimen. As of 30-Aug-2023, 5 of 26 participants (19.2%) in 
Study CP-MGC018-03 experienced at least one AE of Grade 3 severity, regardless of causality, 
including leukopenia, neutropenia, atrial fibrillation, abdominal pain, asthenia, gastrointestinal 
infection, and cerebrovascular accident (1 participant each; 3.8%). Additionally, data from the 
expansion phase of Study CP-MGC018-01 demonstrated that participants with other tumor types 
have fewer AEs with vobramitamab duocarmazine treatment than participants with mCRPC. 
Given the emerging safety profile of the 2.7 mg/kg IV Q4W dose in prostate cancer, the 
observation that participants on Study CP-MGC018-01 with other tumor types had fewer AEs 
with vobramitamab duocarmazine treatment than those with mCRPC, and the desire to minimize 
the possibility of providing participants with an ineffective dose, the higher dose of 2.7 mg/kg 
Q4W was chosen initially for the Part 2 cohorts in other advanced solid tumors. Following 
review of available safety data and per the Dear Investigator Letter, dated 22 July 2024, 
participants in Part 2 who were receiving 2.7 mg/kg will receive a reduced dose of 2.0 mg/kg 
Q4W. To mitigate potential late onset toxicity, participants may not receive more than 6 doses of 
vobramitamab duocarmazine. 
Refer to the MGC018 IB for additional information on the safety profile of vobramitamab 
duocarmazine. 
2.5 
Risk Benefit Assessment  
The following sections provide a brief summary of the risks and potential benefits associated 
with vobramitamab duocarmazine administration.  
2.5.1 
Risk Assessment  
Refer to the MGC018 IB for detailed information on the risks of vobramitamab duocarmazine. 
Based on the clinical and non-clinical experience to date, important identified risks include 
neutropenia (including neutrophil count decreased), thrombocytopenia (including platelet count 
decreased), pleural effusion, and pericardial effusion. Identified risks include infusion related 
reaction (IRR), palmar-plantar erythrodysesthesia (PPE) syndrome, skin hyperpigmentation, 
anemia, and pyrexia. Important potential risks include ocular toxicity. 
Fatal events of pneumonitis, pleural effusion, and cardiac events have occurred in Study 
CP-MGC018-03. As of 03-Jul-2024, 2 of 3 fatal cardiac events developed in participants with 
known pre-existing cardiovascular disease. A causal association between these events and 
vobramitamab duocarmazine has not been established. Refer to the MGC018 IB for detailed 
information. 
The sponsor will continue to mitigate and monitor potential and identified risks based on 
protocol-mandated prophylactic measures and management guidelines, and close surveillance for 
early identification of potential risks. 
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2.5.1.1 
SARS-CoV-2 (COVID-19) Guidance  
The study investigators must ensure that their institution can provide the protocol-specified 
safety and efficacy assessments during the coronavirus disease-2019 (COVID-19) pandemic. All 
procedures should continue per protocol and associated study documents. Prospective protocol 
waivers are not permitted, and participants will not be included in this study without proper 
eligibility assessment, including performance of planned tests, and written informed consent 
according to national laws and regulations. Enrollment and continuing participation in the study 
should follow any national, local, or institutional guidance related to COVID-19.  
Telemedicine visits may be considered, in alignment with national and local guidance, to monitor 
AEs and any other medical issues as necessary (see Section 9). 
The risk of treatment delays associated with the COVID-19 pandemic is not increased by 
participation in the clinical trial. If participants are unable to receive study treatments at the 
enrolling site, continuing participation at another open site should be considered in consultation 
with the sponsor and in accordance with local and national guidance. Direct-to-participant 
shipment of oral study treatment should be considered per Section 6.5.2. 
Remote monitoring of clinical data using electronic medical records will follow all local and 
national guidelines regarding the access to and protection of identifiable medical information. 
As with any infection, confirmed cases of severe acute respiratory syndrome-coronavirus-2 
(SARS-CoV-2) infection or suspected infection should be reported as AEs or SAEs (if 
seriousness criteria are met) per Section 12.2. All medications and treatment administered for 
these respective events and corresponding unscheduled visits must be entered in the electronic 
data capture (EDC) system. 
No increased risk to participants is anticipated as a result of receiving SARS-CoV-2 vaccines, 
which are permitted during the study. 
2.5.2 
Benefit Assessment  
Refer to the MGC018 IB for detailed information on preliminary antitumor activity observed 
with vobramitamab duocarmazine. Data from Study CP-MGC018-01 has demonstrated 
antitumor activity with vobramitamab duocarmazine treatment at doses of 2.0 mg/kg and above 
as measured by objective tumor reduction in multiple tumor types. 
2.5.3 
Overall Assessment  
Part 1 of the study will enroll participants with mCRPC previously treated with one prior ARAT. 
Participants may also have received up to one prior docetaxel-containing regimen, but no other 
prior chemotherapy agents for prostate cancer, except a taxane-containing regimen administered 
for < 60 days as bridging to lutetium-177 vipivotide tetraxetan. Prior PARP inhibitor, 
immunotherapy (e.g., checkpoint inhibitor, sipuleucel-T), radiopharmaceutical (radium-223 
dichloride, and lutetium-177 vipivotide tetraxetan) are allowed, as long as the participant has 
received no more than 3 total lines of therapy for mCRPC. Given the relatively poor prognosis 
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and lack of treatment options with demonstrated clinical benefit, this population is considered 
appropriate for studies of novel therapies.  
While docetaxel has demonstrated clinical benefit for patients with mCRPC, and cabazitaxel for 
patients with mCRPC after prior ARAT and docetaxel, this study does not require participants to 
have received either agent. First, because some participants may not be eligible for or wish to 
receive chemotherapy, and second, due to concerns that cumulative bone marrow toxicity from 
more than one prior chemotherapy regimen may result in an unacceptable risk of severe 
cytopenias from vobramitamab duocarmazine. For patients with mCRPC who are not eligible for 
or do not wish to receive docetaxel and/or cabazitaxel, participation on a clinical trial of an 
investigational agent with preliminary signs of activity in mCRPC such as vobramitamab 
duocarmazine may represent a reasonable option. Understanding the impact of prior 
chemotherapy on selected vobramitamab duocarmazine-related toxicities (e.g., cytopenias, 
pleural and pericardial effusions, and hand-foot syndrome) will be very helpful in ensuring 
selection of an appropriate dose and patient population for further study if warranted by the data 
from Study CP-MGC018-03.  
Part 2 of the study will enroll participants with relapsed or refractory, unresectable, locally 
advanced or metastatic solid tumors who have failed at least one standard of care systemic 
therapy for advanced or metastatic disease. These participants also have a relatively poor 
prognosis and lack of available treatment options with demonstrated clinical benefit; thus, this 
population is considered appropriate for studies of novel therapies. 
Currently available clinical and non-clinical data for vobramitamab duocarmazine indicate an 
acceptable benefit-risk profile that supports the conduct of this Phase 2 study. 
The protocol incorporates risk mitigation measures including eligibility criteria, participant 
monitoring, toxicity management, dose modification, discontinuation criteria, and interim 
analyses of each vobramitamab duocarmazine arm (Part 1) and tumor-specific cohort (Part 2) for 
futility. An Independent Data Monitoring Committee (IDMC) will provide study oversight and 
evaluate cumulative clinical data at regular intervals.  
 
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3 
STUDY PURPOSE AND OBJECTIVES  
3.1 
Primary Objective  
Primary Objective  
Estimand Description 
Part 1: To evaluate the efficacy of vobramitamab 
duocarmazine in mCRPC at two dose levels as 
measured by rPFS by investigator assessment using 
PCWG3 criteria. 
Population: Intent-to-treat 
Variable: rPFS 
Intercurrent events: 
1) Subsequent anticancer therapy prior to rPFS event: 
censored 
2) Missing ≥ 2 consecutive scheduled tumor 
assessments immediately followed by documented 
progression or death: censored 
3) Study treatment discontinuation: ignored 
Summary measure: Kaplan-Meier estimates of rPFS  
Part 2: To evaluate the efficacy of vobramitamab 
duocarmazine in select solid tumors as measured by 
investigator assessment of ORR per RECIST v1.1. 
Population: Response evaluable 
Variable: ORR 
Intercurrent events: 
1) Subsequent anticancer therapy: while not having 
started subsequent anticancer therapy  
2) Disease progression: while not having evidence of 
progression 
3) Death due to any reason: while being alive 
4) Study treatment discontinuation: ignored  
Summary measure: Proportion of participants who 
achieve a BOR of confirmed CR or PR per 
RECIST v1.1 
Abbreviations: BOR: best overall response; CR: complete response; ORR: objective response rate; PR: partial 
response; PCWG3: Prostate Cancer Clinical Trials Working Group 3; RECIST: Response Evaluation Criteria in 
Solid Tumors; rPFS: radiographic progression-free survival. 
 
3.2 
Secondary Objectives  
Secondary Objectives 
Outcome or Endpoint 
To characterize the frequency and severity of AEs and 
overall tolerability observed with vobramitamab 
duocarmazine. 
Frequency and severity of AEs, SAEs, and AEs 
leading to study treatment discontinuation. 
To evaluate the efficacy of vobramitamab 
duocarmazine as measured by PSA (Part 1 only). 
PSA response rate per PCWG3 criteria; time to PSA 
progression per PCWG3 criteria, duration of PSA 
response per PCWG3 criteria. 
PSA percent change over time and best PSA percent 
change. 
To evaluate the efficacy of vobramitamab 
duocarmazine in participants with RECIST-evaluable 
disease as measured by ORR and DoR by investigator 
assessment using PCWG3 criteria (Part 1 only). 
ORR and DoR per PCWG3 criteria. 
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Secondary Objectives 
Outcome or Endpoint 
To evaluate the effect of vobramitamab duocarmazine 
on SSEs (Part 1 only). 
Time to first SSE. 
To evaluate the efficacy of vobramitamab 
duocarmazine in participants with select solid tumors 
as measured by DoR and PFS by investigator 
assessment using RECIST v1.1 (Part 2 only). 
DoR and PFS per RECIST v1.1. 
Abbreviations: AE: adverse event; ADA: anti-drug antibody; DoR: duration of response; IV: intravenous; 
ORR: objective response rate; PCWG3: Prostate Cancer Clinical Trials Working Group 3; PFS: progression-free 
survival; PK: pharmacokinetics; PSA: prostate specific antigen; Q4W: once every 4 weeks; RECIST: Response 
Evaluation Criteria in Solid Tumors; SAE: serious adverse event; SSE: symptomatic skeletal event. 
 
3.3 
Exploratory Objectives  
Exploratory Objectives 
Outcome or Endpoint 
To explore the effect of vobramitamab duocarmazine 
dose on OS. 
OS 
To explore the relationship between B7-H3 expression 
and efficacy. 
Relationships between B7-H3 expression and tumor 
response and/or other endpoints. 
To characterize the PK of vobramitamab 
duocarmazine. 
Concentrations and PK parameters for vobramitamab 
duocarmazine (and metabolites as appropriate). 
To characterize immunogenicity of vobramitamab 
duocarmazine. 
Incidence of ADA formation against vobramitamab 
duocarmazine. 
To evaluate the exposure-response relationship 
between vobramitamab duocarmazine exposure and 
select efficacy and safety variables. 
Logistic regression curves relating vobramitamab 
duocarmazine indices of exposure (i.e., Cmax and AUC) 
to incidence of key efficacy (e.g., rPFS) and safety 
(AEs). 
Abbreviations: AE: adverse event; AUC: area under the concentration-time curve; Cmax: maximum concentration; 
OS: overall survival; rPFS: radiographic progression-free survival. 
 
Results of exploratory objectives may not be included in the clinical study report (CSR) or 
database lock unless they represent meaningful findings.  
 
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4 
STUDY DESIGN  
4.1 
Overall Study Design  
Study CP-MGC018-03 is an open-label, two-part, Phase 2 study assessing the efficacy, safety, 
and tolerability of vobramitamab duocarmazine.  
In Part 1 of the study, approximately 100 participants will be randomized 1:1 to one of two dose 
levels of vobramitamab duocarmazine (2.0 mg/kg Q4W and 2.7 mg/kg Q4W). Part 1 will enroll 
participants with mCRPC previously treated with one prior ARAT (abiraterone, enzalutamide, or 
apalutamide) for prostate cancer in either the metastatic or non-metastatic, castration-sensitive or 
castration-resistant setting. Participants may also have received up to one prior docetaxel-
containing regimen for prostate cancer, and up to 3 total prior lines of therapy for mCRPC. 
Enrollment will use a central randomization scheme with stratified permuted blocks. 
Randomization will be stratified based on 1) presence of visceral disease (yes vs no), 2) prior 
taxane (yes vs no) and 3) region (US/Canada vs other). 
Per the Dear Investigator Letter, dated 22 July 2024, participants on treatment in Part 1 will 
discontinue vobramitamab duocarmazine, complete an EOTV, and enter the follow-up period. 
Part 2 of the study consists of participants with unresectable, locally advanced or metastatic anal 
SCC, HNSCC, melanoma, squamous NSCLC, or SCLC whose disease has progressed following 
at least one prior line of standard systemic therapy for advanced or metastatic disease. 
Participants initially received vobramitamab duocarmazine 2.7 mg/kg Q4W. Per the Dear 
Investigator Letter, dated 22 July 2024, participants in Part 2 who were receiving 2.7 mg/kg must 
lower their dose to 2.0 mg/kg Q4W and will receive a maximum of 6 cycles of treatment. Each 
disease-specific cohort planned to use a Simon’s 2-stage design and enroll up to approximately 
40 participants each if both stages were conducted. Part 2 of the study was closed to enrollment 
prior to reaching the Stage 1 enrollment target(s). 
The study treatment schema is presented in Figure 1. 
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Figure 1 
Study Schema  
 
Abbreviations: HNSCC: head and neck squamous cell carcinoma; mCRPC: metastatic castration-resistant 
prostate cancer; NSCLC: non-small cell lung cancer; ORR: objective response rate; Q4W: once every 
4 weeks; R: randomization; SCC: squamous cell carcinoma; SCLC: small cell lung cancer. 
Participants will receive vobramitamab duocarmazine at their assigned dose until protocol-
specified progressive disease (PD), AE requiring discontinuation, physician decision, withdrawal 
of consent, allowed treatment duration is reached, or other treatment discontinuation criteria are 
met per protocol.  
Tumor assessments are performed Q8W for 24 weeks on study treatment then Q12W, regardless 
of dose delay, until PD. Tumor assessments are performed at the EOTV except if the prior 
assessment was ≤ 12 weeks of the EOTV and results are available for tumor response 
assessment. 
Participants will be followed for safety throughout the study. Any participant who discontinues 
study treatment should complete an EOTV. The EOTV should be performed within 30 days 
following the last dose of study treatment whenever possible. 
4.1.1 
Part 1 Study Design  
Part 1 of the study has pre-planned interim and final analyses. The interim analysis will be 
performed on each vobramitamab duocarmazine arm based on PSA response rate at 8 weeks 
when 20 PSA evaluable participants in each vobramitamab duocarmazine arm have been 
Arm A
2.0 mg/kg Q4W
Arm B
2.7 mg/kg Q4W
mCRPC
N=100
R 1:1
Part 1
Part 2
Stage 1
Stage 2
ENROLLMENT COMPLETED
ENROLLMENT CLOSED EARLY
 
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enrolled and followed for at least 8 weeks. The final rPFS analysis will be conducted when all 
participants on Part 1 have been randomized and followed for rPFS for at least 6 months. 
An IDMC will provide study oversight and evaluate cumulative clinical data at regular intervals 
(see Section 14.2). If at any time during Part 1 of the study it becomes apparent that one or both 
doses of vobramitamab duocarmazine have unacceptable toxicity, poor tolerability, or limited 
efficacy, that arm of the study may close to enrollment early while the other arm continues to 
enroll. If only one arm closes to enrollment, participants on that arm will stay on that arm and be 
analyzed according to their originally assigned arm, but be offered the opportunity to switch to 
the other dose.
Prior to Amendment 2, the study contained a control arm. Participants who enrolled prior to 
Amendment 2 and were randomized to the control arm may choose to stay on the control arm or 
discontinue study treatment. Participants who choose to discontinue study treatment may 
re-enroll on the study after implementation of Amendment 2 and be randomized to one of the 
vobramitamab duocarmazine arms if they meet eligibility criteria (including washout period). 
Participants assigned to one of the vobramitamab duocarmazine arms prior to Amendment 2 will 
stay on their assigned arm under Amendment 2 onwards with no changes to their study 
treatment.
4.1.2 
Part 2 Study Design 
Part 2 of the study was closed to enrollment prior to completing the Stage 1 enrollment target(s).
Part 2 planned to use Simon’s 2-stage design for each tumor-specific expansion cohort. A futility 
assessment was to be conducted at the end of Stage 1 on a pre-specified number of response-
evaluable participants in each tumor-specific expansion cohort (Section 14.1 and Section 14.9). 
Enrollment was to be paused separately for each cohort while the analysis was conducted. Upon 
passing futility assessment, each cohort may have enrolled additional participants (up to a total 
of 37 to 42 response-evaluable participants per cohort; Table 1) to further evaluate antitumor 
activity, safety, tolerability, PK, and immunogenicity.
Table 1
Part 2 Cohort Enrollment (Closed to Enrollment)
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4.2 
Study Treatment Discontinuation  
Participants will continue to receive study treatment as specified in the protocol until any one of 
the following conditions are met: 
• Adverse event requiring treatment discontinuation 
• Completed treatment per protocol 
• Death 
• Lost to follow up 
• Physician decision 
• Progressive disease – clinical progression  
• Progressive disease – objective radiographic progression per PCWG3 criteria (Part 1) 
or RECIST v1.1 (Part 2) 
• Protocol deviation requiring treatment discontinuation 
• Study terminated by sponsor 
• Participant decision to discontinue study treatment 
• Participant withdrew consent from study 
 
An isolated increase in PSA is not a condition for study treatment discontinuation for Part 1 
participants. Participants with rising PSA levels only (i.e., in the absence of confirmed 
radiographic or clinical progression) will continue to receive study treatment per PCWG3 
recommendations until radiographic PD (76). 
The investigator must make every effort to confirm PD per PCWG3 criteria or RECIST v1.1, as 
appropriate. However, in instances when participants have progressive symptoms and signs of 
metastatic cancer for whom it is not possible or feasible to undergo radiologic assessment, 
investigators may discontinue study treatment due to “progressive disease – clinical 
progression.” Use of this condition for discontinuing participants from study treatment should be 
restricted to cases in which it is not clinically appropriate for the participant to undergo further 
radiologic assessment and where there is clinical confidence for disease progression in the 
absence of radiographic confirmation. Special consideration should be given to ensure that other 
possible reasons, particularly AEs, are not a more accurate description of the reason for study 
treatment discontinuation in these cases. 
By discontinuing from study treatment, the participant is not withdrawn from the study unless 
they withdraw consent to participate in any further follow up. Participants must be followed for 
progression (if discontinued in the absence of progression) and survival following treatment 
discontinuation, per the study schedule. 
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If a participant withdraws consent, they will be asked specifically if they are withdrawing 
consent for study treatment or for further participation in the study including follow up (e.g., 
survival follow up). 
4.2.1 
Lost to Follow Up  
A participant is considered lost to follow up (LTFU) if the participant fails to return for 
scheduled visits and is non-responsive to repeated contact attempts. Site personnel are expected 
to make at least 2 attempts (e.g., by telephone call, text message, email, certified letter, etc.) to 
contact participants who fail to attend a scheduled visit or who the site is otherwise unable to 
follow. These contact attempts should be documented in the participant’s medical record. 
4.3 
Participant Study Discontinuation  
Participants who are no longer on treatment may continue to be followed on the study as 
specified in the protocol until any of the following conditions are met: 
• 
Completed protocol-defined follow-up period (Section 9.15)  
• Death 
• Lost to follow up 
• Study terminated by sponsor 
• Participant withdrew consent from study 
 
4.4 
Definition of End of Study  
The end of the overall study is defined as the date of last participant last visit.  
Refer to Section 16.10 for criteria related to discontinuation of the entire study.  
 
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5 
ELIGIBILITY CRITERIA  
Participants must meet all the inclusion criteria. Participants will be excluded from the study if 
they meet any exclusion criteria. No exceptions to these criteria will be granted by the sponsor. 
5.1 
Inclusion Criteria  
1. Participant must provide signed informed consent prior to initiation of any study-
related tests or procedures not part of standard of care. The participant must also be 
willing and able to comply with all study procedures. 
2. Age ≥ 18 years old.  
3. Participant must have one of the following cancer types: 
a. Part 1: Histologically confirmed adenocarcinoma of the prostate without 
evidence of neuroendocrine differentiation, signet cell, or small cell features. 
b. Part 2: Histologically confirmed squamous carcinoma of the anus, melanoma, 
HNSCC, squamous NSCLC, or SCLC. 
4. Participant must meet the following criteria regarding cancer disease state: 
a. Part 1: Metastatic castration-resistant prostate cancer. Participants must have 
≥ 1 metastatic (measurable or non-measurable per PCWG3) lesion that is 
present on magnetic resonance imaging (MRI), computed tomography (CT), 
or bone scan obtained ≤ 28 days prior to initiation of study treatment.  
b. Part 2: Locally advanced or metastatic, unresectable disease. Participants must 
have at least one measurable lesion per RECIST v1.1 that is present on MRI 
or CT obtained ≤ 28 days prior to initiation of study treatment. Participants 
with cutaneous or subcutaneous disease not assessable by imaging are eligible 
if the lesions are measurable with calipers. Lesions to be used as measurable 
disease for the purpose of response assessment must not reside in a field that 
has been subjected to prior radiotherapy or must have clearly progressed 
following radiotherapy. 
5. Participant must meet the following criteria regarding recent cancer progression: 
a. Part 1: Tumor progression at study entry documented by PSA or imaging per 
PCWG3 criteria, defined as ≥ 1 of the following 3 criteria:  
i. 
Progressive disease in measurable disease. 
ii. 
Bone disease progression defined by the appearance of ≥ 2 new bone 
lesions. 
iii. 
PSA progression defined as ≥ 2 sequential rises in PSA obtained ≥ 1 
week apart with a minimal starting value of ≥ 1 ng/mL. A PSA value 
≥ 2 ng/mL is required at study entry. 
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b. Part 2: Tumor progression on or following their most recent systemic anti-
cancer treatment as defined per RECIST v1.1. Participants who were 
intolerant of their most recent study treatment and did not have an objective 
response to that treatment are eligible even in the absence of disease 
progression on or following that treatment. 
6. Participant must meet the following criteria regarding prior anti-cancer therapies: 
a. Part 1: Received one prior ARAT regimen (abiraterone, enzalutamide, or 
apalutamide) for prostate cancer. An ARAT regimen is defined as ≥ 60 days 
duration of therapy. ARAT regimen may have been received in either the 
metastatic or non-metastatic setting, and in either the castration-sensitive or 
castration-resistant setting. Participants who received a second ARAT regimen 
for < 60 days as bridging therapy while awaiting lutetium-177 vipivotide 
tetraxetan are also eligible. Participants who received an ARAT regimen 
because they were randomized to the control arm of this study under Protocol 
Amendment 1 and are re-enrolling on an experimental arm after 
implementation of Amendment 2 are also eligible regardless of the duration of 
that ARAT treatment. 
b. Part 2: At least one prior line of systemic therapy for unresectable or 
metastatic disease and no more than two prior lines of cytotoxic 
chemotherapy. Participants with HNSCC or melanoma must have received a 
prior PD-1 or PD-L1 inhibitor for advanced or metastatic disease.  
7. Availability of archival or formalin-fixed paraffin-embedded (FFPE) tumor tissue 
sample. Participants may undergo a fresh tumor biopsy to obtain a specimen for 
testing if an archival tumor sample is not available. Determination of B7-H3 status is 
not required to be eligible. Participants with bone-only mCRPC without available 
tumor tissue and who are not amenable to fresh biopsy are eligible. 
8. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 
9. Life expectancy ≥ 24 weeks. 
10. Part 1 only: Willing and able to maintain ongoing ADT with a GnRH/luteinizing 
hormone-releasing hormone modulator on study, or prior bilateral orchiectomy. 
11. Acceptable laboratory parameters as follows: 
a. Platelet count ≥ 100 × 103/µL without platelet transfusion and/or growth 
factors within 28 days prior to initiation of study treatment. 
b. Absolute neutrophil count ≥ 1.5 × 103/µL without growth factors within 
28 days prior to initiation of study treatment. 
c. Hemoglobin ≥ 9.0 g/dL without whole blood or red blood cell transfusion 
and/or growth factors within 28 days prior to initiation of study treatment. 
d. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 3.0 × 
upper limit of normal (ULN). For participants with hepatic tumor lesions, 
ALT/AST ≤ 5 × ULN. 
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e. Total bilirubin ≤ 1.5 × ULN except if attributed to Gilbert’s syndrome. 
Participants with Gilbert’s syndrome are eligible if conjugated bilirubin is 
within normal limits. 
f. Creatinine clearance > 50 mL/min per Cockcroft-Gault equation. 
g. Albumin ≥ 3.0 g/dL. 
h. Part 1 only: Serum testosterone ≤ 50 ng/dl or ≤ 1.7 nmol/L. 
12. People of childbearing potential (POCBP), defined as not surgically sterilized 
(hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) and between 
menarche and 1-year post menopause, and male participants with a partner who is a 
POCBP must agree to use highly effective methods of contraception according to 
Section 8.1.3 from the time of consent through 27 weeks after last dose of study 
treatment. Participants must agree to abstain from sperm donation through 27 weeks 
after last dose of study treatment. 
13. POCBP must have a negative highly sensitive urine or serum pregnancy test 
performed within 72 hours prior to initiation of study treatment. Participants must 
agree to abstain from egg donation during the study. 
14. Not pregnant or breastfeeding, and must be willing to avoid initiating a pregnancy 
within the projected duration of the study, starting with screening visit through 
27 weeks after the last dose of study treatment. 
 
5.2 
Exclusion Criteria  
Clinical significance of underlying medical or psychiatric conditions is determined by the 
investigator. Sponsor consultation with the medical monitor is encouraged if there is a concern to 
clarify the exclusion criteria. 
1. Any underlying medical or psychiatric condition impairing participant’s ability to 
receive, tolerate, or comply with the planned treatment or study procedures. 
2. Part 1: Prior receipt of up to one prior docetaxel-containing regimen for prostate 
cancer (in either the metastatic or non-metastatic, castration-sensitive or castration-
resistant setting) is permitted. Participants who received an additional taxane-
containing regimen (e.g., additional docetaxel or cabazitaxel) for < 60 days as 
bridging therapy while awaiting lutetium-177 vipivotide tetraxetan are also eligible. 
Other prior chemotherapy for prostate cancer is not allowed. 
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3. Part 1: Prior receipt of one or more of the following anticancer therapies is permitted 
but not required: first generation anti-androgens (e.g., nilutamide, bicalutamide), oral 
ketoconazole, PARP inhibitor, immunotherapy (e.g., checkpoint inhibitor, 
sipuleucel-T), or radiopharmaceutical (e.g., radium-223 dichloride, lutetium-177 
vipivotide tetraxetan). However, participants must not have received > 3 total prior 
lines of therapy for mCRPC (bridging therapy followed by lutetium-177 vipivotide 
tetraxetan counts as one line). Participants who were randomized to the control arm of 
this study and are re-enrolling on an experimental arm after implementation of 
Amendment 2 are eligible regardless of the number of prior lines of therapy for 
mCRPC. 
a. Note: Participants with a known history of documented BRCA mutation 
(germline or somatic) are not eligible unless they received prior treatment 
with a PARP inhibitor where such treatment is available, indicated, and 
tolerated. 
4. Another hematologic or solid tumor ≥ stage 1 malignancy that completed surgery, last 
dose of radiotherapy, or last dose of systemic anti-cancer therapy ≤ 2 years from first 
dose of study treatment. Participants who had curative therapy for localized 
malignancy are eligible. 
5. Untreated, symptomatic central nervous system (CNS) metastasis. Participants with 
history of prior CNS metastasis must have been treated. The following criteria are 
exclusionary at the time of enrollment: 
a. Concurrent treatment for CNS disease (e.g., surgery, radiation, corticosteroids 
≥ 10 mg prednisone/day or equivalent). 
b. Progression of CNS metastases on MRI or CT < 4 months after surgery or the 
last day of prior radiotherapy or systemic anti-cancer therapy for CNS 
metastases. 
c. Concurrent leptomeningeal disease or spinal cord compression. 
6. Active viral, bacterial, or fungal infection requiring systemic treatment within 1 week 
of initiation of study treatment.  
7. Known chronic hepatitis B virus (HBV) infection (defined by detectable HBV surface 
antigen and HBV DNA ≥ 500 IU/mL). For Czech Republic and other countries 
where required by local authorities only: HBV testing is required; testing should 
follow local clinical practice guidelines/standards. 
a. Participants with resolved HBV infection (as evidenced by detectable HBV 
surface antibody, detectable HBV core antibody, undetectable HBV DNA, and 
undetectable HBV surface antigen) are eligible. 
8. Known current hepatitis C virus (HCV) infection (defined by detectable HCV RNA). 
Participants with a history of resolved hepatitis C with detectable HCV antibody are 
eligible. For Czech Republic and other countries where required by local 
authorities only: HCV testing is required; testing should follow local clinical 
practice guidelines/standards. 
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9. Known history of positive test for human immunodeficiency virus (HIV) unless all 
the following criteria are met:  
a. Cluster of differentiation (CD)4+ lymphocyte count ≥ 350/µL. 
b. HIV viral load (HIV RNA) < 400 copies/mL. 
c. Maintained on approved antiretroviral therapy for a minimum of 4 weeks.  
For Czech Republic and other countries where required by local authorities 
only: HIV testing is required; testing should follow local clinical practice 
guidelines/standards. 
10. Prior autologous/allogeneic stem cell or tissue/solid organ transplant. 
11. Known hypersensitivity to recombinant proteins, polysorbate 80, or any excipient 
contained in the drug formulation for vobramitamab duocarmazine or other study 
treatments. 
12. Received one or more of the following anticancer treatments within the specified 
exclusionary time frame: 
a. Major surgery within 4 weeks prior to initiation of study treatment. 
b. Systemic cytotoxic anti-neoplastic therapy within 4 weeks prior to initiation of 
study treatment. 
c. ARAT within 4 weeks prior to initiation of study treatment. 
d. Investigational therapy within 4 weeks prior to initiation of study treatment. 
e. Small molecule targeted or kinase inhibitors within 5 half-lives prior to 
initiation of study treatment. 
f. Chimeric antigen receptor T-cell therapy within 4 weeks prior to initiation of 
study treatment. 
g. Radiopharmaceutical (e.g., radium-223 dichloride, lutetium-177 vipivotide 
tetraxetan) for mCRPC within 2 months prior to initiation of study treatment. 
h. Radiation therapy within 4 weeks prior to initiation of study treatment. 
Palliative, limited field radiation for symptom control to soft tissues or bone 
lesions is excluded within 2 weeks prior to initiation of study treatment. 
i. Part 1 only: Use of products that have published anti-prostate cancer activity 
and/or are known to decrease PSA levels (specifically, saw palmetto and 
pomegranate juice/extract) within 4 weeks prior to initiation of study 
treatment. Use of 5-alpha-reductase inhibitors is allowed as long as the 
participant has been on a stable dose for at least 2 months prior to study entry. 
13. Prior treatment with any B7-H3 targeted agent for cancer. 
14. Clinically significant cardiovascular disease including but not limited to: 
a. Myocardial infarction or unstable angina within 12 months prior to initiation 
of study treatment. 
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b. Stroke or transient ischemic attack within 12 months prior to initiation of 
study treatment. 
c. Clinically significant cardiac arrythmia within 12 months prior to initiation of 
study treatment. 
d. Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic 
blood pressure > 100 mmHg. 
e. Congestive heart failure (New York Heart Association class II–IV). 
f. Pericarditis. 
g. Myocarditis. 
h. Left ventricular ejection fraction (LVEF) < 50%. 
i. Prolongation of corrected QT interval per Fridericia’s formula (QTcF) 
> 480 milliseconds. 
15. Clinically significant venous insufficiency (e.g., pain, skin tightness, skin changes of 
venous stasis, pitting edema not controlled with diuretics or compression stockings). 
16. Clinically significant pulmonary compromise including pneumonia, pneumonitis, or a 
requirement for supplemental oxygen use to maintain adequate oxygenation, or 
history of ≥ Grade 3 drug-induced or radiation pneumonitis. 
17. Evidence of pleural effusion. Asymptomatic trace pleural fluid without prior 
intervention (e.g., thoracentesis) is allowed. 
18. Evidence of pericardial fluid or effusion. Trace pericardial fluid is exclusionary. 
19. Evidence of ascites. Trace peritoneal fluid is allowed. 
20. Unresolved toxicity > Grade 2 related to prior therapy (i.e., prior chemotherapy, 
radiation, immunotherapy, etc.).  
21. Contraindications to the use of corticosteroid treatment. 
22. Employees of MacroGenics, Inc. 
23. Prisoners or other individuals who are involuntarily detained. 
24. Vaccination with any live virus vaccine within 30 days prior to initiation of study 
treatment. Inactivated annual influenza vaccination and non-live SARS-CoV-2 
vaccinations are allowed at any time. 
 
 
 
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6 
STUDY TREATMENTS 
6.1 
Description of Dosing Regimens 
An overview of study treatments to be administered during this study is presented in Table 2.
Table 2
Overview of Study Treatments
Product
Dose
Schedule 
Route of Administration
Vobramitamab 
duocarmazine 
2.0 mg/kg a, b  
Once every 4 weeks 
IV 
Vobramitamab 
duocarmazine 
2.7 mg/kg a, c 
Once every 4 weeks 
IV 
a 
Prednisone 40 mg PO twice daily will be administered on the first 3 days of each cycle after administration 
of vobramitamab duocarmazine. 
b 
Part 2 dosing regimen. Participants may receive a maximum of 6 cycles of treatment. 
c 
Per the Dear Investigator Letter, dated 22 July 2024, participants in Part 2 who were receiving 2.7 mg/kg 
must lower their dose to 2.0 mg/kg Q4W. 
Abbreviations: IV: intravenous; PO: orally; Q4W: every 4 weeks. 
6.1.1 
Vobramitamab Duocarmazine Dosing Regimen 
Vobramitamab duocarmazine is administered Q4W at the assigned dose for each arm. 
Vobramitamab duocarmazine is administered as an IV infusion over approximately 60 minutes 
(-5 or +15 minute window). Do not administer vobramitamab duocarmazine as an IV push or 
bolus.
Dosing is based on actual body weight. An exception to weight-based dosing is made for 
participants weighing ≥ 100 kg; doses will be based on 100 kg for these participants. Refer to the 
pharmacy manual for instructions on weight-based dosing.
Participants on vobramitamab duocarmazine will be monitored on site for 2 hours following 
completion of Cycle 1 Day 1 infusion. Monitoring may be reduced to 1 hour following 
subsequent infusions if no IRR occurs. Participants also may be requested to stay on site to 
facilitate PK sample collection per Appendix 2.
For participants who enrolled on Part 1 prior to Amendment 2 and were randomized to one of the 
two vobramitamab arms, their dosing regimen will not change upon implementation of 
Amendment 2.
6.1.2 
Comparator Product Dosing Regimen(s) (Part 1) 
For participants who enrolled on Part 1 prior to Amendment 2, were randomized to the control 
arm, and wish to continue to receive abiraterone (with prednisone) or enzalutamide, refer to the 
local prescribing information for details on dosage and administration.
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6.2 
Method of Assigning Participants to Treatment Groups  
Part 1 
Eligible participants will be randomized centrally using interactive response technology (IRT). 
Instructions for randomization will be provided via IRT. Every effort should be made to 
minimize the time between randomization and initiation of study treatment. It is recommended 
that subjects commence study treatment as soon as possible after randomization. 
Enrollment will use a central randomization scheme with stratified permuted blocks. Note: for 
stratification, visceral disease is defined as liver, lung, or other non-nodal soft tissue metastases. 
Participants will be randomized in a 1:1 ratio between the two treatment arms:  
1. Experimental arm A: vobramitamab duocarmazine 2.0 mg/kg IV Q4W 
2. Experimental arm B: vobramitamab duocarmazine 2.7 mg/kg IV Q4W 
 
Randomization will use the following 3 stratification factors: 
1. Presence of visceral disease (yes vs no) 
2. Prior taxane (yes vs no) 
3. Region (US/Canada vs other) 
 
Participants assigned to the control arm prior to its removal in Amendment 2 who would like to 
receive vobramitamab duocarmazine treatment may discontinue the study and be re-randomized 
to one of the vobramitamab duocarmazine arms after a 4-week washout period if they meet 
eligibility criteria. Participants assigned to one of the vobramitamab duocarmazine arms prior to 
Amendment 2 will stay on their assigned arm under Amendment 2 onwards with no changes to 
their study treatment. 
Part 2 
Initially, eligible participants were assigned via IRT to receive vobramitamab duocarmazine at 
2.7 mg/kg Q4W. Per the Dear Investigator Letter, dated 22 July 2024, participants who were 
receiving 2.7 mg/kg Q4W under Protocol Amendment 4 must lower their dose to 2.0 mg/kg 
Q4W. The total number of doses of vobramitamab duocarmazine is capped at 6. 
6.3 
Blinding  
Not applicable. This is an open-label study. No blinding of site personnel or participants will be 
employed.  
6.4 
Emergency Unblinding  
Not applicable. This is an open-label study. 
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6.5 
Study Drugs and Supplies  
The study sponsor will supply vobramitamab duocarmazine, comparator drugs (abiraterone or 
enzalutamide), and prednisone (for use as post-infusion prophylaxis). The sponsor is not 
responsible for the supply of any premedication or concomitant medication (e.g., ADT). 
6.5.1 
Vobramitamab Duocarmazine  
 
 
 
 
Information on the formulation of vobramitamab duocarmazine is included in the pharmacy 
manual. 
6.5.2 
Comparator Products  
For participants who enrolled prior to Amendment 2, were randomized to the control arm of 
Part 1, and wish to continue to receive their assigned ARAT, commercially available 
formulations of abiraterone, prednisone, and enzalutamide will be supplied. 
For participants unable to visit the site (e.g., due to the COVID-19 public health emergency), 
direct-to-participant shipment of oral study treatment may be implemented, where allowed per 
local regulations and if requested by the investigator. Where direct-to-participant shipments are 
deemed necessary, the process must be coordinated between the site and sponsor staff following 
standard direct-to-participant procedures for arranging shipment and adhering to associated 
approvals and documentation requirements. For participants able to visit the site, but who request 
to reduce visit frequency or for who limited access to the site is expected, an additional supply of 
oral study treatment may be provided. 
6.6 
Preparation and Administration  
Information on the storage, dose preparation, and administration of study treatments is included 
in the pharmacy manual. 
6.7 
Packaging and Labeling  
Information on the packaging and labeling of study treatments is included in the pharmacy 
manual. 
Clinical supplies will be affixed with a label in accordance with Good Manufacturing Practice 
(GMP) and regulatory requirements. 
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6.8 
Treatment Compliance  
Vobramitamab duocarmazine will be administered by healthcare professionals under the 
supervision of the investigator. For participants who enrolled prior to Amendment 2, were 
randomized to the control arm, and wish to continue to receive their assigned ARAT, ARAT will 
be dispensed at the study site. 
Records of vobramitamab duocarmazine dose calculation, administration, and dosing regimen 
will be accurately maintained by site staff. The study monitors, designated by the sponsor, will 
review study pharmacy and participant medical records according to the clinical monitoring plan. 
6.9 
Accountability  
Accurate accounting of all study treatments must be maintained. The investigator agrees to keep 
an inventory of study treatments using the institution’s drug accountability logs or logs provided 
by the sponsor. The investigator will maintain records of temperature monitoring of study drug. 
Study drug disposition records must be kept in compliance with applicable guidelines and 
regulations. 
A pharmacy manual will be provided to the investigator or designee. When the study is 
completed, copies of all study treatment accountability records must be provided to the sponsor. 
Original drug accountability records must be maintained with the rest of the documentation for 
inspection by the study monitors.  
6.10 
Study Drug Disposition at End of Study  
All unused study drugs will be destroyed on site unless return to depot is authorized by the 
sponsor or its representative. 
 
 
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7 
POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE 
MEASURES  
7.1 
Premedication and Prophylaxis for Vobramitamab Duocarmazine  
Premedication for Infusion Related Reaction 
Premedication as specified below is strongly recommended to mitigate the potential occurrence 
of IRR with administration of vobramitamab duocarmazine. Equivalent medications may be 
substituted based on the local practice of medicine and availability. 
Approximately 30 minutes before each vobramitamab duocarmazine infusion, administer: 
• Acetaminophen 650–1000 mg orally (PO) or ibuprofen 400 mg PO 
• Diphenhydramine 50 mg PO or IV, or equivalent H1 antagonist 
• Famotidine 40 mg PO or 20 mg IV, or equivalent H2 antagonist 
• Dexamethasone 4 mg IV, or equivalent corticosteroid 
 
For subsequent administration of vobramitamab duocarmazine to participants who had IRRs that 
were not adequately or only moderately controlled, additional medications (e.g., ibuprofen 
400 mg PO, or an increased dose of dexamethasone) may be considered as part of the 
premedication regimen. For participants who do not have an IRR of any grade after two 
consecutive infusions of vobramitamab duocarmazine, dexamethasone premedication may be 
reduced by 50% at the next infusion and discontinued at the infusion after that if no IRR is 
observed. 
Prophylaxis for Fluid Retention and/or Palmar-Plantar Erythrodysesthesia 
To mitigate potential occurrence of fluid retention and PPE, prednisone 40 mg PO twice daily 
(BID) will be administered on the first 3 days of each cycle after administration of vobramitamab 
duocarmazine. 
To mitigate potential occurrence of PPE, consider clobetasol 0.05% cream, or corticosteroid 
cream per local practice, prophylactically applied to palms and soles for the first 12 weeks of 
vobramitamab duocarmazine treatment (see Section 7.3.5). 
7.2 
Dose Modification and Dose Delay  
7.2.1 
Vobramitamab Duocarmazine Dose Delay and Interruption  
Participants who experience toxicity will have vobramitamab duocarmazine held pending 
assessment, management, and resolution of the toxicity. If the toxicity is assessed to be unrelated 
to vobramitamab duocarmazine or does not necessitate study treatment discontinuation, then the 
participant may reinstitute vobramitamab duocarmazine per guidelines outlined below and in 
Section 7.3. 
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A dose delay ≤ 28 days is allowed for AEs irrespective of attribution to study treatment or for 
reasons other than AEs. All protocol-specified procedures at the missed dosing visit should be 
performed and treatment reinstituted as if the delay had not occurred. 
A dose delay > 28 days will result in discontinuation of vobramitamab duocarmazine unless the 
investigator and sponsor medical monitor (or qualified designee) agree that the participant is 
deriving benefit (e.g., evidence of ongoing disease control defined as radiographic stable disease 
(SD) or better and/or PSA response). 
7.2.2 
Vobramitamab Duocarmazine Dose Reduction  
Vobramitamab duocarmazine dose may be reduced for toxicity per Section 7.3. Up to a 
maximum of 3 dose reductions are allowed for toxicity per participant. If a fourth dose reduction 
is required, permanently discontinue vobramitamab duocarmazine dosing. Dose reductions for 
vobramitamab duocarmazine are described in Table 3. 
Table 3 
Vobramitamab Duocarmazine Dose Reduction Algorithm  
Initial Dose 
First Dose Reduction 
Second Dose Reduction 
Third Dose Reduction 
2.7 mg/kg 
2.0 mg/kg 
1.5 mg/kg 
1.0 mg/kg 
2.0 mg/kg 
1.75 mg/kg 
1.5 mg/kg 
1.0 mg/kg 
 
7.3 
Management of Potential Adverse Events Related to Vobramitamab 
Duocarmazine  
7.3.1 
Guidelines for Management of Adverse Events Related to 
Vobramitamab Duocarmazine  
Guidelines for management of specific vobramitamab duocarmazine-related AEs are detailed in 
Section 7.3.2 through Section 7.3.9. Refer to Table 4 for dose modification guidelines for all 
other vobramitamab duocarmazine-related AEs (i.e., for vobramitamab duocarmazine-related 
AEs not specified in the protocol). Follow local institutional guidelines for management of AEs 
considered not related to vobramitamab duocarmazine. 
Note: For AE management, baseline is defined as the most recent measurement prior to the first 
dose of study treatment (e.g., Cycle 1 Day 1 pre-dose). 
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Table 4 
Guidelines for Vobramitamab Duocarmazine-Related Adverse 
Events Not Specified in the Protocol  
Grade 
Dose Modification Guidelines 
1 
No dose modification required. 
2 
Consider holding vobramitamab duocarmazine until ≤ Grade 1 or baseline, then resume at current 
dose. If same toxicity recurs at Grade 2 consider dose reduction. 
Intolerable 2 
or any 3 
Hold vobramitamab duocarmazine until ≤ Grade 1 or baseline.  
Reduce dose by one dose level. 
4 
Permanently discontinue vobramitamab duocarmazine. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.2 
Infusion Related Reaction  
Infusion reactions associated with vobramitamab duocarmazine administration should be 
managed according to the standard practice of medicine. General guidelines for the management 
of such reactions are provided in this section (Table 5). 
Participants should be monitored for the development of IRR during infusions. Medications and 
resuscitation equipment for the treatment of severe hypersensitivity reactions must be available 
for immediate use for IRR. All supportive measures consistent with optimal care will be 
provided throughout the study according to institutional standards. 
It may be difficult to distinguish between IRR and emerging infection as the cause of fever. 
Participants should be evaluated for presence of infection, with acquisition of cultures, viral 
testing, and implementation of empiric antibiotic therapy based on the investigator’s assessment. 
Refer to the table below for guidance regarding the management of IRR. 
Changes in the infusion of vobramitamab duocarmazine including interruption of the infusion, 
duration of interruption, and reduction in infusion rate must be recorded. 
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Table 5 
Management of Infusion Related Reaction  
Grade 
Medical Care Guidelines 
Infusion Modification Guidelines 
1 
Reduce infusion rate by 50% 
Monitor for worsening of IRR. 
With evidence of improvement, infusion rate 
may be increased to original rate as tolerated 
after 30 minutes. 
Consider additional infusion prophylaxis prior to 
next infusion; see Section 7.1. 
2 
Stop infusion 
Administer supportive medications as 
appropriate: 
• 
Diphenhydramine 25-50 mg IV. 
• 
Acetaminophen (650–1000 mg) or 
ibuprofen (400 mg) PO. 
• 
Oxygen and bronchodilators as needed. 
If improved to ≤ Grade 1, infusion may resume 
with a 50% reduction in infusion rate. 
Monitor for worsening of IRR. 
Discontinue infusion if symptoms recur.  
Consider additional infusion prophylaxis prior to 
next infusion; see Section 7.1. 
3 
Stop infusion, disconnect tubing 
Aspirate drug from vascular access device. 
Administer supportive medications as 
appropriate: 
• 
Diphenhydramine 25-50 mg IV. 
• 
Dexamethasone (or equivalent) 20 mg IV. 
• 
Acetaminophen (650 mg) or ibuprofen 
(400 mg) PO. 
• 
IV fluids, oxygen, bronchodilators. 
• 
Epinephrine. 
 
Discontinue the current infusion. 
Participant may resume treatment with the next 
scheduled dose if symptoms completely resolve 
within 12 hours. A 50% reduction in infusion 
rate is required for the next scheduled dose of 
vobramitamab duocarmazine. 
Consider additional infusion prophylaxis prior to 
next infusion; see Section 7.1. 
Permanently discontinue vobramitamab 
duocarmazine for Grade 3 IRR lasting 
> 12 hours or a second occurrence of Grade 3 
IRR. 
4 
Stop infusion, disconnect tubing 
Aspirate drug from vascular access device. 
Treat as for Grade 3 and as appropriate for a life-
threatening condition. 
Permanently discontinue vobramitamab 
duocarmazine. 
 
7.3.3 
Diarrhea  
Participants should be monitored closely for evidence of diarrhea or other change in bowel 
habits. Participants with diarrhea should be treated per institutional standard practice. Guidelines 
for dose modification are provided in Table 6. 
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Table 6 
Dose Modification for Diarrhea  
Grade 
Dose Modification Guidelines 
Grade 1 
Closely monitor until resolution. No dose modification required. 
Grade 2 
Hold vobramitamab duocarmazine until ≤ Grade 1, then resume at current 
dose. 
Grade 3 (despite use of optimal 
anti-diarrheal treatment) 
Hold vobramitamab duocarmazine until ≤ Grade 1. Reduce dose by one dose 
level. 
Grade 4 
Permanently discontinue vobramitamab duocarmazine. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.4 
Pneumonitis  
Noninfectious pneumonitis may result in fatigue, shortness of breath, cough, low oxygen 
saturation, or respiratory distress. If a participant presents with signs or symptoms of pulmonary 
toxicity, the participant should be evaluated for potential pneumonitis. An evaluation for 
infection should be performed. Advise participants to notify their treating physician immediately 
if they experience new or worsening shortness of breath, cough, or respiratory distress. 
Management and dose modification guidelines are outlined in Table 7. 
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Table 7 
Management of Noninfectious Pneumonitis  
Grade 
Definition (CTCAE v5.0) 
Medical Care Guidelines 
Dose Modification Guidelines 
1 
Asymptomatic; clinical or 
diagnostic observations only; 
intervention not indicated. 
Radiologic assessments (CT 
scan and/or chest x-ray) should 
be performed as clinically 
indicated. 
Consider systemic 
corticosteroids (0.5–1.0 mg/kg/d 
prednisone or equivalent) until 
improvement, followed by 
gradual taper over > 4 weeks. 
Repeat chest imaging in 3–4 
weeks or sooner if the patient 
becomes symptomatic. 
Monitor weekly for respiratory 
symptoms, lung exam, and pulse 
oximetry. 
If no radiographic improvement 
on follow-up, treat as Grade 2. 
Hold vobramitamab 
duocarmazine until resolved, 
then resume current dose. 
2 
Symptomatic; medical 
intervention indicated; limiting 
instrumental ADL a 
Radiologic assessments (CT 
scan and/or chest x-ray) should 
be performed as clinically 
indicated. 
Give prednisone 1–2 mg/kg/d 
and taper over 4–6 weeks or 
sooner as clinically indicated. 
Participant must be evaluated by 
a pulmonary specialist. 
Consider bronchoscopy with 
bronchoalveolar lavage. 
Monitor at least once per week 
for respiratory symptoms, lung 
exam, and pulse oximetry. 
If no clinical improvement after 
48–72 hours of prednisone, treat 
as Grade 3.  
Permanently discontinue 
vobramitamab duocarmazine. 
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Table 7 
Management of Noninfectious Pneumonitis  
Grade 
Definition (CTCAE v5.0) 
Medical Care Guidelines 
Dose Modification Guidelines 
3 
Severe symptoms; limiting 
self-care ADL b; oxygen 
indicated 
Hospitalize and initiate 
supportive care.  
Radiologic assessments (CT 
scan and/or chest x-ray) should 
be performed as clinically 
indicated. 
Give methylprednisolone IV 1–2 
mg/kg/d. If no improvement 
after 48 hours, may add 
immunosuppressive agent (e.g., 
infliximab 5 mg/kg c, or 
mycophenolate mofetil IV 1 g 
twice a day, or IVIG for 5 days, 
or cyclophosphamide.  
Taper corticosteroids over 4–6 
weeks.   
Participant must be evaluated by 
a pulmonary specialist.  
Bronchoscopy with lavage 
and/or biopsy when clinically 
feasible should be performed.  
The pneumonitis event must be 
followed until resolution. 
Permanently discontinue 
vobramitamab duocarmazine. 
4 
Life-threatening respiratory 
compromise; urgent intervention 
indicated (e.g., tracheotomy or 
intubation) 
Manage as Grade 3 event. 
Hospitalize and initiate maximal 
supportive care. 
Permanently discontinue 
vobramitamab duocarmazine. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
a 
Instrumental ADLs include preparing food, shopping, using the telephone, housekeeping, doing laundry, using 
transportation, managing money, and managing medications. 
b 
Self-care ADLs include feeding, continence, transferring/ambulating, using the toilet, dressing, bathing, and 
taking medications. 
c 
Infliximab doses > 5 mg/kg contraindicated in moderate or severe heart failure (see Infliximab Prescribing 
Information). 
Abbreviations: ADL: activities of daily living; CT: computed tomography; CTCAE: Common Terminology Criteria 
for Adverse Events; IV: intravenously; IVIG: intravenous immunoglobulin. 
 
7.3.5 
Palmar-Plantar Erythrodysesthesia  
Participants should limit sun exposure and apply broad-spectrum sunscreen to exposed skin 
when outdoors. Any measures such as frozen gloves or socks or scalp cooling cap to prevent 
cutaneous toxicity or alopecia are left to the investigator’s judgment. Use of concomitant 
medications with a known risk for skin toxicity and/or photosensitivity are to be avoided if 
possible (see Section 8.1.1). 
For any grade toxicity, evaluate participant use of concomitant medications and herbal 
supplements and discontinue any products known to exacerbate mucocutaneous toxicity. 
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Supportive care per institutional practice should be used to manage PPE. Guidelines for grading 
and dose modification are described in Table 8. Avoid pressure and tight clothing on palms and 
soles. 
Consider clobetasol 0.05% cream, or corticosteroid cream per local practice, prophylactically 
applied to palms and soles for the first 12 weeks of vobramitamab duocarmazine treatment. 
Table 8 
Dose Modification for Palmar-Plantar Erythrodysesthesia  
Grade 
Definition (CTCAE v5.0) 
Dose Modification Guidelines 
1 
Minimal skin changes or dermatitis (e.g., 
erythema, edema, or hyperkeratosis) without pain 
No dose modification required. Initiate supportive 
care measures. Closely monitor; advise 
participant to conduct daily self-assessment. 
2 
Skin changes (e.g., peeling, blisters, bleeding, 
fissures, edema, or hyperkeratosis) with pain; 
limiting instrumental ADL a 
Hold vobramitamab duocarmazine until 
≤ Grade 1. Reduce dose by one dose level. 
3 
Severe skin changes (e.g., peeling, blisters, 
bleeding, fissures, edema, or hyperkeratosis) with 
pain; limiting self-care ADL b 
Hold vobramitamab duocarmazine until 
≤ Grade 1. Reduce dose by one dose level. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
Note: Grade 4 and 5 severity are not available per CTCAE v 5.0. 
a 
Instrumental ADLs include preparing food, shopping, using the telephone, housekeeping, doing laundry, using 
transportation, managing money, and managing medications. 
b 
Self-care ADLs include feeding, continence, transferring/ambulating, using the toilet, dressing, bathing, and 
taking medications. 
Abbreviations: ADL: activities of daily living; CTCAE: Common Terminology Criteria for Adverse Events. 
 
7.3.6 
Ocular Adverse Events  
Ocular toxicity, including, but not limited to, dry eye, photophobia or blurry vision, has been 
observed in participants treated with ADCs including vobramitamab duocarmazine, and could 
occur at any time during treatment with vobramitamab duocarmazine. Prophylactic eye drops 
(e.g., corticosteroid, antihistamine, artificial tears) are recommended for participants 3 times per 
day, or as needed. Participants are advised not to wear contact lenses or rub their eyes on the day 
of infusion. Baby shampoo and a soft cloth should be used to clean eyelashes and closed eyelids, 
and a warm compress at bedtime may be used to decrease any possible inflammation on the 
eyelid’s surface. 
Participants with dry eye, photophobia, or blurry vision that persists for more than 72 hours or 
worsens, or signs/symptoms suggestive of keratitis, conjunctivitis, or uveitis irrespective of 
duration, should obtain a prompt ophthalmology evaluation for further assessment and 
management, including local topical care and/or immune suppression as appropriate. 
Management guidance for ocular toxicity is provided in Table 9.  
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Table 9 
Management of Ocular Symptoms  
Grade 
Medical Care Guidelines 
Dose Modification Guidelines 
1 
No specific therapy required. Daily cleansing 
with warm, clean cloth. Apply lubricating eye 
drops. 
Monitor for worsening symptoms. 
No dose modification required. 
2 
Consider topical/ocular corticosteroids, 
antihistamine, artificial tears. 
Participants should have weekly symptomatic 
ocular assessments by the investigator until the 
symptoms resolve to Grade 1 or baseline or are 
deemed to be irreversible by the investigator. 
Hold vobramitamab duocarmazine until 
≤ Grade 1. If event resolves to ≤ Grade 1 in 
≤ 14 days, may resume vobramitamab 
duocarmazine at the same dose level. If the event 
takes > 14 days to resolve to ≤ Grade 1, reduce 
dose by one dose level. 
3  
Consider topical/ocular corticosteroids, 
antihistamine, artificial tears. 
Consider ophthalmology consultation. 
Participants should have weekly symptomatic 
ocular assessments by the investigator until the 
symptoms resolve to Grade 1 or baseline or are 
deemed to be irreversible by the investigator. 
Hold vobramitamab duocarmazine until 
≤ Grade 1. Reduce dose by one dose level. 
Permanently discontinue vobramitamab 
duocarmazine if ≥ Grade 3 toxicity recurs on 
subsequent cycles despite best supportive care. 
4  
Permanently discontinue vobramitamab duocarmazine 
Consult ophthalmology within 24 hours. 
Treat as for Grade 3 and as appropriate for a life-threatening condition. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.7 
Hematologic Adverse Events  
Complete blood count (CBC) is monitored per Appendix 1. Consider monitoring CBC weekly 
or more frequently based on the participant’s medical history and incidence of myelosuppressive 
events during vobramitamab duocarmazine administration. 
No specific treatment or vobramitamab duocarmazine dose modifications are required for 
lymphopenia, regardless of CTCAE grade, unless associated with opportunistic infection. If the 
participant develops an opportunistic infection with concurrent lymphopenia, vobramitamab 
duocarmazine dosing should be delayed until resolution of lymphopenia and the opportunistic 
infection (see Table 4 for general guidance). 
7.3.7.1 
Neutropenia  
Use of granulocyte colony-stimulating factor (G-CSF) is permitted after Cycle 1 Day 1. Perform 
a CBC for a measured temperature of ≥ 100.4°F (38°C) or evidence of infection. Neutropenic 
complications, including neutropenic fever of any grade, should be managed promptly with 
antibiotic support per local guidelines and use of G-CSF according to current American Society 
of Clinical Oncology (ASCO) guidelines for use of white blood cell growth factors. 
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Table 10 
Management of Neutropenia  
Grade 
Medical Care Guidelines 
Dose Modification Guidelines 
1 
No specific therapy required. Consider G-CSF 
with next cycle per institutional standards. 
No dose modifications are required. 
2 
No specific therapy required. Consider G-CSF 
with next cycle per institutional standards. 
No dose modifications are required.  
3 
Monitor neutrophil counts weekly until ≤ Grade 1. 
Advise participant to take neutropenic precautions 
per institutional standards. G-CSF with next cycle 
is recommended. 
Hold vobramitamab duocarmazine until ANC 
≥ 1000/mm3. Consider reducing dose by one dose 
level. 
4 
Monitor neutrophil counts weekly until ≤ Grade 1. 
Advise participant to take neutropenic precautions 
per institutional standards. G-CSF with next cycle 
is recommended. 
Hold vobramitamab duocarmazine until ANC 
≥ 1000/mm3. Reduce dose by one dose level. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.7.2 
Thrombocytopenia  
Consider transfusion of platelets for thrombocytopenia. Monitor coagulation laboratory tests 
(Table 17). Use of anticoagulants (e.g., coumarins and indandiones, factor Xa inhibitors, 
heparins, thrombin inhibitors) and platelet inhibitors (e.g., aspirin or nonsteroidal 
anti-inflammatory drugs, e.g., ibuprofen) should be held until thrombocytopenia resolves. 
Table 11 
Management of Thrombocytopenia  
Grade 
Medical Care Guidelines 
Dose Modification Guidelines 
1 
No specific therapy required. 
No dose modifications are required. 
2 
No specific therapy required. 
Hold vobramitamab duocarmazine until platelets 
≥ 75,000/mm3, then resume at current dose.  
3 
Monitor platelet counts at least once weekly until 
≤ Grade 1. 
Hold vobramitamab duocarmazine until platelets 
≥ 75,000/mm3. If dose is delayed by > 14 days to 
allow for platelet recovery, reduce dose by one 
dose level, otherwise resume at current dose. 
4 
Monitor platelet counts at least once weekly until 
≤ Grade 1.  
Treat as appropriate for a life-threatening 
condition. 
Hold vobramitamab duocarmazine until platelets 
≥ 75,000/mm3. Reduce dose by one dose level. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.7.3 
Anemia  
Anemia should be evaluated and treated for other underlying etiology e.g., iron, folate, or 
vitamin B12 deficiency, bleeding, thrombocytopenia, coagulopathy, and renal insufficiency. 
Consider transfusion of red blood cells or whole blood for anemia. Caution is recommended in 
participants with ≥ Grade 2 anemia, with appropriate measures taken as clinically indicated. The 
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investigator should refer to current ASCO guidelines for management of cancer-associated 
anemia with erythropoiesis-stimulating agents. 
Table 12 
Management of Anemia  
Grade 
Medical Care Guidelines 
Dose Modification Guidelines 
1 
No specific therapy required. 
No dose modification required. 
2 
Consider iron replacement therapy, 
erythropoiesis-stimulating agent. 
No dose modification required. 
3 
Consider iron replacement therapy, 
erythropoiesis-stimulating agent. 
Consider transfusion if symptomatic. 
Hold vobramitamab duocarmazine until 
≤ Grade 2 or baseline, then resume at current 
dose. Consider reducing dose by one dose level if 
Grade 3 anemia recurs. 
4 
Transfuse with whole blood or packed red blood 
cells. 
Treat as appropriate for a life-threatening 
condition. 
Hold vobramitamab duocarmazine until 
≤ Grade 2 or baseline. Reduce dose by one dose 
level. 
Permanently discontinue vobramitamab 
duocarmazine for Grade 4 anemia that persists 
despite intervention.  
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.8 
Effusions  
Supportive care per institutional practice should be used to manage pleural and pericardial 
effusions. Diuretics, thoracentesis, pericardiocentesis, and other surgical procedures to manage 
the effusions are allowed and should be used according to best practice. Chest x-ray should be 
obtained as indicated to monitor effusion fluid level. Close monitoring of heart and lung function 
is warranted in the presence of effusion.  
For Grade 2 or higher pleural or pericardial effusions, consider corticosteroids: 1 to 2 mg/kg of 
oral prednisone or equivalent per day divided twice daily. Taper corticosteroids (e.g., 5 to 10 mg 
every 1 to 2 weeks from an initial dose above 40 mg prednisone per day) over 4 weeks or as 
clinically indicated. 
Specific guidance for pleural and pericardial effusion is provided Table 13 and Table 14, 
respectively. 
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7.3.8.1 
Pleural Effusion  
Table 13 
Management of Pleural Effusion  
Grade 
Dose Modification Guidelines 
1 
No delay or dose modification required. 
2 
Hold vobramitamab duocarmazine until ≤ Grade 1. Reduce dose by one dose level. 
If Grade 2 pleural effusion recurs, permanently discontinue vobramitamab duocarmazine. 
3 
Hold vobramitamab duocarmazine until ≤ Grade 1. Reduce dose by one dose level.  
If Grade 3 pleural effusion recurs, permanently discontinue vobramitamab duocarmazine. 
4 
Permanently discontinue vobramitamab duocarmazine  
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.8.2 
Pericardial Effusion  
Table 14 
Management of Pericardial Effusion   
Grade 
Dose Modification Guidelines 
2 
Hold vobramitamab duocarmazine until ≤ Grade 1. Reduce dose by one dose level. 
If Grade 2 pericardial effusion recurs, permanently discontinue vobramitamab duocarmazine. 
3 
Hold vobramitamab duocarmazine until ≤ Grade 1. Reduce dose by one dose level.  
If Grade 3 pericardial effusion recurs, permanently discontinue vobramitamab duocarmazine. 
4 
Permanently discontinue vobramitamab duocarmazine 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.3.9 
Cardiac Adverse Events  
Management guidelines for participants experiencing cardiac AEs are described below. 
Table 15 
Management of Cardiac Adverse Events  
Grade 
Medical Care Guidelines 
Dose Modification Guidelines 
1 
No specific therapy required; close monitoring. 
Hold vobramitamab duocarmazine until 
< Grade 1 or baseline. Consider one dose level 
reduction. 
I 
I 
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Table 15 
Management of Cardiac Adverse Events  
Grade 
Medical Care Guidelines 
Dose Modification Guidelines 
2 
Consider cardiology consultation. Evaluate 
cardiac biomarkers e.g., creatine kinase, troponin, 
and beta-natriuretic peptide. Echocardiogram, 
ECG, and CT imaging if clinically indicated. 
Consider corticosteroids: 1 to 2 mg/kg of oral 
prednisone or equivalent per day divided twice 
daily. Taper corticosteroids over 4 weeks or as 
clinically indicated. 
Hold vobramitamab duocarmazine. 
Resume vobramitamab duocarmazine at next 
scheduled dose if toxicity improves to ≤ Grade 1, 
with or without treatment. 
Consider one level dose reduction. 
Permanently discontinue vobramitamab 
duocarmazine for Grade 2 myocarditis 
(regardless of time to improvement/resolution). 
3-4 
Permanently discontinue vobramitamab duocarmazine 
Consider hospitalization and cardiology consultation. 
Evaluate cardiac biomarkers e.g., creatine kinase, troponin, and beta natriuretic peptide. 
Echocardiogram, ECG, and CT imaging if clinically indicated. 
For Grade 3 or 4 myocarditis, begin corticosteroids: 2 to 4 mg/kg of oral or IV methylprednisolone or 
equivalent per day divided twice daily. Continue IV methylprednisolone 2 mg/kg/day for a total of 5 
days then switch to oral prednisolone 1 mg/kg/day × 3 days, then reduce to 60 mg/day prednisolone. 
Reduce prednisolone dose by 10 mg every 7 days (as toxicity allows) until dose is 10 mg/day. Once 
steroid dose is 10 mg/day, reduce by 5 mg every 7 days then stop. Consider infliximab. 
Note: Dose delay > 28 days will result in treatment discontinuation unless otherwise specified (see Section 7.2.1). 
 
7.4 
Management of Potential Adverse Events Related to Comparator 
Products (Part 1)  
For participants who enrolled prior to Amendment 2, were randomized to the control arm, and 
wish to continue to receive their assigned ARAT, management of toxicities related to abiraterone 
and enzalutamide should be per standard of care and based on approved local prescribing 
information or clinical practice guidelines.  
 
 
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8 
CONCOMITANT THERAPY AND RESTRICTIONS  
8.1 
Concomitant Therapy  
All concomitant medications, including ADT, prophylactic pre-infusion medications, and blood 
products administered during the study until 30 days after the last dose of study treatment or until 
initiation of another anticancer therapy, if earlier, must be recorded in the source document and 
on the electronic case report form (eCRF).  
8.1.1 
Prohibited Therapy  
The following rules concerning concurrent treatment(s) apply in this study: 
• Use of any other antineoplastic therapy is prohibited, including but not limited to 
chemotherapy or other small molecules, biologics, radiotherapy (including 
radiopharmaceutical), hormonal therapy (other than protocol-specified treatment with a 
GnRH modulator for participants on Part 1), or other ARAT (e.g., apalutamide, 
darolutamide, enzalutamide, or abiraterone). 
o For participants who require palliative radiotherapy (i.e., cumulative dose less 
than 3000 rads, limited field distribution) for reasons other than PD, study drug 
may be interrupted for up to 28 days. Palliative radiotherapy may not be given 
concurrently with study drug. Treatment with palliative radiotherapy should be 
initiated at least 24 hours after receiving study drug, and re-initiation of study 
drug may begin 2 weeks after completion of palliative radiotherapy. If palliative 
radiotherapy fields overlap tumor lesions that are designated target lesions, the 
participant may continue on study but will no longer evaluable for objective 
response from the time palliative radiotherapy is initiated. 
• Part 1 only: Use of saw palmetto and pomegranate juice/extract is prohibited. Use of 
5-alpha reductase inhibitors is only allowed if the participant was on a stable dose for at 
least 2 months prior to study entry; they may not be newly started on study. 
• Participants may not receive other investigational drugs during the period of study 
participation. 
• Participants should not receive vaccination(s) with any live virus vaccine from 30 days 
prior to initiation of study treatment through 120 days after the last dose of study 
treatment. Inactivated annual influenza vaccination and non-live SARS-CoV-2 
vaccinations are allowed. 
o Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, bacillus Calmette-Guérin (BCG), and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally 
killed (inactivated) virus vaccines and are permitted. However, intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are prohibited. 
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• Vobramitamab duocarmazine precautions: 
o The following medications have a known risk of skin toxicity and/or 
photosensitivity and are to be avoided if possible: retinoids, denosumab, 
tetracyclines, sulfonamides. 
 
8.1.2 
Permitted Therapy  
Participants may receive the following concurrent therapy: 
• Antiemetics, antidiarrheal, anticholinergics, antispasmodics, antipyretics, antihistamines, 
analgesics, antibiotics and other antimicrobials, histamine receptor antagonists or proton 
pump inhibitors, and other medications intended for supportive care. 
• Transfusions or growth factors are permitted to treat symptoms or signs of anemia or 
thrombocytopenia.  
• Prophylactic use of growth factors is allowed after Cycle 1 Day 1. 
o For any G-CSF product, the prescribing information or summary of product 
characteristics for details on description, administration, and precautions for use 
will be used. 
• Use of bisphosphonates or receptor activator of nuclear factor kappa-B ligand (RANK-L) 
inhibitors is allowed. 
 
Participants with mCRPC who have not undergone bilateral orchiectomy must be maintained on 
a GnRH modulator throughout the study. The choice of GnRH modulator is at the discretion of 
the investigator. Dose and dose schedule (without interruption) will be consistent with the 
prescribing information and should only be adjusted if clinically indicated to maintain castrate 
concentrations of testosterone (serum testosterone ≤ 50 ng/dl or ≤ 1.7 nmol/L). 
8.1.3 
Contraception  
Participants who may become pregnant are required to use highly effective contraceptive 
measures as specified below. Male participants are required to use a condom from the time of 
consent through 27 weeks after the last dose of study treatment regardless of the method of 
contraception of their female partner of childbearing potential. In addition, male participants 
must have their partners of childbearing potential use another method of contraception from the 
time of consent through 27 weeks after the last dose of study treatment. 
Note: female of childbearing potential is defined as not surgically sterilized (hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy) and between menarche and 1-year post 
menopause.   
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• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral  
o Intravaginal  
o Transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulation:  
o Oral  
o Injectable 
o Implantable   
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomy is considered a highly effective birth control method provided that the 
vasectomized partner is the sole sexual partner of the female of childbearing potential 
and that the vasectomized partner has received medical assessment of the surgical 
success. 
• Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the participant. 
 
8.2 
Restrictions  
8.2.1 
Fluid and Food Intake  
There are no requirements for fasting and no restrictions for fluid and food intake by participants 
on vobramitamab duocarmazine during the study. However, it is recommended that, to the extent 
possible, participants have an adequate fluid intake on days associated with PK sampling.  
8.2.2 
Participant Activity Restrictions  
There are no restrictions on participant activities and no requirement for participant confinement 
during the study. However, participants on vobramitamab duocarmazine are advised to limit 
direct sun exposure and to use a broad-spectrum sunscreen when outdoors. Participants are 
advised not to wear contact lenses or rub their eyes on the day of infusion. Participants should be 
advised to avoid activities that promote skin chafing, prolonged or untoward skin pressure, 
occlusive skin dressings, or hot tub baths.  
 
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9 
STUDY PROCEDURES  
This section provides a general description of the procedures and assessments associated with 
this study. The timing of the study procedures, including allowable time windows, is presented in 
Appendix 1. All data should be recorded in source documents and entered into the eCRF.  
Alternative methods for conducting study assessments may 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 
 
If alternative methods are used, local laboratory reference ranges will be documented and 
submitted to the sponsor. Local laboratory test results, laboratory accreditation (if possible), and 
reports of tumor assessments should be retrieved and documented in the participant’s study 
records. 
9.1 
Informed Consent  
The investigator is responsible for ensuring that the participant provides informed consent prior 
to performing any study-related assessments, evaluations, or procedures that are not part of 
standard-of-care for the participant’s disease. Informed consent for this study must be provided 
by signing an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved 
informed consent form (ICF). A copy of the relevant signed ICF must be provided to the 
participant and the original maintained according to institutional procedures. The participant’s 
medical records will include documentation of the informed consent process.  
9.2 
Screening Period  
Participants may receive the first dose of study treatment up to 28 days from signing the ICF. 
The screening period is defined as the time from signing the ICF until treatment assignment in 
the IRT system. At the screening visit, participants will enter the study upon providing informed 
consent. No screening activities outside of usual standard-of-care should be performed prior to 
obtaining informed consent from the participant. 
Participants who sign the ICF but fail to meet the inclusion and/or exclusion criteria are defined 
as screen failures. Demographic information, reason for screen failure, and SAEs related to study 
procedures must be recorded on the eCRF for screen failures. 
9.3 
Registration and Enrollment  
The participant must be registered with the sponsor after eligibility is confirmed.  
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The following information is required during registration: 
• Participant identification number 
• Date of signed informed consent 
• Presence of visceral disease (yes or no) (Part 1 only) 
• Prior taxane (yes vs no) (Part 1 only) 
• Region (US/Canada vs other) (Part 1 only) 
• Tumor type (Part 2 only) 
 
Instructions for registration will be provided by the sponsor prior to site initiation. Instructions 
for randomization will be provided via IRT. 
A participant is considered enrolled to the study once the participant has completed registration 
and has been assigned to a study treatment arm by randomization. 
9.4 
Medical History  
A complete medical history should be obtained during the screening visit. All concurrent medical 
conditions in the last 60 days and any significant past medical conditions (e.g., hospitalizations, 
surgeries, chronic conditions, non-prostate cancer history, etc.) should be collected. Any 
untoward event that occurs prior to the first dose of study treatment should be recorded as 
medical history and not as an AE unless it is due to a protocol-related procedure. 
9.4.1 
Prostate Cancer History (Part 1)  
Prostate cancer characteristics at initial diagnosis and at study entry will be collected. Prior 
prostate cancer treatment will be recorded on the eCRF.  
Sites are requested to provide the following additional information: 
• Type of disease progression at study entry per PCWG3 recommendations (76). Record 
whether progression was manifested by PSA alone, bone ± lymph nodes by location, 
lymph nodes by location only, or viscera (± other sites). Record whether progression 
by imaging at study entry involved the growth or enlargement of pre-existing lesions, 
the development of new lesions, or both. 
• All available PSA values in the medical record up to 12 weeks prior to study entry or 
the 3 most recent values at least 2 weeks apart. 
• Gleason score. 
• Available BRCA1, BRCA2, and ATM results. 
• Available microsatellite instability (MSI) status and tumor mutational burden (TMB) 
results. 
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9.4.2 
Other Cancer History (Part 2)  
Cancer characteristics at initial diagnosis and at study entry will be collected. Prior cancer 
treatment will be recorded on the eCRF.  
Sites are requested to provide the following additional information: 
• All cohorts: MSI status and TMB data (if available). 
• Anal carcinoma: HPV status of the tumor (if available). 
• HNSCC: HPV status of the tumor (if available). 
• Melanoma: BRAF, KIT, and NRAS mutation status (if available). 
• NSCLC: EGFR, KRAS, ALK, ROS1, BRAF, NTRK, MET, ERBB2/HER2/neu, and 
PD-L1 status (if available). 
 
9.5 
Prior and Concomitant Medications and Procedures  
Record all medications, blood products, and procedures administered for 30 days prior to study 
treatment administration until 30 days after the last dose of study treatment or until initiation of 
another anticancer therapy. For participants in Part 1, record ongoing ADT on the concomitant 
medications eCRF. 
9.6 
Physical Examination  
The investigator or qualified designee will perform physical examination of all participants. Full 
physical examination will be performed at screening and at the end of treatment visit (EOTV).  
Full physical examination includes height (screening only), weight, and examination of HEENT 
(head, eyes, ears, nose, and throat), lymph nodes, heart, chest, lungs, abdomen, extremities, 
neurologic system, and total body skin examination (TBSE). In the absence of symptoms or 
disease-related requirements, examination of primary or secondary sexual organs may be 
deferred. 
All other on-study physical examinations will be directed physical examinations based on 
participant signs, symptoms, and tumor location. 
9.6.1 
Vital Signs  
Vital signs include temperature, pulse, blood pressure, respiratory rate, and oxygen saturation 
(pulse oximetry). It is recommended vital signs are obtained in a seated, semi-recumbent, or 
supine position after appropriate physical rest.  
9.6.2 
Height and Weight  
Weight will be measured per the schedule in Appendix 1. Height is measured at screening only. 
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9.7 
Performance Status  
Performance status will be assessed using the ECOG scale (Table 16). 
Table 16 
Eastern Cooperative Oncology Group Performance Status  
Grade 
Description 
0 
Fully active, able to carry on 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 or office work) 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry-on any self-care. Totally confined to bed or chair. 
5 
Dead 
 
9.8 
Laboratory Tests  
9.8.1 
Clinical Laboratory Tests  
Blood and urine samples will be collected as described in Table 17. Both local and central 
laboratory testing will be used. 
Local laboratories should be used for all clinical decision-making, including but not limited to 
decisions regarding study treatment dosing and dose adjustments, if needed. Necessary local 
laboratory testing should be performed as required by the clinical situation.  
Central laboratory testing will be used to determine eligibility (with the exception of pregnancy 
testing, which will be performed locally) and to assess overall safety in the study, unless the 
sponsor medical monitor approves the use of a local laboratory test result, for example, in place 
of an unanalyzable or unavailable central laboratory test result. 
Clinical laboratory tests should be performed and reviewed before administration of study 
treatment. 
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Table 17 
Clinical Laboratory Tests  
Hematology: 
Hemoglobin 
Hematocrit 
Platelets 
Leukocytes 
Absolute neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils 
 
Serum chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Amylase 
Aspartate aminotransferase 
Bicarbonate 
Bilirubin: total, direct, and indirect  
Blood urea nitrogen or urea 
Calcium 
Chloride 
Creatinine 
Gamma glutamyl transferase 
Glucose 
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphate 
Potassium 
Protein, total 
Sodium 
Urate (uric acid) 
Cardiac: 
Creatine kinase 
Creatine kinase myocardial band (CK-MB) 
 
Coagulation (local lab only): 
Activated partial thromboplastin time or partial 
thromboplastin time 
Fibrinogen 
Prothrombin international normalized ratio 
 
Endocrine: 
Thyroid-stimulating hormone 
Thyroxine, free; or triiodothyronine, free 
 
Urinalysis (local lab only): 
Protein 
Occult blood 
If abnormal protein or occult blood, perform reflex test 
for microscopic evaluation 
 
Tumor marker/Other (Part 1 only): 
Prostate-specific antigen 
Testosterone 
 
Pregnancy test (local lab only; Part 2 only): 
Serum or urine human chorionic gonadotropin (hCG) 
 
Infectious disease (Czech Republic and other 
countries where required by local authorities only; 
local lab only):  
HIV, HCV, and HBV tests at screening per local 
guidelines (see Section 5.2) 
 
9.8.2 
Central Laboratory Tests  
Unless otherwise stated, PK, immunogenicity, and biomarker assays will be performed in a 
central laboratory designated by the sponsor. Additional details on collection, processing, 
storage, and shipping of central laboratory samples will be provided in the laboratory manual. 
PK, immunogenicity, and biomarker specimens will be collected according to the schedules in 
Appendix 2. 
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9.8.2.1 
Blood Samples  
It is recommended to collect blood samples contralateral to the site of IV infusion of 
vobramitamab duocarmazine. If an indwelling catheter is used, the fluid in the catheter will be 
removed and discarded prior to the collection of the blood sample. 
PK sampling will be performed in participants receiving vobramitamab duocarmazine per 
Table 24. Select sites will not be required to collect PK samples. The sponsor will inform the 
study site on the need for PK sampling at that site. 
9.8.2.2 
Tumor Biopsy Specimens  
Eligible participants must have an identified archival FFPE tumor specimen block or at least 
5 unstained slides from archival tumor specimen or fresh biopsy (except participants with 
bone-only mCRPC not amenable to biopsy) for immunohistochemistry (IHC) determination of 
B7-H3. Results of B7-H3 IHC testing are not required for eligibility. Tumor specimens will be 
analyzed retrospectively and will not be used to determine eligibility. 
Tumor lesions for biopsy should be lesions that are accessible with acceptable clinical risk in the 
judgment of the investigator and should not be the same lesions used as PCWG3 or RECIST 
target lesions. Multiple lesions may be used to obtain the biopsy sample. Lesions for biopsy 
should be of sufficient size to enable acquisition of at least 2 tumor biopsy cores using a 
16-gauge biopsy needle. Exceptions to the gauge of the needle may be considered after 
consultation with the sponsor’s medical monitor. Up to 3 additional biopsy cores may be 
obtained if this can be performed with acceptable clinical risk in the judgment of the investigator. 
Excisional biopsies are allowed if these can be performed with acceptable clinical risk in the 
judgment of the investigator. Immediate confirmation of the adequacy of the biopsy specimen 
and the presence of malignant cells in the tumor biopsy are strongly encouraged. Additional 
instructions for the processing and storage of tumor biopsy specimens are provided in the 
laboratory manual. 
9.9 
Tumor Assessments  
Tumor assessments will be performed per the schedules in Appendix 1. If scans are performed 
outside of the scheduled visit window, and the participant has not progressed, every attempt 
should be made to perform subsequent scans at their originally scheduled time points (calculated 
from Cycle 1 Day 1). 
Baseline (screening) tumor assessments include CT and/or MRI scan of the chest, abdomen and 
pelvis. Subsequent tumor assessments will image the chest, abdomen and pelvis. The same 
imaging modality and procedures (e.g., the same CT contrast protocol) as those of the baseline 
assessment should be used. 
CT or MRI scan of the brain or other areas of disease involvement will be performed when 
clinically indicated (e.g., history of or suspicion of current brain metastases); these scans are to 
be repeated throughout the study if there is evidence of disease at screening. 
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For participants with mCRPC (Part 1) or any participant with signs and/or symptoms of bone 
involvement (Part 2), technetium-99m bone scan will be performed at screening and at each 
tumor assessment on study to evaluate bone lesions. For participants with equivocal new bone 
lesion(s) on bone scan consider obtaining additional imaging to evaluate new lesion(s) for tumor 
involvement, e.g., x-ray, CT, or MRI. In situations where bone scan ﬁndings are suggestive of a 
ﬂare reaction or the apparent new lesion(s) may represent trauma, additional imaging with other 
modalities such as MRI or ﬁne-cut CT, should be obtained to conﬁrm these results. 
Tumor response will be assessed according PCWG3 criteria (76) in Part 1 or RECIST v1.1 (77) 
in Part 2 (see Section 11.1.1). 
9.10 
Electrocardiography  
Twelve-lead ECGs will be obtained per Appendix 1 and as clinically indicated to evaluate 
potential cardiac AEs. The ECG acquired will be a single tracing. If the single ECG tracing 
demonstrates an abnormality, additional ECG tracings should be obtained to evaluate the ECG 
abnormality. ECGs will be performed at the local institution and interpreted by the investigator 
or medically qualified delegate.  
ECG tracings must be performed after the participant has been resting in a supine position (or 
semi-recumbent if supine is not tolerated) for at least 5 minutes. ECGs should be obtained prior 
to other study procedures (e.g., blood draws) scheduled at the same time. Environmental 
distractions and other circumstances that may induce changes in heart rate should be minimized 
where possible.  
At visits where ECGs and time-matched PK samples are collected, ECGs should be performed 
prior to obtaining the time-matched PK sample. 
Actual times of the ECG tracings will be recorded on the eCRF. The original ECG tracing(s) will 
be stored in the participant’s record as source data. 
9.11 
Echocardiography  
Echocardiograms (or multigated acquisition [MUGA] scans) will be obtained and analyzed 
locally in all participants. The same modality should be used throughout the study for any given 
participant. Echocardiograms (or MUGA scans) performed will be evaluated for any change in 
LVEF from baseline (screening). 
9.12 
Ophthalmic Examination  
Ophthalmic examination will be performed by an ophthalmologist per Appendix 1. The 
examination will include visual acuity testing (with correction), fundoscopic examination, and 
tonometry. Other directed studies (e.g., optical coherence tomography) will be performed as 
clinically indicated.  
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9.13 
Symptomatic Skeletal Events (Part 1 Only)  
Symptomatic skeletal events (SSEs) are a clinical study endpoint to describe skeletal morbidity 
defined as new symptomatic pathological fracture, requirement for radiation therapy to relieve 
bone pain, spinal cord compression, or tumor-related orthopedic surgical intervention. These 
events must be recorded in the source document and on the SSE eCRF regardless of relationship 
to PD. 
9.14 
End of Treatment Visit  
The end of treatment visit (EOTV) should be performed within 30 days after the participant has 
met study treatment discontinuation criteria and before initiation of any subsequent anticancer 
therapies. It is recognized that participants may go to other facilities for continuing care or may 
elect not to return to the study site. Therefore, failure to return for an EOTV will not be 
considered a protocol deviation. Whenever possible, all required procedures and tests should be 
performed. 
Tumor assessments are not required at the EOTV for participants who had a previous scan 
performed within 12 weeks of the EOTV. 
9.15 
Post-Treatment Follow-Up Period  
The post-treatment follow-up period is approximately 6 months and includes the following 
assessments: 
• Survival follow up: Survival status is assessed approximately Q12W (± 14 days) for 
up to 6 months from last dose of study treatment or until withdrawal of consent, 
LTFU, death, or end of study, whichever occurs first. The first survival follow-up 
assessment will be scheduled 12 weeks after the last dose of study treatment. 
Participants may be followed via clinic visit, telephone, paper mail, or other electronic 
contact. Updated survival status may be requested by the sponsor at any time during 
the study (i.e., regardless of the interval since the prior assessment). 
• Tumor response status: Tumor imaging is performed approximately Q12W (± 14 days) 
from last tumor response assessment for up to 6 months from last dose of study 
treatment for all participants who discontinue from study treatment due to reasons 
other than PD (e.g., toxicity) until PD, death, initiation of another anticancer therapy, 
withdrawal of consent, LTFU, or end of study, whichever occurs first. 
• Part 1 only: Serum testosterone and PSA are assessed approximately Q12W 
(± 14 days) from last tumor response assessment for up to 6 months from last dose of 
study treatment for all participants who discontinue from study treatment due to 
reasons other than PD (e.g., toxicity) until PD, death, initiation of another anticancer 
therapy, withdrawal of consent, LTFU, or end of study, whichever occurs first. 
 
For Part 2, the duration of follow-up may be reduced from 6 months at the discretion of the 
sponsor. Any decision to reduce the follow-up duration will be communicated to the site.  
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The definition of another anticancer treatment after discontinuation of study treatment includes, 
but is not limited to, chemotherapy, hormonal therapy, gene therapy, immunotherapy, 
cryotherapy, biologics, systemic radiation, or surgery for prostate cancer. 
 
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10 
ASSESSMENT OF PHARMACOKINETICS AND 
PHARMACODYNAMICS  
10.1 
Pharmacokinetic Assessments  
Serum concentrations of vobramitamab duocarmazine (conjugated and total antibody) will be 
measured using validated bioanalytical methods. Plasma concentrations of the payload, SYD986, 
will be measured using a liquid chromatography-tandem mass spectrometry assay. 
Analysis of concentration data will be used to estimate PK parameters for vobramitamab 
duocarmazine (conjugated and total antibody) and SYD986 (and metabolites if appropriate) in 
participants with sufficient concentration data to calculate PK parameters. If applicable, these PK 
parameters may include maximum concentration (Cmax), area under the concentration-time curve 
until time t (AUCt), area under the concentration-time curve for a dosing interval (AUCtau), 
trough concentration (Ctrough), and time-to-maximal concentration (Tmax). 
Population PK analyses and exposure-response analyses may be conducted using data from this 
study alone or combined with data from other studies. 
10.2 
Immunogenicity Assessments  
Anti-drug antibodies (ADAs) against vobramitamab duocarmazine will be detected using 
validated assay methods. Samples positive for ADA will be saved for future evaluation of 
neutralizing antibody activity. Exposure by ADA status analyses may be performed to assess the 
relationship between ADA positivity and vobramitamab duocarmazine (conjugated and total 
antibody) and SYD986. 
10.3 
Biomarker Assessments  
Biomarker samples will be prospectively collected and retrospectively analyzed.  
The following assessments may be performed: 
• Analysis of B7-H3 expression by IHC on archival or fresh pre-treatment tumor 
specimens (if no archival specimen is available). Relationships between B7-H3 
expression and efficacy and other endpoints may be assessed. 
 
 
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11 
ASSESSMENT OF EFFICACY  
11.1 
Efficacy Assessments  
11.1.1 
Tumor Response Assessments  
Tumor response assessments will be determined using CT and/or MRI. Bone scans will be 
obtained, in addition to CT and/or MRI, to evaluate bone metastasis. Target and non-target 
lesions will be designated per PCWG3 (Part 1) or RECIST v1.1 (Part 2) criteria at screening and 
evaluated approximately Q8W for the first 24 weeks and Q12W thereafter (or as clinically 
indicated) until PD, death, initiation of another anticancer therapy, withdrawal of consent, LTFU, 
or end of study, whichever occurs first. At each tumor response assessment time point, the 
overall tumor response status will be determined by investigators based on assessment of target 
and non-target lesions as well as appearance of any new lesions per PCWG3 criteria (76) in 
Part 1 or RECIST v1.1 (77) in Part 2. 
After receipt of the last dose of study treatment, participants will enter a post-treatment 
follow-up period (Section 9.15). 
For statistical analysis, objective tumor response will be determined by investigators. Study 
treatment dosing decisions will also be made on the basis of local investigator assessment of 
tumor response per PCWG3 (Part 1) or RECIST v1.1 (Part 2). 
If the response assessment is equivocal, it is recommended to continue study treatment and 
reassess tumor burden at the next scheduled assessment or sooner if clinically indicated. Note, an 
isolated increase in PSA is not a condition for study treatment discontinuation in Part 1. 
Requirements for determination and confirmation of radiographic progression per PCWG3 are 
summarized in Table 18. Refer to Eisenhauer et al. for RECIST v1.1 guidelines (77). 
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Table 18 
Radiographic Progressive Disease per Prostate Cancer Working 
Group 3  
Visit Date 
Criteria for Bone Progression 
Criteria for Soft Tissue Progression 
Week 8 
2 or more new lesions compared to 
baseline bone scan. 
Progressive disease on CT or MRI 
Requires confirmation scan at least 
6 weeks later with ≥ 2 additional lesions 
compared to week 8 scan. 
No confirmation scan required. 
Week 16 or later 
2 or more new lesions compared to week 
8 bone scan. 
Progressive disease on CT or MRI 
Requires confirmation scan at least 
6 weeks later for persistence or increase 
in number of lesions. 
No confirmation scan required. 
Note: Adapted from Scher et al. (76). 
Note: The first bone scan completed after baseline will be considered the “Week 8 bone scan” regardless of 
whether the scan is obtained at Week 8 or at an unscheduled assessment. 
Abbreviations: CT: computed tomography; MRI: magnetic resonance imaging 
 
11.1.2 
Survival Assessments  
Participants who discontinue from study treatment will be assessed for survival status as 
described in Section 9.15. 
 
 
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12 
ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY  
The safety assessment is based on AEs occurring from the first administration of study treatment 
until 30 days after the last dose of study treatment or until initiation of another anticancer 
therapy, whichever comes first. Events that occur during the follow-up period will be captured 
and followed if they are considered by the investigator to be treatment related. The safety 
assessment is based on signs, symptoms, physical examination findings, and laboratory test 
results. 
12.1 
Definitions  
12.1.1 
Adverse Event  
An AE means any untoward medical occurrence associated with the use of a drug in humans. 
AEs may or may not be drug related. An AE is: 
• Any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of a medicinal product. 
• Any medical occurrence that is new or has increased in severity or frequency from the 
baseline condition. 
• Any abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
12.1.2 
Adverse Drug Reaction  
An adverse drug reaction (ADR) is a noxious and unintended response to the medicinal product 
related to any dose. The phrase “response to a medicinal product” means that a causal 
relationship between a drug and an AE is at least a reasonable possibility. 
12.1.3 
Adverse Event of Special Interest  
An adverse event of special interest (AESI) is an AE of scientific and medical concern specific to 
the sponsor’s study treatment, for which ongoing monitoring and rapid communication by the 
investigator to the sponsor may be appropriate. An AESI may be serious or non-serious. 
12.1.4 
Serious Adverse Event  
An SAE is any AE that results in any of the following outcomes: 
• Death. 
• Life-threatening (immediate risk of death). 
• Inpatient hospitalization for longer than 24 hours or prolongation of existing 
hospitalization (even if the event is Grade 1). 
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• Persistent or significant disability or incapacity. 
• Congenital anomaly/birth defect. 
• Important medical events (i.e., jeopardize the participant or require intervention to 
prevent one of the other outcomes listed above). 
 
12.1.5 
Assessment of Causality  
Assessment of causality is a determination that describes the relationship or association of the 
drug with an AE.  
This assessment of causality is made by the investigator based on 1) temporal relationship of the 
event to the administration of study treatment; 2) whether an alternative etiology has been 
identified, and 3) biological plausibility.  
Causality assessments that are considered not related to study treatment: 
• None: The event is related to an etiology other than the study treatment. An 
alternative etiology should be documented in the participant’s medical record. 
• Unlikely: The event is unlikely to be related to the study treatment and likely to be 
related to factors other than study treatment. An alternative explanation is more likely 
(e.g., concomitant drugs, concomitant disease), or the relationship in time suggests 
that a causal relationship is unlikely. 
 
If an SAE causality assessment is “unlikely” or “none”, the investigator should document the 
likely causative mechanism for the event. 
Causality assessments that are considered related to study treatment: 
• Possible: There is a temporal association of the event with the administration of the 
study treatment. There is a plausible mechanism for relationship to the study 
treatment. However, there is an alternative explanation, such as the participant’s 
clinical status or underlying disease. 
• Probable: There is a temporal association of the event with the administration of 
study treatment. There is a plausible mechanism for relationship to the study 
treatment. There is no other reasonable explanation. 
• Definite: There is a temporal association of the event with the administration of study 
treatment. There is a plausible mechanism for relationship to the study treatment. 
Causes other than the study treatment are ruled out, or the event re-appeared on re-
exposure to the study treatment. 
 
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12.1.6 
Severity Criteria  
Severity grade will be assessed using the National Cancer Institute (NCI) CTCAE v5.0.  
For AEs not contained in CTCAE v5.0, the investigator may assign intensity according to the 
following general CTCAE v5.0 grading scale: 
• Grade 1 = Mild; asymptomatic or mild symptoms, clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL. 
• Grade 3 = Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.  
• Grade 4 = Life-threatening consequences; urgent intervention indicated. 
• Grade 5 = Death related to AE. 
 
12.2 
Adverse Event Collection and Documentation  
12.2.1 
All Adverse Events  
AEs and SAEs reported between the time the participant signs the ICF and the administration of 
the first dose of study treatment will be captured as concurrent medical history unless the events 
(AEs and SAEs) are attributed to protocol-specified procedures.  
PD or events related to PD are considered efficacy endpoints, and not reported as AEs or SAEs. 
AEs and SAEs will be reported if it is unclear whether the event is due to PD. 
Events attributed to protocol-specified procedures will be collected on the AE eCRFs and SAE 
report form, as appropriate.  
AEs, regardless of seriousness, severity, or relationship to study treatment, are documented in the 
source and the eCRF, including:  
• Duration, severity, and seriousness of each AE,  
• Action taken with respect to the study treatment(s), 
• Investigator’s attribution/causality assessment, 
• Any medications used to treat the AE, 
• Outcome of the event(s). 
 
A diagnosis should be recorded when signs and symptoms are due to a common etiology (e.g., 
cough, runny nose, sneezing, sore throat, and head congestion should be reported as “upper 
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respiratory infection”). All treatment measures for AE management will be recorded. All 
non-serious AEs should be entered into the eCRFs within 10 days of study site awareness. 
Clinical Laboratory Changes: Clinical laboratory test results are evaluated by the investigator for 
clinical significance. The investigator is responsible for reviewing the results of all laboratory 
tests in a timely manner. The investigator may repeat the laboratory test or request additional 
tests to verify the results of laboratory tests.  
Clinically significant laboratory abnormalities are reported as AEs. A laboratory abnormality is 
considered clinically significant if: 
• Associated with discontinuation of study treatment, study treatment dose reduction or 
delay, or required intervention.  
• Suggestive of disease or organ toxicity.  
 
Laboratory abnormalities associated with a diagnosed AE are not reported as separate AEs. For 
example, report renal failure or hematuria, not the laboratory abnormality elevated creatinine or 
urine red blood cells increased. 
The appropriate CTCAE v5.0 term should be used to report the laboratory abnormality; for 
example, as neutrophil count decreased (not neutropenia), platelet count decreased (not 
thrombocytopenia), and anemia (not hemoglobin decreased). 
The sponsor reports all suspected unexpected serious adverse reactions (SUSARs) to the 
investigator according to applicable regulatory reporting requirements. The investigator must 
report SUSARs to the appropriate IEC/IRB as required by the IEC/IRB. 
The participant may be provided with a Study CP-MGC018-03 wallet card. 
12.2.2 
Serious Adverse Events  
All SAEs, regardless of causality, occurring from first administration of study treatment through 
30 days after the last dose of study treatment or until initiation of another anticancer therapy, if 
earlier, must be reported to the sponsor. SAEs related to study treatment may be reported at any 
time, regardless temporal relationship to study treatment dosing. The investigator should report 
the SAE to the sponsor. 
• Within 24 hours of becoming aware of an SAE, the investigator should send the 
sponsor a completed SAE report form by email, 
 
The SAE report form and completion guidelines, and contact 
information for reporting SAEs, are provided by the sponsor. Upon receipt of SAE 
follow-up information, a follow-up SAE report form should be submitted within 
24 hours of becoming aware of the follow-up information. SAEs should be entered 
into the eCRFs within 5 calendar days of the site’s awareness. 
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• The investigator must follow all SAEs until resolution and record the date of 
resolution. Resolution of an event is defined as the return to pre-treatment status or 
stabilization of the condition with the expectation that it will remain chronic. 
Unresolved SAEs must be followed until: 
o The event resolves. 
o The event stabilizes. 
o The event returns to baseline, if a baseline value/status is available. 
o The event can be attributed to etiology other than the study treatment or to 
factors unrelated to study conduct. 
o It becomes unlikely that any additional information can be obtained 
(participant or health care practitioner refusal to provide additional 
information, lost to follow up after demonstration of due diligence with 
follow-up efforts). 
• Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the study must be reported as a SAE, except: 
o A standard hospitalization for administration of study treatment. 
o A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling, PK or 
biomarker blood sampling).  
o Hospitalizations not intended to treat an acute illness or AE (e.g., social 
reasons such as pending placement in long-term care or hospice facility). 
o Surgery or procedure planned before entry into the study (must be 
documented in the eCRF). 
• Any SAE of suspected transmission of an infectious agent via a medicinal product 
will be reported. 
 
The sponsor reserves the right to request additional information for any participant with ongoing 
AEs/SAEs at the end of the study, if judged necessary. 
12.2.3 
Pregnancy  
All pregnancies in female participants or female partners of male participants must be reported to 
the sponsor. The pregnancy exposure form is sent to the sponsor within 24 hours of study site 
awareness. The reporting period is from consent through 27 weeks after the last dose of study 
treatment, or initiation of another anticancer therapy. Abnormal pregnancy outcomes (e.g., 
spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs, and reported according to the method in Section 12.2.2.  
The investigator must attempt to follow the pregnancy to term or termination and report the 
outcome and health status of the mother and child. The investigator should discuss with and 
encourage the pregnant partner to allow collection of follow-up information. The pregnant 
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partner information release form must be signed prior to collecting follow-up information. 
Follow-up information will be collected for all live newborns at birth and 6 months after birth. 
Information will be collected to assess study treatment effects on the newborn. If appropriate, 
follow up will be extended. 
12.2.4 
Special Reporting Situations  
12.2.4.1 
Sponsor Notification of Adverse Events of Special Interest  
AESIs will be followed as part of standard safety monitoring activities by the sponsor. The 
sponsor must be notified of these AESIs regardless of seriousness (i.e., serious and nonserious 
AESIs). Some AESIs must be reported immediately to the sponsor within 24 hours of the study 
site’s awareness of the event. See Table 19 for a list of protocol-specific AESIs with reporting 
requirements including the timeframe within the events are entered in the eCRF. 
Table 19 
Adverse Events of Special Interest  
Adverse Event of Special Interest 
Reporting Requirement 
Infusion related reaction ≥ Grade 2 
For Grade 2 events: 
Within 10 days of the study site’s 
awareness of the event. 
For ≥ Grade 3 events: 
Within 24 hours of the study site’s 
awareness of the event. 
Ocular toxicity (i.e., keratitis, conjunctivitis, blepharitis, 
keratoconjunctivitis sicca) ≥ Grade 2 
For Grade 2 events: 
Within 10 days of the study site’s 
awareness of the event. 
For ≥ Grade 3 events: 
Within 24 hours of the study site’s 
awareness of the event. 
Stevens-Johnson syndrome or toxic epidermal necrolysis 
Within 24 hours of the study site’s 
awareness of the event. 
Pleural effusion ≥ Grade 3 
Within 24 hours of the study site’s 
awareness of the event. 
Pericardial effusion ≥ Grade 3 
Within 24 hours of the study site’s 
awareness of the event. 
Cardiac adverse event of any grade 
For ≤ Grade 2 events: 
Within 10 days of the study site’s 
awareness of the event. 
For ≥ Grade 3 events: 
Within 24 hours of the study site’s 
awareness of the event. 
 
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12.2.4.2 
Overdose  
Overdose is any vobramitamab duocarmazine dose ≥ 20% more than the protocol-specified dose. 
In the event of an overdose, the participant should be closely monitored for AEs. 
Any AE resulting from overdose must be reported to the sponsor within 24 hours of awareness. 
All AEs associated with an overdose will be recorded in the eCRF. 
12.2.4.3 
Product Quality Issues  
Any suspected transmission of an infectious agent via a medicinal product, or other product 
quality issue that results in an event of clinical consequence are considered AEs. The AE 
resulting from a product quality issue should be reported within 24 hours of awareness of the 
event. See Section 13 for product quality complaint (PQC) handling. 
12.2.4.4 
Discontinuation of Study Treatment Due to an Adverse Event  
Any AE not related to PD that results in study treatment discontinuation must be reported to the 
sponsor within 24 hours of discontinuation. Follow up of the AE will continue until resolution or 
stabilization of the AE unless the participant withdraws consent for further follow up. 
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13 
PRODUCT QUALITY COMPLAINT HANDLING  
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or 
packaging, i.e., any dissatisfaction relative to the identity, quality, durability, or reliability of a 
product, including its labeling or package integrity. A PQC may have an impact on the safety and 
efficacy of the product. Timely, accurate, and complete reporting and analysis of PQC 
information from studies are crucial for the protection of participants, investigators, and the 
sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established 
procedures in conformity with regulatory requirements worldwide to ensure appropriate 
reporting of PQC information; all studies conducted by the sponsor or its affiliates will be 
conducted in accordance with those procedures. 
13.1 
Procedures  
Any PQC associated with an investigational product or non-investigational product supplied by 
the sponsor will be reported according to the instructions provided in the pharmacy manual. 
All initial PQCs must be reported to the sponsor by study-site personnel within 24 hours of 
awareness of the event. 
If the PQC occurs in the setting of an SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.2.2, SAEs). A sample of 
the suspected product should be maintained under the correct storage conditions for further 
investigation if requested by the sponsor. 
13.2 
Contacting Sponsor Regarding Product Quality  
The name(s) (and corresponding telephone numbers) of the individuals who should be contacted 
regarding PQCs are listed on the contact information page(s) provided in the pharmacy manual. 
 
 
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14 
STATISTICAL ANALYSIS  
This section outlines the statistical methodology and principles used for data analysis in this 
study. A separate statistical analysis plan (SAP) and statistical programming plan (SPP) will 
further describe the details regarding statistical methods and govern the statistical analysis.  
14.1 
Determination of Sample Size  
The planned sample sizes are described below. Study enrollment is closed. 
In total, up to approximately 382 participants were to enroll in the study, including 
182 participants in Part 1 and approximately 200 participants planned in Part 2. However, the 
number of participants enrolled could not be determined precisely in advance and was to be 
determined by the safety profile and early evidence of clinical benefit. 
Part 1 
Approximately 100 participants as planned per Amendment 2 will be randomized in a 1:1 ratio to 
each of the two vobramitamab duocarmazine arms. Randomization will be stratified by 3 
stratification factors: 1) visceral disease (yes vs no), 2) prior taxane (yes vs no), and 3) region 
(United States/Canada vs other). The historic benchmarks for each vobramitamab duocarmazine 
arm to compare with are 25% PSA response rate and 8 months median rPFS observed on the 
control arm of the PRESIDE trial of docetaxel after enzalutamide (78). 
Since the goal of this part of the study is to select one of two vobramitamab duocarmazine doses 
for further study in participants with mCRPC, Simon’s randomized Phase 2 selection design (79) 
was used to determine the sample size for each arm. The planned sample size of 50 per arm 
would provide 76% probability of correctly selecting the best dose assuming 66% and 59% rPFS 
rates at 6 months (equivalent to 10 vs 8 months median rPFS) for the two vobramitamab 
duocarmazine arms, respectively. Sample size determination based on traditional hypothesis 
testing would be prohibitively large for a Phase 2 study. A sample size of 350 per arm would be 
required to have 70% power to detect 59% vs 66% rPFS rate between two arms at 1-sided 0.1 
alpha level. Comparing each arm to a fixed benchmark would also require an unfeasibly large 
sample size of 160 per arm in order to have 70% power to reject a fixed null rPFS rate of 59% at 
a 1-sided 0.1 alpha level under an alternative rPFS rate of 66% for each arm, respectively. As 
both doses being tested fall within the range of doses that demonstrated biological activity based 
on CP-MGC018-01 study data, there is minimal risk of choosing a dose that is not biologically 
active. All available safety and efficacy data from this study will be used to justify the dose 
ultimately selected for further study (e.g., in a later registrational study). 
For PSA response rate, the planned sample size of 50 per arm would provide 84% power to reject 
25% null rate at 1-sided 0.1 alpha level for each vobramitamab duocarmazine arm at an 
alternative rate of 40%.  
Total enrollment in Part 1 was planned be up to approximately 120 participants to account for 
participants originally enrolled on the control arm per Amendment 1. Due to unexpected rapid 
enrollment in Part 1, this part of the study enrolled a total of 182 participants. 
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Part 2 
Part 2 of the study was closed to enrollment prior to completing the Stage 1 enrollment target(s). 
Part 2 planned to enroll up to approximately 200 response-evaluable participants, consisting of 
approximately 40 participants for each of 5 tumor-specific cohorts (Table 20). For each cohort, 
Simon’s 2-stage design (80) is used to test null hypothesis H0: p ≤ p0 vs alternative hypothesis 
H1: p = p1 at 1-sided significance level ≤ 0.1 (alpha) with the power of approximately 80%, 
where p0 is the benchmark response rate representing a lack of tumor response and p1 is the 
target response rate representing evidence of sufficient tumor response worthy of further 
development. Specifically, for each cohort, Stage 1 will enroll n1 response-evaluable participants. 
If the number of responses in a tumor-specific cohort enrolled in Stage 1 is less than or equal to 
the prespecified number of responses (r1), then enrollment for the tumor-specific cohort will be 
stopped for futility, otherwise, cohort enrollment will continue to Stage 2 to enroll an additional 
n2 response-evaluable participants. At the end of Stage 2, if the number of tumor responses out of 
all n = n1+n2 response-evaluable participants is at least r, then the null hypothesis H0 will be 
rejected, and the cohort is considered to have sufficient efficacy for further development. 
Simon’s 2-stage design parameters for each tumor-specific cohort are provided in Table 20.  
 
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Table 20
Simon’s Two-Stage Design Parameters
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14.2 
Independent Data Monitoring Committee  
An IDMC will oversee the ongoing monitoring and interpretation of safety data from all parts of 
this study (Part 1 and Part 2). An IDMC charter will be reviewed and approved by the IDMC 
prior to study initiation. The IDMC will evaluate aggregate safety data and efficacy data for the 
futility analysis in Part 1. 
The first IDMC meeting will occur after 20 participants in each arm of Part 1 have been enrolled 
and completed at least 1 cycle of treatment or after approximately 6 months from first 
enrollment, whichever comes first. The IDMC may meet at any time if emergent safety data 
warrant a safety review. Reviews will continue in approximate 6-month intervals (± 1 month). If 
an IDMC meeting is scheduled to occur near the time of the planned futility analysis for Part 1, 
the timing of the meeting may be adjusted to align with the futility analysis. 
The IDMC will be empowered to recommend changes to the study including discontinuation or 
modification of a study treatment arm, cohort, or overall termination of the study as appropriate. 
The IDMC will be provided with clinical data tables and listings for these reviews. Additional 
details on the IDMC may be found in the IDMC charter. 
14.3 
Analysis Populations  
Study analyses will be performed on the following populations: 
• Safety Population: All participants who received any dose of study treatment. This 
population will be used to summarize safety data. Participants will be analyzed 
according to the actual study treatment received. This population will also be used to 
summarize baseline data for biomarker and immunogenicity analyses and for 
supplementary analyses of rPFS, PFS, and OS. 
• Intent-to-Treat (ITT) Population: All participants*. Participants will be analyzed 
according to the study treatment assigned. This population will be used for summary 
of baseline data and analyses of rPFS, OS, and other efficacy endpoints where 
applicable. 
• Tumor Response Evaluable Population: All participants* who received at least one 
dose of study treatment and had RECIST-evaluable disease per PCWG3 (Part 1) or 
RECIST v1.1 (Part 2) at baseline (i.e., participants with bone-only disease are 
excluded from this population). This population will be used for efficacy analyses 
related to tumor response and will be analyzed according to the study treatment 
assigned. 
• PSA Response Evaluable Population: All participants in Part 1* who received at 
least one dose of study treatment, with a baseline PSA ≥ 2 ng/mL and at least one 
post-baseline PSA measurement. This population will be used to calculate and 
summarize PSA response rates according to the study treatment assigned. 
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• PK Evaluable Population: All participants who received at least one dose of study 
treatment, date and time of dose administration and relative PK sample collection are 
known, and have sufficient concentration data to derive at least one PK parameter. 
Participant data may be excluded from PK analysis at the discretion of the 
pharmacokineticist. 
• ADA Evaluable Population: All participants who received at least one dose of 
vobramitamab duocarmazine and have at least one ADA sample. 
 
* Note: participants in Part 1 who were assigned to the control arm prior to its removal in 
Amendment 2 and who were re-randomized to a vobramitamab duocarmazine arm will be 
analyzed as a separate cohort for safety and efficacy endpoints. 
14.4 
Demographics and Baseline Characteristics  
Participant disposition, demographics, baseline characteristics, cancer history, prior cancer 
therapy, and medical history will be summarized using descriptive statistics. 
14.5 
Study Treatment Exposures and Concomitant Medications  
Study treatment exposures and concomitant medications will be summarized by descriptive 
statistics. The summary of study treatment exposure will include descriptive statistics as well as 
frequency counts for the number of doses or cycles received, the total dose actually administered 
as well as the total dose intended, and the dose intensity which is calculated as percentage of 
total dose actually administered divided by total dose intended during whole treatment period. 
Concomitant medications are coded using the World Health Organization Drug Dictionary. 
14.6 
Pharmacokinetic, Exposure-Response, Immunogenicity, and 
Biomarker Analyses  
14.6.1 
Pharmacokinetic Analysis  
Concentrations and PK parameters for vobramitamab duocarmazine will be summarized by dose 
cohort using descriptive statistics including number of participants, arithmetic mean, standard 
deviation, minimum, median, maximum, geometric mean, and coefficient of variation of the 
mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate.  
Population PK analyses may be conducted using nonlinear mixed effects methodology. Data 
from this study may be pooled with data from other studies for analysis. A covariate analysis 
may be performed to relate the effect of intrinsic and extrinsic participant factors to exposure. 
14.6.2 
Exposure-Response Analyses  
Exposure-response analysis to assess the relationship between vobramitamab duocarmazine 
exposure indices derived from population PK analyses and select efficacy and AEs may be 
evaluated. 
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14.6.3 
Immunogenicity Analysis  
Incidence of ADA, including treatment-emergent and treatment-boosted ADA, will be assessed 
as absolute occurrence (n) and percent (%) of participants and will include ADA titer level. For 
participants who have a treatment-emergent ADA positive result, time to first treatment-emergent 
ADA positive result and the time course of ADA positivity will be summarized. 
14.6.4 
Biomarker Analysis  
Summary statistics for parameters listed in Section 10.3 will be summarized. Analyses may be 
presented graphically, with possible associations between baseline B7-H3 expression and 
efficacy (e.g., tumor response, rPFS) explored. 
14.7 
Efficacy Endpoints and Analyses  
Efficacy analyses will consist of descriptive statistics and corresponding 95% 2-sided confidence 
intervals (CIs) when appropriate. Participants assigned to the control arm of Part 1 prior to its 
removal in Protocol Amendment 2 who were re-randomized to a vobramitamab duocarmazine 
arm will be analyzed for efficacy as a separate cohort. 
14.7.1 
Primary Efficacy Endpoints and Analysis  
14.7.1.1 
Radiographic Progression-Free Survival per PCWG3 (Part 1)  
In Part 1, the primary efficacy endpoint is rPFS determined by the investigator. The rPFS is 
defined as the time from the date of randomization to the date of first documented PD per 
PCWG3 or death from any cause, whichever occurs first. Radiographic PD per PCWG3 is 
defined in Section 11.1.1 and Table 18 as follows: 
• Progression in soft tissue lesions per RECIST v1.1 (77) 
• Progression in bone lesions per PCWG3 criteria: 
o At least 2 new lesions (compared to baseline) are observed on first post-
baseline scan (Week 8 scan), and the next scan (confirmatory at least 6 weeks 
later) on Week 16 shows at least 2 additional new lesions   
o At least 2 new lesions (compared to Week 8 scan) are observed on a scan 
performed after Week 8, and the next scan (confirmatory at least 6 weeks 
later) show persistence or increase in number of new lesions 
 
For participants without an event of PD or death at the time of data cutoff for rPFS analysis, the 
rPFS will be censored at the date of the last tumor assessment. Specifically, the censoring rules 
described in Table 21 will apply to the analysis of rPFS. 
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Table 21
Censoring Rules for Primary Analysis of Radiographic Progression-
Free Survival 
Situation
Date
Outcome
No baseline tumor assessment 
Randomization date 
Censored 
Death prior to first scheduled 
tumor assessment 
Date of death 
Progressed 
No post-baseline tumor assessment 
in absence of death prior to first 
scheduled tumor assessment 
Randomization date 
Censored 
Documented progressive disease 
Date of progressive disease 
Progressed 
Initiation of subsequent anticancer 
therapy in absence of documented 
progressive disease 
Date of last tumor assessment prior to 
initiation of subsequent anticancer 
therapy 
Censored 
Death or documented progression 
immediately after missing two or 
more consecutive scheduled tumor 
assessments 
Date of last tumor assessment prior to 
missed tumor assessments 
Censored 
The Kaplan-Meier method will be used to generate rPFS curves and estimate the median rPFS 
along with 95% confidence intervals (CIs) for each study treatment arm. The method of 
Brookmeyer and Crowley (81) will be used to construct 95% CI for median rPFS. The 95% CIs 
for rPFS rates at 6, 8, and 12 months will be calculated by normal approximation after log(-log) 
transformation. A sensitivity analysis will be performed that includes documented PD or death as 
a rPFS event regardless of when it occurs during the study. Supplementary analyses may be 
performed based on the Safety Population. 
The analysis of rPFS will occur when all participants in Part 1 have been followed for rPFS for at 
least 6 months. The 2.0 mg/kg Q4W dose of vobramitamab duocarmazine will be selected for 
further study if it demonstrates promising efficacy, unless there is compelling additional activity 
at the higher dose and it has an acceptable safety and tolerability profile. Efficacy, safety, and 
exposure-response variables will inform the selection decision. 
14.7.1.2 
Objective Response Rate per RECIST v1.1 (Part 2) 
In Part 2, best overall response (BOR) will be categorized using RECIST v1.1 as CR, PR, SD, 
PD, or NE. To qualify as an objective response, CR and PR require confirmation at least 4 weeks 
after initial observation of CR or PR, and SD requires observation at least once after 6 weeks 
from the start of study treatment. BOR will be evaluated from the start of study treatment. 
The number and percent of participants with BOR per RECIST v1.1 will be summarized. The 
ORR is estimated as the proportion of participants in the Tumor Response Evaluable Population 
who achieve a BOR of confirmed CR or PR per RECIST v1.1.
Disease control rate (DCR) is defined as the percentage of tumor response-evaluable participants 
who experienced response of CR, PR, or SD for at least 3 months. 
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ORR and DCR will be summarized and the 2-sided 95% exact binomial CI will be calculated. 
14.7.2 
Secondary Efficacy Endpoints and Analyses  
14.7.2.1 
Prostate-Specific Antigen Response (Part 1)  
PSA response is defined as a ≥ 50% decline in PSA from baseline with PSA confirmation 
≥ 3 weeks after the first documented reduction in PSA of ≥ 50%. The PSA response rate will be 
calculated as the proportion of participants with a PSA response in the PSA Response Evaluable 
Population. PSA response rates at 8 weeks, 12 weeks, and at any time will be summarized. The 
2-sided 95% exact binomial CI for PSA response rate will be calculated. 
Duration of PSA response is defined as the time from the date of first documented PSA response 
to the earliest date of PSA progression. Participants without PSA progression at the time of 
analysis will be censored to the date of their last PSA assessment. Kaplan-Meier method will be 
applied to estimate duration of PSA response. 
The percent change in PSA from baseline over time will be summarized and presented by spider 
plot. The best PSA percent change from baseline will be presented by waterfall plot. 
14.7.2.2 
Time to Prostate-Specific Antigen Progression (Part 1)  
Per PCWG3, PSA progression is defined as follows: 
• In participants with a decrease in PSA from baseline: ≥ 25% increase and an absolute 
increase of ≥ 2 ng/mL above the nadir value, which is confirmed by a consecutive 
second value obtained ≥ 3 weeks later. 
• In participants with no decrease in PSA from baseline: ≥ 25% increase and an 
absolute increase of ≥ 2 ng/mL above the baseline value after 12 weeks. 
 
Time to PSA progression is defined as the time from the date of randomization to the first 
documented PSA progression. Participants without PSA progression at the time of analysis will 
be censored to the date of their last PSA assessment. Kaplan-Meier method will be applied to 
estimate time to PSA progression. 
14.7.2.3 
Progression-Free Survival per RECIST v1.1 (Part 2)  
In Part 2, PFS is defined as the time from the first dose date to the date of first documented PD 
per RECIST v1.1 or death from any cause, whichever occurs first. For participants without an 
event of PD or death at the time of data cut-off for PFS analysis, PFS will be censored at the date 
of the last tumor assessment. Specifically, the censoring rules described in Table 21 will be 
applied as primary analysis of PFS. Supplementary analyses may be performed based on the 
Safety Population. 
Analysis of PFS will be the same as that described for rPFS (Section 14.7.1.1). 
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14.7.2.4 
Objective Response Rate per PCWG3 (Part 1)  
In Part 1, BOR will be categorized using PCWG3 as CR, PR, SD, PD, or NE. To qualify as an 
objective response, CR and PR require confirmation at least 4 weeks after initial observation of 
CR or PR, and SD requires observation at least once after 6 weeks from the start of study 
treatment. BOR will be evaluated from the start of study treatment. 
The number and percent of participants with BOR per PCWG3 criteria will be summarized. The 
ORR is estimated as the proportion of participants in the Tumor Response Evaluable Population 
who achieve a BOR of confirmed CR or PR without prior confirmed bone progression per 
PCWG3. 
Disease control rate (DCR) is defined as the percentage of tumor response-evaluable participants 
who experienced response of CR, PR, or SD for at least 3 months. 
ORR and DCR will be summarized and the 2-sided 95% exact binomial CI will be calculated.  
14.7.2.5 
Duration of Response (Part 1 and Part 2)  
The DoR will be calculated as the time from the date of initial tumor response (CR or PR) to the 
date of first documented PD or death from any cause, whichever occurs first. DoR is calculated 
only for participants with a tumor response (CR or PR). For participants without an event of PD 
or death at the time of data cutoff for DoR analysis, the DoR will be censored at the date of the 
last tumor assessment. Specifically, the last three situations described in Table 21 will be 
applied. The Kaplan-Meier method will be used to generate DoR curves and estimate the median 
DoR along with 95% CIs. The DoR analyses will be performed only if there are enough 
responders to render the analyses meaningful. 
14.7.2.6 
Tumor Size Change Over Time (Part 1 and Part 2)  
For participants with measurable disease at baseline, the tumor size is defined as the sum of 
diameters of the target lesions. The tumor size change from baseline over time will be 
summarized and presented by spider plot. The best tumor size change from baseline will be 
presented by waterfall plot.  
14.7.2.7 
Time to First Symptomatic Skeletal Event (Part 1)  
An SSE is defined as any of the following events: new symptomatic pathological fracture, 
requirement for radiation therapy to relieve bone pain, spinal cord compression, or tumor-related 
orthopedic surgical intervention. The time to first SSE is defined as the time from the date of 
randomization to the first occurrence of SSE. Participants without an event of SSE at the time of 
analysis will be censored at the last SSE assessment. The Kaplan-Meier method will be applied 
to estimate time to first SSE. 
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14.7.3 
Exploratory Efficacy Endpoints and Analyses  
14.7.3.1 
Overall Survival (Part 1 and Part 2)  
OS is defined as the time from the date of randomization (Part 1) or first dose (Part 2) to the date 
of death from any cause. For participants without an event of death at the time of data cutoff for 
OS analysis, OS will be censored at the time the participant is last known to be alive.  
The Kaplan-Meier method will be used to generate OS curves and estimate the median OS along 
with 95% CIs. The method of Brookmeyer and Crowley (81) will be used to construct 95% CI 
for median OS. The 95% CIs for OS rates at 12, 18, and 24 months will be calculated by normal 
approximation after log(-log) transformation. Supplementary analyses may be performed based 
on the Safety Population. 
14.8 
Safety Endpoints and Analyses  
Participants assigned to the control arm prior to its removal in Protocol Amendment 2 who were 
re-randomized to a vobramitamab duocarmazine arm will be analyzed for safety as a separate 
cohort. 
14.8.1 
Adverse Events  
Treatment-emergent AEs will be summarized in tables and listings. Tables will display the 
number and percent of participants that experience the given AE. AEs prior to the first dose of 
study treatment (e.g., due to study-related procedures) will be presented in listings only. 
AEs will be coded to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. 
AEs will be summarized by system organ class (SOC) and preferred term (PT), relationship to 
study treatment, and highest severity. The following AEs will be summarized:  
• All treatment-emergent AEs 
• Treatment-emergent AEs with CTCAE severity ≥ Grade 3 
• Treatment-related AEs 
• Treatment-related AEs with CTCAE severity ≥ Grade 3 
• SAEs 
• Treatment-related SAEs 
• AEs resulting in discontinuation of study drug 
• AEs leading to interruption of study drug 
• Fatal AEs 
• AESIs 
 
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An overall summary of treatment-emergent AEs will display the number and percent of 
participants who experience at least one event of each of the above types.  
14.8.2 
Laboratory Values  
Summaries of laboratory values will display descriptive statistics for numerically quantified labs. 
Summaries will be grouped by laboratory panel and will be displayed by visit for each laboratory 
parameter. Shift tables may be produced. 
14.8.3 
Other Safety Endpoints  
ECGs will be collected and analyzed for evidence of cardiac toxicity, including prolongation of 
QT interval. LVEF will be evaluated by echocardiogram or MUGA and changes from baseline 
summarized. Vital signs and weight will be summarized with descriptive statistics at each visit 
and time point collected. Shift tables may be produced. 
14.9 
Interim Analyses  
In Part 1, one futility analysis will be performed on each vobramitamab duocarmazine arm based 
on PSA response rate at 8 weeks on the first 20 PSA evaluable participants in each vobramitamab 
duocarmazine arm. At the futility analysis, if the probability of true PSA response rate for a 
vobramitamab duocarmazine arm greater than or equal to 40% is <10%, that is, if ≤ 25% (5/20) 
PSA response rate is observed, enrollment to that arm may stop unless other data warrant 
continuing enrollment. 
14.10 
Other Assessments or Analyses  
Additional analyses, if any, will be defined in the SAP.  
 
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15 
QUALITY CONTROL AND ASSURANCE  
Quality review activities will be undertaken to ensure accurate, complete, and reliable data. The 
sponsor and/or its representatives will: 
• Provide instructional material to the study sites, as appropriate. 
• Conduct a study training session (investigator meeting or study initiation visit) to 
instruct the investigators and study coordinators. This session will give instruction on 
the protocol, the completion of the eCRFs, and study procedures. 
• Make periodic visits to the study site to monitor protocol compliance and general 
Good Clinical Practice (GCP) compliance. 
• Be available for consultation and stay in contact with the study site personnel by mail, 
e-mail, telephone, and/or fax. 
• Review and evaluate eCRF data and use standard computer checks to detect and query 
errors in data collection. 
• Conduct a quality review of the database. 
 
15.1 
Monitoring, Auditing, and Inspections  
To ensure the safety of participants in the study, compliance with applicable regulations, and 
ensure accurate, complete, and reliable data, the investigator will keep records of laboratory 
tests, clinical notes, and medical records in the participant files as source documents for the 
study. 
The sponsor or its designee will monitor the study on a regular basis throughout the study period 
according to the clinical monitoring plan. The investigator will allocate adequate time for such 
monitoring activities. The study monitor periodically will conduct a cross-check of the 
participant data recorded on eCRFs against source documents at the study site. The investigator 
will also ensure that the monitor is given access to all the above noted study-related documents, 
source documents (regardless of media) and study-related facilities (e.g., investigational 
pharmacy, etc.), and has adequate space to conduct the monitoring visit. Queries may be raised if 
any datum is unclear or contradictory. The investigator and study site personnel must address all 
queries in a timely manner. 
Participation as an investigator in this study implies acceptance of the potential for inspection by 
the study sponsor or representatives, US or non-US government regulatory authorities, IRB/IEC 
and applicable compliance and quality assurance offices. The investigator will permit study-
related audits and inspections and will provide access to all study-related documents (e.g., source 
documents, regulatory documents, data collection instruments, study data etc.). The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g., pharmacy, 
diagnostic laboratory, etc.).  
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If planned on-site monitoring visits are not possible (e.g., as a result of the COVID-19 public 
health emergency), the sponsor may perform remote monitoring visits to maintain oversight of 
the clinical site. Remote monitoring of clinical data using electronic medical records will follow 
all local and regional guidelines regarding access to and protection of participants’ identifiable 
medical information. 
15.2 
Data Collection and Management  
Site personnel record all data for each participant through eCRFs using an EDC system provided 
and approved by the sponsor. Study sites must complete eCRFs for each participant in a timely 
manner shortly after each participant’s visit. The investigator must sign the investigator’s 
statement in each participants eCRF. 
The EDC system automatically generates queries resulting from the computer checks embedded 
into the system to ensure data accuracy, quality, consistency, and completeness. Manual queries 
resulting from review by monitors, medical coders, and data management staff are also generated 
from within the EDC system. Study sites are expected to resolve the queries and correct the 
entered data accordingly. Every change to data is captured in the EDC system audit trail. Upon 
completion of the study, or after reaching a pre-specified point in the study, data management 
will lock the database and generate the SAS datasets necessary for analysis and reporting. Each 
study site will receive the eCRFs for each of their participants.  
 
 
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16 
ADMINISTRATIVE CONSIDERATIONS  
16.1 
Institutional Review Board or Independent Ethics Committee 
Approval  
The study protocol, any related documents, and participant-facing materials will be submitted to 
the IRB/IEC for review and approval. Written approval of the study protocol and ICFs will be in 
the possession of the investigator and the sponsor before the study treatment is shipped to the 
investigator’s site. This approval must include the date of review, the protocol title and/or study 
number and version number, and ICF version number or date. A stamped version of the IRB-
approved consent is acceptable. If the IRB/IEC or institution uses its own unique number for the 
protocol instead of the sponsor’s number, that unique number should be noted on the approval 
statement. The investigator should provide the sponsor with a statement of compliance from the 
IRB/IEC indicating compliance with the applicable regulations in the region and International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH). 
Protocol modifications or changes may not be initiated without approval from the sponsor and 
prior written IRB/IEC approval (when required), except when necessary to eliminate immediate 
hazards to the participants. Such modifications will be submitted to the IRB/IEC; and written 
verification that the modification was submitted should be obtained. The investigator must 
submit all changes and updates to required documents to the IRB/IEC. 
16.2 
Ethical Conduct of the Study  
The study will be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with current ICH Guidelines for Good Clinical 
Practice (ICH E6), and all applicable regulations including Protection of Human Subjects 
(21 CFR [Code of Federal Regulations] 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312.60−312.69). 
16.3 
Participant Information and Consent  
The investigator will obtain, document, and retain IRB/IEC-approved written informed consent 
from the participant, as specified in Section 9.1. Where required, the investigator will use an 
appropriately translated and IRB/IEC-approved version. The sponsor reserves the right to delay 
initiation of the study at a site where ICFs do not meet the standards of applicable local 
regulations or ICH E6. 
Information should be given to the participant in both oral and written form, and participants 
must be given ample opportunity to inquire about details of the study. The ICF must be signed 
and dated by the participant and by the person who conducted the discussion of the informed 
consent.  
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16.4 
Participant Confidentiality  
Participants will be assigned a unique identifier by the sponsor. All laboratory specimens, 
evaluation forms, reports, and other records that are transferred to the sponsor will contain the 
identifier only; participant names or any information that would make the participant identifiable 
will not be transferred. Clinical information will not be released without written permission of 
the participant except as necessary for monitoring by the relevant regulatory authorities, the 
sponsor, or the sponsor’s representative. The investigator must comply with all local applicable 
privacy regulations regarding the protection of participant data.  
The contract between sponsor and study sites specifies responsibilities of the parties related to 
data protection, including handling of data security breaches and respective communication and 
cooperation of the parties. 
Information technology systems used to collect, process, and store study-related data are secured 
by technical and organizational security measures designed to protect such data against 
accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
16.5 
Source Documents  
Source data in a clinical study are the original records or certified copies where clinical 
observations are first recorded, which may include, but are not limited to, the participant’s 
medical file, original laboratory reports, histology, and pathology reports (as applicable). The 
investigator is responsible for maintaining adequate and accurate medical records from which 
accurate information will be entered into the eCRFs. 
16.6 
Retention of Data  
All essential documents, including eCRFs, source documents (regardless of media), and signed 
ICFs, should be retained by the investigator, per the guidance in ICH E6 or other regulatory 
retention requirements. There may be other circumstances for which the sponsor is required to 
maintain study records for longer periods; therefore, the sponsor should be contacted before 
study records are removed from the control of the study site for any reason. The investigator 
must obtain written permission from the sponsor prior to destruction of study documents. 
16.7 
Sample Retention and Secondary Research  
Samples acquired for protocol-specified assays are retained according to local and regional 
regulatory requirements. If the participant consents to the use of their study samples for 
secondary research purposes, samples may be used for exploratory testing and retained up to 
15 years from the end of study. Where allowed by local regulation, participant samples may be 
retained for long-term storage at a sponsor-designated facility in the US after the study has 
concluded. 
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16.8 
Financial Disclosure  
The investigator and sub-investigators are required to disclose in writing any applicable financial 
arrangement as defined in US regulation. The principal investigator’s disclosure will be signed 
and dated prior to participating in the study. 
The information, as defined in 21 CFR 54, will be collected about the investigators, their spouses 
and each dependent child. Investigators must update the sponsor with any changes in reported 
information up to 1 year following the end of the study. 
In accordance with Securities and Exchange Commission regulation (17 CFR 229.404), 
investigators and sub-investigators must disclose if they are employees of the sponsor, or if an 
immediate family member of a sponsor employee, officer, or director. 
16.9 
Publication and Disclosure Policy  
Data collected in this clinical study belong to the study sponsor. The publication terms regarding 
use of the study data will be noted in the clinical trial agreement and are outlined below. This 
includes authorship: scheduling and prioritizing analyses for reports, publications, and 
presentations; and developing a review and approval process. 
• The sponsor will comply with all applicable requirements for publication of study 
results. In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
16.10 
Discontinuation of the Study or Study Sites  
Site participation may be discontinued by the sponsor, the investigator, a regulatory authority, or 
an IRB/IEC. The study may be discontinued by a regulatory authority or at the discretion of the 
sponsor. 
Administrative or safety-related criteria for study termination include: 
• Identification of an unacceptable safety risk to participants 
• Poor enrollment or other evidence of study futility 
• Business decision 
 
If enrollment in the study is prematurely terminated by the sponsor for reasons other than a 
safety finding that poses unacceptable risk to study participants, participants already enrolled on 
the study may continue to receive study treatment until disease progression, a decision by the 
participant and/or physician that the treatment is no longer in their best interest, or other 
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treatment discontinuation criteria are met. The sponsor may elect to provide access to the study 
treatment via an alternative mechanism rather than leaving the study open (e.g., a Named Patient 
Program). 
16.11 
Summary of Results (European Union Member States)  
Within 1 year from the end of the study in all EU Member States concerned, the sponsor will 
submit a summary of the clinical study results to the EU Clinical Trials Information System 
(CTIS). The content of the results summary is outlined in Clinical Trials Regulation (CTR) 
Annex IV. The results will be accompanied by a lay summary. The content of the lay summary is 
outlined in CTR Annex V. 
16.12 
Identification of the Coordinating Principal Investigator  
A coordinating principal investigator will be appointed by the sponsor medical monitor prior to 
the end of the study. 
The coordinating principal investigator’s responsibilities include review of the final CSR. 
Agreement with the final CSR will be documented by the dated signature of the coordinating 
principal investigator. 
 
 
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17 
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Appendix 1 
Time and Events Schedule  
Table 22 
Schedule of Events (Every 4 Week Cycle)  
EVALUATION/ 
PROCEDURE 
Screening 
Day -28 
to -1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 2 
Cycles 
3–6 
Cycles 
3–6 
EOTV 
Day 1 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 1 
(±3d) 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 1 
(±3d) 
Day 15 
(±1d) 
Administer vobramitamab 
duocarmazine 
 
X 
 
 
X 
 
 
X 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/ cancer history 
X 
 
 
 
 
 
 
 
 
 
Tumor specimen a 
X 
 
 
 
 
 
 
 
 
 
Registration/randomization 
X 
 
 
 
 
 
 
 
 
 
Telemedicine visit 
 
 
X 
 
 
X 
 
 
X 
 
Full physical exam 
X 
 
 
 
 
 
 
 
 
X 
Directed physical exam 
 
X 
 
X 
X 
 
X 
X 
 
 
Vital signs b 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Vital sign: oxygen saturation b 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight c 
X 
X 
 
 
X 
 
 
X 
 
X 
ECOG performance status c 
X 
X 
 
 
X 
 
 
X 
 
X 
Electrocardiogram c, d 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Echocardiogram (or MUGA) 
X 
 
 
 
 
 
 
 
 
X 
Ophthalmic exam f 
X 
 
 
 
 
 
 
C4D1 
 
X 
Chemistry c 
X 
X 
 
X 
X 
 
X 
X 
 
X e 
Hematology c 
X 
X 
 
X 
X 
 
X 
X 
 
X e 
Endocrine  
X 
 
 
 
 
 
 
 
 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
X 
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Table 22 
Schedule of Events (Every 4 Week Cycle)  
EVALUATION/ 
PROCEDURE 
Screening 
Day -28 
to -1 
Cycle 1 
Cycle 1 
Cycle 1 
Cycle 2 
Cycle 2 
Cycle 2 
Cycles 
3–6 
Cycles 
3–6 
EOTV 
Day 1 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 1 
(±3d) 
Day 8 
(±1d) 
Day 15 
(±1d) 
Day 1 
(±3d) 
Day 15 
(±1d) 
Cardiac labs 
X 
 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
Pregnancy test (Part 2 only) g 
X 
X 
 
 
X 
 
 
X 
 
X 
HIV, HBV, HCV test (only 
where required) h 
X 
 
 
 
 
 
 
 
 
 
PSA (Part 1 only) c 
X 
X 
 
 
X 
 
 
X 
 
X 
Testosterone (Part 1 only) c 
X 
X 
 
 
X 
 
 
X 
 
X 
SSE (Part 1 only) i 
 
X 
 
 
X 
 
 
X 
 
X 
CT/MRI j 
X 
Q8W (± 7 days) from C1D1 for 24 weeks then Q12W (± 14 days) 
X j 
Bone scan j, k 
X 
Q8W (± 7 days) from C1D1 for 24 weeks then Q12W (± 14 days) 
X j 
Tumor assessment per 
PCWG3 (Part 1) or RECIST 
v1.1 (Part 2) j 
X 
Q8W (± 7 days) from C1D1 for 24 weeks then Q12W (± 14 days) 
X j 
Concomitant medications 
Continuous 
Concomitant procedures 
Continuous 
Adverse events 
Continuous 
PK/ADA 
See Appendix 2 
Note: Assessments/procedures are performed prior to dosing/dispensing of study treatment for each cycle unless otherwise specified. A treatment cycle is every 
4 weeks (28 days ± 3 days). There must be at least 25 days between each vobramitamab duocarmazine administration in a given participant. 
a 
Participants may undergo a fresh tumor biopsy to obtain a specimen for testing if a suitable archival tumor specimen is not available (see Section 9.8.2.2). 
b 
Vital signs include temperature, pulse, blood pressure, respiratory rate, and oxygen saturation (pulse oximetry). 
c 
If assessed within 72 hours before C1D1, the assessment does not need to be performed on C1D1. Blood samples may be collected up to 72 hours in advance 
of all cycles. 
d 
On C1D1 and C2D1, ECG is assessed prior to infusion of vobramitamab duocarmazine and at end (± 15 minutes) of infusion. ECGs should be performed 
prior to obtaining the time-matched PK sample. At C3–C6 D1, ECG is assessed prior to infusion of vobramitamab duocarmazine. During non-dosing 
in-person visits, ECGs are assessed at one time point. 
e 
If assessed within 2 weeks before EOTV, the assessment does not need to be performed at EOTV except if clinically indicated. 
f 
Ophthalmic examinations including visual acuity testing (with correction), fundoscopic examination, and tonometry are performed at screening, C4D1 
(± 7 days), and EOTV and at other time points as clinically indicated. Other directed studies (e.g., optical coherence tomography) will be performed as 
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clinically indicated. Participants with ocular symptoms or findings at the on-treatment exam should have repeat ophthalmic exams as clinically indicated (see 
also Section 7.3.6; participants should have weekly ocular assessments if AE ≥ Grade 2). If the most recent ophthalmic exam was within the last 60 days, a 
repeat ophthalmic exam at EOTV is not required unless clinically indicated.  
g 
People of childbearing potential only. Samples may be obtained up to 72 hours in advance of all cycles. Results must be reviewed before study treatment 
infusion on C1D1 and all subsequent cycles. If screening test is performed within 72 hours of first infusion, repeat of the test on C1D1 is not required. 
h 
HIV, HBV, and HCV testing only if required by local authorities (e.g., Czech Republic). Testing should follow local clinical practice guidelines/standards. 
i 
SSE assessment for C1D1 should record events that occurred from time of signing informed consent to assessment on that day (C1D1).  
j 
Target and non-target lesions will be designated at screening. Tumor assessments are performed Q8W (± 7 days) from C1D1 for 24 weeks then Q12W 
(± 14 days) (regardless of dose delay) until PD. Tumor assessments are performed at EOTV except if prior tumor assessment was ≤ 12 weeks of EOTV and 
results are available for tumor response assessment. 
k 
Bone scans will be obtained for all participants with mCRPC (Part 1) or any participant with signs and/or symptoms of bone involvement (Part 2). 
Abbreviations: ADA: anti-drug antibodies; AE: adverse event; C: cycle; CT: computed tomography; D: day; ECG: electrocardiogram; ECOG: Eastern 
Cooperative Oncology Group; EOTV: end of treatment visit; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; 
MRI: magnetic resonance imaging; MUGA: multigated acquisition scan; PCWG3: Prostate Cancer Clinical Trials Working Group 3; PD: progressive disease; 
PK: pharmacokinetics; PSA: prostate-specific antigen; Q4W: every 4 weeks; Q8W: every 8 weeks; Q12W: every 12 weeks; RECIST: Response Evaluation 
Criteria in Solid Tumors; SSE: symptomatic skeletal event. 
 
 
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Table 23 
Schedule of Events - Post-Treatment Follow-up Period  
EVALUATION/ 
PROCEDURE 
Follow-up Visit 
(before PD or subsequent anticancer therapy) a 
Q12W 
(± 14 days) 
Survival Follow Up 
Q12W 
(± 14 days) 
PSA (Part 1 only) 
X 
 
Testosterone (Part 1 only) 
X 
 
CT/MRI 
X 
 
Bone scan b 
X 
 
Tumor assessment per PCWG3 (Part 1) or 
RECIST v1.1 (Part 2) 
X 
 
Survival follow up 
 
X c 
a 
Participants who discontinue study treatment for reasons other than PD (e.g., toxicity) will continue PSA (Part 1 only), testosterone (Part 1 only), and tumor 
assessments Q12W (calculated from Cycle 1 Day 1) from last tumor response assessment for up to 6 months from last dose of study treatment until PD, 
death, initiation of another anticancer therapy, withdrawal of consent, LTFU, or end of study, whichever occurs first. 
b 
Bone scans will be obtained for all participants with mCRPC (Part 1) or any participant with signs and/or symptoms of bone involvement (Part 2). 
c 
Survival status is assessed approximately Q12W for up to 6 months from last dose of study treatment or until withdrawal of consent, LTFU, death, or end of 
study, whichever occurs first. The first survival follow-up assessment will be scheduled 12 weeks after the last dose of study treatment. 
Abbreviations: CT: computed tomography; EOTV: end of treatment visit; LTFU: lost to follow up; MRI: magnetic resonance imaging; PCWG3: Prostate Cancer 
Clinical Trials Working Group 3; PD: progressive disease; PSA: prostate-specific antigen; Q8W: every 8 weeks; Q12W: every 12 weeks; RECIST: Response 
Evaluation Criteria in Solid Tumors. 
 
 
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Appendix 2 
Pharmacokinetics and Immunogenicity Collection Schedules  
Note: select sites will not be required to collect PK samples. The sponsor will inform the study site on the need for PK sampling at 
that site. 
Table 24 
Pharmacokinetic Sample Collection Schedule  
Cycle 
Day 
Timepoint 
 
Window 
PK:  
Total Ab and 
Conjugated Ab 
(serum) 
PK: 
SYD986 
(plasma) 
ADA: 
(serum) 
1 
1 
Pre-infusion 
N/A 
X 
X 
X 
1 
1 
EOI 
+ 10 min 
X 
X 
 
1 
1 
2–4 h after EOI 
N/A 
X 
X 
 
1 
1 
6–8 h after EOI 
N/A 
X 
X 
 
1 
15 
Day 15 
N/A 
X 
X 
X 
2 
1 
Pre-infusion 
N/A 
X 
X 
X 
2 
1 
EOI 
+ 10 min 
X 
X 
 
2 
15 
Day 15 
N/A 
X 
X 
 
3, 4, 5, and 6 
1 
Pre-infusion 
N/A 
X 
X 
X 
3, 4, 5, and 6 
1 
EOI 
+ 10 min 
X 
X 
 
IRR a 
N/A 
N/A 
N/A 
X 
X 
X 
EOTV 
N/A 
EOTV 
N/A 
X 
X 
X 
Note: Actual start of infusion times, EOI times, and PK/ADA sample collection times will be recorded on the eCRFs. Do not collect PK samples from infusion 
port. Pre-infusion PK samples may be collected before start of infusion on visit day (dosing day) or day before infusion. When collecting multiple samples, 
collect the PK sample first. 
a 
PK and ADA samples may be obtained at additional time points in participants who experience signs and symptoms of IRR. Samples should be obtained as 
soon as possible after onset of IRR, if feasible. See laboratory manual for details on sample collection. 
Abbreviations: ADA: anti-drug antibody; Ab: antibody; EOI: end of infusion; EOTV: end of treatment visit; N/A: not applicable; IRR: infusion related reaction; 
PK: pharmacokinetic.  
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Appendix 3 
Principal Investigator’s Agreement  
Study Title: 
A Phase 2, Open-Label Study of Vobramitamab Duocarmazine in 
Participants with Metastatic Castration-Resistant Prostate Cancer and 
Other Solid Tumors (TAMARACK) 
Study Number: 
CP-MGC018-03 
 
I have read the protocol described above. 
I understand that the information in this protocol is confidential and must not be disclosed, other 
than to those directly involved in the execution of, or the ethical review of the study, without 
written authorization from the sponsor. It is, however, permissible to provide information to a 
participant to obtain consent. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the sponsor. 
I agree to conduct this trial according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with ICH guidelines on GCP and with the applicable regulatory requirements. 
Signed: 
 
Date: 
 
Printed name: 
 
Title: 
 
Affiliation: 
 
Address: 
 
Phone number: 
 
 
 
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CP-MGC018-03 Protocol Amendment 5 (19-Aug-2024)
This is the electronic signature page for the above referenced document.
User Task: eSignatories Approval
Data Management/Statistics Approval
(Intended or Designee)
20-Aug-2024 13:37:19 GMT+0000
User Task: eSignatories Approval
opment Approval (Intended or
Designee)
20-Aug-2024 17:52:24 GMT+0000
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