Product Number or USAN Name MacroGenics, Inc.

Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

CLINICAL STUDY PROTOCOL: INSERT NUMBER

ORIGINAL PROTOCOL/AMENDMENT #

Study Title: Brief, concise and clear titles are preferred.

Study Number: Enter number
Study Phase: Phase #
Product Name: Include USAN or brand name here. If USAN/brand names not
available, remove product name.
Product Number: Use product number, if no product name is available. If the USAN
or brand name is available, removed the product number.
IND Number: Enter number, or TBD if not yet known
EudraCT Number: Enter number, or NA if not applicable
Indication: Enter indication
Coordinating Enter name, TBD, or delete if no CPI will be used.
Principal
Investigator:
Sponsor: MacroGenics, Inc.
9704 Medical Center Drive
Rockville, MD 20850
USA
301-251-5172
Sponsor’s Medical Refer to study contact list
Monitor:

Confidentiality Statement
This document is confidential. It contains proprietary information of MacroGenics, Inc. that
can only be used for the purpose of reviewing or performing this study. Any use, viewing or
disclosure of such information that is not authorized in writing by the Sponsor is strictly
prohibited.
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REVISION HISTORY
Status Date

Protocol Version DD Month YYYY

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Template Instructions:

Instructional text (green font, italics) contains advice to the author, expectations of content,
format, or source, and should be followed to the extent possible unless not applicable to a
specific study. Instructional text should be deleted once the draft document is developed.

Suggested text/example text (purple font) is provided to aid the author. Example text may be
modified to suit the planned clinical study or deleted entirely.

Standard text (black font and gray highlighting) is not to be modified. However, minor changes
are acceptable, provided they do not change requirements for the section and are approved by the
Functional Area Head. Remove gray highlighting just prior to second team review.

Generally, section titles should not be changed; however, optional subsections may be added or
deleted as appropriate.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

TABLE OF CONTENTS
SPONSOR SIGNATURES..............................................................................................................
RATIONALE FOR PROTOCOL AMENDMENT #.......................................................................
LIST OF ABBREVIATIONS........................................................................................................
1 SYNOPSIS.........................................................................................................................
2 BACKGROUND INFORMATION...................................................................................
2.1 Disease Background.................................................................................................
2.2 Rationale for Study...................................................................................................
2.3 Background on Study Agent(s).................................................................................
2.4 Dose Selection..........................................................................................................
2.5 Risk Benefit Assessment...........................................................................................
2.5.1 Risk Assessment.............................................................................................
2.5.2 Benefit Assessment.........................................................................................
2.5.3 Overall Assessment.........................................................................................
3 STUDY PURPOSE AND OBJECTIVES..........................................................................
3.1 Primary Objective.....................................................................................................
3.2 Secondary Objectives...............................................................................................
3.3 Exploratory Objectives.............................................................................................
4 STUDY DESIGN..............................................................................................................
4.1 Overall Study Design................................................................................................
5 ELIGIBILITY CRITERIA................................................................................................
5.1 Inclusion Criteria......................................................................................................
5.2 Exclusion Criteria.....................................................................................................
6 STUDY TREATMENTS...................................................................................................
6.1 Description of Dosing Regimens..............................................................................
6.2 Blinding....................................................................................................................
6.3 Emergency Unblinding.............................................................................................
6.4 Study Treatment Supplies.........................................................................................
6.5 Study Infusion Preparation.......................................................................................
6.6 Treatment Compliance..............................................................................................
6.7 Accountability...........................................................................................................
6.8 Investigational Product Disposition at End of Study................................................
7 POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE
MEASURES......................................................................................................................
7.1 Infusion Related Reactions Including Cytokine Release Syndrome........................
7.1.1 Grading and Management of Infusion Reactions...........................................
7.1.2 Premedication and Prophylaxis......................................................................
7.1.3 Management of Observed Infusion Reactions................................................
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7.2 Immune-related Adverse Events...............................................................................

8 CONCOMITANT THERAPY AND RESTRICTIONS....................................................
8.1 Concomitant Therapy...............................................................................................
8.1.1 Prohibited Therapy.........................................................................................
8.1.2 Permitted Therapy...........................................................................................
8.1.3 Contraception..................................................................................................
8.2 Restrictions...............................................................................................................
8.2.1 Fluid and Food Intake.....................................................................................
8.2.2 Patient Activity Restrictions...........................................................................
9 STUDY PROCEDURES...................................................................................................
9.1 Informed Consent.....................................................................................................
9.2 Screening Period.......................................................................................................
9.3 Registration and Enrollment.....................................................................................
9.4 Medical History........................................................................................................
9.5 Prior and Concomitant Medications and Procedures................................................
9.6 Physical Examination...............................................................................................
9.6.1 Vital Signs.......................................................................................................
9.7 Laboratory Tests.......................................................................................................
9.7.1 Safety Tests.....................................................................................................
9.7.2 Central Laboratory Tests.................................................................................
9.7.2.1 Blood Samples......................................................................................
9.7.2.2 Tissue Samples......................................................................................
9.7.3 Other Laboratory Tests...................................................................................
9.8 Tumor Assessments..................................................................................................
9.9 End of Treatment Visit..............................................................................................
9.10 Post-Treatment Follow Up........................................................................................
10 ASSESSMENT OF PHARMACOKINETICS AND
PHARMACODYNAMICS...............................................................................................
10.1 Pharmacokinetics Assessments.................................................................................
10.2 Pharmacodynamic/Biomarker Assessments.............................................................
10.3 Immunogenicity Assessments...................................................................................
11 ASSESSMENT OF EFFICACY.......................................................................................
11.1 Efficacy Assessments................................................................................................
11.1.1 Disease Response Assessments......................................................................
11.1.2 Survival Assessments......................................................................................
12 ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY..........................
12.1 Definitions................................................................................................................
12.1.1 Adverse Event.................................................................................................
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12.1.2 Adverse Drug Reaction...................................................................................

12.1.3 Adverse Event of Special Interest...................................................................
12.1.4 Serious Adverse Event....................................................................................
12.1.5 Assessment of Causality.................................................................................
12.1.6 Severity Criteria..............................................................................................
12.2 Adverse Event Collection and Documentation.........................................................
12.2.1 All Adverse Events.........................................................................................
12.2.2 Serious Adverse Events..................................................................................
12.2.3 Pregnancy.......................................................................................................
12.2.4 Special Reporting Situations...........................................................................
12.2.4.1 Sponsor Notification of Adverse Events of Special Interest.................
13 PRODUCT QUALITY COMPLAINT HANDLING........................................................
14 STATISTICAL ANALYSIS...............................................................................................
14.1 Determination of Sample Size..................................................................................
14.2 Analysis Populations................................................................................................
14.3 Demographics and Baseline Characteristics.............................................................
14.4 Study Treatment Exposures and Concomitant Medications.....................................
14.5 Pharmacokinetic/Pharmacodynamic Analysis..........................................................
14.5.1 Pharmacokinetic Analysis...............................................................................
14.5.2 Immunogenicity Analysis...............................................................................
14.5.3 Pharmacodynamic Analysis............................................................................
14.6 Efficacy and Endpoint Analyses...............................................................................
14.6.1 Response Endpoints and Analyses..................................................................
14.6.2 Analysis of Tumor Size Change Over Time...................................................
14.6.3 Time-to-Event Endpoints and Analyses..........................................................
15 REFERENCE LIST...........................................................................................................

LIST OF TABLES
Table 2 Treatment Cohorts...............................................................................................
Table 3 NCI CTCAE Version 5.0 Grading of Infusion-Related Reactions......................
Table 4 Adverse Events of Special Interest......................................................................
Table 5 Response Rates and 95% Confidence Intervals..................................................
Table 6 Censoring Rules for Primary Analysis of PFS...................................................

LIST OF FIGURES
No table of figures entries found.
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Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

LIST OF APPENDICES
APPENDIX 1 TIME AND EVENTS SCHEDULE
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

SPONSOR SIGNATURES

Study Title: Should match title page

Study Number: Enter number

This clinical study protocol has been approved by the sponsor:

Signed: See Appended Electronic Signature Page Date:

Medical Monitor Name, Credentials
Title, Clinical Research
MacroGenics, Inc.

Signed: See Appended Electronic Signature Page Date:

Statistician Name, Credentials
Title, Biostatistics
MacroGenics, Inc.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

Amendments

RATIONALE FOR PROTOCOL AMENDMENT #

Summarize the overall rationale (one primary driver) for the changes implemented in a
protocol amendment above the summary table; the table will include a brief description of the
changes and impacted sections. Include only changes made from the original protocol or from
the previous amendment (including, if necessary, protocol clarification letter content) and not
a cumulative summary. Sample text is provided below:

The primary changes in Amendment # include the following:

 Increased the total enrollment to # patients.

 Required female patients of childbearing potential to use highly effective
contraception for the duration of the study and up to 120 days after discontinuation of
study treatment.
 Divided enrollment was into two cohorts in Dose Expansion, specifically North
American and Asian cohorts, each enrolling an equal amount of 30 patients each.

The table below summarizes the substantive modifications to the body of the protocol.
Corresponding changes were made to the synopsis. Unless changes to the synopsis were unique
to the synopsis, they are not included in the summary. Minor editorial, formatting, and
typographical changes were also made.

A redline version showing detailed changes to the protocol will be provided upon request.

An example of a Summary of Changes table is provided below.

Section Change Implemented Rationale

Synopsis Neutropenia If rationale
Section xx.y Additional CBC will be collected on Day 4, 11, and 18 of cycle described above
1. Column may not
be needed for
simple
amendments.
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Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

LIST OF ABBREVIATIONS
Generation of the List of Abbreviations is recommended after the first review cycle.

Terms that are used once within the document do not need to be abbreviated. Only terms that
are used multiple times within the document need to appear in the List of Abbreviations.
Commonly used units of measure do not need to be included. Do not capitalize a spelled out
abbreviation unless it would normally be capitalized when spelled out within the protocol text
[(Food and Drug Administration (FDA), objective response rate (ORR)].

The List of Abbreviations should be presented in table format, as shown in the example below.

The list of abbreviations of specialist terms does not include general scientific abbreviations of
temperature, weight and volume.

AE adverse event
AESI adverse event of special interest
ALT alanine aminotransferase
ANC absolute neutrophil count
AST aspartate aminotransferase
CFR Code of Federal Regulations
Product Number or USAN Name MacroGenics, Inc.
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1 SYNOPSIS
The synopsis is a summary document. Do not copy and paste whole sections of the protocol
into the synopsis. The synopsis should be able to function as a standalone summary document
and for this reason should not include cross-references to other sections of the protocol. In
general, abbreviations and acronyms should be spelled out at first use in both the synopsis and
the protocol body.

Sponsor: MacroGenics, Inc. IND Number:

Name of Product: Should match the header.

Study Title: Should match title page.

Study Number: Insert number.

Study Phase: Insert phase.

Investigator(s)/Centers:
Enter the number of planned centers in US and/or globally. In a dose escalation-cohort expansion study,
identify the number study centers in the dose escalation and cohort expansion separately.
Additional information on phased country or site opening may be included.

Primary Objective(s): Should match Section 3

Secondary Objective(s): Should match Section 3

Study Treatment:
Source is Section 3.1.1 of the IB. Should include mechanism of action.

Study Design:
Summarize from Section 4.1. Limit study design to one page. May include schematic.

Dose Limiting Toxicities: Optional/Modify as applicable.

DLTs will be defined based on drug-related adverse events (AEs) (or laboratory abnormalities) that occur during
the first cycle of study treatment. The severity of AEs will be graded according to the National Cancer Institute
Common Terminology Criteria for Adverse Events v X.X (NCI CTCAE v X.X). DLTs will be defined separately
for hematologic and non-hematologic events.

Number of Patients Enrolled:

Provide the number of patients expected to be enrolled, per phase of the study if appropriate.
The number of patients

Patient Population/Key Entry Criteria:

Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

Provide a summary that includes description of the population based on key inclusion/exclusion criteria. DO
NOT list all inclusion/exclusion criteria.

The study population

Duration of Treatment and Study Duration:

Summarize from Section 4.1. Leave the detail in the protocol body.
Treatment for

Criteria for Evaluation: Summary statements only. Leave the detail in the protocol body.
Safety Assessments:
The safety assessment is based on

Statistical Methods:
Should include a brief summary and not the entire statistical plan as presented in Section 14.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

2 BACKGROUND INFORMATION

2.1 Disease Background

Applicable clinical, epidemiological, or public health background for context of the study

A summary of relevant clinical research

2.2 Rationale for Study

Discuss the background of the current therapeutic landscape, including any limitations,
controversies and unmet medical needs. Provide a rationale for the study. Limit the rationale
to 1 page.

2.3 Background on Study Agent(s)

Nonclinical studies necessary to support clinical studies have been performed and are
summarized in the Investigator’s Brochure (IB).

For first-in-human studies, summarize one paragraph each for in vitro or in vivo activity, PK
and ADME, toxicology.

Include a brief summary of safety and clinical experience, if available. Summary should be
consistent with Sections 5 and 6 of the IB.

2.4 Dose Selection

Include a description of and justification for the route of administration, dosage, dosage
regimen, and treatment period(s). For initial protocols, briefly summarize the interspecies
memo.

2.5 Risk Benefit Assessment

May be copied from the IMPD, or Section 6 of the IB

2.5.1 Risk Assessment

Therapeutic Risks

Non-therapeutic Risks

2.5.2 Benefit Assessment

There.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

2.5.3 Overall Assessment

The protocol incorporates.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

3 STUDY PURPOSE AND OBJECTIVES

Check against Section 14 for consistency.

3.1 Primary Objective

The primary objective is the main reason for performing the study. Enter the corresponding
outcome measurement or endpoint.

Primary Objective Outcome or Endpoint

To evaluate the safety and tolerability of MGDXXX in patients AEs and SAEs
with advanced solid tumors AEs leading to
discontinuation

3.2 Secondary Objectives

The secondary objectives are goals that will provide further information on the use of the
compound. Each objective should be expressed as a statement of purpose, e.g., to evaluate, to
assess, to determine, to compare, etc.

Secondary Objective Outcome or Endpoint

To evaluate the PK/PD/ADA of MGDXXX in patients with Study drug
advanced solid tumors concentrations
Summary PK
parameters
Incidence of ADA
To assess preliminary clinical activity of MGDXXX ORR, DoR, PFS

3.3 Exploratory Objectives

Exploratory objectives, if applicable, should be expressed as a statement of purpose similar to
secondary objectives. This section can be deleted if not applicable to the study.

Exploratory Objective Outcome or Endpoint

Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

Results of exploratory objectives may not be included in the Clinical Study Report or database
lock unless they represent meaningful findings.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

4 STUDY DESIGN

4.1 Overall Study Design

Describe the overall plan and design using a study schema, figure, or table as appropriate.
Avoid duplication of text in multiple sections. For first in human studies consider language
for sentinel dosing of patients 24-48 hours apart. Consider landmark analysis in study design.
Consider flexible language in the duration of any proposed efficacy follow-up period to allow
for study closure.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

5 ELIGIBILITY CRITERIA
Patients must meet all the inclusion criteria. Patients will be excluded from the study if they meet
any exclusion criteria. No exceptions to these criteria will be granted by the sponsor.

5.1 Inclusion Criteria

The sample inclusion criteria can be adapted/added to/deleted as needed. The criteria re.
informed consent and items related to contraception are standardized text and should not be
altered.

1. .

5.2 Exclusion Criteria

The sample exclusion criteria can be adapted/added to/deleted as needed.

Clinical significance of underlying conditions and judgments related to the best interests of the
patient are determined by the investigator. Sponsor consultation with the medical monitor is
encouraged where there is a concern.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

6 STUDY TREATMENTS

6.1 Description of Dosing Regimens

Describe all study drug dosing regimens, including sequencing of combination therapy if
applicable. Consider graphic or tabular representation.

Table 1 Treatment Cohorts

Module
A B
Arm
Control Arm √ √ √ √
Experimental Arm 1 √ √ √ √

6.2 Blinding
Select the most appropriate text for the study.

Open-label, no blinding at site level:

This is an open-label study.

Open-label using central randomization via IRT:

This is an open-label study.

Blinded study with unblinded site pharmacist who is dispensing drug:

6.3 Emergency Unblinding

Not applicable. This is an open-label study.

or if appropriate, describe the emergency unblinding procedures.

6.4 Study Treatment Supplies

Describe the investigational study treatment(s) using text from Section 3 of the IB. For first-
in-human protocols, provided by Regulatory CMC. Include statement on custom vehicles for
dilution if applicable. Describe if the combination agent or comparator is provided by MG or
obtained commercially.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

6.5 Study Infusion Preparation

Information on the packaging, labeling, storage, preparation, and administration of study
treatments, active comparators, and placebo may be found in the Pharmacy Manual.

6.6 Treatment Compliance

The study treatment(s) will be administered by healthcare professionals under the supervision of
the investigator. Records of dose calculation, administration, and dosing regimen will be
accurately maintained by site staff. The monitor will review study pharmacy and patient medical
records according to the clinical monitoring plan.

6.7 Accountability
Accurate accounting of all study treatments must be maintained. The investigator agrees to keep
an inventory of study treatments using the institution’s drug accountability logs or logs provided
by the sponsor. The investigator will maintain records of temperature monitoring of study
treatment. Drug disposition records must be kept in compliance with applicable guidelines and
regulations.

A Pharmacy Manual will be provided to the investigator or designee. When the study is
completed, copies of all study treatment accountability records must be provided to the sponsor.
Original drug accountability records must be maintained with the rest of the documentation for
inspection by the study monitors.

6.8 Investigational Product Disposition at End of Study

All unopened vials of study treatment will be destroyed on site unless return to depot is
authorized by the sponsor or its representative.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

7 POTENTIAL ADVERSE EVENTS AND SUPPORTIVE CARE

MEASURES

7.1 Infusion Related Reactions Including Cytokine Release Syndrome

Highlighted gray text should not be altered, unless there is significant rationale.

7.1.1 Grading and Management of Infusion Reactions

Select and include the grading and management statements and tables based upon the agent
under study.

Use for CTCAE v4.03. Infusion reactions will be categorized as follows:

Use for CTCAE v5.0

IRR, CRS and allergic reactions should be graded according to the criteria in Table 2.

Table 2 NCI CTCAE Version 5.0 Grading of Infusion-Related Reactions

System Injury, Poisoning and Procedural
Immune System Disorders
Organ Class Complications
Preferred Cytokine Release
Infusion–related Reaction Allergic Reaction
Term Syndrome

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5
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7.1.2 Premedication and Prophylaxis

Grayed highlighted text should not be altered unless there is significant rationale. Refer to
safety information for the product regarding the appropriate infusion prophylaxis.

7.1.3 Management of Observed Infusion Reactions

Grayed highlighted text should not be altered, unless there is significant rationale

The following are suggested treatment guidelines for the investigator regarding the management
of infusion reactions. Equivalent medications may be substituted based on the local practice of
medicine and availability.

Management of Infusion-related Reactions

Grade Intervention Outcome
1 Section 7.1.2.
2
3 or 4 Section 7.1.2.

All changes in the infusion of study treatment(s), including interruption of the infusion and its
duration as well as reductions in infusion rate and duration, must be recorded.

7.2 Immune-related Adverse Events

Grayed highlighted text in this section and subsections should not be modified unless there is
significant rationale for doing so.

Blockade of immune checkpoints is associated with immune-related adverse events (irAEs) due
to disruption of normal immune tolerance (2-4).

Include applicable subsections below; do not alter grayed highlighted text unless there is
significant rationale.

8 CONCOMITANT THERAPY AND RESTRICTIONS

8.1 Concomitant Therapy

All concomitant medications, including prophylactic pre-infusion medications, and blood
products administered during the patient’s participation in the study until 30 days following the
last dose of study treatment or until the start of a subsequent systemic anticancer therapy, if
earlier, must be recorded in the source document and on the electronic Case Report Form
(eCRF).
Product Number or USAN Name MacroGenics, Inc.
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8.1.1 Prohibited Therapy

The following rules concerning concurrent treatment(s) apply in this study:

8.1.2 Permitted Therapy

Patients may receive the following concurrent therapy:

8.1.3 Contraception
Male and female patients are required to use highly effective contraceptive measures as specified
below. Male patients are required to use a condom regardless of his WOCBP partner’s method of
contraception.

8.2 Restrictions
Describe any restrictions on patient diet or activity. If there are not restrictions, omit the
section.

8.2.1 Fluid and Food Intake

Optional

8.2.2 Patient Activity Restrictions

Optional
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9 STUDY PROCEDURES
Provide a description of all study procedures in this section. Assessments that are not
applicable to the study may be removed.

This section provides a general description of the procedures and assessments associated with
this study. The timing of the study procedures is presented in Appendix 1. All data should be
recorded in source documents and entered into the eCRF.

9.1 Informed Consent

Evaluate whether only the patient may consent, or if a legally authorized person may consent.

The investigator is responsible for.

9.2 Screening Period

Patients may receive the first dose up to.

9.3 Registration and Enrollment

The patient must be registered with the sponsor after they meet all eligibility criteria.

Enter the protocol-specific required information for registration and enrollment. If using IRT
include relevant details.

9.4 Medical History

A complete medical history should be obtained during the screening visit. All concurrent medical
conditions in the last <interval> days and any significant past medical conditions
(e.g., hospitalizations, surgeries, chronic conditions, prior cancer history, etc.) should be
collected. Any untoward event that occurs prior to the first dose of study treatment should be
recorded as medical history and not as an AE unless it is due to a protocol-related procedure.

9.5 Prior and Concomitant Medications and Procedures

Record all.

9.6 Physical Examination

Add any product-specific evaluations that need to occur based on observed toxicities. For
example: total body skin exam.

The investigator will.

Product Number or USAN Name MacroGenics, Inc.
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9.6.1 Vital Signs

Vital signs include temperature, pulse, blood pressure, and respiratory rate. It is recommended
vital signs are obtained in a seated, semi-recumbent, or supine position after an appropriate rest.

9.7 Laboratory Tests

9.7.1 Safety Tests

Insert table of laboratory tests including CBC, CMP, coagulation and UA. Cross-check
against the clinical laboratory assessments selected by the medical monitor in the approved
Protocol Concept Document for the study. Indicate whether these are local or centrally tested.

9.7.2 Central Laboratory Tests

Use this section to describe sample collection for any laboratory assessments (other than
safety laboratory tests) that are not analyzed at the clinical site.

Error: Reference source not found.

9.7.2.1 Blood Samples

Blood samples for PK, immunogenicity, pharmacodynamic, or biomarker assessments will be
collected from the arm contralateral to the site of IV infusion. If an indwelling catheter is used,
the fluid in the catheter will be removed and discarded prior to the collection of the blood
sample.

Enumerate the types of blood samples to be collected for pharmacodynamic and biomarker
assessments.

9.7.2.2 Tissue Samples

Enumerate the types of biopsy samples (e.g., fresh, archival, FFPE tumor specimen block,
number of stained/unstained slides required) to be collected for pharmacodynamic and
biomarker assessments.

9.7.3 Other Laboratory Tests

Describe requirements for any laboratory tests that are not centralized and are not safety labs.
This includes tests that may be done locally for study qualification.
Product Number or USAN Name MacroGenics, Inc.
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9.8 Tumor Assessments

Ensure that this section is consistent with the standard measures for evaluation of the disease
under study.

9.9 End of Treatment Visit

The end of treatment visit.

9.10 Post-Treatment Follow Up

The post-treatment follow-up period includes the following:


Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

10 ASSESSMENT OF PHARMACOKINETICS AND

PHARMACODYNAMICS

10.1 Pharmacokinetics Assessments

Serum.

10.2 Pharmacodynamic/Biomarker Assessments

Describe what you expect to measure from the samples collected (e.g.: change from baseline,
% of population with…). Assessments may be broken out by Dose Escalation, Cohort
Expansion, or both. Describe if analysis will be prospective or retrospective.

10.3 Immunogenicity Assessments

Generation of anti-drug antibodies (ADA) will be monitored using a <specify> method.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

11 ASSESSMENT OF EFFICACY

11.1 Efficacy Assessments

11.1.1 Disease Response Assessments

Discuss the methods, intervals for assessments, and whether the assessment will be made
locally by the investigator or assessed centrally. Sample text may not be suitable for ADC or
other targeted products.

Treatment of patients …criteria (5).

11.1.2 Survival Assessments

Survival status is assessed approximately every <interval> for <interval> after study treatment
discontinuation until withdrawal of consent, LTFU, death, or end of the study.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

12 ADVERSE EVENT REPORTING AND ASSESSMENT OF SAFETY

The safety assessment is based on adverse events (AEs) occurring from the first administration
of study treatment until 30 days after the last dose of study treatment or until the start of another
systemic anticancer therapy, whichever comes first. The assessment is based on signs,
symptoms, physical examination findings, and laboratory test results.

12.1 Definitions

12.1.1 Adverse Event

An AE means.

12.1.2 Adverse Drug Reaction

Adverse drug reaction.

12.1.3 Adverse Event of Special Interest

An adverse event of special interest.

12.1.4 Serious Adverse Event

An SAE is any AE.

12.1.5 Assessment of Causality

Assessment of Causality is a determination that describes the relationship or association of the
drug with an AE..

12.1.6 Severity Criteria

Assessment of severity grade will be made using the NCI-CTCAE choose Version 4.03 or 5.0.

12.2 Adverse Event Collection and Documentation

12.2.1 All Adverse Events

AEs and SAEs

.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

12.2.2 Serious Adverse Events

Determine if safety reporting will be done using a paper form or using the Safety Gateway.
Amend language in the SAE sections accordingly.

All SAEs…

12.2.3 Pregnancy
All pregnancies

12.2.4 Special Reporting Situations

12.2.4.1 Sponsor Notification of Adverse Events of Special Interest

AESIs in Table 3.

Table 3 Adverse Events of Special Interest

AESI Reporting Requirement
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

13 PRODUCT QUALITY COMPLAINT HANDLING

A product quality complaint (PQC) is defined
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

14 STATISTICAL ANALYSIS
Describe the methods of analysis for the following parameters. Do not describe specific CSR
tables and listings in the protocol. Rather, refer the reader to the Statistical Analysis Plan or
Statistical Programming Plan.

This section outlines the statistical methodology and principles used for data analysis in this
study. A separate statistical analysis plan (SAP) and statistical programming plan (SPP) further
describe the details regarding statistical methods and govern the analysis.

14.1 Determination of Sample Size

Sample text for phase 1 study:

The study plans to enroll approximately up to xx patients (up to xx in the dose escalation phase
and up to xx in the dose expansion phase).

The sample size of up to xx patients for the dose escalation phase is based on 3+3 design with
planned xx dose cohorts. Additional patients may be enrolled if the enrollment to a dose cohort is
expanded or intermediate dose levels are evaluated in the dose escalation phase.

The dose expansion phase plans to enroll approximately xx patients, consisting of xx patients in
each of xx tumor specific cohorts. The sample size for each tumor specific cohort is primarily
based on providing preliminary estimation of responses. Table 3 provides the 2-sided 95%
confidence interval (CI) for a number of potential responses among xx patients.

Table 4 Response Rates and 95% Confidence Intervals

Sample Size Number of Responses Response Rate (%) 95% Confidence Interval
(%)

14.2 Analysis Populations

The study analyses will be performed on the following populations (choose ones that apply):

14.3 Demographics and Baseline Characteristics

Patient disposition, demographics, baseline characteristics, disease history, medical history, and
prior cancer treatment will be summarized using descriptive statistics.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

14.4 Study Treatment Exposures and Concomitant Medications

Study treatment exposures and concomitant medications will be summarized by descriptive
statistics. The summary of study treatment exposure will include descriptive statistics as well as
frequency counts for the number of doses or cycles received, the total dose actually
administrated as well as the total dose intended, and the dose intensity which is calculated as
percentage of total dose actually administrated divided by total dose intended during whole
treatment period. Concomitant medications are coded using the WHO Drug Dictionary.

14.5 Pharmacokinetic/Pharmacodynamic Analysis

14.5.1 Pharmacokinetic Analysis

Summary statistics will be tabulated for PK parameters by dose.

14.5.2 Immunogenicity Analysis

The proportion of patients who are negative for study treatment-specific ADA at baseline and
become positive in this assay, the proportion of patients who are negative at baseline and remain
negative, and those who have positive ADA at baseline that increases or decreases in titer over
the course of treatment will be summarized.

14.5.3 Pharmacodynamic Analysis

Summary statistics for pharmacodynamic parameters listed in Section 10.2 and changes from
baseline will be summarized. Analyses may be presented graphically with possible associations
between changes in pharmacodynamic measures of interest and study treatment dose and
exposure.

14.6 Efficacy and Endpoint Analyses

14.6.1 Response Endpoints and Analyses

The objective response rate (ORR)….

14.6.2 Analysis of Tumor Size Change Over Time

Tumor size is defined as the sum of diameters of the target lesions. Tumor size change from
baseline over time will be summarized and may be presented by spider plot. The best tumor size
change from baseline will be presented by waterfall plot.

14.6.3 Time-to-Event Endpoints and Analyses

Consider other endpoints than survival-based endpoints. Landmark analysis, and composite
endpoints to enable rapid endpoint accrual and study completion.

Progression-free survival (PFS) will be defined ….

Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

Table 5 Censoring Rules for Primary Analysis of PFS

Situation Date Outcome

The method of Brookmeyer and Crowley (1) will be used.

15 REFERENCE LIST
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

Appendix 1 Time and Events Schedule

For ease and readability, limit the number of footnotes to ≤ 10. Where appropriate, use
footnotes to define time windows for procedures and other relevant information important for
the conduct of the study and data collection. A sample table is provided below. To prevent
formatting errors, insert a new table when authoring the protocol. The table may be copied
directly from the Protocol Concept Document.
Product Number or USAN Name MacroGenics, Inc.
Clinical Study Protocol: <Insert protocol number> Original Protocol/Amendment #, DD Month YYYY

1. Brookmeyer R and Crowley J, A Confidence Interval for the Median Survival Time.
Biometrics, 1982. 38: p. 29-41.
2. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al.,
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med,
2010. 363(8): p. 711-23.
3. Robert C, Thomas L, Bondarenko I, O'Day S, JW MD, Garbe C, et al., Ipilimumab
plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med, 2011.
364(26): p. 2517-2526.
4. Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, et al., B7-H3 and B7-H4
expression in non-small-cell lung cancer. Lung Cancer, 2006. 53(2): p. 143-151.
5. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al., Guidelines for
the evaluation of immune therapy activity in solid tumors: immune-related response
criteria. Clin. Cancer Res, 2009. 15(23): p. 7412-7420.

Reference list is generated here but moved in our documents to a section much earlier in
the document (see section 15 above) – consider if this might be what breaks the link;
alternatively could it be the use of the “Convert Citations and Bibliograph to Unformatted
Citations.