Clinical trial NCT04157517
Conditions: Neoplasms Melanoma
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2019-12-12; Completion date: 2023-12-20
Enrollment: 45 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study has 2 phases.

The main aims of Phase 1b are:

* to check for side effects from modakafusp alfa in adults with locally advanced or metastatic solid tumors.
* to learn how much modakafusp alfa adults can receive without getting any major side effects from it.

The main aims of Phase 2 are:

* to check for side effects from modakafusp alfa when given together with pembrolizumab in adults with metastatic cutaneous melanoma which cannot be completely removed by surgery.
* to learn how these medicines improve their symptoms.

Participants will receive modakafusp alfa for up to 1 year (Phase 1b) or modakafusp alfa given together with pembrolizumab for up to 2 years (Phase 2). Those whose symptoms improve might continue treatment for longer.

In both phases of the study, participants will revisit the study clinic within 30 days after their last dose or before they start other cancer treatment, whichever happens first.

Detailed description:
The drug being tested in this study is called modakafusp alfa (TAK-573). Modakafusp alfa is being tested to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity as single agent (SA) or in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors. The study will consist of 2 phases: Phase 1b dose escalation and a Phase 2 dose expansion.

The study will enroll approximately 114 participants (approximately 30 participants in Phase 1b dose escalation phase; 3-9 participants in safety-lead in and 25 participants for each expansion cohort (3 cohorts) of Phase 2.

The dose escalation phase will enroll participants with solid tumors. The dose escalation phase is to evaluate SA recommended phase 2 dose (RP2D).

The dose expansion phase in combination with pembrolizumab will be initiated with a safety lead-in phase once the SA RP2D is determined for modakafusp alfa. The dose expansion will include participants with one of following 3 disease indications:

I. Unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-disease programmed cell death protein 1 (PD1) containing treatments in the metastatic setting.

II. Unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting.

III. Unresectable/metastatic cutaneous melanoma naïve to prior anti-PD1 containing treatments in the metastatic setting.

This multi-center trial will be conducted in the United States and Australia. Participants with demonstrated clinical benefit may continue treatment beyond 1 year for Phase 1b and 2 years for Phase 2 if approved by the sponsor. The overall time to participate in this study is 55 months. All participants will make an end of treatment (EOT) visit 30 days after receiving their last dose of study drug or before the start of subsequent systemic anticancer therapy, whichever occurs first for a safety follow up assessment.

Arms: arm 1: Modakafusp alfa 0.1 to 6 milligram per kilogram (mg/kg), infusion, intravenously, once on Day 1 of each 21-days treatment cycle for up to 1 year. arm 2: Melanoma with primary resistance to prior anti-PD1, acquired resistance to prior anti-PD1 or naïve to anti-PD1.

Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years. The starting dose of modakafusp alfa for dose expansion safety lead-in phase will be the RP2D determined in the previous Phase 1b dose escalation phase. arm 3: Melanoma With Primary Resistance to prior anti-PD1. Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety-lead in phase. arm 4: Melanoma With Acquired Resistance to prior anti-PD1. Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety lead-in phase. arm 5: Modakafusp alfa, infusion, intravenously, once on Day 1 of each 21-days treatment cycle and pembrolizumab 400 mg infusion, intravenously, once every 6 weeks for up to 2 years, in participants with unresectable/metastatic cutaneous melanoma naive to prior line of anti-PD1 containing treatments in the metastatic setting. The dose of modakafusp alfa for dose expansion phase will be the modakafusp alfa RP2D in combination with pembrolizumab determined in the previous Phase 2 dose expansion safety lead-in phase.
Interventions: intervention 1: Modakafusp Alfa intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Modakafusp alfa intravenous infusion. intervention 2: Pembrolizumab intravenous infusion.

Protocol documents:
Prot_000.pdf: 


PROTOCOL
An Open-Label, Dose-Escalation Phase 1b/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Modakafusp Alfa 
(TAK-573) as a Single Agent and in Combination With Pembrolizumab in Adult Patients 
With Advanced or Metastatic Solid Tumors
A Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study
Sponsor:
Takeda Development Center Americas, Inc. (TDCA)
Lexington, MA 
Study Number:
TAK-573-1001
Compound:
Modakafusp alfa (TAK-573) 
Date:
28 July 2022
Amendment Number: 06
Amendment History: 
Date
Amendment Number
Region
28 July 2022
6
Global
16 November 2021
5
Global
11 August 2021
4
Global
08 March 2021
3
Global
12 March 2020
2
Global
22 October 2019
1
Global
05 August 2019
Initial Protocol
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, as 
is information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
The names and contact information for the medical monitor and responsible medical officer are in 
the Study Manual.




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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
prescribing information, and any other product information provided by the sponsor. I agree to 
conduct this study in accordance with the requirements of this protocol and also to protect the 
rights, safety, privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs are defined in Section 10.0 of this protocol.

Terms outlined in the clinical study site agreement.

Responsibilities of the investigator (Appendix C).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)


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1.3
Protocol Amendment 6 Summary of Changes 
This section describes the changes in the protocol incorporating Amendment 6. The primary reasons 
for this amendment are to: 

Update “modified Response Evaluation Criteria in Solid Tumors” (mRECIST) criteria to 
“Response Evaluation Criteria in Solid Tumors” (RECIST) throughout the protocol.

Define the number and timing of prior lines of anti-PD1 therapy permitted for enrollment into 
the phase 2 dose expansion cohorts.

Exclude enrollment of patients with acral lentiginous melanoma into some parts of the study.

Exclude enrollment of patients with a history of immune-related adverse events (AEs) related 
to anti-PD1/PD-L1 treatment that required treatment discontinuation.

Clarify the timing of pregnancy tests and that pregnancy tests can be urine or serum. 

Clarify the exclusion criteria regarding a prohibited history of immune-related AEs and
exclusion for persistent toxicity.

Update excluded concomitant medications regarding exceptions for chronic concomitant 
steroid usage. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
Protocol Amendment 6
Summary of Changes Since the Last Approved Protocol
Change
Number
Section(s) Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
2.0 Study Summary
7.1 Inclusion Criteria
7.2 Exclusion Criteria
Restrictions for pregnancy, sperm/ova 
donation, and breastfeeding during and 
after study participation were revised.
Update.
2.
2.0 Study Summary
7.1 Inclusion Criteria
The number and timing of prior lines of 
anti-PD1 therapy permitted for enrollment 
into the phase 2 dose expansion cohorts I 
and II were clarified or revised. 
Update.
3.
2.0 Study Summary
7.2 Exclusion Criteria
Patients with acral lentiginous melanoma 
are excluded in phase 2 except for the 
safety lead-in phase. 
Update.


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Protocol Amendment 6
Summary of Changes Since the Last Approved Protocol
Change
Number
Section(s) Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
4.
2.0 Study Summary
7.2 Exclusion Criteria
Exclusion criterion #5 regarding a history 
of immune-related AEs related to treatment 
with prior checkpoint inhibitor was 
changed to exclude a history of 
immune-related AEs related to 
anti-PD1/PD-L1 treatment that required 
treatment discontinuation (phase 2).
Clarification.
5.
7.2 Exclusion Criteria
Exclusion #2 for persistent toxicity 
updated. 
Update.
6.
2.0 Study Summary
7.2 Exclusion Criteria
Pregnancy tests can be urine or serum.
Clarification.
7.
2.0 Study Summary
7.2 Exclusion Criteria
8.9.1 Contraception and 
Pregnancy Avoidance 
Procedures9.3.9 Pregnancy 
Testing
10.4 Procedures for Reporting 
Drug Exposure During 
Pregnancy and Birth Events
Gender-neutral language was applied.
Update.
8.
10.4 Procedures for Reporting 
Drug Exposure During 
Pregnancy and Birth Events
The time period for reporting pregnancies 
on study was updated.
Update.
9.
8.9.1 Contraception and 
Pregnancy Avoidance 
Procedures
New section and table added to clarify 
highly effective contraceptive measures.
Update.
10.
8.7 Excluded Concomitant 
Medications and Procedures
Exceptions for chronic concomitant steroid 
usage updated.
Update.
11.
8.8.1 Premedication
Revised the requirements for 
premedications.
Update.
12.
8.10.1 Infusion-Related 
Reactions
Revised recommendations for managing 
IRRs. 
Update.


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Protocol Amendment 6
Summary of Changes Since the Last Approved Protocol
Change
Number
Section(s) Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
13.
2.0 Study Summary
9.3.14 Disease Assessment
Table 16.a Schedule of Events: 
Screening, Baseline, Cycle 1, 
and Cycle 2 (Phase 1b Dose 
Escalation)
Table 16.b Schedule of Events, 
Continued: Cycle 3 Through 
Cycle 6 (Phase 1b Dose 
Escalation)
Table 16.c Schedule of Events, 
Continued: Cycle 7 Through 
EOT and Follow-up (Phase 1 
Dose Escalation)
Table 16.d Schedule of Events: 
Screening, Baseline, Cycle 1, 
Cycle 2, and Cycle 3 (Phase 2 
Dose Expansion)
Table 16.e Schedule of Events, 
Continued: Cycle 4 Through 
EOT and Follow-up (Phase 2 
Dose Expansion)
Reference for immune RECIST criteria 
added, and mRECIST updated to RECIST. 
Update. 
14.
9.3.14 Disease Assessment
Table 16.d Schedule of Events: 
Screening, Baseline, Cycle 1, 
Cycle 2, and Cycle 3 (Phase 2 
Dose Expansion)
Table 16.e Schedule of Events, 
Continued: Cycle 4 Through 
EOT and Follow-up (Phase 2 
Dose Expansion)
Guidelines for the use of contrast-enhanced 
computed tomography scans were revised. 
Update.
15.
Table 16.d Schedule of Events: 
Screening, Baseline, Cycle 1, 
Cycle 2, and Cycle 3 (Phase 2 
Dose Expansion)
Table 16.e Schedule of Events, 
Continued: Cycle 4 Through 
EOT and Follow-up (Phase 2 
Dose Expansion)
Timing of required pregnancy tests was 
clarified.
Clarification.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 6 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................15
3.0
STUDY REFERENCE INFORMATION ......................................................................22
3.1
Study-Related Responsibilities.................................................................................22
3.2
Principal Investigator...............................................................................................22
3.3
List of Abbreviations ...............................................................................................23
3.4
Corporate Identification...........................................................................................25
4.0
INTRODUCTION.........................................................................................................26
4.1
Modakafusp Alfa (TAK-573) Background...............................................................26
4.1.1
Modakafusp Alfa Targets.................................................................................26
4.1.2
Modakafusp Alfa Nonclinical Pharmacology...................................................28
4.2
Pembrolizumab Background....................................................................................30
4.3
Known and Potential Benefits and Risks..................................................................31
4.3.1
Nonclinical Safety Summary of Modakafusp Alfa ...........................................31
4.3.2
Clinical Safety of Modakafusp Alfa.................................................................31
4.3.3
Potential Effects Based on Nonclinical and Clinical Studies of Modakafusp 
Alfa .................................................................................................................32
4.3.4
Potential Effects of Pembrolizumab.................................................................34
4.3.5
Potential Overlapping Toxicities......................................................................34
4.3.6
Potential Pharmacokinetic Drug Interactions and Other Forms of Interaction...35
4.4
Rationale for the Proposed Study.............................................................................35
4.4.1
General Rationale for Modakafusp Alfa in Solid Tumors.................................35
4.4.2
...37
4.4.3
Rationale for Phase 2 Expansion Phase Cohorts...............................................38
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................39
5.1
Objectives................................................................................................................39
5.1.1
Primary Objective............................................................................................39
5.1.2
Secondary Objectives ......................................................................................40
5.1.3
Exploratory/Additional Objectives...................................................................40
5.2
Endpoints.................................................................................................................41
5.2.1
Primary Endpoints ...........................................................................................41


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5.2.2
Secondary Endpoints .......................................................................................41
5.2.3
Additional/Exploratory Endpoints....................................................................42
6.0
STUDY DESIGN..........................................................................................................44
6.1
Overview of Study Design.......................................................................................44
6.1.1
Phase 1b Single-Agent Dose Escalation...........................................................44
6.1.2
Phase 2 Dose Expansion ..................................................................................45
6.2
Number of Patients ..................................................................................................46
6.3
Duration of Study ....................................................................................................46
6.3.1
Duration of an Individual Patient’s Study Participation....................................46
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................46
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......47
6.3.4
Total Study Duration .......................................................................................48
6.3.5
Posttrial Access ...............................................................................................49
7.0
STUDY POPULATION................................................................................................49
7.1
Inclusion Criteria .....................................................................................................49
7.2
Exclusion Criteria ....................................................................................................51
8.0
STUDY DRUG .............................................................................................................53
8.1
Study Drug Administration......................................................................................53
8.2
Definitions of Dose-Limiting Toxicities...................................................................53
8.3
Phase 1b Modakafusp Alfa SA Dose Escalation Schema..........................................54
8.4
Phase 2 Modakafusp Alfa Dose Expansion ..............................................................56
8.5
Additional Safety Stopping Rules ............................................................................57
8.6
Dose Modification Guidelines..................................................................................57
8.6.1
Intrapatient Dose Escalation.............................................................................57
8.6.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle...................57
8.6.3
Criteria for Treatment Interruption and Dose Reduction...................................58
8.6.4
Criteria for Discontinuing of Treatment with Study Drugs...............................61
8.7
Excluded Concomitant Medications and Procedures ................................................63
8.8
Permitted Concomitant Medications and Procedures................................................63
8.8.1
Premedication..................................................................................................63
8.8.2
Postinfusion Medication ..................................................................................64
8.8.3
Other Permitted Concomitant Medications and Procedures..............................64
8.9
Precautions and Restrictions ....................................................................................65
8.9.1
Contraception and Pregnancy Avoidance Procedures.......................................65
8.10
Management of Specific Adverse Reactions ............................................................67


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8.10.1
Infusion-Related Reactions..............................................................................67
8.10.2
Low Platelet Counts.........................................................................................69
8.10.3
Management of Immune-Mediated Adverse Events.........................................69
8.11
Blinding and Unblinding..........................................................................................69
8.12
Description of Investigational Agents ......................................................................69
8.13
Preparation, Reconstitution, and Dispensation..........................................................70
8.13.1
Modakafusp Alfa .............................................................................................70
8.13.2
Pembrolizumab................................................................................................70
8.14
Packaging and Labeling...........................................................................................70
8.15
Storage, Handling, and Accountability.....................................................................70
8.15.1
Modakafusp Alfa .............................................................................................70
8.15.2
Pembrolizumab................................................................................................71
9.0
STUDY CONDUCT......................................................................................................71
9.1
Study Personnel and Organizations..........................................................................71
9.2
Arrangements for Recruitment of Patients................................................................71
9.3
Study Procedures.....................................................................................................71
9.3.1
Informed Consent ............................................................................................72
9.3.2
Patient Demographics......................................................................................72
9.3.3
Medical History...............................................................................................72
9.3.4
Physical Examination ......................................................................................72
9.3.5
Patient Height..................................................................................................73
9.3.6
Patient Weight .................................................................................................73
9.3.7
Vital Signs.......................................................................................................73
9.3.8
ECOG Performance Status...............................................................................73
9.3.9
Pregnancy Testing ...........................................................................................73
9.3.10
Concomitant Medications and Procedures........................................................74
9.3.11
TEAEs.............................................................................................................74
9.3.12
ECG ................................................................................................................74
9.3.13
Clinical Laboratory Evaluations.......................................................................74
9.3.14
Disease Assessment.........................................................................................76
9.3.15
Biomarker, Pharmacodynamic, and PK Samples..............................................79
9.3.16
DNA Measurements ........................................................................................83
9.3.17
Immunogenicity Sample Collection .................................................................83
9.4
Completion of Study (for Individual Patients)..........................................................83
9.5
Discontinuation of Modakafusp Alfa Treatment and Patient Replacement ...............83


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9.6
Study Compliance....................................................................................................84
9.7
Posttreatment Follow-up Assessments (PFS and OS)...............................................84
10.0
ADVERSE EVENTS ....................................................................................................84
10.1
Definitions...............................................................................................................84
10.1.1
Pretreatment Event Definition..........................................................................84
10.1.2
AE Definition ..................................................................................................84
10.1.3
SAE Definition................................................................................................85
10.1.4
Adverse Events of Special Interest (AESI).......................................................86
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................86
10.2.1
AESI Reporting ...............................................................................................87
10.3
Monitoring of AEs and Period of Observation .........................................................88
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........88
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................89
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........89
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................89
12.0
DATA HANDLING AND RECORDKEEPING............................................................89
12.1
eCRFs......................................................................................................................90
12.2
Record Retention .....................................................................................................90
13.0
STATISTICAL METHODS..........................................................................................91
13.1
Determination of Sample Size..................................................................................91
13.1.1
Phase 1b Dose Escalation ................................................................................91
13.1.2
Phase 2 Dose Expansion ..................................................................................91
13.2
Analysis Sets ...........................................................................................................92
13.3
Analysis of Demographics and Other Baseline Characteristics.................................92
13.4
Efficacy Analysis.....................................................................................................92
13.5
PK Analysis.............................................................................................................93
13.5.1
PK Noncompartmental Analysis ......................................................................93
13.5.2
PK Sampling Intended for Population PK Analysis..........................................93
13.6
Pharmacodynamic Analysis .....................................................................................93
13.7
PK/Pharmacodynamic Analysis ...............................................................................94
13.8
PK/QTc Analysis.....................................................................................................94
13.9
Immunogenicity Analyses........................................................................................94
13.10 Safety Analysis........................................................................................................94
13.11
..................................................................................94
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................95


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14.1
Study-Site Monitoring Visits ...................................................................................95
14.2
Protocol Deviations..................................................................................................96
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................96
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................96
15.1
IRB and/or IEC Approval ........................................................................................96
15.2
Patient Information, Informed Consent, and Patient Authorization...........................97
15.3
Subject Confidentiality ............................................................................................98
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................99
15.4.1
Publication.......................................................................................................99
15.4.2
Clinical Trial Registration................................................................................99
15.4.3
Clinical Trial Results Disclosure....................................................................100
15.5
Insurance and Compensation for Injury..................................................................100
16.0
REFERENCES............................................................................................................101
16.1
Table 16.a Schedule of Events: Screening, Baseline, Cycle 1, and Cycle 2 (Phase 
1b Dose Escalation) ...............................................................................................104
16.2
Table 16.b Schedule of Events, Continued: Cycle 3 Through Cycle 6 (Phase 1b 
Dose Escalation)....................................................................................................106
16.3
Table 16.c Schedule of Events, Continued: Cycle 7 Through EOT and Follow-up 
(Phase 1 Dose Escalation)......................................................................................107
16.4
Table 16.d Schedule of Events: Screening, Baseline, Cycle 1, Cycle 2, and Cycle 3 
(Phase 2 Dose Expansion)......................................................................................111
16.5
Table 16.e Schedule of Events, Continued: Cycle 4 Through EOT and Follow-up 
(Phase 2 Dose Expansion)......................................................................................113
16.6
Table 16.f Serial PK (Serum) Sample Breakdown: Phase 1b Dose Escalation ........118
16.7
Table 16.g Serial PK (Serum) Sample Breakdown: Safety Lead-in Phase of Phase 2 
Dose Expansion.....................................................................................................120
16.8
Table 16.h Sparse Serum PK Sampling Schedule to Characterize PK of 
Modakafusp Alfa and Pembrolizumab During Phase 2 Expansion Phase (excluding 
Safety Lead-In Periods) .........................................................................................122
16.9
Appendix F Protocol History .................................................................................129
16.9.1
Protocol Amendment 5 ..................................................................................129
16.9.2
Protocol Amendment 4 Summary of Changes................................................130
16.9.3
Protocol Amendment 03 Summary of Changes..............................................132
16.9.4
Protocol Amendment 2 Summary of Changes................................................136
16.9.5
Protocol Amendment 1 Summary of Changes................................................137




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Figure 6.a
Study Schema ....................................................................................................44
LIST OF APPENDICES
Appendix A
Schedules of Events .........................................................................................104
Appendix B
PK Sampling Tables.........................................................................................118
Appendix C
Responsibilities of the Investigator...................................................................123
Appendix D
Investigator Consent to Use of Personal Information........................................125
Appendix E
Description and Operating Characteristics of the BLRM for Dose Escalation...126
16.9
Appendix F Protocol History............................................................................129


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2.0
STUDY SUMMARY
Name of Sponsor: 
Takeda Development Center Americas, Inc. (TDCA)
Compound: Modakafusp alfa (TAK-573), henceforth 
referred to as “modakafusp alfa.”
Title of Protocol: An Open-Label, Dose Escalation Phase 
1b/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics and Antitumor 
Activity of Modakafusp Alfa (TAK-573) as a Single 
Agent and in Combination with Pembrolizumab in Adult 
Patients with Advanced or Metastatic Solid Tumors
EudraCT No.: Not applicable
Study Number: TAK-573-1001
Phase: 1b/2
Study Design:
This is an open-label, phase 1b/2 study designed to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics and antitumor response of modakafusp alfa as a single agent (SA) and in combination with 
pembrolizumab in patients with advanced or metastatic solid tumors. 
The study consists of 2 phases. 
PHASE 1b
PHASE 2 DOSE EXPANSION
Phase 1b will enroll patients with advanced/metastatic solid tumors that have no standard therapeutic option, are 
intolerant to those therapies, or have refused them.
The modakafusp alfa SA dose escalation phase is designed to determine the SA recommended phase 2 dose (RP2D) 
and schedule of modakafusp alfa for further testing. The single-agent RP2D may be either the maximum tolerated 
dose (MTD) based on DLTs or a pharmacologically active dose (PAD) defined by the PK/pharmacodynamic model or 
exposure-response (ER) analysis in place. 
A minimum of 3 patients will be enrolled at the SA starting dose of modakafusp alfa 0.1 mg/kg administered once 
every 3 weeks (Q3W). Doses will be escalated as follows: 0.1, 0.2, 0.4, 0.75, 1.5, 3 and 6 mg/kg. Patients will be 
assessed for DLTs until Cycle 2 Day 1 (C2D1) can be administered from a safety standpoint. If there are no DLTS in 
the first cohort of 3 evaluable patients dosed at 0.1 mg/kg, Bayesian Logistic Regression Model (BLRM) guided by 
Modakafusp Alfa 
+ Pembrolizumab 
Safety Lead-in 
Any patient type of 
the expansion 
cohorts (N = 3 to 9 
patients).
Modakafusp Alfa + Pembrolizumab 
Expansion
Unresectable/metastatic cutaneous 
melanoma with primary resistance to no 
more than 2 prior lines of anti-PD1 
containing treatments in the metastatic 
setting (N = 25 patients) 
Unresectable/metastatic cutaneous 
melanoma with acquired resistance to no 
more than 2 prior lines of anti-PD1 
containing treatments in the metastatic 
setting (N = 25 patients)
Unresectable/metastatic cutaneous 
melanoma naïve to prior line of anti-PD1 
containing treatments in the metastatic 
setting (N = 25 patients). 
Modakafusp Alfa SA 
Dose Escalation
Patients with 
advanced/metastatic 
tumors to determine 
RP2D (all comers, up 
to N = 30 patients).


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the Escalation with Overdose Control (EWOC) principle will be used in successive dose escalation cohorts to estimate 
the next dose level. More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing 
dose level are all permissible following discussions between the sponsor and the investigators, if such measures are 
needed for patient safety or for a better understanding of dose-related
toxicity, exposure, or pharmacodynamics. It is estimated that approximately 30 patients will be enrolled until either 
the MTD and/or PAD is identified. 
Phase 2 Dose Expansion
Enrollment into Phase 2 expansion in combination with pembrolizumab will be initiated once the RP2D of 
modakafusp alfa has been determined in Phase 1b of the study.
The combination treatment cohorts will begin with a safety-lead in period to evaluate safety and tolerability during the 
Cycle 1 dose-limiting toxicity (DLT) evaluation period of modakafusp alfa with pembrolizumab. If there are no DLTs 
in the first 3 patients during Cycle 1 of the safety lead-in period with modakafusp alfa SA RP2D in combination with 
pembrolizumab 400 mg once every 6 weeks (Q6W), the combination dose and regimen could be selected for the 
3 expansion cohorts described below. If there is 1 DLT in the initial 3 patients in the safety-lead in period, an 
additional 3 patients will be enrolled at the same modakafusp alfa RP2D in combination with pembrolizumab 400 mg 
Q6W. If there are ≥2 DLTs in the first 3 patients at the modakafusp alfa SA RP2D, enrollment will resume at one dose 
lower than that of the modakafusp alfa RP2D in combination with pembrolizumab. Other approved dosing regimens 
(eg, 200 mg Q3W) for pembrolizumab could be tested in the safety-lead in period if 400 mg Q6W in combination with 
modakafusp alfa at one dose lower than RP2D is intolerable. For the safety lead-in period, patient enrollment will be 
staggered between the first and second patients by 7 days. The second and third patients can be dosed concurrently if 
the first patient has gone through the Day 8 visit without clinically significant acute toxicities. Patients enrolled in the 
safety lead-in phase could have any of the 3 melanoma disease categories described below. 
Following completion of the safety lead-in phase and review of safety data, the combination cohorts, including 
patients in the safety-lead phase, will enroll patients with unresectable/metastatic melanoma in the following 
subgroups:
I.
Unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of 
anti-PD1 containing treatments in the metastatic setting.
II.
Unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 prior lines of 
anti-PD1 containing treatments in the metastatic setting. 
III.
Unresectable/metastatic cutaneous melanoma naïve to prior line of anti-PD1 containing treatments in the 
metastatic setting.
A Bayesian predictive probability design will be used to allow multiple futility analyses for early termination due to 
futility. Up to 25 patients will be enrolled in each cohort in phase 2.
Primary Objective:
The primary objective is to determine the safety and tolerability of modakafusp alfa as SA in patients with locally 
advanced or metastatic solid tumors (phase 1b) and in combination with pembrolizumab in unresectable/metastatic 
cutaneous melanoma (phase 2 safety lead-in), and to evaluate the efficacy of modakafusp alfa in combination with 
pembrolizumab in patients with unresectable/metastatic cutaneous melanoma (phase 2 expansion only). 
Secondary Objectives: 

To define the MTD and/or PAD of modakafusp alfa SA, if applicable (phase 1b).

To select the RP2D of modakafusp alfa SA (phase 1b) and in combination with pembrolizumab (phase 2 safety 
lead-in).

To evaluate modakafusp alfa PK as a SA (phase 1b) or in combination with pembrolizumab (phase 2 safety 
lead-in).

To assess the preliminary antitumor activity of modakafusp alfa as a SA (phase 1b) 

To further characterize the antitumor effect of modakafusp alfa in combination with pembrolizumab based on 


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immune Response Evaluation Criteria in Solid Tumors (iRECIST) in expansion cohort patients (phase 2 
expansion).

To evaluate safety and tolerability of modakafusp alfa in combination with pembrolizumab (phase 2 expansion).

To characterize the immunogenicity of modakafusp alfa in patients with solid tumors (phase 1b and phase 2). 
Patient Population
For both phase1b and phase 2 of the study, eligible patients must have histologically confirmed advanced 
(locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors. Please see below for eligibility 
criteria. 
Phase 1b Dose Escalation: Patients with locally advanced or metastatic solid tumors.
Phase 2 Dose Expansion: 
The combination cohorts, including patients in the safety-lead phase, will enroll patients with one of the following 
3 disease indications: 
I.
Unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 prior lines of 
anti-PD1 containing treatments in the metastatic setting.
II.
Unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 prior lines of 
anti-PD1 containing treatments in the metastatic setting. 
III.
Unresectable/metastatic cutaneous melanoma naïve to prior anti-PD1 containing treatments in the 
metastatic setting. 
Please refer to the Eligibility Section for Inclusion and Exclusion details. 
Number of Patients:
Phase 1b Dose Escalation: ~30 patients
Phase 2 Dose Expansion: 3 to 9 safety lead-in patients for 
combination therapy; 25 patients for each expansion 
cohort (3 cohorts) = ~84 patients. 
Total: up to ~ 114 patients.
Number of Sites: 
Phase 1b Dose Escalation: approximately 3 to 4 sites.
Total number of sites: up to approximately 22.
Dose Level(s):
Modakafusp alfa: 0.1, 0.2, 0.4, 0.75, 1.5, 3.0, and 
6.0 mg/kg in a 21-day treatment cycle.
Pembrolizumab: 400 mg in a 6-week treatment cycle.
Route of Administration:
Modakafusp alfa: Intravenous (IV)
Pembrolizumab: Intravenous (IV)
Duration of Treatment: Patients may receive SA 
modakafusp alfa for 1 year or modakafusp alfa in 
combination with pembrolizumab for up to 2 years. 
Patients with demonstrated clinical benefit can continue 
treatment beyond this point if approved by the sponsor. 
Period of Evaluation: The estimated time frame for 
study completion is 55 months (12 months of enrollment 
in escalation, 18 months of enrollment in expansion, 24 
months of treatment, and 1 month of follow-up).
Main Criteria for Inclusion:
1.
Adult patients aged ≥18 years. 
2.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
3.
Life expectancy >12 weeks according to investigator's judgment.
4.
Phase 1b dose escalation: Eligible patients must have histologically confirmed advanced (locoregionally 
recurrent, not amenable to curative therapy) or metastatic solid tumors. 
5.
Measurable disease per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). At least 1 
target lesion amenable for biopsy is required for enrollment in phase1b. A minimum of 1 target lesion for 
response assessment is required for enrollment in phase 2. A separate lesion amenable for biopsy is required for 
enrollment in phase 2 for cohort I and II (post futility analysis) and all patients (safety-lead in and expansion) with 
subgroup cohort III melanoma.
6.
Phase 1b Dose Escalation: Patients with histologically confirmed advanced locally (locoregionally recurrent, not 


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amenable to curative therapy) or metastatic solid tumors. 
Phase 2 Dose Expansion: 
The combination cohorts, including patients in the safety-lead phase, will enroll patients with 
unresectable/metastatic melanoma in the following 3 subgroups: 
I.
Unresectable/metastatic histologically confirmed cutaneous melanoma with primary resistance to no 
more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting.
II.
Unresectable/metastatic histologically confirmed cutaneous melanoma with acquired resistance to no 
more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting. 
III.
Unresectable/metastatic histologically confirmed cutaneous melanoma naive to prior anti-PD1 
containing treatments in the metastatic setting. 

Patients with BRAF V600E mutant melanoma may have received prior BRAF inhibitor therapy. 

For cohorts I and II, there is no limitation of total number of prior line(s) of therapy, but the number of 
prior line(s) containing anti-PD1 must be ≤2 in the metastatic setting. 

For cohort III, patients who received an anti-PD-1 treatment in the adjuvant setting must have completed 
that treatment at least 6 months prior to enrollment and must not have progressed on the anti-PD1 
adjuvant treatment.

Primary resistance is defined as a best response of PD or SD<6 months to an anti-PD1 alone or in 
combination with other agents (ie, CTLA4) in the initial anti-PD1 containing treatment. 

Acquired resistance is defined as progression following a best response of CR, PR, or SD >6 months to a 
prior anti-PD1 alone or in combination with other agents (ie, CTLA4).
7.
Reproductively female patients who:

Are postmenopausal for at least 2 years before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, due to unknown risks and potential harm to an unborn child/infant, must 
agree to the following:
–
Agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method 
at the same time, from the time of signing the informed consent through 7 days after the last dose of 
modakafusp alfa or 4 months after the last dose of pembrolizumab, whichever is longer, OR
–
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
–
Agree not to donate an egg or eggs (ova) or breastfeed a baby during the study through 7 days after the 
last dose of modakafusp alfa and 4 months after the last dose of pembrolizumab, whichever is longer.
8.
Reproductively male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the study and through 7 days after the last dose of 
modakafusp alfa (no restriction for pembrolizumab) OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.)

Agree not to donate sperm during the study and through 7 days after the last dose of modakafusp alfa (no 
restriction for pembrolizumab). 
9.
Voluntary written consent must be given before performance of any study-related procedure not part of standard 


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medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice 
to future medical care.
10. Adequate bone marrow reserve and renal and hepatic function based on the following laboratory parameters: 

Absolute neutrophil count (ANC) ≥1.0 × 109/L, platelet count ≥75.0 × 109/L, and hemoglobin ≥80 g/L 
without growth factor or transfusion support for ANC and platelets in the preceding 2 weeks.

Total bilirubin ≤1.5 times the upper limit of normal (ULN).

Serum alanine aminotransferase or aspartate aminotransferase ≤3.0 times the ULN (<5 times the ULN if liver 
enzyme elevations are due to liver metastases).

Creatinine <1.5 times the ULN or estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 using the 
Modification of Diet in Renal Disease (Levey et al. 2006) or Chronic Kidney Disease Epidemiology 
Collaboration (Levey et al. 2009) equations.
11. Patients must agree to the applicable biopsy requirements as detailed in the Schedule of Events. 
Main Criteria for Exclusion:
1.
Treatment with any SoC or investigational anticancer drug within 28 days or 5 half-lives before administration of 
modakafusp alfa, whichever came first. The washout period is 3 weeks for previous major surgery, 2 weeks for 
previous radical radiation (including chemoradiation and whole-brain radiation), and 5 days from last dose for 
focal radiation for symptomatic metastases. 
2.
Persistent toxicity from previous treatments that has not resolved to ≤ National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 5 (NCI CTCAE v.5) Grade 1 prior to administration of 
modakafusp alfa, except for alopecia, G2 neuropathy, and G2 asthenia/fatigue.
3.
History of any of the following ≤6 months before first dose: New York Heart Association Grade III or IV 
congestive heart failure, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, 
any ongoing symptomatic cardiac arrhythmias of Grade >2, pulmonary embolism, or symptomatic 
cerebrovascular events, or any other serious cardiac condition (eg, symptomatic pericardial effusion or restrictive 
cardiomyopathy). Chronic, stable atrial fibrillation on stable anticoagulant therapy, including low 
molecular-weight heparin, is allowed. 
4.
Baseline QT interval corrected by the Fridericia method (QTcF) >480 msec (Grade ≥2), history of congenital long 
QT syndrome, or torsades de pointes.
5.
History of immune-related AEs related to anti-PD1/PD-L1 treatment that required treatment discontinuation 
(phase 2).
6.
Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially 
increase the risk of adverse events (AEs) or has compromised ability to provide written informed consent.
7.
History of uncontrolled brain metastasis or previously treated metastases receiving corticosteroid 
dose >20 mg/day of prednisone equivalent at the time of receiving the first dose of modakafusp alfa. Note:
Patients with carcinomatosis meningitis or leptomeningeal disease are excluded, regardless of clinical stability.
8.
Patients with uveal (ocular) or mucosal melanoma are excluded (phase 2). 
9.
Patients with acral lentiginous melanoma are excluded in phase 2 except for the safety lead-in phase. 
10. Ongoing or active infection.
11. Known history of HIV infection or any other relevant congenital or acquired immunodeficiency. 
12. Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C infection viral load. Note: 
Patients who have a positive HBV core antibody can be enrolled but must have an undetectable hepatitis B viral 
load. 
13. Autoimmune disease requiring systemic immunosuppressive therapy. Patients with immune mediated endocrine 
deficiency from previous therapy with stable hormone replacement are exceptions. 
14. History of severe allergic or anaphylactic reactions to recombinant proteins or excipients used in modakafusp alfa 
or pembrolizumab formulation. 
15. Patients who are lactating and breastfeeding or have a positive serum or urine pregnancy test during the screening 
period.
Main Criteria for Evaluation and Analyses: 


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The primary endpoints are:

Frequency and severity of TEAEs according to NCI CTCAE v.5 (phase 1b and phase 2 safety lead-in).

Number of patients with DLTs (phase 1b and phase 2 safety-lead in).

Number/percentage of patients with 1 or more SAEs (phase 1b and phase 2 safety-lead in).

Number/percentage of patients with 1 or more TEAE leading to dose modification and/or treatment 
discontinuation (phase 1b and phase 2 safety-lead in).

Overall response rate (ORR) (complete response [CR] + partial response [PR]) assessed according to RECIST 
V1.1 for melanoma patients (phase 2 expansion).
The secondary endpoints are:

MTD or PAD, if available (phase 1b).

RP2D (phase 1b and phase 2 safety-lead in).

Frequency and severity of TEAEs according to the NCI CTCAE V. 5 (phase 2 expansion).

Number/percentage of patients with 1 or more SAEs (phase 2 expansion).

Number/percentage of patients with 1 or more TEAE leading to dose modification and/or treatment 
discontinuation (phase 2 expansion).

PK parameters for dose escalation phase (phase 1b) and safety lead-in phase of dose expansion (phase 2 
safety-lead in):
–
Maximum observed concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration versus time curve from time 0 to time t (AUCt).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Terminal disposition phase half-life (t1/2z).
–
Clearance.
–
Volume of distribution at steady state (Vss).

Overall response rate (ORR) (complete response [CR] + partial response [PR]) assessed according to RECIST 
v1.1 for dose escalation phase (phase 1b). 

Disease control rate (DCR) (CR + PR + stable disease [SD]) (phase 1b and phase 2 expansion).

DOR (phase 1b and phase 2 expansion).

Time to progression (TTP) (phase 1b and phase 2). 

Progression-free survival (PFS) assessed according to RECIST v1.1. (phase 1b and phase 2 expansion).

Overall survival (OS) (phase 1b and phase 2). 

Efficacy measures of ORR, DCR, DOR, TTP, and PFS based on iRECIST (phase 2 expansion). 

Anti–modakafusp alfa antibody incidence and titer (phase 1b and phase 2 expansion). 
Statistical Considerations: 
An adaptive BLRM that implements EWOC will be used for dose escalation recommendations and estimation of the 
MTD starting with the second dose level. In dose escalation, the PK parameters will be summarized using descriptive 
statistics. Individual modakafusp alfa concentration-time data and individual PK parameters will be presented in 
listings and tabulated using summary statistics by dose cohort. Individual and mean concentration-time profiles will 
be plotted by dose cohort.
Primary efficacy endpoints include ORR for melanoma patients in the expansion cohorts. Secondary efficacy 
endpoints include ORR for patients in phase 1b dose escalation, DCR, DOR, TTP, PFS, and OS. No formal statistical 
tests will be performed for these efficacy endpoints. ORR and DCR will be summarized using descriptive statistics 


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with 95% CIs. PFS and OS will be analyzed descriptively using the Kaplan-Meier method for the safety analysis set. 
DOR will also be analyzed using the Kaplan-Meier method for the response-evaluable analysis set.
Sample Size Justification: 
It is expected that approximately 30 patients will be enrolled in the phase 1b escalation phase. A minimum of 
3 patients will be enrolled at the starting dose level. Starting from the second dose level, an adaptive BLRM guided by 
the EWOC principle will be used for all subsequent dose escalation recommendations. 
Up to 25 patients will be enrolled in each of the 3 combination therapy cohorts. A Bayesian predictive probability 
design was used to allow multiple interim analyses for early termination due to futility. Assuming 3 to 9 safety lead-in 
patients, the total sample size for phase 2 can be up to 84. 


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities except for those identified in Appendix C
(Responsibilities of the Investigator). The identified vendors will perform specific study-related 
activities either in full or in partnership with the sponsor. 
3.2
Principal Investigator
Takeda will select a signatory coordinating investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (CSR) and by doing so agrees that it accurately describes 
the results of the study.


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3.3
List of Abbreviations 
Term
ADA
antidrug antibody
ADR
adverse drug reaction 
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC∞
area under the serum concentration-time curve from time 0 to infinity
AUClast
area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUCt
area under the plasma concentration versus time curve from 0 to time t 
BLRM
Bayesian Logistic Regression Model
C1D1
Cycle 1 Day 1
C2D1
Cycle 2 Day 1
CD38+
CD38-expressing
cfDNA
cell-free DNA
CFR
Code of Federal Regulations
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
Cmax
maximum observed serum concentration
CNS
central nervous system
COVID-19
coronavirus disease 2019
CPI
checkpoint inhibitor
CR
complete response
CRO
contract research organization
CRS
cytokine release syndrome
CT
computed tomography
DCR
disease control rate
DLT
dose-limiting toxicity 
DOR 
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
EOT
end of treatment
EWOC
Escalation with Overdose Control
FDA
[United States] Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
IB
Investigator’s Brochure


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Term
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IFN
interferon
IFNα
interferon-alpha
IFNα2b
interferon-alpha 2b
Ig
immunoglobulin
IL
interleukin
IND
investigational new drug
irAE
immune-related adverse event 
IRB
institutional review board
iRECIST
immune Response Evaluation Criteria in Solid Tumors
IRR
infusion-related reaction
IV
intravenous(ly)
IVIG
intravenous immunoglobulins
KD
disassociation constant
mAb
monoclonal antibody
MDRD
Modified Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
MDRD
Modification of Diet in Renal Disease 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
NLCB
no longer clinically benefitting
NSCLC
non–small-cell lung cancer
ORR
overall response rate
OS
overall survival
PAD
pharmacologically active dose
PBMC
peripheral blood mononuclear cell
PD
progressive disease; disease progression
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PT
Preferred Term
QTcF
QT interval with Fridericia correction method
Q3W
once every 3 weeks
Q6W
once every 6 weeks


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Term
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RO
receptor occupancy
RP2D
recommended phase 2 dose
SA
single agent 
SAE
serious adverse event
SD
stable disease
SOC
standard of care
SSE
symptomatic skeletal event
SUSARs
suspected unexpected serious adverse reactions
t1/2z
terminal disposition phase half-life
TAK-573
modakafusp alfa 
TBNK
quantification of T cells, B cells, and natural killer cells
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed serum modakafusp alfa concentration
TME
tumor microenvironment
ULN
upper limit of normal
US
United States 
Vss
volume of distribution at steady state
3.4
Corporate Identification 
TDC
Takeda Development Center Americas, Inc. (TDCA)


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4.0
INTRODUCTION
4.1
Modakafusp Alfa (TAK-573) Background
Modakafusp alfa (TAK-573), henceforth referred to as “modakafusp alfa,” is a recombinant 
humanized immunoglobulin (Ig) G4 anti-CD38 monoclonal antibody fused to 2 attenuated 
interferon-alpha 2b (IFNα2b) moieties. Modakafusp alfa is produced by recombinant DNA 
technology in a mammalian cell expression system and is purified by a process that includes 
specific viral inactivation and removal steps. The CD38 antibody portion of modakafusp alfa 
directs the attenuated IFNα2b portion to CD38-expressing (CD38+) cells, thus achieving a high 
local concentration of IFNα2b at the surface of these target cells. On CD38-negative cells, the 
attenuation results in approximately 130,000-fold reduced potency compared with IFNα2b.
Modakafusp alfa has a high binding affinity (dissociation constant [KD]) for human and 
cynomolgus CD38, with a KD of 168 pM and 1.25 nM, respectively. Modakafusp alfa can potently 
inhibit proliferation of CD38+ multiple myeloma (MM) cells (half-maximal inhibitory 
concentration [IC50] 19.9 pM), whereas potency on CD38-negative cells is approximately 
2500-fold lower. The antibody portion of modakafusp alfa is an IgG4 isotype (unlike the IgG1 
isotype of daratumumab) and therefore has limited effector capacity to induce antibody-dependent 
cell mediated cytotoxicity, antibody-dependent cellular phagocytosis, or complement activation 
against normal CD38+ cells. Modakafusp alfa does not modulate the adenosine 
diphosphate-ribosyl cyclase activity of CD38, unlike daratumumab. 
Interferon-α2b (Intron A) by comparison has similar potency to modakafusp alfa on CD38+ cells 
(IC50 12.3 pM) but on CD38-negative cells is approximately 130,000-fold more potent than 
modakafusp alfa (EC50 [half-maximal effective concentration] ~0.37 pM). 
A brief background of modakafusp alfa is provided in the following sections. More detailed 
information is provided in the Investigator’s Brochure (IB).
4.1.1
Modakafusp Alfa Targets
The tumor cell surface-expressed antigen CD38 is uniformly and highly expressed on multiple 
myeloma (MM) cells (Lin et al. 2004; Santonocito et al. 2004) and at lower levels on various 
lymphoid and myeloid cells and some solid organs (Deaglio et al. 2008). Being highly expressed 
on the myeloma cell surface and showing lower expression on normal cells makes CD38 an 
appropriate target for delivering drugs (cytokines, radioisotopes (Green et al. 2014), and toxins 
(Bolognesi et al. 2005; Goldmacher et al. 1994) to receptor-expressing cells. A promising moiety 
to be conjugated to an anti-CD38 monoclonal antibody (mAb) is the cytokine interferon-alpha 
(IFNα), which is currently approved—although seldom used—for maintenance treatment for MM, 
metastatic melanoma, follicular lymphoma, or hairy cell leukemia. IFNα has direct inhibitory 
effects on some tumors and is a potent stimulator of both the innate and adaptive immune systems. 
Systemic toxicity of IFN-α, however, precludes the use of the cytokine at therapeutically effective 
doses in the majority of patients. By reducing the binding affinity of IFNα (KD) for its IFNα 
receptor, modakafusp alfa is expected to limit binding of attenuated IFNα to its receptor on 


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non-CD38-\-expressing cells. In contrast, binding of modakafusp alfa with high affinity via its 
CD38 targeting moieties is expected to increase the local concentration of attenuated IFNα on 
CD38+ target cells, thereby inducing desired on-target interferon (IFN) pathway activation. In 
addition, IFNα pathway activation induces up-regulation of CD38 messenger RNA and protein 
levels in malignant cells of patients with B cell chronic lymphocytic leukemia (Bauvois et al. 
1999), suggesting that modakafusp alfa may be able to increase CD38 target expression in MM 
and other CD38+ immune cells, thus overcoming the limitations seen with drugs such as 
daratumumab which depletes CD38+ immune cells. modakafusp alfa increases CD38 expression 
on MM cells in vitro, which further supports this hypothesis.
CD38 is a multifunctional ectoenzyme involved in cell adhesion and transmembrane signaling. It 
is overexpressed in hematologic tumors, where it is believed to play a role in tumor cell migration 
and metastasis. CD38 has been reported to be highly expressed in the majority of MM 
patient-derived tumor cells (Lin et al. 2004). CD38 is an approximately 45 kDa transmembrane 
glycoprotein expressed by immature hematopoietic cells, downregulated in mature cells, and 
re-expressed at higher levels by activated lymphocytes, such as T cells, B cells, dendritic cells, and 
natural killer (NK) cells (Funaro et al. 1990). 
Early bone marrow cells, which are crucial for long-term (sustained) marrow recovery, do not 
express CD38, but committed progenitor bone marrow cells, B cells in germinal centers, 
terminally differentiated plasma cells, and activated tonsils are CD38+ (Chillemi et al. 2013). 
Deaglio et al (Deaglio et al. 2008) reviewed the main tissues and cells where CD38 is present, as 
summarized in Table 4.a. CD38 is also found in a soluble form in normal and pathological fluids 
(2018).
Recent data suggests that CD38 is a major mechanism of acquired resistance to PD1/PD-L1 
blockade, causing CD8+ T-cell suppression (Bauvois et al. 1999).


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Table 4.a
Reported Distribution of Human CD38
Tissue
Cellular Distribution
Putative Function
Bone marrow
Hematologic precursors plasma cells
Homing and apoptosis; marker of 
precursor cell commitment
Thymus
Throughout thymic development
Unknown
Spleen/lymph nodes
Germinal center B cells
Rescue from apoptosis
Blood
T, B, NK, and monocyte subsets; platelets and 
erythrocytes; hematologic precursors plasma cells
Interaction with endothelium
Gut
Intraepithelial and lamina propria lymphocytes
Mucosal immunity
Brain
Purkinje cells; neurofibrillary tangles
Memory process
Prostate
Epithelial cells
Unknown
Pancreas
β cells
Insulin secretion
Bone
Osteoclasts
Bone resorptions
Eye
Retinal cells
Vision process
Muscle
Sarcolemma of smooth and striated muscle
Muscle contraction
Source: Deaglio et al 2008 (Deaglio et al. 2008).
4.1.2
Modakafusp Alfa Nonclinical Pharmacology
Modakafusp alfa effectively induces apoptosis in high-expressing CD38+ human myeloma cells 
as demonstrated in a caspase activation assay (EC50 23 pM); no apoptotic effects are observed with 
normal human peripheral blood mononuclear cells (PBMCs). Modakafusp alfa elicited a low level 
of cytokine release (tumor necrosis factor alpha, interleukin [IL]-6, IL-8, interferon-gamma 
[IFN-γ], and IL-2) from human PBMCs in vitro and therefore, is unlikely to induce cytokine 
release syndrome (CRS) in the clinic.
Modakafusp alfa is active in multiple human myeloma xenograft models and induces complete 
regressions at tolerated doses. A single dose of 10 mg/kg modakafusp alfa in the NCI-H929 human 
myeloma xenograft model resulted in complete regressions in all treated animals. In comparative 
xenograft studies using the H929 model, modakafusp alfa had more robust antitumor activity than 
established myeloma therapies, including bortezomib, lenalidomide, and daratumumab. 
Furthermore, under conditions of suboptimal dosing of modakafusp alfa, strong synergy has been 
observed with other standard treatment agents such as bortezomib and lenalidomide. Details of 
these in vivo experiments can be found in the modakafusp alfa IB.
The nonclinical rationale for a potential antitumor benefit in patients with solid tumors is presented 
in detail in Section 4.4.1.
4.1.2.1
Toxicology Studies
A series of toxicological studies in cynomolgus monkeys was conducted 
 
.


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No remarkable toxicity was noted following a single administration of modakafusp alfa at dose 
levels up to 20 mg/kg via 1-hour intravenous (IV) infusion. Neopterin levels (a biomarker of IFN 
biological activity) were measured; increases in neopterin were noted at 24 hours postdose and 
were still above baseline up to 240 hours postdose.
Three repeat-dose toxicity studies were performed in cynomolgus monkeys where modakafusp 
alfa was administered by a 1-hour IV infusion: a 15- or 22-day non-Good Laboratory Practice 
(non-GLP), dose range–finding, once-weekly or twice-weekly study at dose levels of 3 or 10 
mg/kg; a pivotal, 29-day, GLP study at dose levels of 3, 10, or 30 mg/kg weekly; and a follow-up 
4-week GLP study at dose levels of 0.3, 3, or 10 mg/kg weekly. The results of these 3 studies were 
similar; the results of the 29-day GLP study are discussed below. 
Administration of modakafusp alfa in all groups was well tolerated in the pivotal GLP study after 
the first and second dose. During the third and fourth doses, clinical signs were noted at all dose 
levels during the infusion. Clinical signs ranged from mild to severe and consisted of 1 or more of 
the following: vomiting; retching; salivation; swelling of both eyelids; pallor of the lips, muzzle, 
and chin; increased activity; presence of red spots on the limbs and axillary, inguinal, and 
urogenital areas; vocalizing; piloerection; ptosis; coldness to touch; changes in activity; 
respiratory distress; and/or unresponsiveness. The majority of these clinical signs started at 
approximately 5 minutes after the start of infusion and mostly subsided on the same day; the 
exception was the presence of red spots, which persisted for 1 or 2 more days. During the third 
dose, the reaction was severe enough in 1 male at 30 mg/kg to require the cessation of dosing, after 
which the animal recovered. Diphenhydramine was administered 30 minutes before the start of the 
fourth dose on Day 22 (males only); however, immediately following the fourth dose, 4 males at 
the mid- and high-dose groups had severe reactions, and 3 were preterminally euthanized. The 
study was terminated before the fourth dose in females. 
The weight of evidence is consistent with these responses being the result of secondary effects 
arising from antidrug antibody (ADA) formation and not a direct effect of modakafusp alfa. 
Concurrent with the onset of clinical signs during or shortly after the third and/or fourth dose, all 
animals had developed ADAs that were associated with decreased or undetectable exposure to 
modakafusp alfa and decreasing levels of the IFN biomarker neopterin, which were markedly 
elevated after the first and second doses. This antibody response included IgE class antibodies and 
activation of complement (increases in Bb and SC5b-9 split products of the complement pathway). 
Macroscopic and microscopic pathology findings unique to preterminally euthanized animals 
consisted of lung edema and vascular leukocytosis in the lung and liver, which likely contributed 
to the poor clinical condition and death of the animals, as well as minimal hematopoietic 
hypocellularity in the bone marrow.
Routine clinical chemistry examination of all animals done at weekly intervals was unremarkable 
except for an increase in total protein due to an increase in serum globulin content, a decrease in 
serum albumin (30 mg/kg females only), and a decreased albumin-globulin ratio at 10 and 
30 mg/kg in females and at 30 mg/kg in males. These findings were consistent with an acute phase 
response and were accompanied by increases in C-reactive protein serum levels and elevations in 


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IL-6 in a total of 5 animals administered modakafusp alfa on Day 1 (1 animal) or Day 15 (4 
animals). There were no modakafusp alfa–related increases in IFN-γ, TNF, IL-4, IL-5, or IL-2.
Additionally, minimal-to-slight decreases in total mean white blood cell counts and in neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, and large unstained cells were noted on Days 2 
and 7 in the animals administered modakafusp alfa in all dose groups. The decreases in leukocyte 
counts were not dose related and remained, for the most part, within the reference range.
From Day 14 to end of treatment ([EOT]; Day 23 for males and Day 24 for females), there were 
slight-to-moderate increases in mean leukocyte counts due to increases in lymphocytes, basophils,
eosinophils, and large unstained cells in the animals administered modakafusp alfa in all dose 
groups, which were concurrent with the development of an ADA response. Additionally, there 
were decreases in red blood cell (RBC) counts, hemoglobin, and hematocrit with increased 
reticulocytes in all dose groups from Day 14 to EOT.
In all dose groups of both preterminally and terminally euthanized animals, macroscopic and 
microscopic changes were observed in the spleen and consisted of increased spleen weight 
correlating with follicular lymphoid hypercellularity, sinus histiocytosis, and sinus dilatation. The 
incidence and severity of lymphoid hypercellularity were generally proportional to dose, with no 
clear relationship to dose for sinus histiocytosis and dilatation. Concurrent follicular hyalinization 
or follicular lymphoid degeneration/necrosis was noted in 1 female dosed with 3 mg/kg and in 1 
male dosed with 10 mg/kg, respectively. Bone marrow hematopoietic hypercellularity was present 
at 30 mg/kg. These histologic findings may have been partially confounded by the development of 
the ADA response. After a 21-day (males) or 28-day (females) recovery period, there was nearly 
complete recovery of splenic sinus dilation and complete recovery of all other spleen findings.
The marked immunogenic response of the monkeys to modakafusp alfa was not unexpected 
considering the presence of human IFN sequences, which are known to be highly immunogenic in 
monkeys, as is already known from previous experience with PEGIntron.
A no-observed-adverse-effect level was not identified in the pivotal GLP toxicity study, as adverse 
clinical signs were noted at the low dose of 3 mg/kg; however, 3 mg/kg was considered the highest 
nonseverely toxic dose.
4.2
Pembrolizumab Background
Pembrolizumab is a humanized immunoglobulin G4 (IgG4) mAb with a high specificity of 
binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and programmed cell death 
protein 2 ligand (PD-L2). Preclinical data demonstrated the high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable clinical safety profile as an IV 
immunotherapy for advanced malignancies. Pembrolizumab is indicated for treatment across 
multiple indications (Keytruda (pembrolizumab) PI 2018). 




















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evaluate the efficacy of modakafusp alfa in combination with pembrolizumab in patients with 
unresectable/metastatic cutaneous melanoma (phase 2 expansion).
5.1.2
Secondary Objectives
The secondary objectives are:

To define the MTD and/or PAD of modakafusp alfa SA, if applicable (phase 1b).

To select the RP2D of modakafusp alfa SA (phase 1b) and in combination with 
pembrolizumab (phase 2 safety lead-in).

To evaluate modakafusp alfa PK as a SA (phase 1b) or in combination with pembrolizumab 
(phase 2 safety lead-in).

To assess the preliminary antitumor activity of modakafusp alfa as a SA (phase 1b). 

To further characterize the antitumor effect of modakafusp alfa in combination with 
pembrolizumab based on immune Response Evaluation Criteria in Solid Tumors (iRECIST) in 
expansion cohort patients (phase 2 expansion).

To evaluate safety and tolerability of modakafusp alfa in combination with pembrolizumab 
(phase 2 expansion).

To characterize the immunogenicity of modakafusp alfa in patients with solid tumors (phase 
1b and phase 2).
5.1.3
Exploratory/Additional Objectives
The exploratory/additional objectives are:

To assess modakafusp alfa CD38 RO of peripheral immune cells in patients treated with 
modakafusp alfa as a SA (phase 1b) or in combination with pembrolizumab (phase 2).

To explore predictive biomarkers of response (phase 1b and phase 2).

To evaluate the effect of modakafusp alfa on QTcF intervals (phase 1b and phase 2 safety 
lead-in).

To evaluate the relationship between administered dose and exposure of modakafusp alfa, RO 
of CD38, and IFN pathway induction as evaluated by gene expression changes and production 
of cytokines/chemokines (phase 1b and phase 2).

To evaluate the relationship between evidence of IFN pathway induction (as described above) 
with evidence of activation of the innate and/or adaptive immune response as assessed by 
changes in immunophenotype and T-cell antigen receptor (TCR) clonality of peripheral blood 
and tumor (phase 1b and phase 2).

To evaluate the relationship between modakafusp alfa exposure and/or CD38 RO with 
immune cell activation (as described above), and clinical response (phase 1b and phase 2).


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
To evaluate correlations between baseline tumor IFN pathway gene expression with either the 
degree of IFN pathway induction or the level of immune cell activation on treatment (phase 1b 
and phase 2).

To characterize germline DNA variants for correlations with clinical outcome, 
pharmacodynamic effects, and PK (phase 1b and phase 2).

To further characterize the antitumor effect of modakafusp alfa based on changes in the tumor 
growth rate between the most immediate pretreatment period and on treatment (phase 1b and 
phase 2).

To characterize serum PK of pembrolizumab when administered in combination with 
modakafusp alfa (phase 2).

To assess the Type I interferon (IFN) gene expression signature in peripheral blood (phase 1b 
and phase 2).

To evaluate correlations with clinical outcome with either the on-treatment immunophenotype 
of the tumor microenvironment or changes in the immunophenotype from baseline (phase 2).
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoints are:

Frequency and severity of TEAEs according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE v5) (phase 1b and phase 2 
safety lead-in).

Number of patients with DLTs (phase 1b and phase 2 safety-lead in).

Number/percentage of patients with 1 or more SAEs (phase 1b and phase 2 safety-lead in).

Number/percentage of patients with 1 or more TEAE leading to dose modification and/or 
treatment discontinuation (phase 1b and phase 2 safety-lead in).

Overall response rate (ORR) (complete response [CR] + partial response [PR]) assessed 
according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) for 
melanoma patients (phase 2 expansion).
5.2.2
Secondary Endpoints

MTD or PAD (as defined in 6.1.1), if available (phase 1b). 

RP2D for SA and in combination with pembrolizumab, respectively (phase 1b and phase 2 
safety lead-in). 

Frequency and severity of TEAEs according to the NCI CTCAE v5 (phase 2 expansion).


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
Number/percentage of patients with 1 or more SAEs (phase 2 expansion).

Number/percentage of patients with 1 or more TEAE leading to dose modification and/or 
treatment discontinuation (phase 2 expansion).

PK parameters after the first dose of modakafusp alfa on Cycle 1 Day 1 (C1D1) and on Cycle 2 
Day 1 (C2D1) for dose escalation phase (phase 1b) and on Cycle 1 Day 1 (C1D1) and Cycle 3 
Day 1 (C3D1) for the phase 2 safety lead-in phase of dose expansion:
–
Maximum observed concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration versus time curve from time 0 to time t (AUCt).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Terminal disposition phase half-life (t1/2z).
–
Clearance.
–
Volume of distribution at steady state (Vss).

ORR (CR + PR) assessed according to the RECIST v1.1 for patients in dose escalation (phase 
1b).

Disease control rate (DCR) (CR + PR + stable disease [SD]) (phase 1b and phase 2).

DOR (phase 1b and phase 2).

TTP (phase 1b and phase 2). 

Progression-free survival (PFS) assessed according to RECIST v1.1 (phase 1b and phase 2)

OS (phase 1b and phase 2). 

Efficacy measures of ORR, DCR, DOR, TTP, and PFS based on iRECIST (phase 2 
expansion). 

Anti–modakafusp alfa antibody incidence and titer (phase 1b and phase 2).
Definitions and timeframes of primary and secondary endpoints are provided in Section 6.3.3.
5.2.3
Additional/Exploratory Endpoints
The exploratory endpoints are:

Tumor mutations characterized from cell-free DNA (cfDNA) and quantification of circulating 
tumor cells (CTCs) will be evaluated at baseline and assessed for correlations with clinical 
response. 

Genomic and protein expression of baseline tumor tissue.

Germline mutations and polymorphisms as assessed by whole exome sequencing of peripheral 
blood.


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
Change of QTcF interval using data from PK time matched triplicated electrocardiogram 
(ECG) readings.

Induction of modakafusp alfa–induced gene expression changes, including type I IFN 
signature, assessed in peripheral blood and tumor.

Fold-change in plasma levels of IP-10 and other cytokines/chemokines.

Immune cell activation as assessed in peripheral blood and tumor by (a) immunophenotypic 
changes and (b) evaluation of TCR diversity.

Modakafusp alfa antitumor effect size based on observed change in tumor growth rate using 
prescreening, screening, and on-treatment diagnostic imaging, as available.

Serum PK of pembrolizumab when administered in combination with modakafusp alfa. 

Cellular CD38 RO of peripheral blood assessed at time points surrounding the first and second 
modakafusp alfa SA administrations (phase 1b) and at time points surrounding the first and 
third modakafusp alfa administrations when in combination with pembrolizumab (phase 2).

Modakafusp alfa–induced Type I IFN gene expression signature in the peripheral blood (phase
1b and phase 2).

Immunophenotypic evaluations of the tumor and tumor microenvironment utilizing 
multiplexed immunohistochemistry or similar methodologies.


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6.0
STUDY DESIGN
6.1
Overview of Study Design
This is an open-label, phase 1b/2 study designed to evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics and antitumor response of modakafusp alfa as a SA 
and in combination with pembrolizumab in patients with advanced or metastatic solid tumors. 
Please see Section 7.0 for complete eligibility criteria.
The study consists of 2 phases as shown in Figure 6.a. 
Figure 6.a
Study Schema
PHASE 1b
PHASE 2 DOSE EXPANSION
RP2D: recommended phase 2 dose; SA: single agent.
6.1.1
Phase 1b Single-Agent Dose Escalation
Phase 1b will enroll patients with advanced/metastatic solid tumors that have no standard 
therapeutic option, are intolerant to those therapies, or have refused them.
The modakafusp alfa SA dose escalation phase is designed to determine the SA RP2D and 
schedule of modakafusp alfa for further testing. The single-agent RP2D may be either the MTD 
based on DLTs or a PAD defined by the PK/pharmacodynamic model or exposure-response (ER) 
analysis in place. 
A minimum of 3 patients will be enrolled in the starting dose cohort of modakafusp alfa 0.1 mg/kg 
administered Q3W. Doses will be escalated as follows: 0.1, 0.2, 0.4, 0.75, 1.5, 3 and 6 mg/kg. 
Patients will be assessed for DLTs until Cycle 2 Day 1 (C2D1) can be administered from a safety 
Modakafusp alfa 
+ Pembrolizumab 
Safety Lead-in 
Any patient type of 
the expansion 
cohorts (N = 3 to 9 
patients).
Modakafusp alfa + Pembrolizumab 
Expansion
Unresectable/metastatic cutaneous melanoma 
with primary resistance to no more than 2 
prior lines of anti-PD1 containing treatments 
in the metastatic setting (N = 25 patients) 
Unresectable/metastatic cutaneous melanoma 
with acquired resistance to no more than 2 
prior lines of anti-PD1 containing treatments 
in the metastatic setting (N = 25 patients)
Unresectable/metastatic cutaneous melanoma 
naïve to prior line of anti-PD1 containing 
treatments in the metastatic setting (N = 25 
patients). 
Modakafusp alfa 
SA Dose Escalation
Patients with 
advanced/metastatic 
tumors to determine 
RP2D (all comers, 
up to N = 30 
patients).


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standpoint. If there are no DLTs in the first cohort of 3 evaluable patients dosed at 0.1 mg/kg, 
Bayesian Logistic Regression Model (BLRM) guided by the Escalation with Overdose Control 
(EWOC) principle will be used in successive dose escalation cohorts to estimate the next dose 
level. More conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing dose level are all permissible following discussions between the sponsor and the 
investigators, if such measures are needed for patient safety or for a better understanding of the 
dose-related toxicity, exposure, or pharmacodynamics. It is estimated that approximately 30 
patients will be enrolled until either the MTD and/or PAD is identified. 
6.1.2
Phase 2 Dose Expansion
Enrollment into phase 2 expansion in combination with pembrolizumab will be initiated once the 
RP2D of modakafusp alfa has been determined in phase 1b. 
The combination treatment cohorts will begin with a single safety-lead in period to evaluate safety 
and tolerability during the Cycle 1 DLT evaluation period of modakafusp alfa with 
pembrolizumab. If there are no DLTs in the first 3 patients during Cycle 1 of the safety lead-in 
period with modakafusp alfa SA RP2D in combination with pembrolizumab 400 mg Q6W, the 
combination dose and regimen could be selected for the 3 disease cohorts described below. If there 
is 1 DLT in the initial 3 patients in the safety-lead in period, an additional 3 patients will be 
enrolled at the same modakafusp alfa RP2D in combination with pembrolizumab 400 mg Q6W. If 
there are ≥2 DLTs in the first 3 patients at the modakafusp alfa SA RP2D, enrollment will resume 
at the next lower dose level of modakafusp alfa RP2D in combination with pembrolizumab. Other 
approved pembrolizumab dosing regimens (eg, 200 mg Q3W) could be tested in the safety-lead in 
period if 400 mg Q6W in combination with modakafusp alfa at one dose lower than RP2D is 
intolerable. 
For the safety lead-in period, patient enrollment will be staggered between the first and second 
patients by 7 days. The second and third patients can be dosed concurrently if the first patient in the 
cohort has gone through the Day 8 visit without clinically significant acute toxicities. Patients 
enrolled in the safety lead-in phase could have any of the 3 melanoma disease categories described 
below. 
Following completion of the safety lead-in phase and review of safety data, phase 2 of the study 
will further explore the safety and efficacy of modakafusp alfa treatment in combination with 
pembrolizumab. The combination cohorts, including patients in the safety-lead phase, will enroll 
patients with unresectable/metastatic melanoma in the following subgroups:
I.
Unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 
prior lines of anti-PD1 containing treatments in the metastatic setting.
II. Unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 
prior lines of anti-PD1 containing treatments in the metastatic setting. 
III. Unresectable/metastatic cutaneous melanoma naïve to prior anti-PD1 containing 
treatments in the metastatic setting.


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Up to 25 patients will be enrolled in each of the 3 cohorts in phase 2. A Bayesian predictive 
probability design will be used to allow multiple futility analyses for early termination due to 
futility.
If modakafusp alfa in combination with pembrolizumab is safe and meaningful clinical activity is 
seen, additional expansion cohorts may be added to assess other tumor types. 
6.2
Number of Patients
It is expected that approximately 30 patients will be enrolled in the phase 1b dose escalation phase 
at approximately 3 to 4 sites. Up to 25 patients will be enrolled in each of the 3 combination 
therapy cohorts. A Bayesian predictive probability design was used to allow multiple interim 
analyses for early termination due to futility. Assuming 3 to 9 safety lead-in patients, the total 
sample size for phase 2 can be up to 84 patients.
The study is expected to enroll up to 114 patients overall. 
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients may receive modakafusp alfa as a SA for up to 1 year or in combination with 
pembrolizumab for up to 2 years. Patients with demonstrated clinical benefit can continue 
treatment beyond those points if approved by the sponsor. These patients can continue receiving 
treatment in this study or in any of the poststudy access modalities described in the protocol 
(Section 6.3.5). Patients may discontinue treatment when they meet any of the discontinuation 
criteria stated in the protocol (Section 9.6).
All patients will have an EOT visit 30 days (+10 days) after receiving the last dose of study drug or 
before the start of subsequent systemic anticancer therapy, whichever occurs first, to permit 
detection of any delayed TEAEs and to resolve any ongoing events. Patients with unresolved 
TEAEs will continue the periodic safety follow-up until complete resolution or stabilization 
(established as sequelae) occurs.
Patients who discontinue study treatment for reasons other than progressive disease (PD) will 
continue PFS follow-up every 12 ± 1 weeks from the EOT visit until the occurrence of PD, lost to 
follow-up, consent withdrawal, death, start of subsequent systemic anticancer therapy, or study 
termination, whichever occurs first. After disease progression or starting another systemic 
anticancer therapy, all patients will be followed every 12 ± 1 weeks for OS until death or study 
termination. 
6.3.2
End of Study/Study Completion Definition and Planned Reporting
No additional data will be collected, and the final analyses for the clinical study report will be 
conducted, after all patients enrolled in the study have discontinued from the trial either because 
modakafusp alfa is discontinued or because patients remaining on treatment have been transferred 
to an open-label rollover study, a single-patient investigational new drug (IND), or any other 
regulated form to access an investigational drug (Section 6.3.5).




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Table 6.a
Primary and Secondary Endpoints for Disclosure
Endpoint
Phase
Definition
Maximum Time Frame
drug to the date of first 
documentation of PD 
according to RECIST 
v1.1 or death due to any 
cause, whichever occurs 
first.
OS
Phase 1b and phase 2
The time from the date of 
first dose of study drug to 
the date of death due to 
any cause. 
Up to ~55 months.
DCR 
Phase 1b and phase 2
CR + PR + SD
Up to ~55 months.
DOR
Phase 1b and phase 2
The time from the date of 
first documentation of a 
PR or better to the date of 
first documentation of PD 
for responders (PR or 
better).
Up to ~55 months.
TTP
Phase 1b and phase 2
The time from the date of 
the date of the first dose 
of study drug to the date 
of first documentation of 
PD according to RECIST 
v1.1.
Up to ~55 months.
ORR, DCR, DOR, TTP, and PFS 
based on iRECIST.
Phase 2 expansion
See above.
Up to ~55 months.
Modakafusp alfa–induced Type I 
IFN gene expression signature in 
peripheral blood.
Phase 1b and phase 2
See Section 13.6.
Up to ~55 months.
Anti-modakafusp alfa antibody 
incidence and titer.
Phase 1b and phase 2
See Section 13.6.
Up to ~55 months.
AUCt : area under the plasma concentration versus time curve from 0 to time t; CxDx: Cycle x Day x; CL: clearance; 
Cmax: maximum observed concentration; CR: complete response; DCR: disease control rate; DOR: duration of 
response; DLT: dose-limiting toxicity; IFN: interferon; RECIST v1.1: Response Evaluation Criteria in Solid Tumors, 
Version 1.1; ORR: overall response rate; OS; overall survival; PFS: progression-free survival; PK: 
pharmacokinetic(s); PR: partial response; RO: receptor occupancy; SAE: serious adverse event; SD: stable disease; 
t1/2z: terminal disposition phase half-life; TEAE: treatment-emergent adverse event; tmax: time of first occurrence of 
Cmax.
6.3.4
Total Study Duration
The estimated time frame for study completion is 55 months (12 months of enrollment in 
escalation, 18 months of enrollment in expansion, 24 months of treatment, and 1 month of 
follow-up).


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6.3.5
Posttrial Access
At the end or termination of the study (Section 9.4), ongoing patients may continue to receive 
modakafusp alfa as a SA or in combination with pembrolizumab in an extension phase of this 
study or will be given the opportunity to enroll in a separate open-label rollover study, a 
single-patient IND, or other regulated access to continue receiving modakafusp alfa as a SA or in 
combination with pembrolizumab if, in the opinion of the investigator and confirmed by the 
sponsor, they have experienced a clinically important benefit from modakafusp alfa or in 
combination with pembrolizumab received in the study, have no alternative therapeutic option, 
and would be harmed without continued access. Patients may receive modakafusp alfa as a SA for 
up to 1 year or in combination with pembrolizumab for up to 2 years.
6.3.5.1
Duration of Posttrial Access
Continued access to modakafusp alfa will be terminated for individuals who are no longer 
benefitting from modakafusp alfa (eg, they have completed the recommended course of therapy or 
their disease has resolved), the benefit-risk no longer favors the individual, if modakafusp alfa 
becomes available either commercially or via another access mechanism, or when an alternative 
appropriate therapy becomes available. Posttrial access may be terminated in a country or 
geographical region where marketing authorization has been rejected, the development of 
modakafusp alfa has been suspended or stopped by the sponsor, or modakafusp alfa can no longer 
be supplied.
7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Adult patients aged ≥18 years. 
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
3. Life expectancy >12 weeks according to investigator’s judgment.
4. Phase 1b dose escalation: Eligible patients must have histologically confirmed advanced 
(locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors. 
5. Measurable disease per RECIST v1.1. At least 1 target lesion amenable for biopsy is required 
for enrollment in phase 1b. A minimum of 1 target lesion for response assessment is required 
for enrollment in phase 2. A separate lesion amenable for biopsy is required for enrollment in 
phase 2 for cohorts I and II post futility analysis and for all patients (safety lead-in and 
expansion) with subgroup III melanoma. 
6. Phase 1b Dose Escalation: Patients with histologically confirmed advanced locally 
(locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors. 
Phase 2 Dose Expansion: 


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The combination cohorts, including patients in the safety-lead phase, will enroll patients with 
unresectable/metastatic melanoma in the following subgroups: 
I.
Unresectable/metastatic histologically confirmed cutaneous melanoma with 
primary resistance to no more than 2 prior lines of anti-PD1 containing treatments 
in the metastatic setting.
II. Unresectable/metastatic histologically confirmed cutaneous melanoma with 
acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments 
in the metastatic setting. 
III. Unresectable/metastatic histologically confirmed cutaneous melanoma naive to 
prior anti-PD1 containing treatments in the metastatic setting. 

Patients with BRAF V600E mutant melanoma may have received prior BRAF inhibitor 
therapy. 

For cohorts I and II, there is no limitation of total number of prior line(s) of therapy, but the 
number of prior line(s) containing anti-PD1 must be ≤2 in the metastatic setting. 

For the expansion cohort III, patients who received an anti-PD-1 treatment in the adjuvant 
setting must have completed that treatment at least 6 months prior to enrollment and must 
not have progressed on the anti-PD1 adjuvant treatment.

Primary resistance is defined as a best response of PD or SD<6 months to an anti-PD1 
alone or in combination with other agents (ie, CTLA4) in the initial anti-PD1 containing 
treatment. 

Acquired resistance is defined as a progression following a best response of CR, PR, or 
SD >6 months to a prior anti-PD1 alone or in combination with other agents (ie, CTLA4).
7. Reproductively female patients who:

Are postmenopausal for at least 2 years before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential (as defined in Section 9.3.9), due to unknown risks and 
potential harm to an unborn child/infant, must agree to the following:
–
Agree to practice 1 highly effective method of contraception (Section 8.9.1) and 1 
additional effective (barrier) method at the same time, from the time of signing the 
informed consent through 7 days after the last dose of modakafusp alfa or 4 months 
after the last dose of pembrolizumab, whichever is longer, OR
–
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)


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–
Agree not to donate an egg or eggs (ova) or breastfeed a baby during the study and 
through 7 days after the last dose of modakafusp alfa or 4 months after the last dose of 
pembrolizumab, whichever is longer.
8. Reproductively male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception (Section 8.9.1) during the entire study 
treatment period and through 7 days after the last dose of modakafusp alfa (no restriction 
for pembrolizumab), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)

Agree not to donate sperm during the study and through 7 days after the last dose of 
modakafusp alfa (no restriction for pembrolizumab).
9. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
10. Adequate bone marrow reserve and renal and hepatic function based on the following 
laboratory parameters: 

Absolute neutrophil count (ANC) ≥1.0 × 109/L, platelet count ≥75.0 × 109/L, and 
hemoglobin ≥80 g/L without growth factor or transfusion support for ANC and platelets in 
the preceding 2 weeks.

Total bilirubin ≤1.5 times the upper limit of normal (ULN).

Serum alanine aminotransferase or aspartate aminotransferase ≤3.0 times the ULN 
(<5 times the ULN if liver enzyme elevations are due to liver metastases).

Creatinine <1.5 times the ULN or estimated glomerular filtration rate (eGFR) 
≥30 mL/min/1.73 m2 using the Modification of Diet in Renal Disease (MDRD) (Levey et 
al. 2006) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (Levey et al. 
2009) equations.
11. Patients must agree to the applicable biopsy requirements as detailed in the SOE. 
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Treatment with any SoC or investigational anticancer drug within 28 days or 5 half-lives 
before administration of modakafusp alfa, whichever comes first. The washout period is 
3 weeks for previous major surgery, 2 weeks for previous radical radiation (including 
chemoradiation and whole-brain radiation), and 5 days from last dose for focal radiation for 
symptomatic metastases. 


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2. Persistent toxicity from previous treatments that has not resolved to ≤CTCAE v.5 Grade 1 
prior to administration of modakafusp alfa, except for alopecia, Grade 2 neuropathy, Grade 2 
asthenia/fatigue, or autoimmune endocrinopathies with stable replacement therapy. 
3. History of any of the following ≤6 months before the first dose of modakafusp alfa: New York 
Heart Association Grade III or IV congestive heart failure, unstable angina, myocardial 
infarction, unstable symptomatic ischemic heart disease, any ongoing symptomatic cardiac 
arrhythmias Grade >2, pulmonary embolism, symptomatic cerebrovascular events, or any 
other serious cardiac condition (eg, symptomatic pericardial effusion or restrictive 
cardiomyopathy). Chronic, stable atrial fibrillation on stable anticoagulant therapy, including 
low molecular-weight heparin, is allowed. 
4. Baseline QTcF >480 msec (Grade ≥2), history of congenital long QT syndrome, or torsades de 
pointes.
5. History of immune-related AEs related to treatment with prior anti-PD1/PD-L1 that required 
treatment discontinuation (phase 2).
6. Psychiatric illness/social circumstances that would limit compliance with study requirements 
and substantially increase the risk of AEs or has compromised ability to provide written 
informed consent.
7. History of uncontrolled brain metastasis or previously treated metastases receiving 
corticosteroid dose >20 mg/day of prednisone equivalent at the time of receiving the first dose 
of modakafusp alfa. 
Note: Patients with carcinomatosis meningitis or leptomeningeal disease are excluded, 
regardless of clinical stability.
8. Patients with uveal (ocular) or mucosal melanoma (phase 2).
9. Patients with acral lentiginous melanoma are excluded in phase 2 except for the safety lead-in 
phase. 
10. Ongoing or active infection.
11. Known history of HIV infection or any other relevant congenital or acquired 
immunodeficiency. 
12. Known hepatitis B (HBV) surface antigen seropositive or detectable hepatitis C infection viral 
load. Note: Patients with a positive HBV core antibody can be enrolled but must have an 
undetectable hepatitis B viral load. 
13. Autoimmune disease requiring systemic immunosuppressive therapy. Patients with immune 
mediated endocrine deficiency from previous therapy with stable hormone replacement are 
exceptions.
14. History of severe allergic or anaphylactic reaction to recombinant proteins or excipients used 
in modakafusp alfa or pembrolizumab formulation.


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15. Patients who are lactating and/or breastfeeding or have a positive urine or serum pregnancy 
test during the screening period.
8.0
STUDY DRUG
8.1
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
The initial dose should be based on a patient’s weight at screening and only adjusted if there is a 
≥10% change in body weight. 
Investigational sites should refer to the pharmacy manual for preparation of each dose. 
Modakafusp alfa doses <1.5 mg/kg will be administered over 1 hour (±10 minutes). Modakafusp 
alfa doses ≥1.5 mg/kg will be administered over 2 hours (±10 minutes) and could be extended to 4 
hours at the investigator’s discretion. Any decrease in infusion duration must be discussed with 
and agreed upon by the sponsor. If a patient presents with an infusion-related reaction at any dose 
level, the duration of the infusion may be extended per investigator’s discretion. Total time from 
modakafusp alfa dosing solution preparation until end of infusion must not exceed 7 hours.
In the combination treatment cohorts, the recommended pembrolizumab dose of 400 mg will be 
administered as an IV infusion over 30 ±10 minutes Q6W in combination with modakafusp alfa. 
Please see premedication and observation guidelines in Section 8.8.1.
Pembrolizumab will be administered before modakafusp alfa on days when both modakafusp alfa 
and pembrolizumab are given. At least 30 minutes should elapse between the completion of the 
infusion of the first study drug and the initiation of the infusion of the second study drug.
8.2
Definitions of Dose-Limiting Toxicities
Toxicity will be evaluated according to the NCI CTCAE v 5. A DLT is defined as any of the 
following AEs that occur in the escalation phase or in the combination safety lead-in phase during 
Cycle 1 unless they are considered by the investigator to be clearly unrelated to therapy with 
modakafusp alfa.

Any Grade 5 TEAE.

Febrile neutropenia: Grade ≥3 neutropenia (ANC <1.0 × 109/L) with fever and/or infection, 
where fever is defined as a single temperature >38.3°C or sustained temperature of ≥38°C for 
more than 1 hour.

Grade 4 neutropenia lasting >7 days. 

Grade 4 thrombocytopenia lasting more than 7 consecutive days, or if platelet transfusion is 
required, or if Grade ≥2 bleeding happens at any moment. A platelet count <10 × 109/L at any 
time is a DLT.


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
Grade ≥3 thrombocytopenia lasting longer than 14 days or accompanied by Grade ≥2 bleeding.

Any Grade 3 immune-related AEs such as pericarditis, pneumonitis, cardiotoxicity, 
hepatitis, or neurotoxicity.

Delay in the initiation of Cycle 2 by more than 14 days from the calculated start date due to a 
lack of adequate recovery of treatment-related hematological or nonhematologic toxicities.

Any Grade ≥3 nonhematologic toxicity with the following exceptions:
–
Grade 3 arthralgia/myalgia that responds to nonsteroidal anti-inflammatory drugs 
(NSAIDs) within 1 week.
–
Grade 3 fatigue that lasts <3 days.
–
Grade 3 endocrine disorder that is managed with or without therapy and the patient is 
asymptomatic.
–
Grade 3 or 4 inflammatory reaction attributed to a local antitumor response.
–
Grade 3 or 4 asymptomatic laboratory changes (other than renal and hepatic laboratory 
values) that can be successfully corrected (reversion of Grade 4 events to Grade ≤2, 
reversion of Grade 3 events to Grade ≤1 or baseline) within 72 hours.
–
Isolated Grade 3 elevation of ALT and/or AST that resolves to Grade ≤1 or baseline within 
7 days.
–
Grade 3 nausea and/or emesis that can be controlled to Grade <3 in ≤3 days with the use of 
optimal antiemetics (defined as an antiemetic regimen that employs both a 
5-hydroxytryptamine 3 serotonin receptor antagonist and a corticosteroid given in standard 
doses and according to standard schedules).
–
Grade 3 rash and pruritis that respond to a standard treatment and resolve or improve to 
Grade <3 within 7 days.
–
Grade 3 diarrhea that can be controlled to Grade <3 in ≤3 days with appropriate treatment.
–
Any other Grade 3 TEAE for which NCI CTCAE v5 Grade 4 or 5 does not exist or the NCI 
CTCAE does not consider the AE Grade 4 to be life-threatening.

Any Grade 2 nonhematologic toxicity that is considered by the investigator to be related to 
study drug and dose-limiting.
In the dose escalation phase, DLTs are defined as events meeting the criteria above that occur 
before Cycle 2 Day 1 administration. TEAEs meeting DLT definitions occurring in later cycles or 
during expansion will determine the suitability of the MTD as the RP2D.
8.3
Phase 1b Modakafusp Alfa SA Dose Escalation Schema
The 2-parameter BLRM implementing the EWOC principle will be used to inform dose escalation 
decisions and MTD estimation starting from the second dose cohort. The final decision on next 
dose level will be taken jointly by the sponsor and the participating investigators. 


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BLRM with overdose control (Appendix E) will be used to inform dose escalation decisions and 
MTD estimation, along with consideration of other emerging safety, clinical, PK, and 
pharmacodynamic data. Doses will be escalated as shown in Table 8.a.
Table 8.a
Planned Dose Levels
Dose Level
Dose (Unit)
–1
0.05 mg/kg
1
0.1 mg/kg
2
0.2 mg/kg
3
0.4 mg/kg
4
0.75 mg/kg
5
1.5 mg/kg
6
3.0 mg/kg
7
6.0 mg/kg
More conservative dose escalation, evaluation of intermediate doses, and expansion of an existing 
dose level are all permissible following discussions between the sponsor and the investigators, if 
such measures are needed for patient safety or for a better understanding of the dose-related 
toxicity, exposure, or pharmacodynamics. The initial size of each cohort will be approximately 3 
evaluable patients.
Initially, 3 patients will be enrolled at the 0.1 mg/kg starting dose level. The following rules will be 
used only for this initial cohort:

If none of the 3 patients experiences a DLT during the first cycle, the dose may be escalated to 
the next planned dose level.

If 1 of the 3 patients exhibits a DLT, then the cohort will be expanded from 3 patients to a total 
of 6 patients.
–
If no more than 1 patient out of the 6 total patients has a Cycle 1 DLT, 3 patients will be 
enrolled at the next dose level.
–
If 2 of the 6 patients have a Cycle 1 DLT, 3 additional patients will be enrolled. If any of the 
3 additional patients have a Cycle 1 DLT, the starting dose will be considered not tolerated 
and the dose will be de-escalated to 0.05 mg/kg. If none of the 3 additional patients have a 
Cycle 1 DLT, the starting dose may be considered the MTD or may be escalated to the next 
dose level, after consideration of other available safety, clinical, PK, and 
pharmacodynamic data.
–
If 3 or more of the 6 patients experience a Cycle 1 DLT, the starting dose level will be 
considered not tolerated and the dose will be de-escalated 0.05 mg/kg following review of 
all available safety data and approval of the sponsor.


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
If 2 or more of the 3 patients experience a DLT, then the starting dose level will be considered 
too toxic and the dose will be de-escalated to 0.05 mg/kg.
Starting from the second dose level, the BLRM with overdose control will be used for all 
subsequent dose escalation recommendations. The BLRM recommended dose at the end of each 
dosing cohort will be that which has the highest posterior probability of having a DLT rate that is 
≥0.16 and ≤0.33. Following the EWOC principle, the posterior probability of the recommended 
dose having a DLT rate above 0.33 must not exceed 35%. Escalation will continue until one of the 
following stopping rules is met before reaching the maximum number of patients:

At least 6 patients are enrolled at the current dose, the current dose is the BLRM recommended 
dose for the next group of patients, and the observed DLT rate is ≤33%, OR

At least 9 patients are enrolled at the next recommended dose, the BLRM posterior probability 
of the next recommended dose having a DLT rate that falls into the interval (0.16, 0.33) 
exceeds 50%, and the observed DLT rate is ≤33%.
Once either of the above rules has been met, the MTD may be declared. Alternative stopping rules 
may also be considered following discussions between the sponsor and the investigators. 
The description and operating characteristics of the BLRM for dose escalation are included in 
Appendix E.
8.4
Phase 2 Modakafusp Alfa Dose Expansion 
A minimum of 3 patients will be enrolled at the modakafusp alfa RP2D in combination with 
pembrolizumab 400 mg Q6W to evaluate safety and tolerability in a single safety lead-in phase. 
The safety lead-in phase will start with the enrollment of 3 initial patients to evaluate the 
tolerability during the Cycle 1 DLT evaluation period of modakafusp alfa with pembrolizumab. If 
there are no DLTs in the first 3 patients during Cycle 1 of the safety lead-in period with 
modakafusp alfa SA RP2D in combination with pembrolizumab 400 mg Q6W, the combination 
dose and regimen could be selected for the 3 melanoma disease cohorts. 
If there is 1 DLT in the initial 3 patients in the safety-lead in period, an additional 3 patients will be 
enrolled at the same modakafusp alfa RP2D in combination with pembrolizumab 400 mg Q6W. If 
there are ≥2 DLTs in the first 3 patients at the modakafusp alfa SA RP2D, enrollment will resume 
at the next lower dose level of modakafusp alfa RP2D in combination with pembrolizumab. Other 
approved pembrolizumab dosing regimens (ie, 200 mg Q3W) could be tested in the safety-lead in 
period if 400 mg Q6W in combination with modakafusp alfa at one dose lower than RP2D is 
intolerable. For the safety lead-in period, patient enrollment will be staggered between the first and 
second patients by 7 days in the first dose cohort. The second and third patients can be dosed 
concurrently if the first patient in the cohort has gone through the Day 8 visit without clinically 
significant acute toxicities. Subsequent cohorts, if any, will not require staggering between 
patients.


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8.5
Additional Safety Stopping Rules
Patients will be monitored continuously for safety. Circumstances that may warrant enrollment 
hold include the following: 

Fatal Events:
–
A threshold for related fatal AEs of 6% is proposed for the whole trial (dose escalation plus 
expansions). If this mark is passed during the expansion phase, enrollment will be halted, 
and the safety of the dose selected will be re-evaluated. 
–
During dose escalation, enrollment will be stopped if ≥2 related Grade 5 AEs happen in the 
first 12 (16%) patients or if ≥3 (10%) events happen in 30 patients. If escalation goes 
beyond 30 patients, the 6% mortality threshold will be used.

Nonfatal Events:
–
In escalation phase, dose escalation rules based on DLTs and guided by BLRM will be 
implemented. 
–
Additionally, Grade 4 life-threatening, related, nonhematologic AEs must stay <10% 
during the trial once 30 patients have been dosed.
In these circumstances, the final decision about trial execution will be made after a full review of 
the safety data by the sponsor and the Safety Management Team.
8.6
Dose Modification Guidelines
8.6.1
Intrapatient Dose Escalation
Patients who have tolerated treatment with modakafusp alfa well at the initially assigned dose may 
be allowed to increase their doses of modakafusp alfa in subsequent cycles of treatment following 
sponsor and investigator review of the available data. Intrapatient dose escalation will be permitted 
only after all patients in the next higher dose level cohort have completed assessments for Cycle 1 
and a decision has been made that this dose level does not exceed the MTD. 
8.6.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
To begin a new cycle of treatment with either modakafusp alfa alone or in combination with 
pembrolizumab, the patient must meet the following criteria:

ANC must be ≥1000/mm3. Granulocyte-colony stimulating factor (G-CSF) can be used to 
reach this level. 

Platelet count must be ≥50,000/mm3 without transfusion support.


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For therapy to resume, toxicity considered to be related to treatment with modakafusp alfa must 
have resolved to Grade ≤1 or baseline (Grade ≤2 for platelets and neutrophils), or to a level 
considered acceptable by the physician. If the patient does not meet the above-cited criteria for 
retreatment, initiation of the next cycle of treatment should be delayed for 1 week. At the end of 
that week, the patient should be re-evaluated to determine whether the criteria for retreatment 
criteria have been met. 
If a subsequent cycle is delayed more than 14 days because of a related AE, the patient may be 
withdrawn from treatment unless there is clinical benefit as assessed by the investigator, with 
agreement by the sponsor’s medical monitor. Modakafusp alfa dosing may be continued at the 
previously established safe dose level or below.
8.6.3
Criteria for Treatment Interruption and Dose Reduction
All toxicities that occur during the study will be actively managed following the standard of care 
unless otherwise specified in the protocol. 
8.6.3.1
Modakafusp Alfa Dose Modification Guidelines
Table 8.b provides general dose modification recommendations for modakafusp alfa. When the 
dose of modakafusp alfa is withheld on the basis of these criteria, clinical and laboratory 
re-evaluation should be repeated at least weekly or more frequently, depending on the nature of the 
toxicity observed, until the toxicity resolves to Grade ≤1 or baseline. If there are transient 
laboratory abnormalities that, based on investigator assessment, are not clinically significant, 
continuation of therapy without dose modification is permissible upon discussion with the sponsor. 
See details for managing specific AEs in Section 8.10.


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Table 8.b
Dose Modification Recommendations for Toxicities Possibly Related to 
Modakafusp Alfa
Criteria
Action
Grade 1 AEs
No dose reductions or interruptions.
Grade 2 AEs
Patients experiencing Grade 2 AEs considered related to study treatment that 
are not easily managed or corrected and are not tolerable to the patient, or 
AEs that are not acceptable in the investigator’s judgment, should have study 
treatment interrupted until the AE resolves to Grade ≤1 or baseline and then 
restarted at the same dose or, depending on the toxicity, at the previous safe 
dose level or below.
Grade 3, Grade 4 (not life-threatening 
per seriousness criteria), and Grade 4 
asymptomatic laboratory AEs
Hold modakafusp alfa until resolution to Grade ≤1 or baseline, and then 
resume treatment at a reduced dose level. In case of Grade 3 hematological 
toxicity (anemia, thrombocytopenia, neutropenia, or lymphopenia) or Grade 
3 asymptomatic laboratory AEs, the patient can continue at the same dose or 
a reduced dose at the investigator’s discretion. 
Grade 4 (life-threatening per 
seriousness criteria) AEs
Permanently withdraw the patient from the study. 
AEs of all grades
If treatment has been held for >14 consecutive days without resolution of the 
toxicity (to baseline or Grade ≤1), consider permanently discontinuing study 
treatment unless there is clinical benefit for the patient as assessed by the 
investigator and with sponsor’s approval. Treatment can be resumed at a 
reduced dose level after resolution of AEs to Grade ≤1 or baseline.
AE: adverse event.
When a dose reduction occurs, the modakafusp alfa dose will be reduced to the next lower dose 
that has been established as a safe dose during dose escalation. If initial dose adjustment does not 
provide sufficient relief, the dose of modakafusp alfa can be further reduced if the treating 
physician considers that the patient is receiving benefit. In general, after a dose is reduced, it 
should not be re-escalated even if there is minimal or no toxicity with the reduced dose. However, 
if further evaluation reveals that the AE that led to the dose reduction was not study drug related, 
the dose may be re-escalated to the original dose level. If more than 2 dose reductions are required 
for the same AE, the patient should be discontinued from therapy. 
8.6.3.2
Pembrolizumab Dose Modification Guidelines
In this study, the dose of pembrolizumab cannot be modified. Depending on the toxicity observed, 
the infusion of pembrolizumab can be interrupted (in case of IRR, for example), delayed, or 
discontinued. If hypersensitivity or infusion-related events develop, the infusion should be 
temporarily slowed or interrupted, but dose modifications are not allowed. The patient should be 
treated according to the appropriate standard of care. Patients who discontinue pembrolizumab for 
reasons described in the pembrolizumab label other than irAEs may continue modakafusp alfa 
treatment.


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General instructions:
1. It is recommended that the management of irAEs follow NCCN (NCCN 2021) or SITC 
(Puzanov et al. 2017) guidance. If pembrolizumab has been withheld, it can be resumed after 
the AE severity has decreased to Grade 1 or baseline level and corticosteroid has been tapered. 
Pembrolizumab should be permanently discontinued if the AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per 
day within 12 weeks.
2. For severe and life-threatening irAEs, IV corticosteroid treatment should be initiated first 
followed by oral steroid therapy. Other immunosuppressive treatment should be initiated if 
irAEs cannot be controlled by corticosteroids.
Pembrolizumab dose modification guidelines for irAEs are detailed in Table 8.c. 
Table 8.c
Pembrolizumab Dose Modification Guidelines for irAEs
Immune-Related AEs
Toxicity Grade or Conditions 
(CTCAE v5.0)
Action Taken with Pembrolizumab
Pneumonitis
Grade 2 
Withhold.
Grade 3 or 4, or recurrent Grade 2
Permanently discontinue.
Diarrhea/colitis
Grade 2 or 3
Withhold.
Grade 4
Permanently discontinue.
AST/ALT elevation or 
increased bilirubin
Grade 2 
Withhold.
Grade 3 or 4
Permanently discontinue.
Type 1 diabetes mellitus or 
hyperglycemia
New onset type 1 diabetes mellitus 
or Grade 3 or 4 hyperglycemia 
associated with evidence of -cell 
failure
Withhold. 
Hypophysitis
Grade 2 
Withhold.
Grade 3 or 4
Withhold or permanently discontinue.a
Hyperthyroidism
Grade 2
Continue.
Grade 3 or 4
Withhold or permanently discontinue.
Hypothyroidism
Grade 2 to 4
Continue.
Nephritis and renal dysfunction Grade 2
Withhold.
Grade 3 or 4
Permanently discontinue.
Myocarditis
Grade 1 or 2
Withhold.
Grade 3 or 4
Permanently discontinue.


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Table 8.c
Pembrolizumab Dose Modification Guidelines for irAEs
Immune-Related AEs
Toxicity Grade or Conditions 
(CTCAE v5.0)
Action Taken with Pembrolizumab
All other immune-related AEs
Intolerable/persistent Grade 2
Withhold.
Grade 3
Withhold or discontinue based on the type of 
event. Events that require discontinuation 
include, but are not limited to, Guillain-Barre 
Syndrome and encephalitis.
Grade 4 or recurrent Grade 3
Permanently discontinue.
AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; CTCAE: Common 
Terminology Criteria for Adverse Events; GI: gastrointestinal; irAE: immune-related adverse event; IV: intravenous.
a Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating 
physician.
For patients with Grade 3 or 4 immune-related endocrinopathy that does not require withholding of pembrolizumab, 
pembrolizumab may be resumed when the AE resolves to Grade ≤2 and is controlled with hormonal replacement 
therapy or metabolic control has been achieved (in case of type 1 diabetes mellitus).
8.6.4
Criteria for Discontinuing of Treatment with Study Drugs
Patients should discontinue treatment with either modakafusp alfa or pembrolizumab, or both, if 
they meet any of the criteria listed below. Patients who discontinue pembrolizumab for reasons 
other than irAEs may continue modakafusp alfa treatment as a single agent if modakafusp alfa 
discontinuation criteria are not met; patients who discontinue modakafusp alfa may continue 
pembrolizumab as a single agent if pembrolizumab discontinuation criteria are not met. In the 
event of discontinuation of study therapy (modakafusp alfa and pembrolizumab), patients will 
undergo the end of treatment (EOT) visit.
8.6.4.1
Criteria for Discontinuing Modakafusp Alfa 
Study drug must be permanently discontinued if any of the following criteria are met:
1. Patient experiences an AE in Cycle 1 meeting criteria for a DLT that is considered 
life-threatening. 
2. Confirmed progressive disease according to RECIST v1.1.
3. Start of new/subsequent anticancer treatment.
4. Confirmed pregnancy.
5. Patient meets any of the criteria for discontinuation specified in Section 8.10. 
Study drug may be discontinued after discussion with the study sponsor, if any of the following 
criteria are met:
1. Any non-life-threatening AEs if the investigator determines that study continuation is no 
longer in the patient’s best interest.
2. Any AE that changes the benefit-risk assessment for a patient.


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3. Clinical deterioration of the patient as assessed by the investigator.
4. CR. 
5. Unsatisfactory therapeutic response.
6. Study terminated by sponsor.
7. Withdrawal by subject.
8. Subject’s death.
9. Lost to follow-up.
10. Delay of next cycle by more than 14 days.
11. Important protocol deviations from inclusion/exclusion criteria. 
If treatment is discontinued, the EOT visit should be completed within 30 to 40 days after the last 
administration of modakafusp alfa.
8.6.4.2
Criteria for Discontinuing Pembrolizumab
Pembrolizumab will be discontinued if any of the criteria described in Table 8.c or the 
pembrolizumab SmPC have been met. Additionally, pembrolizumab may be discontinued for 
other reasons if it is considered in the best interest of the patient and discussed with the medical 
monitor.
Permanently discontinue pembrolizumab for any of the following:

Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone 
replacement therapy).

Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity.

Grade 3 or 4 nephritis.

Grade 4 severe skin reactions or confirmed Stevens-Johnson syndrome or toxic epidermal 
necrolysis.

AST or ALT greater than 5 × ULN or total bilirubin greater than 3 × ULN.
–
For patients with liver metastases who begin treatment with Grade 2 AST or ALT, if AST 
or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 
week.

Grade 3 or 4 IRRs.

Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within 12 weeks of an irAE.

Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to Grade ≤1 within 12 weeks after last dose 
of pembrolizumab.


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
Any severe or Grade 3 treatment-related AE that recurs.
8.7
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Radical radiation or extended field radiation therapy for disease under study. Local 
radiotherapy for localized painful metastases or at risk of producing complications is permitted 
after agreement with the sponsor’s medical monitor.

Any other anticancer treatment or investigational agent other than modakafusp alfa, including 
agents that are commercially available for indications other than the disease under study that 
are being investigated for the treatment of the disease under study.

Concomitant chronic corticosteroid administration of >20 mg/day of prednisone or equivalent 
unless given as premedication prior to administration of modakafusp alfa to prevent onset and 
severity of IRRs, as premedication prior to administration of certain blood products or for 
exacerbations of respiratory tract disorders, acute pain management, suspected or confirmed 
immune-mediated thrombocytopenia, immune-related AEs, or if tumor flare is suspected.
8.8
Permitted Concomitant Medications and Procedures
8.8.1
Premedication
Due to the occurrence of Grade 2 IRRs in 8 of 17 patients receiving modakafusp alfa at doses of 
0.1 to 1.5 mg/kg Q3W in the current study as of the data cutoff of 23 January 2021, the following 
list of medications are mandatory in all cycles before infusion of modakafusp alfa to prevent 
and/or mitigate this potential AE. 
1. Corticosteroid IV or orally (PO) (dexamethasone 10 mg to 20 mg or equivalent) 60 minutes to 
2 hours before treatment.
2. Acetaminophen 650 mg to 1000 mg PO 60 minutes to 2 hours before treatment.
3. Diphenhydramine or equivalent 25 mg to 50 mg PO approximately 1 hour before treatment.
Montelukast may be given to patients who are intolerant to diphenhydramine or for whom 
diphenhydramine is ineffective. Additional premedications of nonsteroidal anti-inflammatory 
drugs (NSAIDs) and H2 blockers could be added per investigator’s discretion.
Medication(s) shall be administered according to medical standards and at sufficient time prior to 
start of infusion of modakafusp alfa that allows the premedication drugs to exert their effects. 
For the phase 2 expansion phase, the history of IRR to prior CPI treatment will be collected. 
During the infusion and for 6 hours post-infusion in the first 2 treatment cycles, patients should be 
continually monitored by medically qualified staff with access to emergency medical equipment 
and medications to manage IRRs. In Cycle 3 and beyond, patients should be continually monitored 
for at least 2 hours post the end of infusion, and the monitoring duration could be extended per a 




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
Thrombopoietin agonists are allowed for thrombocytopenia management at investigator’s 
discretion. 

Vaccinations to prevent COVID-19 viral infections and other infections (eg, influenza, 
pneumococcus) are allowed at the investigator’s discretion with the following considerations: 
1. Live vaccines are not recommended. 
2. Vaccination and modakafusp alfa dosing on the same day is not recommended. 
3. For patients in the dose escalation, vaccination in the Cycle 1 DLT evaluation period is not 
recommended.
Supportive measures consistent with optimal patient care may be given throughout the study.
8.9
Precautions and Restrictions
An interference with serological testing has been described with the anti-CD38 antibody 
daratumumab. Daratumumab binds to CD38 on RBCs and results in a positive indirect 
antiglobulin test (indirect Coombs test). A daratumumab-mediated positive indirect antiglobulin 
test may persist for up to 6 months after the last daratumumab infusion. Daratumumab bound to 
RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of 
a patient’s ABO and Rh blood type are not affected. Type and screen patients before starting 
modakafusp alfa if this was not performed previously.
Patients should not drive, operate dangerous tools or machinery, or engage in any other potentially 
hazardous activity that requires full alertness and coordination if they experience sedation while 
enrolled in this study.
Patients are to be instructed to limit the use of alcohol while enrolled in this study.
8.9.1
Contraception and Pregnancy Avoidance Procedures
It is not known what effects modakafusp alfa has on human pregnancy or development of the 
embryo or fetus; therefore, patients participating in this study should avoid becoming pregnant or 
impregnating a partner. Patients of reproductive potential should use effective methods of 
contraception through defined periods during and after study treatment as specified below.
Patients must also adhere to any applicable local (country-specified) treatment-specific pregnancy 
prevention guidelines.
Reproductively female patients must meet one of the following:

Postmenopausal for at least 2 years before the screening visit OR

Surgically sterile, OR

If they are of childbearing potential (as defined in Section 9.3.9), due to unknown risks and 
potential harm to an unborn child/infant, must agree to the following:
–
Agree to practice 1 highly effective method of contraception and 1 additional effective 
(barrier) method at the same time (Table 8.d) from the time of signing the informed consent 


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through 7 days after the last dose of modakafusp alfa or 4 months after the last dose of 
pembrolizumab, whichever is longer OR
–
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
–
Agree not to donate an egg or eggs (ova) or breastfeed a baby during the study through 7 
days after the last dose of modakafusp alfa or 4 months after the last dose of 
pembrolizumab, whichever is longer.
Reproductively male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 
one of the following:

Agree to practice effective barrier contraception (Table 8.d) during the entire study treatment 
period and through 7 days after the last dose of modakafusp alfa (no restriction for 
pembrolizumab) OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, and postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)

Agree not to donate sperm during the study and for 7 days after the last dose of modakafusp 
alfa (no restriction for pembrolizumab). 


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Table 8.d
Highly Effective Methods of Contraception
Highly Effective Methods
Additional Effective (Barrier) Methods
Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation
Oral
Intravaginal
Transdermal
Male or female condom with or without spermicide 
(female and male condoms should not be used together)
Progestogen-only hormonal contraception associated with 
inhibition of ovulation
Oral
Injectable
Implantable
Intrauterine device
Cap, diaphragm, or sponge with spermicide
Intrauterine hormone-releasing system
Bilateral tubal occlusion
Vasectomized partner
Sexual abstinence
8.10
Management of Specific Adverse Reactions
8.10.1
Infusion-Related Reactions
An IRR can develop during or shortly after administration of a drug. Signs and symptoms may 
include pruritus, urticaria, fever, rigors/chills, diaphoresis, bronchospasms, and cardiovascular 
collapse. In modakafusp alfa studies, IRRs are designated as AESIs.
Premedication is detailed in Section 8.8.1. Patients should be carefully monitored during 
modakafusp alfa infusions. Trained trial staff at the clinic should be prepared to intervene in case 
of any IRRs and resources necessary for resuscitation (eg, agents such as epinephrine and 
aerosolized bronchodilators; also, medical equipment such as oxygen tanks, tracheostomy 
equipment, and a defibrillator) must be available at bedside.
Patients will be advised to promptly report signs and symptoms that may indicate IRRs, including 
fever, chills, dizziness, nausea, vomiting, flushing, cough, headache, and rash during or soon after 
end of infusion.
Post-medication may be considered at the investigator’s discretion, as medically indicated, and per 
Section 8.8.2.
In case of an infusion reaction, serum samples should be taken for central evaluation of 
immunogenicity and circulating biomarkers (Appendix A). These blood draws must not interfere 
with patient care and blood tests necessary for the acute care of the patient.


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All AESIs will be reported to Takeda Global Pharmacovigilance in an expedited manner 
irrespective of the event’s seriousness or causal relationship as described in Section 10.2.1. When 
recording IRRs in the eCRF, the signs and symptoms should be recorded and should be marked as 
an AESI.
8.10.1.1
IRRs After Modakafusp Alfa Dosing
The recommendations for managing IRRs related to modakafusp alfa are presented in Table 8.e
and Table 8.f.
Table 8.e
Recommendations for Managing Grade 1 and Grade 2 IRRs
IRR
Action
Grade 1 or 2
The infusion should be paused. When the patient’s condition is stable, infusion 
may be restarted at the investigator’s discretion.
Upon restart, the infusion rate should be half of that used before the 
interruption. Subsequently, the infusion rate may be increased at the 
investigator’s discretion. Consider pre- and postmedication before restarting 
the infusion and for future modakafusp alfa administrations.
Grade 2 event of laryngeal edema, or 
Grade 2 event of bronchospasm that 
does not respond to systemic 
therapy. 
Patient must be withdrawn from treatment if the event does not resolve within 
6 hours from onset.
Table 8.f
Recommendations for Managing Grade 3 IRRs
IRR
Action
Any Grade 4 life-threatening event:
Patient must be withdrawn from treatment.
Grade 3 bronchospasm or laryngeal edema:
Patient must be withdrawn from treatment.
Grade 3 events other than bronchospasm or laryngeal 
edema:
Infusion must be stopped, and the patient must be 
observed carefully until resolution of the IRR.
If the intensity of the IRR remains at Grade 3 after 2 
hours:
Patient must be withdrawn from treatment.
If the intensity of the IRR decreases to Grades 1 or 2:
Infusion may be restarted at the investigator’s discretion. 
Administer corticosteroids, acetaminophen, and 
antihistamines per Sections 8.8.1 and 8.8.2 before 
restarting infusion. Within 2 hours upon restart, the 
infusion rate should be half of that employed before the 
interruption. Subsequently, the infusion rate may be 
increased at the investigator’s discretion.
If the intensity of the IRR returns to Grade 3:
The procedure described above may be repeated after 
restart of the infusion at the investigator’s discretion. 
If the intensity of the IRR increases to Grade 3 for a third 
time:
Patient must be withdrawn from treatment.
IRR: infusion-related reaction.


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8.10.1.2
IRRs After Pembrolizumab Dosing
Patients with Grade 1 or 2 infusion reaction may continue to receive pembrolizumab with close 
monitoring. For Grade 3 or 4 infusion reactions, infusion should be stopped and pembrolizumab 
permanently discontinued.
8.10.2
Low Platelet Counts
Treatment decisions will be based on a patient’s platelet counts assessed before any transfusion. 
Low platelet counts (Grade 4) should cause scheduled infusions to be postponed or to be 
permanently discontinued. If at any time the platelet count is less than 10 × 109/L, or if the patient 
shows a bleeding tendency considered to be due to thrombocytopenia occurring after initiation of 
modakafusp alfa treatment, the patient should be withdrawn from modakafusp alfa treatment 
unless clinical benefit is observed and the investigator considers that thrombocytopenia can be 
managed with dose modifications. The investigator can consider the usage of corticosteroids, 
IVIG or thrombopoietin agonists in selected cases depending on severity, duration, transfusion 
requirements, and additional risk factors for bleeding and based on the suspected underlying 
mechanism. Platelet transfusion and close monitoring of platelet counts should follow institutional 
guidelines. 
8.10.3
Management of Immune-Mediated Adverse Events
Pembrolizumab can cause pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, skin adverse 
reactions, IRRs, and other immune-mediated AEs. Monitoring of these AEs is required in both the 
safety lead-in and expansion cohorts in the combination arm. Patients with AEs that are suspected 
to be related to pembrolizumab should be evaluated by appropriate methods, including physical 
examinations, laboratory tests, and imaging. These irAEs will be treated based on standard of care, 
local institutional guidance, the WARNINGS AND PRECAUTIONS section of the package insert, 
and the proper use guidance of pembrolizumab. It is recommended that the management of irAEs 
follow NCCN (NCCN 2021) or SITC (Puzanov et al. 2017) guidance. 
8.11
Blinding and Unblinding
This is an open-label study.
8.12
Description of Investigational Agents
Modakafusp alfa is a humanized anti-CD38, IgG4, mAb fused to an attenuated IFN-α2b. The 
initial frozen liquid modakafusp alfa formulation is used for all phase 1b dose escalation patients. 
The redeveloped lyophilized modakafusp alfa formulation is to be used in dosing phase 2 patients. 
Additional details can be found in the modakafusp alfa IB. 
Pembrolizumab solution for infusion consists of 100 mg/4 mL (25 mg/mL) in a single-dose vial or 
powder for solution for infusion 50 mg (1 vial contains 50 mg pembrolizumab). Please refer to the 
pharmacy manual and the most recent pembrolizumab SmPC for details.


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8.13
Preparation, Reconstitution, and Dispensation
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever the solution and container permit.
8.13.1
Modakafusp Alfa 
Modakafusp alfa is an anticancer drug; as with other potentially toxic compounds, caution should 
be exercised when handling modakafusp alfa. Detailed information is available in the IB and 
pharmacy manual.
8.13.2
Pembrolizumab
Please refer to the most recent SmPC for preparation, reconstitution, and administration 
instructions.
A commercially available IV formulation of pembrolizumab background therapy will be used. In 
countries or study centers where pembrolizumab is designated a noninvestigational product, sites 
will be expected to source this commercially available product through their local hospital 
pharmacy or licensed distributor. In countries or centers where pembrolizumab is designated as an 
investigational product, sites will have pembrolizumab supplied and packaged by the sponsor. 
This supply will be labeled appropriately for investigational use as per the regulations of the 
relevant country health authority.
8.14
Packaging and Labeling
Supplies of modakafusp alfa and pembrolizumab will be labeled according to the current ICH 
guidelines on GCP and Good Manufacturing Practice and will include any locally required 
statements. 
8.15
Storage, Handling, and Accountability
8.15.1
Modakafusp Alfa 
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all modakafusp alfa received and that any discrepancies are reported and resolved 
before use of modakafusp alfa.
Temperature conditions for modakafusp alfa, a list of ancillary supplies approved for use with 
modakafusp alfa, and thawing or reconstitution and dilution procedures for modakafusp alfa vials 
are provided in the pharmacy manual. 
Each modakafusp alfa shipment will include a packing slip listing the contents of the shipment, 
and any applicable forms.
The investigator is responsible for ensuring that deliveries of modakafusp alfa and other study 
materials from the sponsor are correctly received, recorded, and handled, and stored safely and 
properly in accordance with the Code of Federal Regulations (CFR) or national and local 
regulations, and used in accordance with this protocol.


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Only patients enrolled in the study may receive modakafusp alfa, and only authorized staff at the 
investigational center may supply or administer modakafusp alfa. All modakafusp alfa must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions or appropriate instructions with access limited to 
the investigator and authorized staff at the investigational center.
The investigator, institution, or head of the medical institution (where applicable) is responsible 
for modakafusp alfa accountability, reconciliation, and record maintenance (eg, receipt, 
reconciliation, and final disposition records).
A record of modakafusp alfa accountability (modakafusp alfa and other study materials received, 
used, retained, returned, or destroyed) must be prepared and signed by the principal investigator or 
designee, with an account given for any discrepancies. Empty, partially used, and unused 
modakafusp alfa will be disposed of, retained, or returned to the sponsor or designee.
Further guidance and information are provided in the pharmacy manual.
8.15.2
Pembrolizumab
Pembrolizumab must be stored in a secure, limited-access location, according to conditions 
specified on the drug label. The investigator or designee must confirm that appropriate 
temperature conditions have been maintained and that any discrepancies are reported and resolved 
before use. Refer to the pharmacy manual and/or the most recent SmPC for additional details. 
9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and ICH guidelines.
9.1
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country, and 
the contract research organization (CRO) team may be found in the Study Manual. A full list of 
investigators is available in the sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the internal review board (IRB)/independent 
ethics committee (IEC). 
9.3
Study Procedures
Sites will make every effort to see patients in the clinic to complete all study-specified assessments 
as outlined in the SOE (Appendix A). In unavoidable circumstances, such as the COVID-19 public 
health emergency, exceptions can be made for alternative methods for conducting patient visits 


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and performing laboratory and imaging assessments as detailed below. Remote visits and 
telemedicine must comply with national and local laws and regulations. Such instances will be 
documented in the study records and electronic case report form (eCRF) if applicable, and the 
sponsor will be informed.
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow. Evaluations during the screening period are to be conducted 
within 21 days before administration of the first dose of the study drug. Some procedures 
conducted during the screening period that are performed within 4 days of C1D1 may also be used 
as the predose evaluation and do not need to be repeated, unless otherwise specified.
9.3.1
Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
If necessary, informed consent may be obtained from a potential or current trial participant via 
electronic informed consent capabilities or an electronic face-to-face consent interview when these 
individuals are unable to travel to the site.
9.3.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
9.3.3
Medical History
During the screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it and the best response achieved by each one. Available key 
pathology and genomic biomarkers previously obtained from patient’s tumor should be collected. 
In the phase 2 expansion, a patient’s history of IRR to prior CPI therapy will be collected. 
In addition, concomitant medications will be recorded as specified in Section 9.3.10.
The most recent prescreening diagnostic-quality computed tomography (CT) and/or magnetic 
resonance imaging (MRI) scans acquired for disease assessment, if available, should be submitted 
to the imaging core laboratory vendor for storage and for potential retrospective central reading. 
(refer to Section 9.3.14.2). The date of the scan(s) should be indicated. Availability of 
prescreening scan(s) is not a prerequisite for study eligibility. 
9.3.4
Physical Examination
A physical examination will be performed (complete or symptom-directed) per standard of care at 
the times specified in the Schedule of Events (Appendix A).
If an investigator considers it safe and appropriate for a subject to miss a protocol-specified 
physical examination for COVID-19-related reasons, the study site physician or other qualified 
site staff will speak directly with the subject by telephone or other medium (eg, a computer-based 
video communication) to assess subject safety and overall clinical status with a plan for in-person 


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evaluation if signs and symptoms warrant. Such instances will be documented in the study records 
and electronic case report form (eCRF) if applicable, and the sponsor will be informed.
9.3.5
Patient Height
Patient height will be measured during the screening visit only. 
9.3.6
Patient Weight
Patient weight will be measured at the times specified in Appendix A. Initial dose should only be 
adjusted for a ≥10% change in body weight (Section 8.1).
9.3.7
Vital Signs
Vital signs include temperature, pulse, respiratory rate, and oxygen saturation. They include also 
supine, semirecumbent, or seated measurements of diastolic and systolic blood pressure (after 3 to 
5 minutes in this position; all subsequent measurements should be performed in the same initial 
position). Vital signs will be measured at the times specified in Appendix A. 
Blood pressure will be measured every 30 minutes (±5 minutes) during the first 4 infusions, after 
the end of the infusion, and at any moment if the patient complains of symptoms consistent with 
IRR. If the patient experiences hypotension (with or without symptoms) intensive blood pressure 
monitoring according to local practice should be instituted. The patient cannot be released from the 
site until blood pressure has returned to Grade 1 or baseline for at least 1 hour.
Any vital sign value that is judged by the investigator as clinically significant will be recorded both 
in the source documentation and the eCRF as an AE and monitored as described in Section 10.2.
9.3.8
ECOG Performance Status
ECOG performance status (Oken et al. 1982) will be evaluated at the times specified in Appendix 
A.
9.3.9
Pregnancy Testing
Pregnancy tests will be measured at the times specified in Appendix A. A serum or urine 
pregnancy test will be performed for patients of childbearing potential with negative results during 
screening, and again at C1D1 (baseline) if the screening test was performed more than 72 hours 
before the C1D1 dosing. A serum or urine pregnancy test must be performed predose (within 72 
hours prior to dosing) on Day 1 of each cycle with negative results available before modakafusp 
alfa is administered. A serum or urine pregnancy test is required at EOT. 
A patient of childbearing potential is defined as a patient with a uterus/ovary(ies) who (1) has not 
undergone a hysterectomy or bilateral oophorectomy or (2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 
24 consecutive months (ie, has had menses any time in the preceding 24 consecutive months).


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9.3.10
Concomitant Medications and Procedures
Any prior or concomitant medication a patient has had from signing of the ICF through 30 days 
after the last dose of modakafusp alfa or the start of subsequent systemic anticancer therapy, 
whichever occurs first, will be recorded on the eCRF. Trade name and international nonproprietary 
name (if available), indication, and start and end dates of the administered medication will be 
recorded. Medications used by the patient and therapeutic procedures (including any transfusion, 
tumor biopsies) completed by the patient will be recorded in the eCRF. See Sections 8.7 and 
Section 8.8 for a list of medications and therapies that are prohibited or allowed during the study. 
9.3.11
TEAEs
Monitoring of TEAEs, serious and nonserious, will be conducted throughout the study as specified 
in Appendix A. Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of TEAEs and SAEs.
9.3.12
ECG
12-lead ECG measurements will be performed at the time points specified in Appendix A. A 
qualified person will interpret the ECG. Triplicate ECGs will be read centrally. Single ECGs will 
be read locally.
Any ECG finding that is judged by the investigator as clinically significant will be considered a 
TEAE, recorded on the source documentation and in the eCRF, and monitored as described in 
Section 10.2.
Additional ECGs may be obtained as clinically indicated at any time during the study at the 
discretion of the investigator. When the timing of ECG or vital sign measurements coincide with 
the timing of a blood draw (eg, PK sample), the ECG measurements and vital sign measurements 
should be completed first, followed by blood sampling. 
During the dose escalation phase and safety lead-in of the phase 2 expansion, triplicate ECGs for 
initial heart rate-corrected QT interval evaluation and other parameters will be recorded on ECG 
recorders and electronically stored. These timepoints correspond with PK draws. Please refer to 
the PK sampling schedules (Table 16.f and Table 16.g). The ECG recorders will be provided by 
the ECG vendor. The provided recorders should have the capability to transmit ECG recording to 
the site computers so that ECGs are available for local safety assessment on-site by investigators.
The ECG measurements should be completed before the PK/pharmacodynamic blood draw. See
Appendix B for food and beverage intake instructions. 
9.3.13
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed either locally or centrally as indicated in each 
section. 
In extenuating circumstances, such as during the COVID-19 public health emergency, laboratories 
closer to a patient’s home may be utilized for local clinical laboratory assessments provided that 
pertinent laboratory information, including normal reference ranges, are provided to the sponsor or 


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designee. Central laboratory assessments must still be obtained at the site as needed and sent to 
sponsor-designated laboratories. 
Handling of central clinical laboratory blood samples will be outlined in the Laboratory Manual. 
Immunoprofiling (mass cytometric analysis of T, B, and NK lymphocyte subsets), CD38 
occupancy/density, biomarker testing (cytokine and chemokine panel), RNA sequencing, T-cell 
and B-cell receptor sequencing, modakafusp alfa concentrations for PK analysis, and 
immunogenicity testing (ADAs) are to be performed centrally. Decisions regarding eligibility for 
this study may be made using local laboratory determinations. For dosing decisions, local 
hematology and chemistry laboratory results will be used. 
9.3.13.1
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained as 
specified in Appendix A. They will be performed locally only. 
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Chemistry
Hematocrit
Hemoglobin
Platelet count
WBC count
WBC differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils)
Coagulation:
  aPTT
  PT
Albumin
Alkaline phosphatase
ALT
AST
Bilirubin (total)
Blood type b
Blood urea nitrogen
Calcium
Chloride
Creatinine
Glucose (nonfasting)
HCO3 or CO2
Total protein
LDH
Phosphate
Potassium
Sodium
Standard C-reactive protein
Urate or uric acid
Other
TBNK assay (T cells [including CD4+ and 
CD8+ T cells], B cells, and NK cells) a 
ALT: alanine aminotransferase; ANC: absolute neutrophil count; aPTT: activated partial thromboplastin time; 
AST: aspartate aminotransferase; LDH: lactate dehydrogenase; NK: natural killer; PT: prothrombin time; TBNK: 
quantification of T cells [including CD4+ and CD8+ T cells], B cells, and NK cells; WBC: white blood cell. 
a Local analysis if available.
b A sample for blood typing to be taken only at baseline. If applicable, blood banks need to be alerted that the patient is 
going to receive an anti-CD38 antibody that may interfere with blood typing in a manner similar to daratumumab. If 
the blood bank issues a compatibility card, it should be made available to the patient. The patient needs to tell other 
healthcare providers that he/she is receiving an anti-CD38 antibody if, for example, a blood transfusion is needed. 


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If GFR is to be estimated, the MDRD (Levey et al. 2006) or CKD-EPI (Levey et al. 2009)
equations shall be used.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones 
Leukocytes
Nitrite 
Occult blood
pH 
Protein
Specific gravity
Turbidity and color
Urobilinogen
9.3.13.2
TBNK
Blood samples will be collected to measure absolute counts of T cells (including CD4+ and CD8+ 
T cells), B cells, and natural killer cells (TBNK) found within blood at various time points while 
the patient is on study (Table 9.a). Samples will be collected predose and analysis will be 
performed locally only if it is available at the site as specified in Appendix A for patients enrolled 
within phase 1b dose escalation. 
9.3.13.3
Immunosafety Markers
Blood samples for the analysis of immunosafety for patients in pembrolizumab combination 
cohorts are shown in Table 9.c. These tests will be obtained as specified in the SOE Appendix A
and performed locally only. 
Table 9.c
Immunosafety Laboratory Tests
Serum Chemistry
Thyroid-stimulating 
hormone (TSH)
Free 
thyroxine 
(T4)
Cortisol (morning preferred)
9.3.14
Disease Assessment
At screening, CT and/or MRI scans will be performed unless chest, abdominal cavity, and pelvis 
diagnostic quality scans were performed within 5 weeks before the planned first dose of study drug. 
CT and/or MRI scans of the chest, abdominal cavity, and pelvis should be acquired with at least IV 
contrast. The imaging modalities used for a patient should remain consistent throughout the study. 
If IV contrast–enhanced CT scans are contraindicated for a particular patient, a 
noncontrast-enhanced CT of the chest should be acquired in addition to an oral contrast–enhanced 
CT of the abdomen and IV contrast–enhanced pelvic MRI. 
At present, low-dose or attenuation correction CT portions of a combined PET–CT are of limited 
use in anatomically based efﬁcacy assessments, and it is therefore suggested that they should not 
be substituted for dedicated diagnostic contrast-enhanced CT scans for anatomically based 


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RECIST measurements. However, if a site can document that the CT performed as part of a PET–
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET–CT can be used for RECIST measurements. Note, however, that the PET 
portion of the CT introduces additional data that may bias an investigator if it is not routinely or 
serially performed.
Repeat CT and/or MRI scans should be performed every 6 weeks through Cycle 6 and every 9 
weeks thereafter, and as clinically indicated. 
Response assessment will be calendar-based regardless of treatment delays/interruptions. 
Investigator assessment of disease response and progression will be based on RECIST v1.1 
(Section 9.3.14.1) and iRECIST (Seymour et al. 2017) (phase 2 expansion only). Screening and 
on-treatment images, when available, should be submitted to the imaging core laboratory vendor 
for storage and potential retrospective central reading. 
In extenuating circumstances, such as during the COVID-19 public health emergency, patients 
may use an alternative site for imaging with prior notification to the sponsor or designee.
9.3.14.1
RECIST v1.1 and Treatment Beyond Progression 
Because treatment decisions will be made based on local assessment by the investigator, when 
assessing response, special consideration should be given to the tumor response characteristics 
associated with immunotherapy:
1. Measurable tumor size reduction may require a longer treatment duration with immunotherapy 
than with a cytotoxic regimen.
2. Although a rare event, response to immunotherapy may occur after appearance of PD, as 
assessed per conventional RECIST v1.1. In particular, small, new lesions may appear in the 
presence of other responsive target lesions (pseudoprogression).
3. Durable SD may represent antitumor activity of immunotherapy.
Therefore, RECIST v1.1 (Eisenhauer et al. 2009) will be implemented in this study as described 
below.
Contemporary immunotherapy protocols generally allow patients to continue treatment beyond 
initial radiographic evidence of progressive disease following further investigation, as 
accumulating data indicate it is possible that some patients treated with immunotherapy may 
derive clinical benefit beyond initial RECIST-defined progressive disease, which may not be 
captured by radiographic assessments. Therefore, despite an initial RECIST-defined PD, patients 
who are clinically stable and deriving benefit may remain on study until PD has been confirmed in 
subsequent imaging assessments. In this study, patients treated with modakafusp alfa will be 
permitted to continue treatment beyond initial RECIST v1.1-defined progressive disease if the 
following criteria are met:
1. Investigator-assessed overall clinical benefit from continued treatment with modakafusp alfa. 
The assessment of clinical benefit should consider whether the subject is clinically 
deteriorating and unlikely to receive further benefit from continued treatment.


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2. Tolerance of study drug(s).
3. Stable performance status.
4. Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of progressive disease (eg, central nervous system [CNS] metastases).
5. Patient agrees to receive additional modakafusp alfa by signing a separate ICF informing of 
pseudoprogression and the potential risks and benefits of continuing treatment in these 
circumstances.
The decision to continue treatment beyond initial RECIST v1.1-defined progression should be 
discussed with the medical monitor and documented in the study records. Such patients may 
remain on the study and continue to receive monitoring according to the protocol-defined SOEs. 
Any additional post-RECIST v1.1 progression imaging time points acquired in patients that are 
considered clinically stable should also be collected and when available, submitted to the imaging 
core laboratory vendor for storage and potential, retrospective central reading. In general, 
treatment should be discontinued permanently either upon unequivocal evidence of further 
progressive disease based on subsequent imaging assessment or upon investigator’s assessment 
that the subject is unlikely to receive further clinical benefit with continued treatment. For rare 
situations when the confirmatory scan confirms progressive disease, but the investigator believes 
that continued treatment is appropriate, a decision will be made jointly by the investigator and 
sponsor. If the patient experiences rapid clinical deterioration as perceived by the investigator 
before the next scheduled radiographic assessment of original PD, the investigator can discontinue 
study treatment without further objective evidence of disease progression and report it as 
progression. 
9.3.14.2
Requested Prescreening Imaging and Exploratory Tumor Kinetic Modeling
To explore the relationship between response and study drug treatment, diagnostic quality 
prescreening CT and/or MRI scans documenting the patient’s last objective response of SD or 
progressive disease prior to the scan at screening should be collected, as available. The RECIST 
v1.1 response criteria do not take into account the inherent patient-to-patient variability in tumor 
growth rates before treatment and therefore may not distinguish whether “SD,” for example, is a 
reflection of treatment effect versus the natural history of an indolent tumor. A most recent 
prescreening CT and/or MRI scan (performed within a timeframe of no more than 3 months before 
the screening date for this study) will be requested for all patients in this study, if available. 
Collection of these scans may facilitate estimation of prestudy tumor growth rates as part of the 
exploratory modeling exercise intended to characterize the antitumor benefit. Prescreening images, 
when available, should be submitted to the imaging core laboratory vendor for potential 
retrospective central reading.


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9.3.15
Biomarker, Pharmacodynamic, and PK Samples
9.3.15.1
Primary Specimen Collection
The primary specimen collection is presented in Table 9.d; collection of all samples listed are 
mandatory, with the exception of the biopsies specifically for patients within phase 2 with 
melanoma consistent with subgroups I and II. Biopsies are considered optional for those patients 
until futility has been met, at which point they will become mandatory. Blood samples will be 
collected via venipuncture or indwelling catheter at the time points detailed in Appendix B for 
plasma concentration measurements of modakafusp alfa/pembrolizumab and Appendix A for 
biomarker assessments.
The tumor biopsy procedure will be performed by core needle, under radiological guidance if 
indicated, or surgically if the site of disease is superficial and palpable or visible. Timing of tumor 
biopsy procedures can be found in Appendix A. 
A sample for blood typing is to be taken only at screening. Blood banks need to be alerted that the 
patient is going to receive an anti-CD38 antibody that may interfere with blood typing in a manner 
similar to daratumumab. If the blood bank issues a compatibility card, it should be made available 
to the patient. The patient needs to tell other healthcare providers that he/she is receiving an 
anti-CD38 antibody if, for example, a blood transfusion is needed. 
If necessary, plasma samples collected for PK assessments may also be used for exploration of 
pharmacodynamic biomarkers. These plasma PK samples may only be used for this purpose after 
the final PK analysis has been completed.
Details on sample handling, storage, shipment, and analysis are provided in the Laboratory 
Manual.


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Table 9.d
Primary Specimen Collection
Specimen Name in 
Schedule of Procedures
Primary 
Specimen
Primary Specimen 
Derivative 1
Primary Specimen 
Derivative 2
Description of 
Intended Use
Fresh tumor tissue biopsy 
sample
Fresh 
tumor tissue
FFPE block/slides
DNA
RNA
Biomarker 
measurements
Blood sample for mass 
cytometry 
(immunoprofiling)
Blood
PBMC
N/A
Pharmacodynamic 
measurements 
(immunoprofiling)
Blood sample for flow 
cytometry (CD38 
occupancy in PBMCs)
Blood
PBMC
N/A
Pharmacodynamic 
measurements
(CD38 occupancy)
Blood sample for 
immunophenotyping
Blood
N/A
N/A
Pharmacodynamic 
measurements 
Blood sample for receptor 
occupancy
Blood
N/A
N/A
Pharmacodynamic 
measurements
Serum sample for 
circulating biomarkers
Serum
N/A
N/A
Biomarker 
measurements
Blood sample for DNA
Blood
DNA
N/A
Pharmacogenetic 
measurements
Blood sample for RNA
Blood
RNA
N/A
Pharmacodynamic 
measurements
Blood sample for receptor 
sequencing
Blood
DNA
N/A
Pharmacodynamic 
measurements
Blood sample for 
circulating tumor cells
Blood
Cells
N/A
Biomarker 
Measurement
Plasma for cfDNA
Plasma
N/A
N/A
Biomarker 
Measurement
Serum sample for 
modakafusp alfa PK
Serum
N/A
N/A
PK measurements 
(drug 
concentrations)
Serum sample for
Pembrolizumab PK
Serum
N/A
N/A
PK measurements 
(pembrolizumab 
concentrations)
Serum sample for 
immunogenicity (ADA)
Serum
N/A
N/A
Immunogenicity 
measurements 
(ADA)
ADA: antidrug antibody; cfDNA: cell-free DNA; FFPE: formalin-fixed, paraffin-embedded; PBMC: peripheral blood 
mononuclear cell; PK: pharmacokinetic.
9.3.15.2
Fresh Tumor Tissue Biopsy Sample
At least 1 target lesion amenable for biopsy is required for enrollment in phase 1b. A minimum of 
1 target lesion for response assessment is required for enrollment in phase 2. A separate lesion 


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amenable for biopsy is required for enrollment in phase 2 for cohorts I and II post futility analysis 
and for all patients (safety lead-in and expansion) in cohort III.
New (fresh) biopsies at screening and on-treatment will be required for all patients in phase 1b and 
cohort III (safety lead-in and expansion) of phase 2. For patients in cohorts I and II of phase 2, new 
(fresh) screening and on-treatment biopsies will be optional up until futility is met. Once futility 
has been met for either cohort I or II, new (fresh) biopsies will be required at screening and 
on-treatment. 
The timing of on-treatment biopsies will be dependent on when the patient enrolls in the study. For 
patients enrolled in Phase 1b and those enrolled prior to futility being met within the 3 expansion 
cohorts of Phase 2, on-treatment biopsies will be collected on C2D2. For patients enrolled after 
futility has been met within any of the phase 2 expansion cohorts, on-treatment biopsies will be 
collected at the end of Cycle 2 to coincide with imaging assessments, prior to initiating Cycle 3.
The accessible lesion for biopsy should not have been previously irradiated or designated as the 
only target lesion for measurable disease (expansion phase only).
9.3.15.3
PK Measurements
Serum samples for modakafusp alfa and pembrolizumab PK will be collected at the time points 
specified in Appendix B. 
Details regarding the preparation, handling, and shipping of the PK samples are provided in the 
Laboratory Manual. 
The timing, but not the total number of samples, may be modified during the study on the basis of 
emerging PK data if a change in sampling scheme is considered necessary to better characterize 
the PK of modakafusp alfa.
9.3.15.4
Biomarkers and Pharmacodynamic Measurements
In this study, several biomarkers will be assessed to test for correlation with safety and, if possible, 
with efficacy. These biomarkers will be used to identify potential pharmacodynamic activity and 
patients who have a higher probability of response or of adverse reactions to modakafusp alfa. The 
biomarker sample analyses will be performed if or when required. Because new techniques 
continue to be developed, the method and laboratory that will be recommended for the biomarker 
analysis cannot be anticipated. 
For this purpose, blood samples will be collected as detailed in Appendix A. 
9.3.15.4.1
Biomarker Measurements
Blood Sample for Circulating Tumor Cells
During dose expansion only, a whole blood sample will be collected to quantify CTCs at baseline 
and correlate with response to modakafusp alfa. 


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Plasma Sample for cfDNA
A plasma sample will be collected at baseline for evaluation of cfDNA. From the cfDNA, 
circulating tumor DNA will be evaluated to assess tumor mutations.
Serum Samples for Circulating Biomarkers
Serum samples will be collected to monitor circulation biomarker changes upon treatment. These 
biomarkers will be used to identify potential pharmacodynamic activity and patients who have a 
higher probability of response or of adverse reactions to modakafusp alfa. The biomarker sample 
analyses will be performed if or when required. Because new techniques continue to be developed, 
the method and laboratory that will be recommended for the biomarker analysis cannot be 
anticipated. In case of an infusion reaction, blood collection should be performed for central 
evaluation of circulating biomarkers (see Section 8.10.1).
9.3.15.4.2
Pharmacodynamic Measurements
Blood Sample for Flow Cytometry
Blood samples will be collected for flow cytometric analysis as detailed in Appendix A to 
determine CD38 RO and density of peripheral immune cells at baseline and at multiple time points 
around the first and second administrations of modakafusp alfa. 
Blood Sample for Receptor Occupancy
Blood samples will be collected for flow cytometric analysis as detailed in Appendix A to 
determine CD38 RO and density of peripheral blood immune cells, in the presence of 
pembrolizumab, at baseline and at multiple time points surrounding the first and third 
administration of modakafusp alfa.
Blood Sample for Mass Cytometry
Blood samples will be collected for profiling of immune cells before, during, and at the end of 
treatment as detailed in Appendix A using mass cytometry methods. These blood samples will be 
analyzed for the presence and changes of immune cell populations (percentage or 
activation/exhaustion state), including, but not limited to B and T lymphocytes, monocytes, and 
NK cells.
Blood Sample for Immunophenotyping
Blood samples will be collected for assessment of immunophenotypic changes of circulating 
immune cells, induced by modakafusp alfa, utilizing flow cytometry techniques as detailed in 
Appendix A. These blood samples will be analyzed for the presence and changes of immune cell 
populations (percentage or activation/exhaustion state), including but not limited to B and T 
lymphocytes, monocytes, NK cells and dendritic cells.
Blood Sample for RNA
Blood samples for RNA will be collected at the time points specified in Appendix A for 
sequencing to monitor gene expression changes as a pharmacodynamic effect of modakafusp alfa 
administration. Sample analysis will be performed at a central laboratory. 


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Blood Sample for Receptor Sequencing
To monitor for induction of an adaptive immune response, blood samples will be collected to 
sequence T-cell and B-cell receptors. Sample analysis will be performed at a central laboratory. 
9.3.16
DNA Measurements
In this study, a blood sample will be collected from each patient (unless local regulations prohibit 
testing) for a potential pharmacogenetic assessment as detailed in Appendix A. Pharmacogenetic 
assessment potentially includes the association analysis of both known and unknown DNA genetic 
variations to the drug activity. This sample will be analyzed in a central laboratory. 
9.3.17
Immunogenicity Sample Collection
Serum samples for the assessment of antibodies to the drug product including anti–modakafusp 
alfa antibodies will be collected at the time points specified in Appendix A and outlined in the 
Laboratory Manual. Samples must be collected before study drug is administered on a dosing day, 
and optionally at an unscheduled visit for any patient who experiences a Grade ≥2 
hypersensitivity/IRR (Section 8.1). Confirmed positive ADAs will be assayed for titer and binding 
domain specificity characterization. These samples will be analyzed at a central laboratory. In case 
of an infusion reaction, blood collection should be performed for central evaluation of 
immunogenicity (see Section 8.10.1).
9.4
Completion of Study (for Individual Patients)
Patients will be considered to have completed the study if they are discontinued from study drug 
and 1 or more of the following situations occur:

Death.

Consent withdrawal.

Investigator decision.

Study terminated by the sponsor.

Lost to follow-up.

Transfer of patient to a long-term safety study or similar program.
The consequence of consent withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
Once study has been completed, all study procedures outlined for the end of study visit will be 
completed as specified in the SOE (Appendix A). After study completion, no new information will 
be collected from the completed patient and added to the existing data or any database.
9.5
Discontinuation of Modakafusp Alfa Treatment and Patient Replacement
Treatment must be permanently discontinued if any of the criteria detailed in Section 8.6.4 are met. 


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Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in Appendix A. The primary reason for study drug discontinuation will be 
recorded on the eCRF. 
During Cycle 1 of the dose escalation phase, patients who are discontinued prematurely for 
reasons other than a DLT will be replaced. 
9.6
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). The appropriate study personnel will maintain records 
of study drug receipt and dispensing.
9.7
Posttreatment Follow-up Assessments (PFS and OS) 
Patients who stop treatment for any reason other than PD will continue to have PFS follow-up 
visits. The PFS follow-up should occur every 12 ± 1 weeks from the EOT until the occurrence of 
progression, death, the start of subsequent systemic antineoplastic therapy, study termination, or 
until 6 months after the discontinuation of study treatment, whichever occurs first. 
After disease progression or starting another systemic anticancer therapy, all patients will be 
followed every 12 ± 1 weeks for OS until death or study termination. Survivor information and 
death details may be collected by methods that include, but are not limited to, telephone, e-mail, 
mail, or retrieval from online or other databases (eg, Social Security indexes). In addition, the start 
of another anticancer therapy for the disease under study will be collected.
See Appendix A for appropriate assessments during follow-up.
NOTE: Treatment-related SAEs must be reported to the Global Pharmacovigilance department or 
designee. This includes deaths that the investigator considers related to study drug that occur 
during the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it 
does not necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 


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laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life-threatening, or require hospitalization, but may be considered serious when, 
on the basis of appropriate medical judgment, it may jeopardize the patient, require medical or 
surgical intervention to prevent one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 5.0, effective 01 April 2018. The signs and symptoms of disease 
progression should be reported as AEs in the appropriate section of the eCRF, however should not 
be reported by the Preferred Term (PT) of disease progression. Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be reported as an 
AE.
Clarification should be made between an SAE and an AE that is considered severe in intensity 
(Grade 3 or 4) because the terms serious and severe are NOT synonymous. The general term 
severe is often used to describe the intensity (severity) of a specific event; the event itself, however, 


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may be of relatively minor medical significance (such as a Grade 3 headache). This is NOT the 
same as serious, which is based on patient/event outcome or action criteria described above and is 
usually associated with events that pose a threat to a patient’s life or ability to function. A severe 
AE (Grade 3 or 4) does not necessarily need to be considered serious. For example, a white blood 
cell count of 1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe) but may not be 
considered serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations.
10.1.4
Adverse Events of Special Interest (AESI)
An AESI (serious or nonserious) is an AE of scientific and medical concern specific to the product 
or program, for which ongoing monitoring and rapid communication by the investigator to Takeda 
sponsor may be appropriate. Such events may require further investigation in order to characterize 
and understand them. Serious AESIs will be reported to Takeda Global Pharmacovigilance in an 
expedited manner irrespective of the event’s seriousness or causal relationship. Instruction 
regarding how and when AESIs should be reported to Takeda are provided in Section 10.2.1. 
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as single comprehensive event.
Regardless of causality, SAEs must be reported by the investigator to the Takeda Global 
Pharmacovigilance department or designee within 24 hours of becoming aware of the event. This 
will be done by transmitting an electronic data capture (EDC) SAE report, the preferred method of 
reporting SAEs. If access to EDC is not feasible within 24 hours of receiving the event, the paper 
SAE forms should be submitted via fax (see fax numbers below). If a fax is used for transmission, 
site personnel must make every effort to confirm successful transmission of all pages and include 
an e-mail address on the fax cover sheet so that an acknowledgment of receipt can be returned via 
e-mail within 1 business day. 
E-mail submission of scanned SAE forms should only be used in the event fax transmission is not 
possible and EDC transmission is not feasible within 24 hours of receiving the event. If e-mail is 
used, site personnel must make every effort to confirm successful transmission by awaiting 
acknowledgment of receipt via e-mail within 1 business day. 
If SAEs are reported via fax or by e-mail, the EDC system must be updated as soon as possible 
with the appropriate information. A sample of the paper-based SAE form and processing 
directions are in the Study Manual. Information in the SAE report or form must be consistent 
with the data provided on the eCRF.
If information not available at the time of the first report becomes available at a later date, the 
investigator will transmit a follow-up EDC SAE report (or a paper-based SAE form if an EDC 


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SAE report is not feasible) or provide other documentation immediately within 24 hours of 
receipt. Copies of any relevant data from the hospital notes (eg, ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the addressee, if requested.
Fax Numbers
United States and Canada 
+1-800-963-6290
Rest of world
+1-202-315-3560
E-Mail Address
takedaoncocases@cognizant.com
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report.
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the relationship of the event to study drug administration. 
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 5.0, effective date 01 April 2018. The criteria are provided in the Study 
Manual.
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.2.1
AESI Reporting
10.2.1.1
Modakafusp Alfa
An IRR is a type of hypersensitivity reaction that develops during or shortly after administration of 
a drug. Signs and symptoms may include pruritus, urticaria, fever, rigors/chills, diaphoresis, 
bronchospasms, and cardiovascular collapse. Specific management instruction is included in 
Section 8.10.1. In modakafusp alfa studies, IRRs are designated as AESIs. When reporting IRRs in 
the eCRF, the signs and symptoms should be recorded and should be marked as an AESI.
10.2.1.2
Pembrolizumab
The following AEs are considered AESIs: 

Pneumonitis.

Hepatitis.


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
Colitis.

Nephritis.

Dermatologic reactions.

Myocarditis.

IRR.

Endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus, 
and hypophysitis.
Serious AESIs will be reported to Takeda Global Pharmacovigilance in an expedited manner 
irrespective of the event’s causal relationship. Further, patients will be advised to promptly report 
signs and symptoms that may indicate IRRs, including fever, chills, dizziness, nausea, vomiting, 
flushing, cough, headache, and rash during or soon after end of infusion.
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the signing of informed consent through 30 days after 
administration of the last dose of study drug or the start of subsequent anticancer therapy, 
whichever occurs first, and recorded in the eCRFs. The reporting period for irAEs (Section 
8.6.3.2) is extended to 90 days after administration of the last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first, and recorded in the eCRFs. 

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from 
the signing of informed consent through 30 days after administration of the last dose of study 
drug, even if the patient starts nonprotocol therapy, and recorded in the eCRF. The reporting 
period for serious irAEs is extended to 90 days after administration of the last dose of study 
drug. After this period, only related SAEs must be reported to the Takeda Global 
Pharmacovigilance department or designee. SAEs should be monitored until they are resolved 
or are clearly determined to be caused by a patient’s stable or chronic condition or intercurrent 
illness(es). 
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Any participant who is found to be pregnant during the study should be withdrawn and 
modakafusp alfa, and pembrolizumab if applicable, immediately discontinued. In addition, any 
pregnancies in the partner of a study participant during the study should also be recorded, after 
authorization from the study participant’s partner. 
If a participant or a study participant’s partner agrees to their primary care physician being 
informed, the investigator should notify the primary care physician that the participant was 
participating in a clinical study at the time of the pregnancy and provide details of the study drug 
the subject received.


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All pregnancies, including those in partners of study participants, will be followed to final 
outcome using the pregnancy form. The outcome, including any premature termination, must be 
reported to the sponsor. An evaluation after the birth of the child will also be conducted.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail addresses provided in the Study Manual.
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail addresses provided in the Study Manual.
Product complaints in and of themselves are not AEs. If a product complaint or a medication error 
results in an SAE, the SAE should be reported.
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, and IRBs or 
IECs as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an expedited report
within 7 days for fatal and life-threatening events and 15 days for other serious events, unless 
otherwise required by national regulations. The sponsor will also prepare an expedited report for 
other safety issues where these might materially alter the current benefit-risk assessment of an 
investigational medicinal product or that would be sufficient to consider changes in the 
investigational medicinal product’s administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, external data safety monitoring committee, or clinical endpoint committee 
will be used in this study.
12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the data management plan. 
If selected for coding, AEs, medical history, and concurrent conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization Drug Dictionary.


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12.1
eCRFs 
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will supply investigative sites with access to eCRFs and will arrange to 
train appropriate site staff in the use of the eCRF. These forms are used to transmit the information 
collected in the performance of this study to the sponsor, CRO partners, and regulatory authorities. 
Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated ICFs, subject authorization forms regarding the use of 
personal health information (if separate from the ICFs), electronic copy of eCRFs, including the 
audit trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the subject’s chart 
to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the investigator to retain 
essential documents specified in ICH E6 (Section 8) until at least 2 years after the last approval of 
a marketing application for a specified drug indication being investigated or, if an application is 
not approved, until at least 2 years after the investigation is discontinued and regulatory authorities 
are notified. In addition, ICH E6 Section 4.9.5 states that the study records should be retained until 
an amount of time specified by applicable regulatory requirements or for a time specified in the 
Clinical Study Site Agreement between the investigator and sponsor.




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13.2
Analysis Sets
Safety analysis set: The safety analysis set will include all enrolled patients who receive at least 
1 dose (even incomplete) of modakafusp alfa.
Response-evaluable analysis set: The response-evaluable analysis set is a subset of the safety 
analysis set including patients with measurable disease at baseline and at least 1 post-treatment 
response assessment. 
PK analysis set: The PK analysis set will include those patients from the safety analysis set who 
have sufficient data to calculate at least 1 PK parameter for modakafusp alfa. 
13.3
Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics including gender, age, race, weight, height, and other 
parameters as appropriate will be summarized using descriptive statistics. No inferential statistics 
will be carried out. For continuous variables, descriptive statistics (number, mean, standard 
deviation, median, minimum, and maximum) will be provided. For categorical variables, patient 
counts and percentages will be provided. Categories for missing data will be presented if 
necessary.
13.4
Efficacy Analysis
Efficacy endpoints include ORR, DCR, DOR, PFS, and OS. No formal statistical tests will be 
performed for these efficacy endpoints.
ORR is defined as the proportion of patients who achieve CR or PR (determined by the 
investigator) during the study in response-evaluable population.
DCR is defined as the proportion of patients who achieve CR, PR, or SD (determined by the 
investigator) during the study in response-evaluable population.
DOR is the time from the date of first documentation of a PR or better to the date of first 
documentation of PD for responders (PR or better). Responders without documentation of PD will 
be censored at the date of last response assessment that is SD or better.
TTP is the time from the date of the date of the first dose of study drug to the date of the first 
documentation of PD according to RECIST v1.1.
PFS is defined as the time from the date of the first dose of study drug to the date of first 
documentation of PD according to RECIST v1.1 or death due to any cause, whichever occurs first. 
Patients without documentation of PD or death will be censored at the date of the last response 
assessment that is SD or better.
OS is defined as the time from the date of first dose of study drug to the date of death due to any 
cause. Patients without documentation of death at the time of analysis will be censored at the date 
last known to be alive.


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ORR and DCR will be summarized using descriptive statistics with 95% CIs. PFS and OS will be 
analyzed descriptively using the Kaplan-Meier method for the safety analysis set. DOR will also 
be analyzed using the Kaplan-Meier method for the response-evaluable analysis set.
13.5
PK Analysis
13.5.1
PK Noncompartmental Analysis
Modakafusp alfa PK parameters will be estimated using noncompartmental methods with Phoenix 
WinNonlin. The PK parameters will be estimated from the concentration-time profiles for the PK 
analysis set. The following PK parameters will be determined, as permitted by data:

Cmax.

tmax.

AUC∞.

AUClast.

λz.

t1/2z.

CL.

Vss.

Accumulation ratio based on AUCτ. 
Modakafusp alfa PK parameters will be summarized using descriptive statistics. Individual 
modakafusp alfa concentration-time data and individual PK parameters will be presented in 
listings and tabulated using summary statistics by dose cohort. Individual and mean 
concentration-time profiles will be plotted by dose cohort.
13.5.2
PK Sampling Intended for Population PK Analysis
The PK data collected in this study are intended to contribute to future population PK analyses of 
modakafusp alfa. These population PK analyses may include data collected in other modakafusp 
alfa clinical studies. If applicable, the analysis plan for the population PK analysis will be 
separately defined, and the results of these analyses will be reported separately.
13.6
Pharmacodynamic Analysis
During the clinical development of modakafusp alfa, several biomarkers will be assessed to test for 
their correlation with safety and, if possible, with efficacy. Markers that will be studied are 
markers linked either to the drug itself or to the treated disease. Markers of immune system 
activation will be summarized using descriptive statistics. Individual data will be listed. 
Summaries will be provided separately for each study phase and by dose, as applicable.


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13.7
PK/Pharmacodynamic Analysis
Exposure-response relationships between modakafusp plasma exposure and pharmacodynamic 
response (eg, RO, degree of immune activation, changes in cytokines/chemokines, gene 
expression changes) may be explored on an ongoing basis as PK and pharmacodynamic data 
become available to understand the PK-pharmacodynamic relationship of modakafusp alfa and to 
help in estimation of the PAD. Data permitting, mathematical models may be used to describe this 
relationship and such models may be used to predict the dose of modakafusp alfa that provides the 
desired exposure and pharmacological response for future evaluation. If applicable, these data may 
be presented graphically as well as summarized in the clinical study report. 
13.8
PK/QTc Analysis
The PK-time matched triplicate ECG data collected in each patient during the dose escalation 
phase will be pooled to understand the PK-QTc interval relationship of modakafusp alfa. The 
relationship between modakafusp alfa plasma concentration and effects on heart rate and QTcF 
interval will be analyzed using nonlinear mixed effects modeling. These population PK-QTc 
interval analyses may include data collected in other modakafusp alfa clinical studies. As such, the 
analysis plan for the population PK-QTc interval analysis will be separately defined, and the 
results of these analyses will be reported separately and not presented in the clinical study report 
for this study.
13.9
Immunogenicity Analyses
The proportion of patients with positive ADA (transient and persistent, titer and specificity) during 
the study will be summarized. The effect of immunogenicity on modakafusp alfa and 
pembrolizumab PK, pharmacodynamics, safety, and efficacy will be examined, if possible.
Analysis will be based on available data from patients with a baseline assessment and/or 
postbaseline immunogenicity assessment (safety analysis set). Summaries will be provided 
separately for each study phase and by dose, as applicable. These analyses will be exploratory in 
nature, and all results will be descriptive in nature. 
13.10
Safety Analysis
The safety and tolerability of modakafusp alfa will be assessed by the recording of TEAEs (NCI 
CTCAE, Version 5.0), vital signs, chemistry and hematology, urinalysis, ECG, and concomitant 
medications.
AEs will be coded using the MedDRA. TEAEs that occur after administration of the first dose of 
study drug and through 30 days after the last dose of study drug will be summarized by MedDRA 
System Organ Class and PT in the safety analysis set.
13.11




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14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of the primary study 
assessment.
The sponsor will assess any protocol deviation; if it is likely to affect to a significant degree the 
safety and rights of a subject or the reliability and robustness of the data generated, it may be 
reported to regulatory authorities as a serious breach of GCP and the protocol.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the US FDA, the United Kingdom [UK] Medicines and 
Healthcare products Regulatory Agency [MHRA], and the Pharmaceuticals and Medical Devices 
Agency of Japan [PMDA]). If the study site is contacted for an inspection by a regulatory body, the 
sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1. 
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, patients) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct the study 
according to applicable local or regional regulatory requirements and align his or her conduct in 
accordance with the responsibilities of the investigator that are listed in Appendix C. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable federal/local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 


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must also be obtained. Those American sites unwilling to provide names and titles of all members 
because of privacy and conflict of interest concerns should instead provide a Federalwide 
Assurance number or comparable number assigned by the US Department of Health and Human 
Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if 
applicable, subject recruitment materials and advertisements and other documents required by all 
applicable laws and regulations must be submitted to a central or local IRB or IEC for approval. 
The IRB’s or IEC’s written approval of the protocol and subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study, ie, before 
shipment of the sponsor-supplied drug or study-specific screening activity. The IRB or IEC 
approval must refer to the study by its exact protocol title, number, and version date; identify 
versions of other documents (eg, ICF) reviewed; and state the approval date. If required by country 
or regional regulations or procedures, approval from the competent regulatory authority will be 
obtained before commencement of the study or implementation of a substantial amendment. The 
sponsor will ship drug once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from the competent 
authority to begin the trial. Until the site receives notification, no protocol activities, including 
screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the ICF, recruitment 
materials intended for viewing by subjects, local safety reporting requirements, reports, and 
updates regarding the ongoing review of the study at intervals specified by the respective IRB or 
IEC, and submission of the investigator’s final status report to IRB or IEC. All IRB and IEC 
approvals and relevant documentation for these items must be provided to the sponsor or its 
designee.
Patient incentives should not exert undue influence for participation. Payments to patients must be 
approved by the IRB or IEC and sponsor.
15.2
Patient Information, Informed Consent, and Patient Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, subject authorization form (if applicable), and patient 
information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the patient’s personal and personal health information for purposes of conducting 
the study. The ICF and the patient information sheet (if applicable) further explain the nature of the 
study, its objectives, and potential risks and benefits, and the date informed consent is given. The 
ICF will detail the requirements of the participant and the fact that he or she is free to withdraw at 
any time without giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the ICF 
and, if applicable, the subject authorization form. The ICF, subject authorization form (if 


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applicable), and subject information sheet (if applicable) must be approved by both the IRB or IEC 
and the sponsor before use.
The ICF, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF, subject authorization 
form (if applicable), and subject information sheet (if applicable) to the subject. Information 
should be given in both oral and written form whenever possible and in the manner deemed 
appropriate by the IRB or IEC. If the subject is not capable of rendering adequate written informed 
consent, then the subject’s legally acceptable representative may provide such consent for the 
subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to 
(1) inquire about details of the study and (2) decide whether to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines that he or she will participate 
in the study, then the ICF and subject authorization form (if applicable) must be signed and dated 
by the subject, or the subject’s legally acceptable representative, at the time of consent and before 
the subject enters into the study. The subject or the subject’s legally acceptable representative 
should be instructed to sign using their legal names, not nicknames, using a ballpoint pen with 
either blue or black ink. The investigator must also sign and date the ICF and subject authorization 
(if applicable) at the time of consent and before the subject enters into the study; however, the 
sponsor may allow a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original ICF, subject authorization form (if applicable), and subject information 
sheet (if applicable) will be stored in the investigator’s site file. The investigator must document 
the date the subject signs the informed consent in the subject’s medical record. Copies of the 
signed ICF, the signed subject authorization form (if applicable), and subject information sheet (if 
applicable) shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects or the relevant subject’s legally 
acceptable representative in the same manner as the original informed consent. The date the 
revised consent was obtained should be recorded in the subject’s medical record, and the subject 
should receive a copy of the revised ICF.
When appropriate, a separate ICF will inform patients of the possibility of pseudoprogression as 
well as the potential risks and benefits of continuing treatment in these circumstances. 
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.


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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, UK MHRA, Japan PMDA), the sponsor’s designated auditors, 
and the appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents) including, but not limited to, laboratory test result reports, ECG reports, admission and 
discharge summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific authorization 
of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, eg, subject name, address, and other identifier fields 
not collected on the subject’s eCRF.
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the clinical study site agreement. In the event of any discrepancy between the 
protocol and the clinical study site agreement, the clinical study site agreement will prevail.
15.4.2
Clinical Trial Registration
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda will, at a minimum, register interventional 
clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other publicly accessible 
websites on or before start of study, as defined by Takeda policy/standards. Takeda contact 
information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
e-mail/phone or other methods preferred by callers requesting trial information. Once subjects 
receive investigator contact information, they may call the site requesting enrollment into the trial. 


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The investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov, and other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws, and/or regulations. 
15.4.3.1
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the clinical study site agreement regarding the sponsor’s policy on subject compensation 
and treatment for injury. If the investigator has questions regarding this policy, he or she should 
contact the sponsor or sponsor’s designee.


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16.0
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Interferon-alpha to Myeloma Cells with a CD38 Antibody Induces Potent Tumor 
Regression with Reduced Off-Target Activity. PLoS One, 11(9), e0162472.
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Managing toxicities associated with immune checkpoint inhibitors: consensus 
recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity 
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of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced 
Melanoma. JAMA, 315(15), 1600-9.
Santonocito, A. M., Consoli, U., Bagnato, S., Milone, G., Palumbo, G. A., Di Raimondo, F., et al. 
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Seymour, L., Bogaerts, J., Perrone, A., Ford, R., Schwartz, L. H., Mandrekar, S., et al. 2017. 
iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. 
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specified otherwise.
b 
For all participant patients in the trial, QTc duration should be assessed locally with 1 standard local ECG to be collected and read at screening, at predose of 
C1D1 and C2D1, and at EOT. Additional ECGs may be obtained as clinically indicated at any time during the study at the discretion of the investigator. 
Triplicate ECGs will be obtained as described in these SOEs and in Table 16.f. When the timing of triplicate and single (safety) ECGs coincide, the site can use 
the triplicate ECG collection for safety evaluation.
c
Vital signs will be measured before starting the infusion and after the completion of the infusion. Vital signs include temperature, pulse, respiratory rate, and 
blood pressure. Blood pressure will be measured every 30 minutes (±5 minutes) during the first 4 infusions, after the end of the infusion, and at any moment if 
the patient complains of symptoms consistent with an IRR. If the patient experiences hypotension (with or without symptoms), intensive blood pressure 
monitoring according to local practice should be instituted. The patient cannot be released from the site until blood pressure has returned to Grade 1 or baseline 
for at least 1 hour. During the infusion and for 6 hours postinfusion in the first 2 treatment cycles, patients should be continually monitored by medically 
qualified staff with access to emergency medical equipment and medications to manage IRRs. In Cycle 3 and beyond, patients should be continually monitored 
for at least 2 hours after the end of infusion, and the monitoring duration can be extended per a patient’s prior dosing experience.
d 
In case of an infusion reaction of Grade ≥2, blood draws should be performed for central evaluation of immune markers, cytokines, chemokines, and ADAs. The 
following samples should be collected: serum sample for circulating biomarkers, and serum sample for immunogenicity.
e
CT and/or MRI scans will be performed at screening unless chest, abdominal cavity, and pelvis diagnostic quality scans were performed within 5 weeks before 
the planned first dose of study drug. CT and/or MRI scans of the chest, abdominal cavity, and pelvis should be acquired with at least IV contrast. The imaging 
modalities used for a patient should remain consistent throughout the study. If contrast-enhanced CT scans are contraindicated for a particular patient, a 
noncontrast-enhanced CT of the chest should be acquired if possible, in addition to contrast-enhanced CT of the abdomen, and pelvic MRI. Repeat CT and/or 
MRI scans should be performed every other cycle up to Cycle 7 (Day 1 [-7 days] of Cycles 3, 5, and 7), every 3 cycles thereafter, and as clinically indicated. 
Response will be determined locally according to RECIST v1.1 (see Section 9.3.14.1). Screening and on-treatment images, when available, should be 
transferred to the imaging core laboratory vendor for potential retrospective central reading. Clinical decisions will be made per local response assessment. 
Availability of prescreening scan(s) is not a prerequisite for study eligibility (Section 9.3.14.2). If available, the most recent prescreening diagnostic quality CT 
and/or MRI scans dated within 3 months before the planned first dose of modakafusp alfa should be submitted to the imaging core laboratory vendor for 
potential retrospective central reading. The date of the scan should be indicated. Response assessment will be calendar-based regardless of treatment 
delays/interruptions. 
f
Chemistry will include tests listed in Table 9.a. It is not necessary to repeat these tests on C1D1 predose if the tests performed at screening are less than 4 days 
old.
g
A sample for blood typing to be taken only at screening. Blood banks need to be alerted that the patient is going to receive an anti-CD38 antibody that may 
interfere with blood typing in a manner similar to daratumumab. If the blood bank issues a compatibility card, it should be made available to the patient. The 
patient needs to tell other healthcare providers that he/she is receiving an anti-CD38 antibody if, for example, a blood transfusion is needed. 
h
Hematology will include tests listed in Table 9.a. It is not necessary to repeat these tests on C1D1 predose if the tests performed at screening are less than 4 days 
old. 
i 
Blood samples for TBNK (T cells [including CD4+ and CD8+ T cells], B cells, and NK cells) flow cytometric analysis will be obtained predose on indicated 
visits, only if local analysis is available at the site. 
j 
Urinalysis (dipstick) will include tests listed in Table 9.a. Microscopic if clinically indicated only: bacteria, RBCs, WBCs, casts, and crystals.


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k 
A serum or urine pregnancy test will be performed for patients of childbearing potential with negative results during screening and again at C1D1 (baseline) if 
the screening test was performed more than 72 hours before the C1D1 dosing. A serum or urine pregnancy test must be performed at predose (within 72 hours 
prior to dosing) on Day 1 of each cycle with negative results available before modakafusp alfa is administered. A serum or urine pregnancy test is required at 
EOT.
l
At least 1 target lesion amenable for biopsy is required for enrollment in phase 1b. The accessible biopsy lesion should not have been previously irradiated. See 
Section 9.3.15.2 for details. 
m
Blood samples for modakafusp alfa PK will be collected at timepoints specified in Table 16.f below.
n
Immunoprofiling consists of mass cytometric analysis of T, B, and NK lymphocyte subsets, and will be analyzed centrally.
o
Predose.
p 
Predose and at 4 hours (+/- 30 minutes) after the end of infusion.
q 
Blood samples for immunogenicity (ADA) testing will be collected before the dose on Day 1 of every cycle while the patient remains in treatment and, if 
possible, at the EOT follow-up visit. In case of an infusion reaction, blood draws should be performed for central evaluation of immunogenicity. 
r 
One blood sample for DNA will be taken at either screening or C1D1 predose (when it is not possible to collect at screening, samples can be collected at the next 
visit).
s
Patients who discontinue modakafusp alfa for reasons other than PD will continue PFS follow-up every 12±1 weeks from the EOT visit until the occurrence of 
PD, death, the start of subsequent systemic anticancer therapy, study termination, or until 6 months after the discontinuation of study treatment, whichever 
occurs first. PFS will be assessed according to RECIST v1.1 (Section 9.3.14.1).
t 
Patients will be followed for survival every 12±1 weeks until death, loss to follow-up, consent withdrawal, or study termination. Survivor information and death 
details may be collected by methods that include, but are not limited to, telephone, e-mail, mail, or retrieval from online or other databases (eg, Social Security 
indexes). In addition, the start of another anticancer therapy for the disease under study will be collected.










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WBC: white blood cell.
Crosses in parentheses “(X)” indicate tests are to be performed only under certain circumstances as indicated in associated footnote(s).
a Written informed consent must be obtained before performing any protocol-specific procedure. Test results from routine clinical management are acceptable for 
screening if obtained within the specified time window. The screening period is 21 days and runs between ICF signature and first dose unless it is explicitly 
specified otherwise.
b For all participant patients in the trial, QTc duration should be assessed locally with 1 standard local ECG to be collected and read at screening, at predose and at 
the end of modakafusp alfa infusion (+ 30 minute window) of C1D1, C2D1 and C3D1, and at EOT. Additional ECGs may be obtained as clinically indicated at 
any time during the study at the discretion of the investigator. During the safety lead-in dose expansion phase, triplicate ECGs will be obtained as described in 
these SOEs and in Table 16.g. When the timing of triplicate and single (safety) ECGs coincide, the site can use the triplicate ECG collection for safety evaluation.
c Vital signs will be measured before starting the infusion and after the completion of the infusion. Vital signs include temperature, pulse, respiratory rate, oxygen 
saturation, and blood pressure. Blood pressure will be measured every 30 minutes (±5 minutes) during the first 4 infusions, after the end of the infusion, and at any 
moment if the patient complains of symptoms consistent with an IRR. If the patient experiences hypotension (with or without symptoms), intensive blood 
pressure monitoring according to local practice should be instituted. The patient cannot be released from the site until blood pressure has returned to Grade 1 or 
baseline for at least 1 hour. During the first infusion and for 6 hours postinfusion in the first 2 treatment cycles, patients should be continually monitored by 
medically qualified staff with access to emergency medical equipment and medications to manage IRRs. In Cycle 3 and beyond, patients should be continually 
monitored for at least 2 hours before the end of infusion, and the monitoring duration could be extended per a patient’s prior dosing experience.
d In case of an IRR, blood draws should be performed for central evaluation of cytokines, chemokines, complement, immune complex formation and ADAs. The 
following samples should be collected: serum sample for circulating biomarkers and serum sample for immunogenicity.
e The recommended pembrolizumab dose of 400 mg will be administered as an IV infusion over 30 ±10 minutes Q6W. Pembrolizumab will be administered before 
modakafusp alfa on days when both modakafusp alfa and pembrolizumab are given. At least 30 minutes should elapse between the completion of the infusion of 
the pembrolizumab and the infusion of modakafusp alfa. 
f CT and/or MRI scans of the chest, abdominal cavity, and pelvis should be acquired with at least IV contrast. The imaging modalities used for a patient should 
remain consistent throughout the study. If IV contrast-enhanced CT scans are contraindicated for a particular patient, a noncontrast-enhanced CT of the chest 
should be acquired in addition to an oral contrast–enhanced CT of the abdomen and IV contrast–enhanced pelvic MRI. At present, low-dose or attenuation 
correction CT portions of a combined PET–CT are of limited use in anatomically based efﬁcacy assessments, and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast-enhanced CT scans for anatomically based RECIST measurements. However, if a site can document that the CT 
performed as part of a PET–CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET–CT can be used for 
RECIST measurements. Note, however, that the PET portion of the CT introduces additional data that may bias an investigator if it is not routinely or serially 
performed. Repeat CT and/or MRI scans should be performed every other cycle up to Cycle 7 (Day 1 [-7 days] of Cycles 3, 5, and 7), every 3 cycles thereafter, 
and as clinically indicated. Response will be determined locally according to RECIST v1.1 (see Section 9.3.14.1). Screening and on-treatment images, when 
available, should be submitted to the imaging core laboratory vendor for retrospective central reading when it is required. Clinical decisions will be made per 
local response assessment. Availability of prescreening scan(s) is not a prerequisite for study eligibility (Section 9.3.14.2). If available, the most recent 
prescreening diagnostic quality CT and/or MRI scans dated within 3 months before the planned first dose of modakafusp alfa should be submitted to the imaging 
core laboratory vendor for tumor growth rate determination. The date of the scan should be indicated. Response assessment will be calendar-based regardless of 
treatment delays/interruptions.


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g Chemistry will include tests listed in Table 9.a. Chemistry on C1D15 and C3D15 could be assessed in a local hospital if there is no planned PK sampling on those 
visits per Table 16.g and Table 16.h. 
h Hematology will include tests listed in Table 9.a. Hematology on C1D15 and C3D15 could be assessed in local hospital when there is no planned PK sampling on 
those visits per Table 16.g and Table 16.h. 
i Footnote no longer applicable.
j Urinalysis (dipstick) will include tests listed in Table 9.a. Microscopic if clinically indicated only: bacteria, RBCs, WBCs, casts, and crystals.
k A serum or urine pregnancy test will be performed for patients of childbearing potential with negative results during screening and again at C1D1 (baseline) if the 
screening test was performed more than 72 hours before the C1D1 dosing. A serum or urine pregnancy test must be performed at predose (within 72 hours prior 
to dosing) on Day 1 of each cycle with negative results available before modakafusp alfa is administered. A serum or urine pregnancy test is required at EOT.
l Immunosafety lab tests include thyroid-stimulating hormone (TSH), free thyroxine (free T4) and cortisol (morning preferred) repeated every other cycle starting 
from Cycle 3, and at the EOT as detailed in Section 9.3.13.3. These tests are analyzed locally. 
m A minimum of 1 target lesion for response assessment is required for enrollment in phase 2. A separate lesion amenable for biopsy is required for enrollment in 
cohort I and II (post futility analysis) and cohort III (all patients, inclusive of safety-lead in) of phase 2. New (fresh) biopsies at screening and on treatment will be 
required for all patients in cohort III (safety-lead in and expansion) of phase 2. For patients in cohorts I and II of phase 2, new (fresh) screening and on-treatment 
biopsies will be optional up until futility has been met. Once futility has been met for either cohorts I or II, new (fresh) biopsies will be required at screening and 
on-treatment. See Section 9.3.15.2 for details. The accessible lesion for biopsy should not have been previously irradiated or designated as the only target lesion 
for measurable disease. 
n Blood samples for modakafusp alfa PK and pembrolizumab PK will be collected at time points specified in Table 16.g and Table 16.h below. 
o Flow cytometry methodologies will be used to immunophenotype T, B, and NK lymphocyte subsets, and will be analyzed centrally.
p Predose.
q Predose and at 4 hours (+/- 30 minutes) after the end of infusion.
r Blood samples for immunogenicity (ADA) testing will be collected before the dose on Day 1 of every cycle while the patient remains in treatment and, if possible, 
at the EOT follow-up visit. In case of an IRR, blood draws should be performed for central evaluation of immunogenicity.
s
One blood sample for DNA will be taken at either screening or C1D1 predose (when it is not possible to collect at screening, samples can be collected at the next 
visit).
t Patients who discontinue modakafusp alfa for reasons other than PD will continue PFS follow-up every 12±1 weeks from the EOT visit until the occurrence of PD, 
death, the start of subsequent systemic anticancer therapy, study termination, or until 6 months after the discontinuation of study treatment, whichever occurs first. 
PFS will be assessed according to RECIST v1.1.
u Patients will be followed for survival every 12±1 weeks until death, loss to follow-up, consent withdrawal, or study termination. Survivor information and death 
details may be collected by methods that include, but are not limited to, telephone, e-mail, mail, or retrieval from online or other databases (eg, Social Security 
indexes). In addition, the start of another anticancer therapy for the disease under study will be collected.
v A sample for blood typing to be taken only at screening. Blood banks need to be alerted that the patient is going to receive an anti-CD38 antibody that may 
interfere with blood typing in a manner similar to daratumumab. If the blood bank issues a compatibility card, it should be made available to the patient. The 
patient needs to tell other healthcare providers that he/she is receiving an anti-CD38 antibody if, for example, a blood transfusion is needed. 
w A whole blood sample will be collected to quantify CTCs at baseline and correlate with response.


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x Pharmacodynamic samples to be collected for patients enrolled within the safety lead-in and those enrolled within the expansion cohorts prior to futility being 
met.
y After futility has been met within an expansion cohort, the on-treatment biopsy sample should be taken prior to Cycle 3 administration of modakafusp alfa and 
pembrolizumab. For convenience, biopsy can be taken up to a 7 days prior to C3D1, preferably to coincide with imaging assessments of disease. 


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Appendix B
PK Sampling Tables
16.6
Table 16.f
Serial PK (Serum) Sample Breakdown: Phase 1b Dose Escalation
Table 16.f
Serial PK (Serum) Sample Breakdown: Phase 1b Dose Escalation 
Cycle 1
Cycle 2
Cycles 3-6
C1D1
C1D2 a
C1D3 a
C1D4
C2D1 a
C2D2 a
C2D3 a
C2D4 a
D1
Triplicate
ECG b
PK
Triplicate 
ECG b
PK
PK
PK
PK
PK
PK
PK
PK
Predose (within 30 min before start of 
infusion) 
X3
X1
X1
X
End of infusion (10 min)
X3
X1
X1
X
1 h after end of infusion (15 min)
X3
X1
X1
2 h after end of infusion (30 min)
X3
X1
X1
X c
6 h after end of infusion (30 min)
X3
X1
X1
24 h after end of infusion (1 h)
X3
X1
X1
48 h after end of infusion (2 h)
X1
X1
72 h after end of infusion (2 h)
X1 d
X1 d
CxDx: Cycle x Day x; D: Day; ECG: electrocardiogram; h: hour(s); min: minute(s); PK: pharmacokinetic(s).
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the 
blood sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
a Timing of the morning visits should occur at approximately the same time as the morning dosing times on previous days of the cycle. The date/time of the start 
and end of infusions should be recorded accurately. PK samples should only be collected from the contralateral arm and not from the drug infusion arm.


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b Triplicate ECGs are collected before PK sample collection. See also Section 9.3.12. Triplicate 12-lead ECG measurements are performed using an ECG 
recorder. Collection of triplicate ECG begins after patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs 
occurs within 3 minutes of each other and over a 10-minute window. When the timing of triplicate and single (safety) ECGs coincide, the site can use the 
triplicate ECG collection for safety evaluation. The ECG data collected on these ECG recorders can also be used as safety ECGs for assessment on site by 
investigator (ERT will ensure ECG recorders can transmit ECGs for on-site assessment for investigator). On C1D1, patients will abstain from eating food or 
having anything to drink except water from a minimum of 2 hours before collection of the predose ECGs until after collection of the 1 hour after end of 
modakafusp alfa infusion triplicate ECGs. A low-calorie and low-sodium light meal is permitted immediately after the 1-hour postinfusion ECG has been 
collected. Light meals are permissible immediately after collection of the 2-hour and 6-hour postinfusion ECG timepoints. In patients unable to comply with 
these recommendations, any food intake should be limited to the smallest required portion of bland food. 
c Cycle 4 only for dose escalation phase. 
d Only patients receiving modakafusp alfa 0.75 mg/kg or higher. 


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16.7
Table 16.g Serial PK (Serum) Sample Breakdown: Safety Lead-in Phase of Phase 2 Dose Expansion
Table 16.g
Serial PK (Serum) Sample Breakdown: Safety Lead-in Phase of Phase 2 Dose Expansion
Cycle 1
Cycle 3
Cycle 2, Cycle 
4-beyond
D1a
D2 a
D3 a
D4 
D1 a
D2 a
D3 a
D4 a
D1
Triplicate
ECG b
Modak-af
usp alfa 
PK
Pembro-liz
umab PK
Triplicate 
ECG b
Modaka-f
usp alfa 
PK
Modaka-f
usp alfa 
PK
Modaka-f
usp alfa 
PK
Modak-af
usp alfa 
PK
Pembro-liz
umab PK
Modaka-af
usp alfa 
PK
Modaka-f
usp alfa 
PK
Modaka-f
usp alfa 
PK
Modaka-fu
sp alfa PK
Pembro-li
zumab 
PKe
Predose (within 30 
min before start of 
infusion) 
X3
X1
X
X1
X
X
X
End of infusion (10 
min)
X3
X1
X
X1
X
X
X
1 h after end of 
infusion
(15 min)
X3
X1
X1
2 h after end of 
infusion
(30 min)
X3
X1
X1
X c
Xc
6 h after end of 
infusion
(30 min)
X3
X1
X
X1
X
24 h after end of 
infusion 
(1 h)
X3
X1
X1
X d
48 h after end of 
infusion
(2 h)
X1
X1
72 h after end of 
infusion 
(2 h)
X1
X1 
CxDx: Cycle x Day x; D: Day; ECG: electrocardiogram; h: hour(s); min: minute(s); PK: pharmacokinetic(s).


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When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of the 
blood sample. The triplicate ECG measurements should be completed immediately before the corresponding PK blood draw. 
a
Timing of the morning visits should occur at approximately the same time as the morning dosing times on previous days of the cycle. The date/time of the start 
and end of infusions should be recorded accurately. PK samples should only be collected from the contralateral arm and not from the drug infusion arm.
b
Triplicate ECGs are collected before PK sample collection. See also Section 9.3.12. Triplicate 12-lead ECG measurements are performed using an ECG 
recorder. Collection of triplicate ECG begins after patient has rested in supine position for approximately 5 minutes. Each ECG recording of the triplicate ECGs 
occurs within 3 minutes of each other and over a 10-minute window. When the timing of triplicate and single (safety) ECGs coincide, the site can use the 
triplicate ECG collection for safety evaluation. The ECG data collected on these ECG recorders can also be used as safety ECGs for assessment on site by 
investigator (ERT will ensure ECG recorders can transmit ECGs for on-site assessment for investigator). On C1D1, patients will abstain from eating food or 
having anything to drink except water from a minimum of 2 hours before collection of the predose ECGs until after collection of the 1 hour after end of 
modakafusp alfa infusion triplicate ECGs. A low-calorie and low-sodium light meal is permitted immediately after the 1-hour postinfusion ECG has been 
collected. Light meals are permissible immediately after collection of the 2-hour and 6-hour postinfusion ECG timepoints. In patients unable to comply with 
these recommendations, any food intake should be limited to the smallest required portion of bland food. 
c
Cycle 5 only. 
d
Cycle 2 only. 
e
Blood samples for pembrolizumab PK will only be collected at the visits with pembrolizumab dosing (ie, Cycle 1, Cycle 3, Cycle 5, Cycle 7 and beyond).


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16.8
Table 16.h Sparse Serum PK Sampling Schedule to Characterize PK of Modakafusp Alfa and Pembrolizumab During 
Phase 2 Expansion Phase (excluding Safety Lead-In Periods) 
Table 16.h
Sparse Serum PK Sampling Schedule to Characterize PK of Modakafusp Alfa and Pembrolizumab During Phase 
2 Expansion Phase (excluding Safety Lead-In Periods) 
Cycles 1 and Beyond
Day 1
Modakafusp Alfa PK a
Pembrolizumab PK c
Predose (within 30 min before start of infusion) 
X1
X
End of modakafusp alfa infusion (10 minutes)
X1
X
2-4 hours after end of modakafusp alfa infusion
X1 b
X b
Total Timepoints
3
PK: pharmacokinetic(s).
a 
The timing of the morning visits should occur at approximately the same time as previous dosing days. The date/time of the start and end of infusions should be 
recorded accurately. PK samples should only be collected from the contralateral arm and not from the drug infusion arm.
b
Cycles 1, 3, and 5 only. 
C 
Blood samples for pembrolizumab PK will only be collected at the visits with pembrolizumab dosing (ie, Cycle 1, Cycle 3, Cycle 5, Cycle 7 and beyond).


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Appendix C
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments, are NOT performed on potential subjects prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each ICF should contain a subject authorization section that 
describes the uses and disclosures of a subject’s personal information (including personal 
health information) that will take place in connection with the study. If an ICF does not include 
such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.


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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 


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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other identifying personal information. In addition, the investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
UK, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of the investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details, and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in the investigator’s 
own country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.


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Appendix E
Description and Operating Characteristics of the BLRM for Dose Escalation
An adaptive BLRM with overdose control principle (Babb et al. 1998; Neuenschwander et al. 
2008) is used to guide dose escalation decisions and MTD estimation, along with considerations of 
other emerging safety, clinical, PK, and pharmacodynamic data. 
The 2-parameter logistic regression model used is as follows: 
(
) = log() +  log 

 , α >  0,  >  0, 
where 
 is the DLT rate for "#$, and "#$%& is the reference dose. A quantile-based, weakly 
informative, bivariate normal prior will be used for ln(α) and ln(β). This prior will be assigned 
based on pre-study estimates of median DLT at the provisional dose levels as shown in Table 1 
(described by Neuenschwander et al. (Neuenschwander et al. 2008)). 
Table 1
Prior Median and 95% Credible Interval for DLT Probabilities at Each Dose 
Level
Dose Level (mg/kg)
Median DLT Rate
95% Credible Interval for DLT Rate
0.1
0.05
(0, 0.90)
0.2
0.10
(0, 0.92)
0.4
0.20
(0, 0.94)
0.75
0.25
(0, 0.95)
1.5
0.30
(0, 0.96)
3
0.45
(0.01, 0.97)
6
0.50
(0.02, 0.98)
DLT: dose-limiting toxicity.
The model will be updated after each group of approximately 3 patients is enrolled in the current 
dose level. Each subject will participate in only 1 dose cohort. For each dose level, the posterior 
probability of having DLT rates that fall into the following intervals will be estimated:

[0, 0.16]: under-dosing.

[0.16, 0.33]: target toxicity.

[0.33, 1.00]: excessive toxicity.
The next recommended dose will be selected as described in Section 8.3.
The simulations to evaluate the operating characteristics are based on provisional dose levels (0.1, 
0.2, 0.4, 0.75, 1.5, 3, 6 mg/kg), representing the various distributions of toxicity across dose levels, 
detailed as shown in Table 2.


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Table 2
Dose Escalation Simulation Study of the Probability of DLT
Dose Level (mg/kg)
True P(DLT) at each scenario
1
2
3
4
5
6
0.1
0.001
0.01
0.05
0.10
0.25
0.50
0.2
0.02
0.05
0.10
0.20
0.45
0.60
0.4
0.04
0.10
0.20
0.30
0.52
0.70
0.75
0.06
0.20
0.25
0.45
0.60
0.75
1.5
0.08
0.23
0.30
0.55
0.70
0.85
3
0.10
0.26
0.45
0.65
0.80
0.90
6
0.12
0.30
0.50
0.75
0.90
0.99
DLT: dose-limiting toxicity.
The trend of the dose-DLT relationship becomes steeper and MTD is reached earlier from 
Scenario 1 to Scenario 6. Table 3 shows the operating characteristic results. 
Table 3
Operating Characteristics for BLRM Dose Escalation Rule
Scenario
Probability of Recommending a:
Average Proportion of Patients 
Receiving a:
Average Number of 
Patients
Low Dose
Target 
Dose
High Dose
Low Dose
Target 
Dose
High Dose
Per study
Experiencing 
DLT per study
1
100.0
NA
NA
100.0
NA
NA
24.2
1.5
2
16.2
83.8
NA
47.2
52.8
NA
21.4
3.4
3 a
16.1
75.7
6.5
38.7
53.5
7.8
18.9
3.8
4 b
12.8
70.3
11.4
28.5
53.8
17.6
16.1
3.9
5 c
NA
42.0
16.1
NA
61.7
38.3
10.6
3.7
6 d
NA
NA
10.2
NA
NA
100.0
5.9
3.0
BLRM: Bayesian Logistic Regression Model; DLT: dose-limiting toxicity.
Low dose = true DLT rate is [0, 0.16]; target dose = true DLT rate is [0.16, 0.33]; high dose = true DLT rate is [0.33, 
1.00].
a Probability of 1.7% to claim all doses are toxic.
b Probability of 5.5% to claim all doses are toxic.
c Probability of 41.9% to claim all doses are toxic.
d Probability of 89.8% to claim all doses are toxic.
In Scenario 1 where all true DLT rates are below 0.33, the average number of patients required is 
approximately 24 with 1.5 DLTs expected on average. 
The true DLT rates in Scenario 2 increase faster than Scenario 1 but are still all below 0.33, and the 
BLRM has an 83.8% chance of successfully recommending target dose levels. The average 
number of patients required is approximately 21, with 3.4 DLTs expected on average. 
In Scenario 3, there is a 16.1% chance of recommending a lower dose as MTD and a 75.7% chance 
of successfully recommending target dose levels. The average number of patients required is 
approximately 19, with 3.8 DLTs expected on average.


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In Scenario 4, with a faster increase of DLT rate over doses, there is 70.3% chance of claiming the 
target doses as MTD, an 11.4% chance of recommending a toxic dose, and approximately a 5.5% 
chance of claiming all doses are toxic. The average number of patients required is approximately 
16 with 3.9 DLTs expected on average.
Scenario 5 further increases the DLT rate over dose levels and has a 42.0% chance of 
recommending a target dose level as MTD, a 16.1% chance of recommending a toxic dose, and a 
41.9% chance of claiming all doses as toxic. This scenario requires, on average, approximately 11
patients, and results in 3.7 DLTs on average.
When all doses are toxic, as in Scenario 6, there is an 89.8% chance of successfully claiming all 
doses are toxic. The average number of patients required is approximately 6 and 3.0 DLTs are 
expected on average.
The accuracy of the BLRM recommendation relies on the true DLT rate; thus, the safety, clinical, 
PK, and pharmacodynamic data evaluation are combined to support the dose escalation. As an 
example, a hypothetical dose escalation is shown in Table 4 to illustrate how BLRM guides dose 
escalation.
Table 4
Hypothetical Dose Escalation Steps
Step
Dose (mg/kg)
#patients
#DLTs
Next Recommended Dose (mg/kg)
1
0.1
3
0
0.2
2
0.1
3
0
0.2
3
1
0.4
3
0.1
3
0
0.2
3
1
0.4
3
0
1.5
4
0.1
3
0
0.2
3
1
0.4
3
0
0.75
3
2
0.4
5
0.1
3
0
0.2
3
1
0.4
6
2
0.75
3
2
0.2
6
0.1
3
0
0.2
6
1
0.2 mg/kg is claimed as the MTD
0.4
6
2
0.75
3
2
DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
In addition, the BLRM is flexible in handling late-onset toxicities and can be fed with events 
meeting DLT criteria but occurring in later cycles to modulate dose escalation, as needed. 


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16.9
Appendix F Protocol History
Date
Amendment Number
Region
28 July 2022
6
Global
16 November 2021
5
Global
11 August 2021
4
Global
08 March 2021
3
Global
12 March 2020
2
Global
22 October 2019
1
Global
05 August 2019
Initial Protocol
Global
16.9.1
Protocol Amendment 5
This section describes the changes in the protocol incorporating Amendment 5. The primary reasons 
for this amendment are to:

Inform all participating sites that the timeframe for contraception and egg donation has been 
increased to 6 months after study drug administration (modakafusp alfa or pembrolizumab) for 
female patients of childbearing potential enrolled in the study. 

Add urinalysis to required tests at the screening visit, Day 1 of all cycles, and the 
end-of-treatment (EOT) visit. 
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 5
Summary of Changes since the Last Approved Protocol
Change
Number
Section(s) Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Section 2.0 Study Summary 
Section 7.1 Inclusion Criteria 
Section 8.9 Precautions and Restrictions 
The timeframe for contraception and egg 
donation has been amended for female 
patients of childbearing potential enrolled in 
the study. 
Update.
2.
2.0 Study Summary Section
8.9 Precautions and Restrictions 
Restrictions for breastfeeding were added.
Update.
3.
2.0 Study Summary Section
7.1 Inclusion Criteria
Section 8.9 Precautions and Restrictions
The definition of postmenopausal was 
clarified for consistency.
Clarification.
4.
Section 16.4 Table 16.3
Added urinalysis to the screening visit and 
Day 1 of Cycles 2 and 3. 
Update.
5.
Section 16.5 Table 16.e
Added urinalysis to Day 1 of all cycles and 
the EOT visit. 
Update.


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16.9.2
Protocol Amendment 4 Summary of Changes 
This section describes the changes in reference to the protocol incorporating Amendment 4. The 
primary reasons for this amendment are to:

Update the drug name from TAK-573 to modakafusp alfa.

Revise endpoints and clarify text regarding samples for receptor occupancy and 
immunophenotyping. 

Change statement regarding sourcing of pembrolizumab.

Correct modakafusp alfa “injection” to “infusion.”

Revise target response rates and stopping boundaries.

Modify criteria for permitted radiotherapy on treatment. 

Add pembrolizumab time frame to contraception guidelines.

Add description of modakafusp alfa formulations.

Revise description of required biopsies.

Clarify timing of T lymphocyte, B lymphocyte, and natural killer cells (TBNK) blood 
sampling.

Clarify response assessment guidelines and added text regarding disposition of imaging.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only.
Protocol Amendment 4
Summary of Changes since the Last Approved Protocol
Change
Number
Section(s) Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
1.
Title page.
Protocol title corrected. 
Correction. 
2.
Throughout protocol.
Changed TAK-573 to modakafusp alfa. 
Update.
3.
Section 8.15.1 Modakafusp Alfa
Revised modakafusp alfa storage, thawing, 
and reconstitution guidelines.
Update.
4.
2.0 Study Summary
Section 5.1 Objectives
Section 5.2 Endpoints
Section 5.1.3 Exploratory/Additional 
Objectives
Table 6.a
Primary and 
Secondary Endpoints for Disclosure
Downgraded the CD38 receptor occupancy 
objective and endpoint from secondary to 
exploratory. 
Update.


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Protocol Amendment 4
Summary of Changes since the Last Approved Protocol
Change
Number
Section(s) Affected by Change
Description of Each Change and Rationale
Location
Description
Rationale
5.
Section 2.0 Study Summary
Section 5.1 Objectives
Section 5.2 Endpoints
Table 6.a
Primary and 
Secondary Endpoints for Disclosure
Downgraded the Type I interferon gene 
expression signatures objective and endpoint 
to exploratory. 
Update.
6.
Section 2.0 Study Summary
Section 6.1.1 Phase 1b Single-Agent 
Dose Escalation
Added further explanation of Phase 1b dose 
escalation process. 
Clarification.
7.
Section 8.13.2 Pembrolizumab
Changed statement regarding sourcing of 
pembrolizumab.
Update. 
8.
Section 8.1 Study Drug Administration
Section 8.12 Description of 
Investigational Agents
Corrected “injection” to “infusion.”
Correction. 
9.
Section 8.1 Study Drug Administration
Added reference to premedication guidelines. Clarification.
10.
8.7 Excluded Concomitant Medications 
and Procedures
Modified criteria for permitted radiotherapy 
on treatment. 
Update. 
11.
Section 2.0 Study Summary
Section 7.1 Inclusion Criteria
Section 8.9 Precautions and Restrictions
Added pembrolizumab time frame to 
contraception guidelines.
Update. 
12.
10.2.1.2 Pembrolizumab
Added 2 adverse events of special interest.
Update 
13.
Section 8.12 Description of 
Investigational Agents
Added description of modakafusp alfa 
formulations.
Update.
14.
Section 2.0 Study Summary
Section 7.1 Inclusion Criteria
Section 9.3.15 Biomarker, 
Pharmacodynamic, and PK Samples
Table 16.e
Schedule of Events, 
Continued: Cycle 4 Through EOT and 
Follow-up (Phase 2 Dose Expansion)
Revised description of required biopsies. 
Update. 
15.
Section 9.3.13.2 TBNK
Clarified timing of T lymphocyte, B 
lymphocyte, and natural killer cells (TBNK) 
blood sampling.
Clarification.




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(COVID-19) public health emergency. The study design was changed to a phase 1b/2 study, and 
the disease types eligible for enrollment were revised. Study objectives and endpoints, statistical 
methods, and study size estimations were also revised to reflect study design changes. Other 
changes to the study design are described below. In addition, minor grammatical and 
typographical corrections were made.
Summary of Changes since the Last Approved Protocol
Number
Section(s) Affected by Change
Description
Rationale
1.
Title page.
Section 2.0 Study Summary
Section 3.4 Corporate Identification
Update to legal entity.
Update.
2.
Section 2.0 Study Summary
Section 6.3.4 Total Study Duration
Table 6.a Primary and Secondary 
Endpoints for Disclosure
Increased estimated study completion time to 55 
months.
Update.
3.
Section 2.0 Study Summary
Section 4.4.3 Rationale for 
TAK-573 Phase 2 Expansion Phase 
Cohorts
Section 5.0 Study Objectives and 
Endpoints
Section 6.0 Study Design
Section 7.0 Study Population
Section 8.4 Phase 2 TAK-573 Dose 
Expansion
Appendix A Schedules of Events
Added a phase 2 (dose expansion) combination 
treatment phase (TAK-573 + pembrolizumab 
400 mg every 6 weeks) to the study which 
begins with enrollment of at least 3 patients in a 
safety lead-in.
Update.
4.
Section 2.0 Study Summary
Section 7.0 Study Population
Section 9.3.15.2 Fresh Tumor 
Tissue Biopsy Sample
Appendix A Schedules of Events 
Revised tumor biopsy requirements to include 
second sample on or after Cycle 2 and required 
that the lesion was not previously irradiated or 
designated as the only target lesion for 
measurable disease (phase 2 expansion only). 
Update.
5.
Section 2.0 Study Summary
Section 7.0 Study Population
Revised eligibility criteria to reflect changes in 
study design and disease cohorts permitted to 
enroll in phase 2. 
Update.
6.
Section 2.0 Study Summary
Section 5.1.1 Primary Objective
Appendix A Schedules of Events
Revised primary objective to reflect addition of 
phase 2 treatment and disease types as detailed 
above. 
Update.
7.
Section 2.0 Study Summary
Section 5.1.2 Secondary Objectives
Appendix A Schedules of Events
Revised secondary objectives to reflect addition 
of phase 2 treatment and disease types as 
detailed above and added assessment of 
safety/tolerability of both TAK-573 single agent 
(SA) and in combination with pembrolizumab.
Update.


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Summary of Changes since the Last Approved Protocol
Number
Section(s) Affected by Change
Description
Rationale
8.
Section 5.1.3 
Exploratory/Additional Objectives
Appendix A Schedules of Events
Clarified that electrocardiograms are collected to 
evaluate effect of TAK-573 on QTcF (QT 
interval corrected by the Fridericia method) 
intervals (phase 1b and phase 2 safety lead-in); 
removed reference to prostate cancer; changed 
antitumor effect assessments to be based on 
tumor growth rate rather than immune Response 
Evaluation Criteria in Solid Tumors (iRECIST); 
added characterization of CD38 receptor 
occupancy (RO) in the presence of 
pembrolizumab in patients receiving 
combination treatment, and evaluation of 
correlations with clinical outcome with the 
on-treatment immunophenotype of the tumor 
microenvironment or changes in the 
immunophenotype from baseline for patients in 
phase 2. 
Update.
9.
Section 2.0 Study Summary
Section 5.2.1 Primary Endpoints
Appendix A Schedules of Events
Specified that dose-limiting toxicities (DLTs) 
and patients with treatment-emergent adverse 
events (TEAEs), serious adverse events, and 
TEAEs leading to dose modification or 
treatment discontinuation are endpoints only for 
phase 1b and the phase 2 safety lead-in; added 
overall response rate (ORR) per Response 
Evaluation Criteria in Solid Tumors v1.1 for 
phase 2 expansion patients.
Update.
10.
Section 2.0 Study Summary
Section 5.2.2 Primary Endpoints
Appendix A Schedules of Events
Added maximum tolerated 
dose/pharmacologically active dose if available 
from phase1b; added recommended phase 2 
dose for SA TAK-573 and in combination with 
pembrolizumab; specified pharmacokinetic 
(PK) collection for phase 1b and phase 2 safety 
lead-in; applies ORR to patients in phase 1b 
only; specified that efficacy endpoints of disease 
control rate, duration of response, time to 
progression, and progression-free survival per 
mRECIST v 1.1 apply to patients in both phases 
of study; removed references to prostate cancer 
and RECIST v 1.1. 
Update.
11.
Section 5.2.3 
Additional/Exploratory Endpoints
Appendix A Schedules of Events
Removed reference to prostate cancer patients; 
clarified that evaluation of antitumor effect is 
based on tumor growth rate, not iRECIST; added 
pembrolizumab PK, cellular CD38 RO, and 
immunophenotypic evaluation of tumor and 
tumor microenvironment.
Update.
12.
Section 8.2 Definitions of 
Dose-Limiting Toxicities
Changed DLT definition of Grade 4 neutropenia 
from lasting >5 days to lasting >7 days.
Update.


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Summary of Changes since the Last Approved Protocol
Number
Section(s) Affected by Change
Description
Rationale
13.
Section 8.1 Study Drug 
Administration
Section 8.6.3.2 Pembrolizumab 
Dose Modification Guidelines
Section 8.6.4.2 Criteria for 
Discontinuing Pembrolizumab
Appendix A Schedules of Events
Section 8.13.2 Pembrolizumab
Section 8.15.2 Pembrolizumab
Section 10.2.1.2 Pembrolizumab
Added information about pembrolizumab 
dosing, dose reductions, toxicities, and 
discontinuing pembrolizumab.
Update. 
14.
Section 8.6 Dose Modification 
Guidelines
Appendix A Schedules of Events
Dose modification recommendations for 
TAK-573 toxicities were revised. 
Update.
15.
Section 8.10.1 Infusion-Related 
Reactions
Appendix A Schedules of Events
Expanded and revised information regarding 
management of infusion-related reactions; 
added new Section 8.10.3. 
Update.
16.
Section 8.8.1 Premedication
Appendix A Schedules of Events
Revised recommendations for pre- and 
posttreatment infusion medications.
Update.
17.
Section 9.3.7 Vital Signs
Appendix A Schedules of Events
Added pulse and oxygen saturation to vital 
signs. 
Update.
18.
Section 9.3 Study Procedures
Section 9.3.4 Physical Examination
Section 9.3.13 Clinical Laboratory 
Evaluations
Allowed exceptions for alternative methods for 
conducting patient visits and performing 
laboratory and imaging assessments during the 
COVID-19 public health emergency. 
Update.
19.
Section 2.0 Study Summary
Section 6.2 Number of Patients
Section 13.1 Determination of 
Sample Size
Expected study size is increased to 114 patients. Update.
20.
Appendix A Schedules of Events
The Schedule of Event tables have been revised 
and footnotes consolidated to reflect changes in 
study conduct as detailed above.
Update.
21.
Section 4.3 Known and Potential 
Benefits and Risks
Updated safety information in Section 4.3 per 
most recent safety data cutoff (23 January 2021). 
Update.
22.
Section 9.3.13.3 Immunosafety 
Markers
Appendix A Schedules of Events 
Added immunosafety markers to required 
laboratory tests.
Update.
23.
Section 2.0 Study Summary
Section 7.1 Inclusion Criteria
Added missing glomerular filtration rate cutoff. Correction. 
24.
Section 2.0 Study Summary
Section 13.0 Statistical Methods
Statistical methods were revised to include 
addition of phase 2 portion. 
Update.


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Summary of Changes since the Last Approved Protocol
Number
Section(s) Affected by Change
Description
Rationale
25.
Section 9.3.13 Clinical Laboratory 
Evaluations
Section 9.3.15 PSA was deleted.
Update.
26.
Appendix B PK Sampling Tables
Adjusted PK sampling to align with changes in 
study design. 
Update.
27.
9.3.9 Pregnancy Testing
Appendix A Schedules of Events
Frequency and timing of pregnancy testing was 
updated.
Update
16.9.4
Protocol Amendment 2 Summary of Changes 
The changes in the protocol incorporating Amendment 02 are described below. The primary 
reasons for this amendment were to modify the expansion cohorts, include enrollment and imaging 
assessment criteria for CRPC patients, include information about a new AESI, and add 
corticosteroids to the premedication regimen. Minor grammatical, editorial, and formatting 
changes were included for clarification purposes only.
Changes in Amendment 2
1. Updated clinical safety information.
2. Modified the dose expansion phase to include 8 cohorts with up to 7 patients in each one and 
changed the expected enrollment size.
3. Included additional information about IRRs. 
4. Revised the rationale for the dose expansion cohorts. 
5. Defined the dose expansion phase patient population.
6. Increased the expected number of sites.
7. Added a life expectancy requirement to eligibility criteria.
8. Changed the eGFR calculation to the MDRD or CKD-EPI methods.
9. Included enrollment criteria for CRPC patients.
10. Removed plasmapheresis from the list of permitted concomitant medications and procedures. 
11. Revised the exclusion criterion for prior treatment. 
12. Added an exclusion criterion for persistent toxicity.
13. Clarified criteria for discontinuation of TAK-573.
14. Revised instructions about premedications.
15. Clarified permitted concomitant medications in the Cycle 1 DLT evaluation period in the dose 
escalation phase. 
16. Added detail regarding management of IRRs and recording as an AESI. 


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17. Defined the imaging schedule for non-CRPC and CRPC patients.
18. Added a new section describing IRRs as AESIs. 
19. Added a new section detailing how to report AESIs. 
20. Revised the determination of study size to reflect the change in dose expansion cohorts.
21. Removed text about an interim analysis.
22. Removed “Q3W” from the titles of the SOEs. 
23. Revised SOE to reflect change in disease assessment guidelines.
16.9.5
Protocol Amendment 1 Summary of Changes 
The changes in the protocol incorporating Amendment 01 are described below. The primary 
reasons for this amendment were to clarify requirements for laboratory and clinical tests, revise 
dose modification guidelines, and permit corticosteroids. Minor grammatical, editorial, and 
formatting changes were included for clarification purposes only.
Changes in Amendment 1
1. Removed language permitting administration of corticosteroids. 
2. Patients with castration-resistant prostate cancer (CRPC) without visceral disease are excluded 
from the requirement of fresh biopsy.
3. The window for the use of other investigational products was changed from 30 days to 28 days 
before first dose.
4. Removed the requirement to use a Holter monitor for electrocardiogram (ECG) testing. 
5. Modified the definition of a DLT to include Grade 4 neutropenia lasting >5 days. 
6. Revised dose modification recommendations for Grade 3 and Grade 4 adverse events (AEs). 
7. Clarified that vital signs may be measured in a supine or semirecumbant position. 
8. Removed requirement for antiplatelet antibody testing.
9. Clarified that the laboratory measurement urate can also be measured as uric acid.
10. Added text stating that a separate informed consent form (ICF) will be used to address the 
possibility of pseudoprogression.
11. Clarified that the definition of a serious adverse event (SAE) includes the signs and symptoms 
of progressive disease (PD) but does not include the Preferred Term (PT) of disease 
progression.
12. Added laboratory assessment for blood typing and note for potential blood banks.
13. Limited the number of dose reductions to 2 due to the same AE.
14. Added the measurement of anti–TAK-573 antibody incidence and titer as a secondary 
endpoint.


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15. Modified food intake recommendations to allow some food if necessary. 
16. Clarified action of daratumumab on CD38-expressing (CD38+) immune cells.
17. Clarified that pregnancy tests at end of treatment can be urine or serum tests.
18. Added statement that T-cell measurement will include CD4+ and CD8+ T cells.
19. Removed duplication of laboratory tests.
20. Clarified that the blood sample for circulating tumor cells will be collected only during dose 
expansion.
21. Added contact information for SAE reporting and clarified reporting procedures.
22. Removed needle specifications for tumor biopsies.



SAP_001.pdf: 


 
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-573-1001
An Open-Label, Dose-Escalation Phase 1b/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of Modakafusp Alfa (TAK-573) as a Single 
Agent and in Combination with Pembrolizumab in Adult Patients With Metastatic Solid 
Tumors
PHASE 1b/PHASE 2
Version: Final 3.0
Date: 8 November 2021
Prepared by:
, PhD
, Statistics and Quantitative Sciences
Based on:
Protocol Version: Amendment 4
Protocol Date: 11 August 2021
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.


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Statistical Analysis Plan 
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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Approvers:
 Ph.D.
 (Statistical and Quantitative Sciences), Data Science Institute 




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2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
1.2
Summary of Changes.................................................................................................3
2.0
TABLE OF CONTENTS.................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
STUDY DESIGN AND OBJECTIVES...........................................................................8
4.1
Study Design .............................................................................................................8
4.2
Objectives................................................................................................................10
4.2.1
Primary Objective............................................................................................10
4.2.2
Secondary Objectives ......................................................................................10
4.2.3
Exploratory Objectives ....................................................................................11
5.0
ANALYSIS ENDPOINTS.............................................................................................12
5.1
Primary Endpoints ...................................................................................................12
5.2
Secondary Endpoints ...............................................................................................12
5.3
Exploratory Endpoints .............................................................................................13
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................14
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................15
7.1
MTD Estimation......................................................................................................15
7.2
General Principles....................................................................................................16
7.2.1
Data Presentations ...........................................................................................17
7.2.2
Definition of Study Days .................................................................................17
7.2.3
Methods for Handling Missing Data ................................................................17
7.3
Analysis Sets ...........................................................................................................18
7.4
Disposition of Subjects ............................................................................................18
7.5
Demographic and Other Baseline Characteristics.....................................................18
7.6
Medical History and Concurrent Medical Conditions...............................................19
7.7
Medication History and Concomitant Medications...................................................19
7.8
Study Drug Exposure and Compliance.....................................................................20
7.9
Efficacy Analysis.....................................................................................................21
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................24
7.10.1
Pharmacokinetic Analysis................................................................................24
7.10.2
PK/QTc Analysis.............................................................................................26


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7.10.3
Pharmacodynamic Analysis.............................................................................26
7.11
Other Outcomes.......................................................................................................26
7.11.1
Immunogenicity Analysis ................................................................................26
7.12
Safety Analysis........................................................................................................27
7.12.1
Adverse Events................................................................................................27
7.12.2
Clinical Laboratory Evaluations.......................................................................29
7.12.3
Vital Signs.......................................................................................................30
7.12.4
12-Lead ECGs.................................................................................................30
7.12.5
Other Observations Related to Safety...............................................................31
7.13
..................................................................................31
7.14
Changes in the Statistical Analysis Plan...................................................................32
8.0
REFERENCES..............................................................................................................32
APPENDIX A
BY-SUBJECT LISTINGS ............................................................................33
APPENDIX B
DATE IMPUTATION RULES.....................................................................35
APPENDIX C
DESCRIPTION AND OPERATING CHARACTERISTICS OF THE 
BLRM FOR DOSE ESCALATION ..............................................................................38


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3.0
LIST OF ABBREVIATIONS
Abbreviation
Term
ADA
antidrug antibody
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC∞
area under the serum concentration-time curve from time 0 to infinity
AUClast
area under the serum concentration-time curve from time 0 to time of the last quantifiable 
concentration
AUCt
area under the plasma concentration versus time curve from 0 to time t 
BLRM
Bayesian Logistic Regression Model
C1D1
Cycle 1 Day 1
C2D1
Cycle 2 Day 1
CD38+
CD38-expressing
cfDNA
cell-free DNA
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
Cmax
maximum observed serum concentration
CR
complete response
CRO
contract research organization
CT
computed tomography
DCR
disease control rate
DLT
dose-limiting toxicity 
DOR 
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form 
EOT
end of treatment
EWOC
Escalation with Overdose Control
FDA
[United States] Food and Drug Administration
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
IFN
Interferon
IFN-α
interferon-alpha
IFN-α 2b
interferon-alpha 2b


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Ig
immunoglobulin
IL
Interleukin
iRECIST
immune Response Evaluation Criteria in Solid Tumors
IRR
infusion-related reaction
KD
disassociation constant
MDRD
Modified Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MM
multiple myeloma
mRECIST v1.1
modified (or revised) Response Evaluation Criteria in Solid Tumors, Version 1.1
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PAD
pharmacologically active dose
PD
progressive disease; disease progression
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PT
Preferred Term
QTcF
QT interval with Fridericia correction method
Q3W
Every 3 weeks
Q6W
Every 6 weeks
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RO
receptor occupancy
RP2D
recommended phase 2 dose
SA
single agent
SAE
serious adverse event
SD
stable disease
SOC
standard of care
t1/2z
terminal disposition phase half-life
T4
free thyroxine
TEAE
treatment-emergent adverse event
tmax
time of first occurrence of maximum observed serum modakafusp alfaconcentration
TSH
thyroid-stimulating hormone


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4.0
STUDY DESIGN AND OBJECTIVES
4.1
Study Design
This is an open-label, phase 1b/2 study designed to evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics, and antitumor response of modakafusp alfa as a 
single agent (SA) and in combination with pembrolizumab in patients with advanced or 
metastatic solid tumors. 
The study consists of 2 phases as shown in Figure 4-a.
Figure 4-a Study Schema
Phase 1b Single-Agent Dose Escalation
Phase 1b will enroll patients with advanced/metastatic solid tumors that have no standard 
therapeutic option, are intolerant to those therapies, or have refused them.
The modakafusp alfa SA dose escalation phase is designed to determine the single agent 
recommended phase 2 dose (RP2D) and schedule of modakafusp alfa for further testing. The 
single-agent RP2D may be either the maximum tolerated dose (MTD) based on dose limiting 
toxicities (DLTs) or a pharmacologically active dose (PAD) defined by the 
PK/pharmacodynamic model or exposure-response (ER) analysis in place. 
A minimum of 3 patients will be enrolled in the starting dose cohort of modakafusp alfa 0.1 
mg/kg administered every 3 weeks (Q3W). Doses will be escalated as follows: 0.1, 0.2, 0.4, 0.75, 
1.5, 3 and 6 mg/kg. Patients will be assessed for DLTs until Cycle 2 Day 1 (C2D1) can be 
              PHASE 2 DOSE EXPANSION
        
Modakafusp alfa
+ 
Pembrolizumab 
Safety Lead-in 
Any patient type 
of the expansion 
cohorts (N = 3 to 
9 patients).
Modakafusp alfa+ Pembrolizumab 
Expansion
• Unresectable/metastatic cutaneous melanoma 
with acquired resistance to no more than 2 
prior lines of anti-PD1 containing treatments 
in the metastatic setting (N = 25 patients) 
• Unresectable/metastatic cutaneous melanoma 
with primary resistance to no more than 2 
prior lines of anti-PD1 containing treatments 
in the metastatic setting (N = 25 patients) 
• Unresectable/metastatic cutaneous melanoma 
naïve to prior line of anti-PD1 containing 
treatments in the metastatic setting (N = 25 
i
)
Modakafusp alfa
SA Dose Escalation
Patients with 
advanced/metastatic 
tumors to determine 
RP2D (all comers, 
up to N = 30 
patients).
 PHASE 1b


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Statistical Analysis Plan 
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administered from a safety standpoint. If there are no DLTs in the first cohort of 3 evaluable 
patients dosed at 0.1 mg/kg, Bayesian Logistic Regression Model (BLRM) guided by the 
Escalation with Overdose Control (EWOC) principle will be used in successive dose escalation 
cohorts to estimate the next dose level. 
Phase 2 Dose Expansion
Enrollment into phase 2 expansion in combination with pembrolizumab will be initiated once the 
RP2D of modakafusp alfa single agent has been determined in phase 1b. 
The combination treatment cohorts will begin with a single safety-lead in period to evaluate 
safety and tolerability during the Cycle 1 DLT evaluation period of modakafusp alfa in 
combination with pembrolizumab. If there are no DLTs in the first 3 patients during Cycle 1 of 
the safety lead-in period with modakafusp alfa SA RP2D in combination with pembrolizumab 
400 mg every 6 weeks (Q6W), the combination dose and regimen could be selected for the 3 
disease cohorts described below. If there is 1 DLT in the initial 3 patients in the safety-lead in 
period, an additional 3 patients will be enrolled at the same modakafusp alfa RP2D in 
combination with pembrolizumab 400 mg Q6W. If there are ≥2 DLTs in the first 3 patients at the 
modakafusp alfa SA RP2D, enrollment will resume at the next lower dose level of modakafusp 
alfa RP2D in combination with pembrolizumab. Other approved pembrolizumab dosing 
regimens (e.g., 200 mg Q3W) could be tested in the safety-lead in period if 400 mg Q6W in 
combination with modakafusp alfa at one dose lower than RP2D is intolerable. 
For the safety lead-in period, patient enrollment will be staggered between the first and second 
patients by 7 days. The second and third patients can be dosed concurrently if the first patient in 
the cohort has gone through the Day 8 visit without clinically significant acute toxicities. Patients 
enrolled in the safety lead-in phase could have any of the 3 melanoma disease categories 
described below. 
Following completion of the safety lead-in phase and review of safety data, phase 2 of the study 
will further explore the safety and efficacy of modakafusp alfa treatment in combination with 
pembrolizumab. The combination cohorts, including patients in the safety-lead phase, will enroll 
patients with unresectable/metastatic melanoma in the following subgroups:
I.
Unresectable/metastatic cutaneous melanoma with primary resistance to no more than 2 
prior lines of anti-PD1 containing treatments in the metastatic setting.
II.
Unresectable/metastatic cutaneous melanoma with acquired resistance to no more than 2 
prior lines of anti-PD1 containing treatments in the metastatic setting. 


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III.
Unresectable/metastatic cutaneous melanoma naïve to prior anti-PD1 containing 
treatments in the metastatic setting.
If modakafusp alfa in combination with pembrolizumab is safe and meaningful clinical activity 
is seen, additional expansion cohorts may be added to assess other tumor types. 
4.2
Objectives
4.2.1
Primary Objectives
The primary objective is to determine the safety and tolerability of modakafusp alfa as SA in 
patients with locally advanced or metastatic solid tumors (phase 1b) and in combination with 
pembrolizumab in unresectable/metastatic cutaneous melanoma (phase 2 safety lead-in) and to 
evaluate the efficacy of modakafusp alfa in combination with pembrolizumab in patients with 
unresectable/metastatic cutaneous melanoma (phase 2 expansion). 
4.2.2
Secondary Objectives
The secondary objectives are:

To define the MTD and/or the PAD of modakafusp alfa SA, if applicable (phase 1b). 

To select the RP2D of modakafusp alfa SA (phase 1b) and in combination with 
pembrolizumab (phase 2 safety lead-in).

To evaluate modakafusp alfa PK as a SA (phase 1b) in combination with pembrolizumab 
(phase 2 safety lead-in).

To assess the preliminary antitumor activity of modakafusp alfa as a SA (phase 1b).

To further characterize the antitumor effect of modakafusp alfa in combination with 
pembrolizumab based on immune Response Evaluation Criteria in Solid Tumors (iRECIST) 
in expansion cohort patients (phase 2 expansion)

To evaluate safety and tolerability of modakafusp alfa in combination with pembrolizumab 
(phase 2 expansion).

To characterize the immunogenicity of modakafusp alfa in patients with solid tumors (phase 
1b and phase 2). 


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4.2.3
Exploratory Objectives
The exploratory/additional objectives are:

To assess modakafusp alfa CD38 receptor occupancy (RO) of peripheral immune cells in 
patients treated with modakafusp alfa as a SA (phase 1b) or in combination with 
pembrolizumab (phase 2).

To explore predictive biomarkers of response (phase 1b and phase 2).

To evaluate the effect of modakafusp alfa on QTcF intervals (phase 1b and phase 2 safety 
lead-in).

To evaluate the relationship between administered dose and exposure of modakafusp alfa, 
RO of CD38, and IFN pathway induction as evaluated by gene expression changes and 
production of cytokines/chemokines (phase 1b and phase 2).

To evaluate the relationship between evidence of IFN pathway induction with evidence of 
activation of the innate and/or adaptive immune response as assessed by changes in 
immunophenotype and T-cell antigen receptor (TCR) clonality of peripheral blood and tumor
(phase 1b and phase 2).

To evaluate the relationship between modakafusp alfa exposure and/or CD38 RO with 
immune cell activation (as described above), and clinical response (phase 1b and phase 2).

To evaluate correlations between baseline tumor IFN pathway gene expression with either 
the degree of IFN pathway induction or the level of immune cell activation on treatment
(phase 1b and phase 2).

To characterize germline DNA variants for correlations with clinical outcome, 
pharmacodynamic effects, and PK (phase 1b and phase 2).

To further characterize the antitumor effect of modakafusp alfa based on changes in the 
tumor growth rate between the most immediate pretreatment period and on treatment (phase 
1b and phase 2).

To characterize serum PK of pembrolizumab when administered in combination with 
modakafusp alfa (phase 2).

To assess the Type I interferon (IFN) gene expression signature in peripheral blood (phase 1b 
and phase 2).

To 
evaluate 
correlations 
with 
clinical 
outcome 
with 
either 
the 
on-treatment 
immunophenotype of the tumor microenvironment or changes in the immunophenotype from 
baseline (phase 2).


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The primary endpoints are:

Frequency and severity of treatment-emergent adverse events (TEAE) according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
Version 5.0 (phase 1b and phase 2 safety lead-in).

Number of patients with DLTs (phase 1b and phase 2 safety lead-in).

Number/percentage of patients with 1 or more SAEs (phase 1b and phase 2 safety lead-in).

Number/percentage of patients with 1 or more TEAE leading to dose modification and/or 
treatment discontinuation (phase 1b and phase 2 safety lead-in).

Overall response rate (ORR) (complete response [CR] + partial response [PR]) assessed 
according to modified Response Evaluation Criteria in Solid Tumors, Version 1.1 (mRECIST 
v1.1) for melanoma patients (phase 2 expansion).
5.2
Secondary Endpoints
The secondary endpoints are:

MTD or PAD (as defined in Section 6.1.1 of Protocol Amendment 4), if available (phase 1b).

RP2D for SA and in combination with pembrolizumab, respectively (phase 1b and phase 2 
safety lead-in).

Frequency and severity of TEAEs according to the NCI CTCAE v.5 (phase 2 expansion).

Number/percentage of patients with 1 or more SAEs (phase 2 expansion).

Number/percentage of patients with 1 or more TEAE leading to dose modification and/or 
treatment discontinuation (phase 2 expansion).

PK parameters after the first dose of modakafusp alfa on Cycle 1 Day 1 (C1D1) and on Cycle 
2 Day 1 (C2D1) for dose escalation phase (phase 1b) and on Cycle 1 Day 1 (C1D1) and 
Cycle 3 Day 1 (C3D1) for the phase 2 safety lead-in phase of dose expansion, including but 
not limited to:
–
Maximum observed concentration (Cmax).
–
Time of first occurrence of Cmax (tmax).
–
Area under the plasma concentration versus time curve from time 0 to time t (AUCt).
–
Area under the concentration-time curve from time 0 to infinity (AUC∞).
–
Terminal disposition phase half-life (t1/2z).
–
Clearance.


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–
Volume of distribution at steady state (Vss).

Overall response rate (ORR) (complete response [CR] + partial response [PR]) assessed 
according to the mRECIST v1.1 for patients in dose escalation (phase 1b).

Disease control rate (DCR) (CR + PR + stable disease [SD]) (phase 1b and phase 2).

Duration of response (DOR) (phase 1b and phase 2).

Time to progression (TTP) (phase 1b and phase 2).

Progression-free survival (PFS) assessed according to mRECIST v1.1 (phase 1b and phase 
2).

Overall survival (OS) (phase 1b and phase 2). 

Efficacy measures of ORR, DCR, DOR, TTP, and PFS based on iRECIST (phase 2 
expansion)

Anti–modakafusp alfa antibody incidence and titer (phase 1b and phase 2).
Definitions and timeframes of primary and secondary endpoints are provided in protocol Section
6.3.3.
5.3
Exploratory Endpoints
The exploratory endpoints are:

Tumor mutations characterized from cell-free DNA (cfDNA) and quantification of 
circulating tumor cells (CTCs) will be evaluated at baseline and assessed for correlations 
with clinical response. 

Genomic and protein expression of baseline tumor tissue

Germline mutations and polymorphisms as assessed by whole exome sequencing of 
peripheral blood

Change of QTcF interval using data from PK time matched triplicated electrocardiogram 
(ECG) readings.

Induction of modakafusp alfa–induced gene expression changes, including type I IFN 
signature, assessed in peripheral blood and tumor.

Fold-change in plasma levels of IP-10 and other cytokines/chemokines.

Immune cell activation as assessed in peripheral blood and tumor by: (a) immunophenotypic 
changes and (b) evaluation of TCR diversity.

Modakafusp alfa antitumor effect size based on observed change in tumor growth rate using 
prescreening, screening, and on-treatment diagnostic imaging, as available.

Serum PK of pembrolizumab when administered in combination with modakafusp alfa.


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
Cellular CD38 RO of peripheral blood assessed at time points surrounding the first and 
second modakafusp alfa SA administrations (phase 1b) and at time points surrounding the 
first and third modakafusp alfa administrations when in combination with pembrolizumab
(phase 2).

Modakafusp alfa-induced Type I IFN gene expression signature in the peripheral blood 
(phase 1b and phase 2).

Immunophenotypic evaluations of the tumor and tumor microenvironment utilizing
multiplexed immunohistochemistry or similar methodologies.
6.0
DETERMINATION OF SAMPLE SIZE
Phase 1 Dose escalation
It is expected to enroll approximately 30 patients. A minimum of 3 patients will be enrolled in 
the starting dose level. Starting from the second dose level, an adaptive Bayesian Logistic 
Regression Model (BLRM) guided by the Escalation With Over-Dose Control (EWOC)
principle will be used for all subsequent dose escalation recommendations.
Phase 2 Dose expansion
The study will enroll up to 25 patients in each phase 2 dose expansion disease subgroup. A 
Bayesian predictive probability design will be used to allow multiple futility analyses to stop 
early for futility. Enrollment into phase 2 will be initiated once the RP2D of modakafusp alfa has 
been determined in phase 1b of the study.
The combination treatment cohorts will begin with a single safety-lead in period during which 
3 to 9 patients will be evaluated for safety and tolerability during their first cycle of modakafusp 
alfa with pembrolizumab. 
Up to 25 patients will be enrolled in each of the 3 disease subgroup cohorts. Assuming 3 to 9 
safety lead-in patients, the total sample size for phase 2 can be up to 84 patients. 
 
 
 
 
 
 
 
 


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
MTD Estimation
The 2-parameter BLRM implementing the EWOC principle (Babb et. al. 1997, Neuenschwander
et. al. 2008) will be used to inform dose escalation decisions and MTD estimation starting from 
the second dose cohort. The final decision on next dose level will be taken jointly by the sponsor 
and the participating investigators. 
BLRM with overdose control (Appendix C) will be used to inform dose escalation decisions and 
MTD estimation, along with consideration of other emerging safety, clinical, PK, and 
pharmacodynamic data.
More conservative dose escalation, evaluation of intermediate doses, and expansion of an 
existing dose level are all permissible following discussions between the sponsor and the 
investigators, if such measures are needed for patient safety or for a better understanding of the 
dose-related toxicity, exposure, or pharmacodynamics. The initial size of each cohort will be 
approximately 3 evaluable patients.
Initially, 3 patients will be enrolled at the 0.1 mg/kg starting dose level. The following rules will
be used only for this initial cohort:

If none of the 3 patients experiences a DLT during the first cycle, the dose may be escalated 
to the next planned dose level.

If 1 of the 3 patients exhibits a DLT, then the cohort will be expanded from 3 patients to a 
total of 6 patients.
–
If no more than 1 patient out of the 6 total patients has a Cycle 1 DLT, 3 patients will be 
enrolled at the next dose level.
–
If 2 of the 6 patients have a Cycle 1 DLT, 3 additional patients will be enrolled. If any of 
the 3 additional patients have a Cycle 1 DLT, the starting dose will be considered not 
tolerated and the dose will be de-escalated to 0.05 mg/kg. If none of the 3 additional 
patients have a Cycle 1 DLT, the starting dose may be considered the MTD or may be 
escalated to the next dose level, after consideration of other available safety, clinical, PK, 
and pharmacodynamic data.


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–
If 3 or more of the 6 patients experience a Cycle 1 DLT, the starting dose level will be 
considered not tolerated and the dose will be de-escalated 0.05 mg/kg following review 
of all available safety data and approval of the sponsor.

If 2 or more of the 3 patients experience a DLT, then the starting dose level will be 
considered too toxic and the dose will be de-escalated to 0.05 mg/kg.
Starting from the second dose level, the BLRM with overdose control will be used for all 
subsequent dose escalation recommendations. The BLRM recommended dose at the end of each 
dosing cohort will be that which has the highest posterior probability of having a DLT rate that is 
≥0.16 and ≤0.33. Following the EWOC principle, the posterior probability of the recommended 
dose having a DLT rate above 0.33 must not exceed 35%. Escalation will continue until one of 
the following stopping rules is met before reaching the maximum number of patients:

At least 6 patients are enrolled at the current dose, the current dose is the BLRM 
recommended dose for the next group of patients, and the observed DLT rate is ≤33%, OR

If the next recommended dose is a tested dose and has already enrolled 9 patients, the 
BLRM posterior probability of the next recommended dose having a DLT rate that falls into 
the interval [0.16, 0.33) exceeds 50%, and the observed DLT rate is ≤33%. 
Once either of the above rules has been met, MTD may be declared. Alternative stopping rules 
may also be considered following discussions between the sponsor and the investigators. 
The description and operating characteristics of the BLRM for dose escalation are included in 
Appendix C.
Posterior probability of under-toxicity [0,0.16), target toxicity [0.16,0.13), and over-toxicity 
[0.33,1] will be summarized in the CSR based on all the data in the dose escalation phase for 
patients in DLT-evaluable set.
7.2
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4 (SAS Institute, Cary, NC).
For categorical variables, the count and proportions of each possible category value will be 
tabulated. The denominator for the proportion will be based on the number of subjects in the 
analysis sets. For continuous variables, the mean, median, SD, minimum, and maximum values 
will be presented for all patients in the relevant analysis set. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Minimum and maximum are presented using the same number of decimal places as the recorded 
data. Confidence intervals about a parameter estimate will be presented using the same number 
of decimal places as the parameter estimate.


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All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided. 
P-values should be presented to 3 decimal places, with values less than 0.001 presented as 
<0.001.
Baseline values are defined as the last observed value before the first dose of the study drug.
The summary tables will include escalation cohorts, overall for dose escalation phase, safety 
lead-in cohort in expansion phase, and by expansion cohorts and overall for expansion phase and 
overall for both phases as appropriate.  
7.2.1
Data Presentations
Modakafusp alfa Single Agent Dose Escalation: by dose level 
Dose Level 1
Dose Level 2
Dose Level 3
Continue for 
each dose level
Total escalation
Modakafusp alfa + Pembrolizumab Safety Lead-in: by dose level
Safety Lead-in 
Dose Level 1
Safety Lead-in 
Dose Level 2
Continue for 
each dose level
Total Safety 
Lead-in
Modakafusp alfa + Pembrolizumab Dose Expansion: by cohort
Cohort I 
(Primary 
Resistance)
Cohort II 
(Acquired 
resistance)
Cohort III 
(Naïve to Prior 
Anti-PD1)
Total expansion
Total: total escalation, total safety lead-in, total expansion, total population
Total escalation
Total safety 
lead-in
Total expansion
Total
7.2.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the study 
drug (excluding test dose if any). Other study days are defined relative to the study Day 1 and the 
study Day -1 (the day prior to Study Day 1).
7.2.3
Methods for Handling Missing Data
For efficacy and safety data, no imputation of values for missing data will be performed. 
Imputation rules for incomplete dates are described in Appendix B.


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7.3
Analysis Sets

Safety Analysis Set: The safety analysis set will include all enrolled patients who received at 
least one dose (even incomplete) of the study drug. 

Response evaluable Analysis set: The response evaluable analysis set is a subset of the safety 
analysis set including patients with measurable disease at baseline and at least 1 post-
treatment evaluation.

DLT Evaluable Analysis Set: patients who receive all Cycle 1 doses of modakafusp alfa or 
experience a DLT in Cycle 1 in the dose-escalation portion of the study; or patients who or 
receive all Cycle 1 doses of modakafusp alfa in combination with pembrolizumab or 
experience a DLT in Cycle 1 in the safety lead-in portion of the study. 

Pharmacokinetic Analysis Set: patients from the safety analysis set who have sufficient data 
to calculate at least 1 PK parameter for modakafusp alfa.

Immunogenicity-evaluable Analysis Set: Includes patients with a baseline and at least one 
post-baseline immunogenicity assessment.
7.4
Disposition of Subjects
Study information, including the date first subject signed ICF, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint, 
MedDRA Version, WHO Drug Version, and SAS Version is presented. For screen failure 
patients, who signed informed consent and were not treated in the study, demographics and the 
reasons for screen failures will be generated in a summary table. 
The disposition includes the number and percentage of patients in the following categories:
patients in each of the study populations, primary reason off treatment, ongoing (if applicable at 
the time of database lock/data cut-off), participating in PFS follow-up, and the primary reason 
discontinued from the study. This information will be presented by safety analysis set. 
7.5
Demographic and Other Baseline Characteristics
All demographics and baseline characteristics will be summarized by safety analysis set. 
Demographics
Demographic data to be evaluated will include age, sex, race, ethnicity, height, and weight.
Disease characteristics:

Type of cancer

Years since initial diagnosis [ (date of the first dose – date of the diagnosis) / 365.25)].

Anatomic stage


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
Number of sites of cancer involvement

Eastern Cooperative Oncology Group (ECOG) performance status.
Prior therapy

Prior radiation.

Prior surgery/procedure.

Prior systemic anti-cancer therapy.

Lines of prior therapy (descriptive statistics and categorical summary: 0, 1, 2, 3, 4, 5, 6, >6).

Lines of prior therapy initiated within 12 months of the first dose of the study drug
(categorical summary).

Last line of prior therapy

Best response at the last line of therapy
7.6
Medical History and Concurrent Medical Conditions
Medical history and concurrent medical conditions will be coded using the latest MedDRA 
dictionary. Concurrent medical conditions are the ones ongoing or started on or after the day 
inform consent was signed. Medical history and concurrent medical conditions will be 
summarized separately by safety analysis set. Medical history and concurrent medical conditions 
will be listed together along with a flag about whether the medical condition is concurrent or not.
If both start date and stop date are missing, medical condition will be assumed to start before 
inform consent and continue after treatment discontinuation. If only start date is missing, then 
medical condition will be assumed to start before inform consent. If stop date is missing, then 
medical condition will be assumed to continue after treatment discontinuation.
7.7
Medication History and Concomitant Medications
Medication history and Concomitant medications will be coded using the latest World Health 
Organization (WHO) Drug Dictionary. Concomitant medication is defined as the medication 
ongoing or started on or after the first dose date of the study drug through 30 days after the last 
dose of the study drug, or the start of subsequent anti-cancer therapy, whichever occurs first. The 
number and percentage of patients taking concomitant medications will be tabulated by WHO 
standardized medication name. Medication history will also be summarized. Medication history 
and concomitant medication will be listed together with the following flags:
1. Discontinued before the first dose date of the study drug.
2. Started on or after dosing.


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3. Started after 30 days after the last dose of the study drug, or the start of subsequent anti-
cancer therapy, whichever occurs first.
If both start date and stop date are missing, medication will be assumed to start before the first 
dose date of the study drug and continue after treatment discontinuation. If only start date is 
missing, then medication will be assumed to start before the first dose date of the study drug. If 
only stop date is missing, then medication will be assumed to continue after treatment 
discontinuation.
7.8
Study Drug Exposure and Compliance
Extent of Exposure
The exposure to study drugs (modakafusp alfa and Pembrolizumab) will be characterized by 
summaries and descriptive statistics of duration of treatment in weeks, number of treated cycles 
(1, 2, 3, 4, 5, 6, 7-12, >12 and summary statistics), and relative dose intensity will be 
summarized by safety analysis set. 
A treated cycle is defined as a cycle in which any amount of the study drug for at least one of the 
dosing days in the cycle is given. 
Cumulative dose (mg/kg): sum of all doses of the study drug administered to a subject during the 
treatment period.
Relative dose intensity = (actual dose per week / planned dose per week) × 100. The actual dose 
per week adjusts for delays in the start of a cycle and assumes the last cycle is fixed at the 
intended duration.

Date of last exposure of the study drug=min(date of last dose of the study drug + treatment 
interval-1,  date of death, start date of the subsequent treatment-1). This algorithm may be 
adjusted as appropriate by consulting the study clinician. 
Actual dose per week and planned dose per week are calculated as follows:

Actual dose per week: cumulative dose of the study drug in mg/kg / [(date of the last
exposure of the study drug – date of the first dose+1) /7].

Planned dose per week: starting dose of study drug (mg/kg) on C1D1 / treatment interval in
weeks.
Action on Study Drug
The reason for dose modification (increased, reduced, interrupted, withdrawn, delayed, drug 
infusion interrupted, infusion rate increased, infusion rate reduced) of the study drug will be 
summarized by cycle for the safety analysis set.


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7.9
Efficacy Analysis
Response will be assessed according to mRECIST 1.1 for all patients. Response will also be 
assessed according to iRECIST for patients in Phase 2 expansion cohort.
Best Overall Response (BOR)
Best overall response is defined as the best response (per investigator assessment as defined by 
mRECIST 1.1 or iRECIST Criteria) recorded after the first dose of the study drug until a 
subsequent anti-cancer therapy. Response assessments after treatment discontinuation but before 
the initiation of a subsequent anti-cancer therapy should be included in the analysis of BOR. This 
will be ordered from best to worst: Complete Response (CR or iCR), Partial Response (PR or 
iPR), Stable Disease (SD or iSD), Progressive Disease (PD, iUPD or iCPD), Not Evaluable (NE
or iNE).
Waterfall plots for best percentage change in the size of target lesions as per mRECIST 1.1 
criteria will also be presented. The plot will have the following information:
1. Response,
2. Dose,
3. Cohort
4. Phase (escalation, safety lead-in or expansion).
Best overall response will be summarized and listed for all patients in the response evaluable 
analysis set. Overall response will be listed for all patients in the response evaluable set for each 
visit along with percentage change in the size of target lesions per mRECIST 1.1 criteria. If 
target lesion is believed to be present but too small to measure, a value of 5 mm is assigned per 
mRECIST 1.1.
Overall Response Rate (ORR)
The ORR is defined as the proportion of patients who have achieved the best response of CR or 
PR during the study per investigator assessment as defined by mRECIST 1.1 or iRECIST 
Criteria. The ORR will be summarized by frequencies and percentages for patients in the 
response evaluable analysis set. A binomial exact confidence interval will also be provided when 
possible.
Disease Control Rate (DCR)


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The DCR is defined as the proportion of patients who have achieved the best response of CR, PR 
or SD during the study per investigator assessment as defined by mRECIST 1.1 or iRECIST 
Criteria. The DCR will be summarized by frequencies and percentages for patients in the 
response evaluable analysis set. A binomial exact confidence interval will also be provided when 
possible.
Duration of Response (DOR)
The DOR will be tabulated for those patients with a CR or PR during the study per investigator 
assessment as defined by mRECIST 1.1 or iRECIST Criteria in the response evaluable analysis 
set with a reasonable number of responses. The DOR is defined as the number of days from the 
first documentation of a response until progressive disease or death, whichever occurs first. If a 
patient misses two consecutive disease assessments, then follow-up for the primary endpoint will 
be censored at the time of last non-progressive scan prior to the missed interval. 
The censoring rules and censoring date in the analysis of DOR will be the same as for PFS and 
TTP.
DOR (months) = (date of progression or death or censor – date of confirmed response + 
1)/30.4375.
The Kaplan-Meier method will be used to estimate the distribution of DOR. The 25th, 50th 
(median), and 75th percentiles, and the corresponding 2-sided 95% confidence intervals (CIs) 
based on Brookmeyer and Crowley method (Brookmeyer and Crowley 1982), will be presented. 
The number of patients with events and the number of patients censored will be summarized.
DOR for all patients with a response will be listed.
Progression Free Survival (PFS) 
PFS is defined as the time from the date of first dose to the date of PD (or iCPD) (per 
investigator assessment as defined by mRECIST 1.1 or iRECIST Criteria) or the date of death 
due to any cause, whichever occurs first. Patients without documentation of PD (or iCPD) or 
death will be censored at the date of the last response assessment that is SD (iSD) or better, and
prior to or on the date of initiation of alternative anti-cancer therapy if patients start new 
treatments. Patients with no post baseline response assessment will be censored on day 1.
PFS (months) = (earliest date of progression or death or censor – date of first dose + 1)/30.4375.
The analysis of PFS will be based on the safety analysis set with a reasonable number of patients. 
The Kaplan-Meier method will be used to estimate the distribution of PFS. Kaplan-Meier 
survival curves, the 25th, 50th (median), and 75th percentiles, along with associated 2-sided 95% 
confidence intervals (CIs) based on Brookmeyer and Crowley method, and Kaplan-Meier PFS 


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probability estimates with 95% CIs at 3 and 6 months (or later time points if data permits) will be 
presented. The number of patients with events along with the type of events (death or progressive 
disease) and the number of patients censored will be summarized.
PFS for all patients in the safety analysis set will be listed.
Overall Survival (OS)
Overall survival in months is defined as the time from the date of first dose to the date of death 
of any cause [OS (months) = (date of death or censor – date of first dose + 1)/30.4375)]. Patients 
without documentation of death at the time of analysis will be censored at the date last known to 
be alive.
The analysis of OS will be based on the safety analysis set with a reasonable number of patients. 
The Kaplan-Meier method will be used to analyze the distribution of OS. Kaplan-Meier survival 
curves, the 25th, 50th (median), and 75th percentiles, along with associated 2-sided 95% 
confidence intervals (CIs) based on Brookmeyer and Crowley method, and Kaplan-Meier 
estimates with 95% CIs at 6 and 12 months (or later time points if data permits) will be 
presented. The number of patients with events and the number of patients censored will be 
summarized.
OS for all patients in the safety analysis set will be listed.
Time to Progression (TTP)
Time to progression is defined as the time from first dose to the date of first documentation of 
objective progression. Patients without documentation of PD (iCPD) will be censored at the date 
of the last response assessment that is SD or better prior to the date of initiation of alternative 
anti-cancer therapy. Patients with no post baseline response assessment will be censored on day 
1.
TTP (months)= (date of progression or censor – date of first dose + 1)/30.4375).
The Kaplan-Meier method will be used to estimate the distribution of TTP with a reasonable 
number of patients in the response evaluable set. Kaplan-Meier curves, the 25th, 50th (median), 
and 75th percentiles, along with associated 2-sided 95% confidence intervals (CIs) based on 
Brookmeyer and Crowley, and Kaplan-Meier estimates with 95% CIs at 3 and 6 months (or later 
time points if data permits) will be presented. The number of patients with events and the 
number of patients censored will be summarized.


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7.10
Pharmacokinetic/Pharmacodynamic Analysis
7.10.1
Pharmacokinetic Analysis
7.10.1.1
Serum modakafusp alfa Concentrations
Blood samples will be collected at prespecified time points as described in the study protocol for 
the measurement of serum modakafusp alfa concentrations. Individual serum concentration data 
will be listed by patient, dose level, study day, and sampling time. Both nominal (scheduled) and 
actual sampling times will be presented in the listings.
Serum modakafusp alfa concentrations will be summarized by nominal time post dose, grouped 
by dose level, and study day by phases (escalation and expansion). Summary statistics will be 
reported at nominal sampling times with at least 2 patients in the PK evaluable population; 
means will be reported if the number of observations above the lower limit of quantitation 
(NALQ) is ≥50% of the number of patients. The summary statistics will consist of: N, NALQ, 
arithmetic mean, standard deviation (SD), coefficient of variation (CV), geometric mean, CV of 
geometric mean, median, min, and max. Arithmetic mean, geometric mean, median, min, and 
max will be reported on at least 2 non-missing values, while the SD and CV will be reported on 
at least 3 non-missing values. modakafusp alfa concentrations that are below the limit of 
quantitation (BLQ) will be set to zero for calculation of summary statistics, except for geometric 
means, where BLQ values will be considered missing.
Concentration data that are considered anomalous may be excluded from the concentration 
summaries and plots. Evidence or explanations will be provided in the clinical study report to 
justify the exclusion of concentration data.
Mean and individual serum modakafusp alfa concentration data will be plotted over nominal 
sampling time, grouped by dose level, and study day on both linear and semi-logarithmic scales. 
BLQ values will be plotted as zero on a linear scale and treated as missing on a semi-logarithmic 
scale.
7.10.1.2
Serum PK Parameters
The serum PK concentration-time course data will be used to calculate standard PK parameters 
using noncompartmental methods with Phoenix WinNonlin. 
Actual sampling times will be used for the calculation of PK parameters. In the event that actual 
collection times are either unreliable or missing, nominal collection times will be used. For the 
calculation of PK parameters, serum concentrations of modakafusp alfa that are BLQ will be 
treated as zero prior to tmax, missing between tmax and the time of the last measurable 
concentration, and the concentration-time curve will be considered to have terminated at the time 


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of the last measurable concentration. If measurable concentrations are near the lower limit of 
quantification (LLOQ) or imbedded between BLQ concentrations, these values may be excluded 
at the discretion of the Clinical Pharmacologist. Concentration data that are considered 
anomalous may not be used in the calculation of PK parameters; evidence or explanations will be 
provided in the clinical study report to justify the exclusion of data.
The PK parameters including but not limited to the parameters listed below will be determined, 
as permitted by data:

Cmax.

tmax.

AUC∞.

AUClast.

λz.

t1/2z.

CL.

Vss.

Accumulation ratio based on AUCτ. 
Individual PK parameters will be presented in listings PK parameters, and will be summarized 
and grouped by dose level, and study day for patients in the Cycle 1 Day 1 (C1D1) and on Cycle 
2 Day1 (C2D1) for dose escalation phase (phase 1b) and on Cycle 1 Day 1 (C1D1) and Cycle 3 
Day 1 (C3D1) for the phase 2 safety lead-in phase of dose expansion. Arithmetic mean, 
geometric mean, median, min, and max will be reported on at least 2 non-missing values, while 
the SD and CV will be reported on at least 3 non-missing values. Except for tmax, the summary 
statistics will consist of: N, mean, SD, CV, geometric mean, CV of geometric mean, median, 
min, and max. The summary statistics for tmax will consist of: N, median, min, and max.
In addition, box plots will be generated for Cmax versus dose and AUC versus dose for Cycle 1 
Day 1 (C1D1) and Cycle 2 Day 1 (C2D1) for dose escalation phase (phase 1b) and Cycle 1 Day 
1 (C1D1) and Cycle 3 Day 1 (C3D1) for the phase 2 safety lead-in phase of dose expansion. 
Dose proportionality of the PK of TAK-573 will be evaluated by visual inspection of plots of 
individual PK parameter values versus dose. If data permit, regression analysis using a power 
model will also be used to assess dose proportionality.
The PK data collected in this study are intended to contribute to future population PK analyses of 
modakafusp alfa. These population PK analyses may include data collected in other modakafusp 
alfa clinical studies. The analysis plan for the population PK analysis will be separately defined, 
and the results of these analyses will not be reported in the clinical study report.


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7.10.2 PK/QTc Analysis
The PK-time matched triplicate ECG data collected in each patient during the dose escalation 
phase will be pooled to understand the PK-QTc interval relationship of modakafusp alfa. The 
relationship between modakafusp alfa serum concentration and effects on heart rate and QTcF 
interval will be analyzed using proper modeling. These population PK-QTc interval analyses 
may include data collected in other modakafusp alfa clinical studies. As such, the analysis plan 
for the population PK-QTc interval analysis will be separately defined, and the results of these 
analyses will be reported separately and not presented in the clinical study report for this study.
7.10.3
Pharmacodynamic Analysis
During the clinical development of modakafusp alfa, several biomarkers will be assessed to test 
for their correlation with safety and efficacy, if possible. Markers that will be studied are markers 
linked either to the drug itself or to the treated disease. 
Attempts will be made to evaluate potential relationships between both modakafusp alfa dose 
and modakafusp alfa serum exposure versus safety and efficacy data. These analyses will be 
exploratory in nature.
A pharmacodynamic analysis will be included in CSR only if there is a trend.
7.11
Other Outcomes
7.11.1
Immunogenicity Analysis
The immunogenicity of modakafusp alfa will be assessed by determining anti–modakafusp alfa
antibody incidence and characteristics (e.g., titer and specificity). All ADA data will be listed. 
For patients in the immunogenicity evaluable analysis set, percent of patients with positive ADA 
at each timepoint, as well as percent of patients with positive ADA by domain specific assay and 
ADA titers, will be summarized by dose levels by study phases (escalation and expansion). 
Percent of patients with positive ADA at baseline and at any post-baseline time point during the 
study will be reported. Additional summary tables and figures may be generated to assess the 
impact of anti–modakafusp alfa antibodies on the pharmacokinetic profile, drug efficacy, 
pharmacodynamic profile, and clinical safety will be evaluated, if possible. These analyses will 
be exploratory in nature and may be included in CSR if there is a trend.


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7.12
Safety Analysis
7.12.1
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0 or later (based on version at time of database lock). Treatment-emergent is defined 
as any AE that occurs on or after the date of the first dose of any study treatment through 30 days 
after the last dose of any study treatment. 
Treatment-emergent AEs will be summarized by MedDRA system organ class (SOC), and 
preferred term. For summary tabulations the following hematologic abnormalities coded to 
MedDRA preferred terms in the Investigations SOC will be pooled with the appropriate clinical 
terms in the blood and lymphatic system disorders SOC:
MedDRA Preferred Term 
(Investigation SOC)
Mapped to 
(Blood and lymphatic system disorders SOC)
Neutrophil count decreased
Neutropenia
Platelet count decreased
Thrombocytopenia
Hemoglobin decreased
Anemia
While blood cell count decreased
Leukopenia
Treatment-emergent AEs will also be summarized by the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Summary tabulations will include the following categories: 

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs.

Grade 3 or higher drug-related treatment-emergent AEs.

Grade 3 and Grade 4 TEAEs (based on maximum severity).

Grade 3 and Grade 4 drug-related TEAEs (based on maximum severity).

The most commonly reported treatment-emergent AEs (i.e., those events reported by >= 10% 
of all patients in each phase or overall population as appropriate).

Serious treatment-emergent AEs.

Drug-related serious treatment-emergent AEs.

Treatment-emergent AEs resulting in discontinuation of study drug.

Treatment-emergent AEs resulting in study drug modifications (including discontinuation, 
delay, reduction, and interruption).


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
Treatment-emergent AEs resulting in dose delays.

Treatment-emergent AEs resulting in dose reductions.

Treatment-emergent AEs resulting in dose interruptions.

TEAEs leading to death

Treatment emergent AESI – all grades

Treatment emergent AESI grade 3 and above

Treatment emergent AESI grade 3 or 4

Treatment-emergent AEs resulting in infusion rate reductions.

Treatment-emergent AEs resulting in infusion interruptions.

Serious treatment emergent AESI 
All summaries will be by dose levels by phases (escalation, safety lead-in, and expansion) for 
patients in the safety analysis set. 
Patients with the same AE more than once will have that event counted only once within each 
body system, and once within each preferred term. Patients with the same AE more than once 
will have the maximum intensity of that event counted once within each body system, and once 
within each preferred term.
Most commonly reported (at least 10% of all patients in each phase or overall population as 
appropriate) treatment-emergent AEs will be presented by preferred term only. Patients with the 
same AE more than once will have that event counted only once within each preferred term.
An overall summary TEAE table will include numbers and percentages of patients who had any 
TEAE, and qualified TEAEs: drug-related AE, not drug-related AE, grade 3 or higher TEAE, 
grade 3 or higher drug-related AE, serious AE (SAE), drug-related SAE, not drug-related SAE, 
SAEs leading to study drug discontinuation, AEs resulting in study drug discontinuation, and on-
study deaths. On-study death is defined as deaths that occur between the first dose of study drug 
and up to 30 days after the last dose of study drug and deaths assessed related to study drug that 
occur 30 days after the last dose of study drug. 
Most frequent, >5% of all patients in each phase or overall population as appropriate, non-
serious TEAE will be presented by system organ class and preferred terms for clinical trial 
disclosure.
A by-patient listing of DLTs that occur during Cycle 1 of treatment will be presented by dose 
levels for all patients in the DLT evaluable set. Patients will be grouped by the dose level to 
which they were originally assigned, including those who receive subsequent treatment at a 
lower or higher dose level. 


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A by-patient listing of all deaths regardless of whether on study or not will also be presented. In 
this listing, on-study deaths will be flagged.
Adverse Events of Special Interest (AESI)
For modakafusp alfa, infusion-related reactions (IRRs) are designated as AESIs. 
For pembrolizumab, the following AEs are considered AESIs:

Pneumonitis.

Hepatitis.

Colitis.

Nephritis.

Dermatologic reactions.

Myocarditis.

IRR.

Endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes 
mellitus, and hypophysitis. 
7.12.2
Clinical Laboratory Evaluations
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a non-numeric qualifier (eg, less 
than (<) a certain value, or greater than (>) a certain value), the given numeric value will be used 
in the summary statistics, ignoring the non-numeric qualifier. 
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used. Laboratory test results will be summarized according to the scheduled 
sample collection time point. Change from baseline will be presented. Scheduled laboratory 
along with unscheduled lab test results will be listed.
Lab parameters to be analyzed are as follows:

Hematology: hemoglobin, hematocrit, activated partial thromboplastin time (aPTT), platelet 
count, white blood cell (WBC) count, WBC differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), prothrombin time (PT)

Chemistry: albumin, alanine aminotransferase (ALT), alkaline phosphatase, aspartate 
aminotransferase (AST), bilirubin (total), blood urea nitrogen, calcium, chloride, creatinine,
glucose (non-fasting), HCO3 or CO2, LDH, phosphate, potassium, sodium, standard C-
reactive protein, urate or uric acid


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
Urinalysis: protein, glucose, nitrite, occult blood, specific gravity, pH, bilirubin, ketones,
turbidity and color, leukocytes, urobilinogen

Immunosafety markers: thyroid-stimulating hormone (TSH), free thyroxine (T4), cortisol 
(morning preferred)
If GFR is to be estimated, the MDRD or CKD-EPI equations shall be used. References are 
specified in Section 9.3.13.1 of Protocol Amendment 3.
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
version 5.0 or higher. Shift tables from baseline to the worst values will be constructed for 
laboratory parameters. Individual platelet and absolute neutrophil count (ANC) profiles will be 
generated for each dose level. Mean values over time for platelets and ANC will be produced for 
each phase as appropriate.
7.12.3
Vital Signs
Descriptive statistics for vital sign results (diastolic and systolic blood pressure, heart rate, pulse 
rate and body weight) will be summarized as follows:

Baseline value (C1D1 or screening if C1D1 is not available).

Minimum post-baseline value.

Change to Minimum post-baseline value.

Maximum post-baseline value.

Change to Maximum post-baseline value.
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value.
For blood pressure values collected during the infusion (every 30 minutes), the number and 
percentage of patients with changes from pre-infusion blood pressure values will be summarized 
in the following categories:

Increase of diastolic blood pressure of at least 10 mm Hg during any infusion.

Decrease of diastolic blood pressure of at least 10 mm Hg during any infusion.

Increase of systolic blood pressure of at least 20 mm Hg during any infusion.

Decrease of systolic blood pressure of at least 20 mm Hg during any infusion.
7.12.4
12-Lead ECGs
ECG data (ventricular rate, RR interval, PR interval, QT interval, and QTcF interval) will be 
summarized as follows:


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
Baseline value (C1D1 or screening if C1D1 is not available).

Minimum post-baseline value.

Change to Minimum post-baseline value.

Maximum post-baseline value.

Change to Maximum post-baseline value.
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value.
In addition, a categorical analysis of QTcF intervals will be performed for each time point. The 
number and percentage of patients in each QTcF interval (<450 msec, 450-480 msec, >480-
<500 msec, and ≥500msec) will be summarized at baseline and each of the subsequent time 
points. Categories of changes from baseline (≥30 msec and ≥60 msec) will be summarized as 
well.
7.12.5
Other Observations Related to Safety
Shifts from baseline to the worst post-baseline ECOG score will be tabulated. 
7.13
 
 
 
 
 
 
 
 
 
 
Table 7.2 


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7.14
Changes in the Statistical Analysis Plan
See Section 1.2 for summary of changes.
8.0
REFERENCES
1. Babb J, Rogatko A, Zacks S (1998), “Cancer phase I clinical trials: efficient dose 
escalation with overdose control”, Statistics in Medicine,17(10):1103-20.
2. Brookmeyer R, Crowley J (1982), “A confidence interval for median survival time”, 
Biometrics, Vol 38(1):29-41
3. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al (2009),
“New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1)”, Eur J Cancer, 45(2):228-47.
4. Neuenschwander B, Branson M, Gsponer T (2008), “Critical aspects of the Bayesian 
approach to phase I cancer trials”, Statistics in Medicine, 27(13):2420-39.


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Appendix A
By-Subject Listings
In addition to the analysis outputs outlined above in the main text, separate by-patient listings 
will also be generated to include the following information:

Disposition (date of first dose, date of last dose, number of cycles, reason for discontinuation 
of study treatment).

Analysis populations.

Significant protocol deviations.

Demographics and Baseline characteristics 

Disease characteristics 

Medical history and Concomitant medical conditions

Medication history and Concomitant Medication

Prior therapies

Study drug exposure.

TEAEs.

TEAEs leading to study drug discontinuation.

TEAEs resulting in dose modifications (delay, interruption, or reduction).

Grade 3 or higher TEAEs.

Vitals signs for those patients with clinically relevant changes in blood pressure during the 
infusion:
–
Increase of diastolic blood pressure of at least 10 mm Hg during any infusion.
–
Decrease of diastolic blood pressure of at least 10 mm Hg during any infusion.
–
Increase of systolic blood pressure of at least 20 mm Hg during any infusion.
–
Decrease of systolic blood pressure of at least 20 mm Hg during any infusion.

Serious AEs.

Lab measurements.

Vital signs

All deaths

On-study death

DLTs during Cycle 1 in dose escalation and expansion safety lead-in.

Pharmacokinetic concentrations.


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
Pharmacokinetic parameters.

ADA.

Efficacy (response assessments by mRECIST v1.1 and iRECIST criteria, best overall 
response, sum of target lesion diameter, status of non-target lesion, status of new lesion, all 
time to events).


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Appendix B
Date Imputation Rules
Incomplete Dates in the Screening Period
1. If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used.
2. If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used.
3. If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used.
Incomplete Adverse Event Onset Date
Assumption: For on-study Adverse Events.
If year is missing (or completely missing): set to the date of first dose.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year = year of first dose: set the date to the first dose date.
If year < year of first dose: set month and day to December 31st.
If year > year of first dose: set month and day to January 1st.
If month and year are present and day is missing:
If year = year of first dose, and:
If month = month of first dose: set day to day of first dose.
If month < month of first dose: set day to last day of month.
If month > month of first dose: set day to 1st day of month.
If year < year of first dose: set day to last day of month.
If year > year of first dose: set day to 1st day of month.
For all other cases: set to date of first dose.
Incomplete Adverse Event Resolution Date
Assumption: For on-study Adverse Events
If day is missing but month and year are non-missing, impute as the earliest of:
Last day of the month
Date cutoff date


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Death date
If day is missing but month and year are non-missing, impute as the earliest of:
December 31st
Date cutoff date
Death date
Incomplete Concomitant Medication Start Date/Prior Therapy Start Date/Progression Date 
during Prior Anti-Cancer Therapy
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to January 1st.
If year and month are present and day is missing:
Set day to 1st day of month.
Incomplete Concomitant Medication End Date
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to December 31st.
If year and month are present and day is missing:
Set day to last day of the month.
Incomplete Subsequent Anti-Cancer Therapy Start Date
If year is missing (or completely missing): set to date of last dose of study treatment + 1
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year > year of the last dose: Set month and day to January 1st.
If year = year of the last dose: Set month and day to date of last dose of study 
treatment +1.
If year and month are present and day is missing:
Set day to 1st day of month if the resulting imputed date is greater than date of last 
dose.


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Otherwise set the imputed date to date of last dose + 1.


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Appendix C
Description and Operating Characteristics of the BLRM for Dose Escalation
An adaptive BLRM with overdose control principle is used to guide dose escalation decisions 
and MTD estimation, along with considerations of other emerging safety, clinical, PK, and 
pharmacodynamic data. 
The 2-parameter logistic regression model used is as follows: 
(
) = log() +  log 

 , α >  0,  >  0, 
where 
 is the DLT rate for "#$, and "#$%& is the reference dose. A quantile-based, weakly 
informative, bivariate normal prior will be used for ln(α) and ln(β). This prior will be assigned 
based on pre-study estimates of median DLT at the provisional dose levels as shown in Table 1 
(described by Neuenschwander et al. 2008). 
Table 1
Prior Median and 95% Credible Interval for DLT Probabilities at Each Dose 
Level
Dose Level (mg/kg)
Median DLT Rate
95% Credible Interval for DLT Rate
0.1
0.05
(0, 0.90)
0.2
0.10
(0, 0.92)
0.4
0.20
(0, 0.94)
0.75
0.25
(0, 0.95)
1.5
0.30
(0, 0.96)
3
0.45
(0.01, 0.97)
6
0.50
(0.02, 0.98)
DLT: dose-limiting toxicity.
The model will be updated after each group of approximately 3 patients is enrolled in the current 
dose level. Each subject will participate in only 1 dose cohort. For each dose level, the posterior 
probability of having DLT rates that fall into the following intervals will be estimated:

[0,0.16): under-toxicity.

[0.16, 0.33): target toxicity.

[0.33, 1.00]: excessive toxicity.
The simulations to evaluate the operating characteristics are based on provisional dose levels 
(0.1, 0.2, 0.4, 0.75, 1.5, 3, 6 mg/kg), representing the various distributions of toxicity across dose 
levels, detailed as shown in Table 2.


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Table 2
Dose Escalation Simulation Study of the Probability of DLT
Dose Level (mg/kg)
True P(DLT) at each scenario
1
2
3
4
5
6
0.1
0.001
0.01
0.05
0.10
0.25
0.50
0.2
0.02
0.05
0.10
0.20
0.45
0.60
0.4
0.04
0.10
0.20
0.30
0.52
0.70
0.75
0.06
0.20
0.25
0.45
0.60
0.75
1.5
0.08
0.23
0.30
0.55
0.70
0.85
3
0.10
0.26
0.45
0.65
0.80
0.90
6
0.12
0.30
0.50
0.75
0.90
0.99
DLT: dose-limiting toxicity.
The trend of the dose-DLT relationship becomes steeper and MTD is reached earlier from 
Scenario 1 to Scenario 6. Table 3 shows the operating characteristic results. 
Table 3
Operating Characteristics for BLRM Dose Escalation Rule
Scenario
Probability of Recommending a:
Average Proportion of Patients 
Receiving a:
Average Number of 
Patients
Low Dose
Target 
Dose
High Dose
Low Dose
Target 
Dose
High Dose
Per study
Experiencing 
DLT per study
1
100.0
NA
NA
100.0
NA
NA
24.2
1.5
2
16.2
83.8
NA
47.2
52.8
NA
21.4
3.4
3 a
16.1
75.7
6.5
38.7
53.5
7.8
18.9
3.8
4 b
12.8
70.3
11.4
28.5
53.8
17.6
16.1
3.9
5 c
NA
42.0
16.1
NA
61.7
38.3
10.6
3.7
6 d
NA
NA
10.2
NA
NA
100.0
5.9
3.0
BLRM: Bayesian Logistic Regression Model; DLT: dose-limiting toxicity.
Low dose = true DLT rate is [0, 0.16]; target dose = true DLT rate is [0.16, 0.33]; high dose = true DLT rate is [0.33, 
1.00].
a Probability of 1.7% to claim all doses are toxic.
b Probability of 5.5% to claim all doses are toxic.
c Probability of 41.9% to claim all doses are toxic.
d Probability of 89.8% to claim all doses are toxic.
In Scenario 1 where all true DLT rates are below 0.33, the average number of patients required is 
approximately 24 with 1.5 DLTs expected on average. 
The true DLT rates in Scenario 2 increase faster than Scenario 1 but are still all below 0.33, and 
the BLRM has an 83.8% chance of successfully recommending target dose levels. The average 
number of patients required is approximately 21, with 3.4 DLTs expected on average. 
In Scenario 3, there is a 16.1% chance of recommending a lower dose as MTD and a 75.7% 
chance of successfully recommending target dose levels. The average number of patients 
required is approximately 19, with 3.8 DLTs expected on average.


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In Scenario 4, with a faster increase of DLT rate over doses, there is 70.3% chance of claiming 
the target doses as MTD, an 11.4% chance of recommending a toxic dose, and approximately a 
5.5% chance of claiming all doses are toxic. The average number of patients required is 
approximately 16 with 3.9 DLTs expected on average.
Scenario 5 further increases the DLT rate over dose levels and has a 42.0% chance of 
recommending a target dose level as MTD, a 16.1% chance of recommending a toxic dose, and a 
41.9% chance of claiming all doses as toxic. This scenario requires, on average, approximately 
11 patients, and results in 3.7 DLTs on average.
When all doses are toxic, as in Scenario 6, there is an 89.8% chance of successfully claiming all 
doses are toxic. The average number of patients required is approximately 6 and 3.0 DLTs are 
expected on average.
The accuracy of the BLRM recommendation relies on the true DLT rate; thus, the safety, 
clinical, PK, and pharmacodynamic data evaluation are combined to support the dose escalation. 
As an example, a hypothetical dose escalation is shown in Table 4 to illustrate how BLRM 
guides dose escalation.
Table 4
Hypothetical Dose Escalation Steps
Step
Dose (mg/kg)
#patients
#DLTs
Next Recommended Dose (mg/kg)
1
0.1
3
0
0.2
2
0.1
3
0
0.2
3
1
0.4
3
0.1
3
0
0.2
3
1
0.4
3
0
1.5
4
0.1
3
0
0.2
3
1
0.4
3
0
0.75
3
2
0.4
5
0.1
3
0
0.2
3
1
0.4
6
2
0.75
3
2
0.2
6
0.1
3
0
0.2
6
1
0.2 mg/kg is claimed as the MTD
0.4
6
2
0.75
3
2
DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
In addition, the BLRM is flexible in handling late-onset toxicities and can be fed with events 
meeting DLT criteria but occurring in later cycles to modulate dose escalation, as needed.