A Phase 1/2, Open-Label, Multicenter, Dose Escalation and Efficacy Study of mRNA-2416, a Lipid Nanoparticle Encapsulated mRNA Encoding Human OX40L, for Intratumoral Injection Alone or in Combination With Durvalumab for Patients With Advanced Malignancies
Phase: PHASE1
Conditions: Relapsed/Refractory Solid Tumor Malignancies or Lymphoma, Ovarian Cancer
Sponsor: ModernaTX, Inc.

CLINICAL TRIAL PROTOCOL 
A PHASE I/II, OPEN-LABEL, MULTICENTER, DOSE ESCALATION AND 
EFFICACY STUDY OF MRNA-2416, A LIPID NANOPARTICLE 
ENCAPSULATED MRNA ENCODING HUMAN OX40L, FOR 
INTRATUMORAL INJECTION ALONE AND IN COMBINATION WITH 
DURVALUMAB FOR PATIENTS WITH ADVANCED MALIGNANCIES 
Protocol Number: 
mRNA-2416-P101 
Sponsor: 
ModernaTX, Inc. 
200 Technology Square 
Cambridge, MA 02139 
USA 
Phone: +1-617-714-6500 
Protocol Version: 
Amendment Version: 
7.0 
6.0 
Date released: 
10 Jun 2019 
This study will be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP), the Declaration of Helsinki, and applicable regulatory requirements. The information in this study 
protocol is strictly confidential and is available for review to Investigators, study site personnel, the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), and the Regulatory Authorities. 
It will not be disclosed to third parties without written authorization from ModernaTX, Inc. (the Sponsor), 
except to obtain informed consent from persons participating in the trial. Once the protocol is signed, its 
terms are binding for all parties. 
CONFIDENTIAL 
NCT #NCT03323398

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1 
SPONSOR SIGNATURE PAGE 
 
Sponsor: 
ModernaTX, Inc. 
Protocol Number: 
mRNA-2416-P101 
Study Medication: 
mRNA-2416 
Protocol Title: 
A Phase I/II, Open-Label, Multicenter, Dose Escalation and Efficacy Study of 
mRNA-2416, a Lipid Nanoparticle Encapsulated mRNA Encoding Human 
OX40L, for Intratumoral Injection Alone and in Combination with Durvalumab 
for Patients with Advanced Malignancies 
 
Protocol Version: 
Amendment Version: 
7.0 
 
6.0 
 
Date released: 
Approved by: 
10 Jun 2019 
 
 
 
 
 
 
 
 
 
Date 
ModernaTX, Inc. 
PPD

ModernaTX, Inc. 
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INVESTIGATOR AGREEMENT 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will conduct 
the study as outlined herein and will complete the study within the time designated. This trial will be conducted 
according to all stipulations of the protocol, including all statements regarding confidentiality, and according 
to local legal and regulatory requirements and applicable United States federal regulations and International 
Council for Harmonisation (ICH) guidelines. 
 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure they are fully informed 
regarding the drug and the conduct of the study. 
 
I will use only the informed consent form approved by the Sponsor or its representative and will fulfill all 
responsibilities for submitting pertinent information to the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) responsible for this study. 
 
I agree that the Sponsor or its representatives shall have access to any source documents from which case 
report form information may have been generated. I agree that regulatory authorities (FDA, EMA, and other 
local and country-related agencies) can audit and review source documents. 
 
I further agree not to originate or use the name of ModernaTX, Inc. or any of its employees, in any publicity, 
news release, or other public announcement, written or oral, whether to the public, press, or otherwise, relating 
to his protocol, to any amendment hereto, or to the performance hereunder, without the prior written consent 
of ModernaTX, Inc. 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
 
Name of Investigator (Typed or Printed) 
 
 
 
 
 
Institution Name 
 
 
 
 
 
Institution Address 

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Version History and Summary of Changes 
 
Amendment 6.0 
Amendment rationale 
The main purpose of this amendment is to include a new treatment arm for mRNA-2416 in 
combination with durvalumab. This includes new primary study objectives in Phase I to determine 
the MTD/RDE for mRNA-2416 in combination with durvalumab and in Phase II to assess the 
objective response rate of the combination therapy in ovarian cancer based on Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1. 
 
Changes to the protocol 
Section 2 Tabulated Protocol Summary: Updated to reflect main text revisions noted below. 
Section 6 Background and Rationale: Added background information regarding combination 
treatment with CPIs. 
Section 6.2 mRNA-2416 Background: Added results from preclinical efficacy testing of OX40L 
mRNA in combination with αPD-L1. Added summary of safety observed on this study as of 08- 
Feb-2019. 
Section 6.3 Durvalumab Background: New section added including details of the proposed 
durvalumab mechanism and a summary of findings from pre-clinical and clinical studies. 
Section 6.5 Durvalumab Dosing Rationale: New section added providing rationale for the 1500mg 
fixed dose of durvalumab planned for this study 
Section 7 Study Objectives and Endpoints: Updated study endpoints and objectives to be applicable 
for mRNA-2416 alone as well as in combination with durvalumab. 
Section 8.1 Number of Patients: Updated to account for treatment Arm B. 
Section 8.2 Study Design: Updated section and Figure 1 to include treatment Arm B. Also revised 
to include patients with all solid tumors or lymphoma in the Dose Confirmation cohorts. 
Section 8.2.2 Arm A Dose Escalation Biopsy Cohort Enrichment: Specified treatment Arm A. 
Section 8.2.3 Arm B Dose Escalation Period: New section added describing Arm B Dose Escalation 
procedures including the dose levels to be tested. 
Section 8.2.4 Dose Confirmation in Visceral Lesions: Revised to increase clarity. 
Section 8.2.6 Arm B Dose Expansion Period: New section added describing the Arm B Dose 
Expansion period. 
Section 8.3 Study Flow and Expected Duration of Patient Participation: In alignment with the safety 
profile observed during the dose escalation study period, the safety follow-up period has been 
decreased to 90 days following last treatment. Also added details on duration of participation in 
each phase and for each treatment arm. 
Section 8.4.2 Definition of Dose-Limiting Toxicities: Added criteria applicable for treatment Arm 
B. 
Section 8.4.4 Added durvalumab exposure criteria for patients evalubable for dose determination. 

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Section 9.1 Inclusion Criteria: Added criteria for thyroid function, expansion lesion requirements, 
life expectancy and body weight. 
Section 9.2 Exclusion Criteria: Added several new criteria regarding: prior autoimmune or 
inflammatory disorders, immunodeficiency or immunosuppression, toxicities from prior therapies, 
active infections, pneumonitis, carcinomatosis, and involvement in study conduct. 
Section 10.1 Intratumoral Injections: Clarified lesion requirements for Dose Expansion, specified 
dosing regimen for visceral lesions, and specified that no intrapatient dose escalation may occur. 
Section 10.2 Durvalumab Administration: New section added for durvalumab administration. 
Section 10.3 mRNA-2416 Dose Modification: Consolidated details previously contained in other 
sections. 
Section 10.4 Durvalumab Dose Modification and Toxicity Management Guidelines: New section 
added. 
Section 10.5 – 10.7, and 10.9: Sections relocated for clarity. 
Section 10.8 Concomitant Therapy: Added new prohibited concomitant medications for both 
treatment arms. 
Section 10.10 Radiologic Assessments: Clarified baseline imaging requirements and added that 
imaging data may be centrally collected and reviewed. 
Section 10.12.1 Durvalumab Pharmacokinetics: New section added for durvalumab PK. 
Section 10.13 Biomarkers: Specified RNA sequencing will be performed on biopsy samples, added 
collections for durvalumab PK to Table 6. 
Section 10.13.1 Tumor Biopsies: Request for 4-6 passes for optimal results. 
Section 10.13.2 Dose Escalation Biopsy Collection Plan: Organized for clarity. 
Section 10.13.3 Dose Expansion Biopsy Collection Plan: Added groups F, G, and H for patients in 
treatment Arm B. 
Section 10.14.1 Instructions for Male Patients: Added requirements for methods and timing of 
contraception. 
Section 10.14.1 Instructions for Female Patients: Added requirements for methods and timing of 
contraception. 
Section 10.14.3 Pregnancy Reporting: Added sponsor contact for reporting of pregnancies. 
Section 10.15 Overdose Management: Specified that guidance is also applicable for durvalumab. 
Section 12.1.4 Unexpected Adverse Reactions: Specified that expectedness is defined in the 
Investigator Brochures for mRNA-2416 and durvalumab. 
Section 12.1.5 Durvalumab Adverse Events of Special Interest: New section added defining 
durvalumab AESIs. 
Section 13.2 Sample Size Considerations: Added information for Arm B sample sizes. 
Section 13.4.4 PK and Pharmacodynamic Analyses: Details added to align with biomarker section. 
Section 20 References: Added reference. 
Appendix E Dose Modification and Toxicity Management Guidelines for Immune-Mediated, 
Infusion Related, and Non Immune-Mediated Reactions: New guidance added. 

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IRB/FDA Review/Approval 
 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/FDA. 
The changes described in this amended protocol require IRB approval prior to implementation. In 
addition, if the changes herein affect the Informed Consent, sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
amended protocol. 
 
 
 
Amendment 5.0 
Amendment rationale 
The main purpose of this amendment is to include a Dose Confirmation period and a Phase II 
Expansion period for patients with ovarian cancer of epithelial origin. 
 
Changes to the protocol 
Section 2 Tabulated Protocol Summary: Updated to reflect main text revisions noted below. 
Section 3 Schedule of Events: Cytokine profile sampling added. PK and Serum Immunogenicity 
sampling details moved from the footnote to new sections 10.4 and 10.5. 
Section 5 Investigators and Study Administrative Structure: Updated Moderna address and CRO 
contact. 
Section 6.1 Indication Background: Added background information for ovarian cancer. 
Section 6.4 Dosing Rationale: Specified the dosing regimen and rationale for patients that are to 
receive intratumoral injections to visceral lesions. 
Section 6.5 Patient Population: Revised to specify that patients with ovarian cancer of epithelial origin 
will be enrolled during the Dose Confirmation and Expansion periods. 
Section 7 Study Objectives and Endpoints: Primary and Secondary objectives for efficacy per 
RECIST 1.1 added for Phase II. Removed details of PK sample type which is contained in Study Lab 
Manual. 
Section 8.1 Number of Patients: Adjusted in accordance with Study Design. 
Section 8.2 Study Design: Revised to include a Dose Confirmation period and a Phase II Expansion 
period. Removed information now contained in other sections. 
Section 8.2.2 Dose Confirmation in Visceral Lesions: Section revised to describe new study part. 
Section 8.2.3 Phase II Dose Expansion Period: Section added to describe new study part. 
Section 9.1 Inclusion Criteria: Eligibility criteria regarding disease state and prior therapies for 
patients in Dose Confirmation and Phase II Expansion period added. Criteria for visceral lesions 
added. Criteria for TSH removed (Thyroid abnormalities from prior therapies still excluded per 
criteria 3). 
Section 9.2 Exclusion Criteria: Washout period for chemotherapy, radiation, hormonal anti-cancer 
treatment and biologic therapy revised to 14 days. Washout for any other investigational agent or 
treatment with any anti-cancer monoclonal antibody, immunostimulant, or vaccine unchanged as <28 
days prior to C1D1 

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Section 9.3.1 Dose Omissions and Discontinuation of Study Drug Administration: Clarified that 
disease progression or receiving alternate anticancer therapy are reasons for discontinuation of study 
treatment instead of discontinuation from all study procedures. 
Section 10.1 Intratumoral Injections: Added details for intratumoral injections to visceral lesions. 
Section 10.4 Pharmacokinetics and Immunogenicity: Details of PK and IG assessments relocated 
from Schedule of Events table footnote for clarity. 
Section 10.5 Biomarkers: Section revised to contain additional details on sampling and assessments. 
Cytokine profile sampling added. 
Section 10.5.3 Dose Expansion Biopsy Collection Plan: New section added. 
Section 10.7.3 Pregnancy Reporting: Added guidance to also report pregnancies to the CRO. 
Section 10.8 Overdose Management: New section added. 
Section 12.1.1 Adverse Events and Section 12.1.3 Serious Adverse Events: Revised reporting for 
AE/SAEs that are due to disease progression. 
Section 12.5 Follow-up for AEs: Clarified AE follow-up requirements. 
Section 13.2 Sample Size Considerations: Details added for Phase II Dose Expansion. 
Section 13.4.3 Efficacy Analysis: Details added for Phase II efficacy objectives. 
 
Amendment 4.0 
Amendment rationale 
The main purpose of this amendment is to add information regarding injection related reactions and 
recommendations for additional monitoring by investigators to ensure patient safety and updated 
ancillary treatments if reactions are observed. 
 
Changes to the protocol 
Section 10.1 Intratumoral Injections: updated to include careful monitoring for possible injection 
related reactions and a recommendation to observe all patients for a minimum of 1 hour after 
administration of each mRNA-2416 injection. 
Section 10.1.1: Ancillary Treatments: to allow the use of premedications prior to administration of 
mRNA-2416 at the discretion of the treating investigator. If the treating physician decides to 
premedicate their patients, it is recommended to do so prior to the second and subsequent injections, 
and to follow local institutional guidelines for premedication with montelukast, H-1 and H-2 
antagonists. 
 
Amendment 3.0 
Amendment rationale 
The main purpose of this amendment is to clarify pre-treatment biopsy collection details, define study 
visit windows for the Safety and Disease Progression Follow-up visits, and adjust the schedule for 
certain study procedures as described below. 

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Changes to the protocol 
Section 2 Tabulated Protocol Summary, Section 7.3 Secondary Objectives: updated 
pharmacodynamic objective to emergence of antibodies against the drug product as well as OX40L, 
the protein translated by the drug product. 
Section 2 Tabulated Protocol Summary, Section 7.4 Secondary Endpoints: removed duplicate 
mention of duration of response per RECIST/Cheson and removed cytokine levels. 
Section 3: Schedule of Events: Added +7 day visit window for the Safety Follow-up visits 
Section 3: Schedule of Events, Section 10.2 Radiological Assessments: Defined Disease Progression 
Follow-up visit timing as 90 and 180 days following end of treatment and added ± 30 day visit 
window 
Section 3: Schedule of Events: Added ± 24-hour window for C1D8 PK sample 
Section 3: Schedule of Events: Updated occurrence of symptom-directed physical examination to 
beyond cycle 2. 
Section 3: Schedule of Events: Removed sample collection for cytokine analysis 
Section 6.4 Dosing Rationale, Section 8.2.1 Dose Escalation Period: Clarified that dosing occurs on 
day 1 and day 15 of 28-day cycles. 
Section 8.2.1 Dose Escalation Period: Clarified that biopsy enrichment cohorts are separate from the 
3+3 escalation model 
Section 8.2.1.1 Biopsy Cohort Enrichment: Added updates to biopsy site information in Table 2 
Section 9.3 mRNA-2416 Dose Modification: Clarified that requirements apply to study-treatment 
related toxicities. 
Section 12 Assessment of Safety: Clarified that the AE reporting period is defined as after a patient 
signs the ICF through the patient’s last Safety Follow-up visit or study discontinuation, whichever is 
later. Guidance added that from the time of ICF signing to first dose of mRNA 2146, only AEs related 
to study procedures will be collected. Also, once a patient has ended study treatment and has initiated 
any new post-treatment antineoplastic therapy, only AEs suspected to be related to study treatment 
will be collected. 
Section 12.1.3 Serious Adverse Events: Clarified that lack of efficacy of study treatment is not 
considered an SAE. 
Section 13.4.3: Efficacy Analyses: Added that following completion of the study, best response will 
be determined for each patient in accordance with RECIST 1.1 and Cheson guidelines. 
Section 13.4.4 PK and Pharmacodynamic Analyses: Removed reference to cytokine profiling. 
 
IRB/FDA/NIH Review/Approval 
 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/FDA/NIH. 
The changes described in this amended protocol require IRB approval prior to implementation. In 
addition, if the changes herein affect the Informed Consent, sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
amended protocol. 

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Amendment 2.0 
Amendment rationale 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red font for deletions and red underlined for insertions. 
 
Section 2 Tabulated Protocol Summary, Section 7.5 Exploratory Objectives, Section 7.6 Exploratory 
Endpoints and Section 13.4.4 PK and Pharmacodynamic Analyses: removed 
• 
Mutational (neoantigen) load of tumors prior to treatment 
• 
T-cell clonality emergent in tumors and in whole blood during study therapy 
• 
Cytokine (other than TNF and IL-6) analysis 
Section 2 Tabulated Protocol Summary, Section 9.1 Inclusion Criteria and Section 10.6.1 Instructions 
for Male Patients: Modified the use a highly reliable method of birth control from the Screening visit 
through 12 weeks to 120 days after the last dose of study drug 
Section 3: Schedule of Events: Added the assessment of height, removed “Serum Sample for 
Exploratory Biomarker”, removed “T-cell Clonality in Whole Blood” 
Section 5 Investigator and Study Administrative Structure: changed CRO from PSI to PPD and 
Sponsor primary contact information 
Section 6.2 mRNA-2416 Background: included results of the in vivo genotoxicity study in Sprague 
Dawley rats and the in vivo toxicology study in the Cynomolgus Monkey 
Table 2 Group A: included OX40/OX40L expression for analysis 
Section 8.2.1.1 Biopsy Cohort Enrichment, Section 10.1 Intratumoral Injections and Section 10.4 
Tumor Biopsies: removed the option of visceral tumor injection 
Section 10.7 Additional Biomarker Assessments: Added Additional Biomarker Assessments section 
stating exploratory biomarker analysis may be conducted on any remaining tumor and/or blood samples with 
patient consent 
 
Administrative corrections for document consistency, typographical corrections and minor 
clarifications were made throughout the document. 
 
IRB/FDA/NIH Review/Approval 
 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/FDA/NIH. 
The changes described in this amended protocol require IRB approval prior to implementation. In 
addition, if the changes herein affect the Informed Consent, sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
amended protocol. 
Amendment 1.0 
Amendment rationale 
This amendment addresses the following revision requested by a regulatory authority: 
 
Section 3 Schedule of Events: Corrected tumor assessment requirement from C4 to C3 and C5 

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Section 8.2.2.1 Expansion Period Stopping Rules, Section 12 Assessment of Safety and Section 12.2 
AE Collecting and Reporting: Added language to clarify all SAEs/SUSARs and deaths will be 
reported to FDA per 21 CFR 312.32 
Section 8.4.2 Dose-Limiting Toxicities: Clarified the definition of a dose limiting toxicity 
Section 2 Tabulated Protocol Summary and Section 9.1 Inclusion Criteria: Included the following 
inclusion criteria: 
Histologically- or cytologically-confirmed advanced/metastatic solid tumor or lymphoma by 
pathology report and who has received, or been intolerant to, all approved therapies. Advanced solid 
tumors (i.e. including but not limited to melanoma, breast, head and neck squamous cell) and 
lymphomas (i.e. including by not limited to diffuse large B cell lymphoma) of any type are eligible 
for enrollment. 
No limit to the number of prior therapies 
a. Patients who refuse standard treatments may also be considered provided that he/she has been 
made aware of all therapeutic options and it is documented in the study records. 
A minimum of one lesion that is easily accessible for injection, where easily accessible is defined as 
a cutaneous or subcutaneous mass that is palpable and/or visualizable by ultrasound 
a. Biopsy Cohort Enrichment and biopsy component of the Expansion Period only: Patients must 
have a tumor lesion amenable to biopsy and consent to pre-treatment and on-treatment biopsies 
All lesion(s) targeted for the initial injection must be ≥ 0.5 cm on longest diameter, be at least 5 mm 
thick, and have distinct borders based on exam or imaging, not close to critical structures such as major 
vessels, nerves, or airways 
Section 9.3.1 Dose Omissions and Discontinuation of Study Drug Administration: Decreased the recovery 
window for a DLT from 28 days to 14 days and added the following requirement: Patients who experience a 
Grade 3 hypersensitivity reaction or autoimmune events must discontinue from study treatment. 
Section 10.2 Radiologic Assessments: Clarified the criteria for continuation of treatment for a patient that has 
disease progression per RECIST 1.1 
 
Changes to the protocol 
 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red font for deletions and red underlined for insertions. 
 
Section 2 Tabulated Protocol Summary: Simplified summary by including key protocol information 
only. In addition, all changes made throughout the protocol were reflected in the protocol summary. 
Section 3 Schedule of Events: 
• 
Added end of treatment visit 
• 
Clarified safety follow-up visit and added a 180-day safety follow-up visit 
• 
Corrected disease progression follow-up visit – visits at 3 months and 6 months post EOT 
• 
Streamlined footnotes 
• 
Corrected “symptom-directed physical exam” C2-C6 to indicate C2 only 
• 
Consolidated tumor assessment procedure to one line 
• 
Removed “baseline” – baseline assessments are done pre-dose on C1D1 or during screening 

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Section 7.1 Primary Objectives: Modified “recommended phase 2 dose” to “recommended dose for 
expansion” – this change was made throughout the document as appropriate 
Section 7.5 Exploratory Objectives: Changed “irCheson” to “lymphoma response to 
immunomodulatory therapy (LYRIC)” to assessment of overall response rate – this change was made 
throughout the document as appropriate 
Section 7.7 Safety Parameters: Antibodies against OX40L as a safety assessment for dose escalation 
will be reviewed as data are available 
Section 8.1 Number of Patients: Revised total enrollment from 60 to 75 and escalation period 
maximum enrollment from 30 to 55 
Section 8.2 Study Design: Clarified the study design; simplified study schema (Figure 1) 
Section 8.2.1 Dose Escalation Period: Clarified process for escalating a dose and added a provisional 
dose table 
Section 8.2.2.1 Expansion Period Stopping Rules: Revised DLT rate from > 33% to ≥ 33 % and 
revised text for clarification 
Section 8.4.1 Safety Review Committee: Revised text for clarification 
Section 8.4.4 Dose Escalation Procedure: Revised text to clarify the dose escalation procedure and 
adjusted the -1 provisional dose to 0.5 mg, a 50% reduction from the starting dose. Additional dosing 
below the -1 0.5 mg dose will be addressed in a protocol amendment. 
Section 9.1 Inclusion Criteria: Reference section 10.14.1 and 10.14.2 as required male and female 
methods of contraception 
Section 9.3 mRNA-2416 Dose Modification: Revised text for clarification 
Section 9.3.1 Dose Omissions and Discontinuation of Study Drug Administration: Revised text for 
clarification and added an End of Treatment visit 
Section 9.3.2 Discontinuation from the Study: Revised to include the required End of Treatment visit 
and 30 and 180-day Safety Follow-up visits. In addition, moved the language regarding permitted 
radiation to Section 9.4 Prior and Concomitant Medication 
Section 10.1 Intratumoral Injections: Clarified superficial tumor requirements 
Section 10.12 Tumor Biopsies: Revised clearly defined requirements of Group A, Group B and Group 
C 
Administrative corrections for document consistency and typographical corrections were made 
throughout the document. 
 
IRB/FDA/NIH Review/Approval 
 
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/FDA/NIH. 
The changes described in this amended protocol require IRB approval prior to implementation. In 
addition, if the changes herein affect the Informed Consent, sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this 
amended protocol. 

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2 
TABULATED PROTOCOL SUMMARY 
 
Protocol Number 
mRNA-2416-P101 
Title 
A Phase I/II, Open-Label, Multicenter, Dose Escalation and Efficacy Study of 
mRNA-2416, a Lipid Nanoparticle Encapsulated mRNA Encoding Human OX40L, 
for Intratumoral Injection Alone and in Combination with Durvalumab for Patients 
with Advanced Malignancies 
Phase 
I/II 
Indication 
Dose Escalation: Relapsed or refractory advanced solid tumor malignancies or 
lymphoma. 
Dose Expansion: Ovarian cancer of epithelial origin. 
Introduction 
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the 
field of immune-oncology for both solid tumors and hematologic malignancies. The 
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 
(PD-1) receptor and its ligand (programmed death ligand 1 [PD-L1]) are important 
cellular targets that play complementary roles in regulating adaptive immunity. 
Checkpoint inhibitors have induced regressions and improved survival in melanoma 
and non-small cell lung cancer (Robert et al 2015; Borghaei et al 2015). However, 
checkpoint inhibitors alone are not sufficient to induce significant tumor regressions 
in the majority of patients. 
Generating optimal T-cell responses also requires T-cell receptor activation and co- 
stimulation, which can be provided via ligation of tumor necrosis factor (TNF) 
receptor family members, such as OX40. The OX40 receptor (TNFRSF4, cluster of 
differentiation [CD]134) is expressed on activated immune effector cells such as 
T-cells and natural killer (NK) cells (Mallett et al 1990). The ligand for OX40, 
OX40L, is a homo-trimeric protein expressed on antigen-presenting cells 
(Compaan and Hymowitz 2006); binding of OX40 by OX40L in the presence of a 
recognized antigen, such as a tumor neoantigen, enhances the expansion of CD4+ 
and CD8+ T-cells and increases T-cell memory effects while inhibiting T regulatory 
cells. OX40 ligation with agonist antibodies boosts cytokine production and 
enhances anti-tumor immunity (Sugamura et al 2004). As a result, induction of 
expression of OX40L by tumor cells, or other cells presenting tumor antigens to 
immune effector cells, is an attractive method of enhancing local anti-tumor 
immunity and may trigger a specific cell-mediated immune response with systemic 
anti-tumor effects. Durable tumor regressions have been observed in murine mouse 
models treated with single-agent anti-OX40. 
Several agonists of OX40 have entered early-phase clinical trials. Preliminary 
results demonstrate only low-grade adverse events (AEs) coupled with minimal 
activity as a single agent. In a Phase 1 study, the preliminary safety and efficacy of 
PF04518600 was assessed with doses ranging from 0.01 to 3.0 mg/kg administered 
intravenously (IV) every 2 weeks. Treatment-emergent AEs (TEAEs) were Grades 
1 to 2 and were observed in 67.7% of patients; fatigue and decreased appetite were 
the most common TEAEs. One partial response was observed at 0.1 mg/kg, and 14 
patients experienced stable disease across the dose ranges (Diab et al 2016). Similar 
effects were seen in the Phase 1 trial of MOXR0916 (0.2 to 1200 mg IV every 3 
weeks) in which only Grade 1 and 2 TEAEs were observed; the most common 
TEAEs included fatigue, gastrointestinal (GI) symptoms, and infusion reactions. 
Minimal activity was demonstrated, but initial reports indicate that increased 

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immune activation and efficacy may be seen in combination with a PD-L1 inhibitor 
(Infante et al 2016). 
However, most agents currently being tested are administered systemically and can 
activate immune effector cells at sites of active inflammation or immune reactivity 
outside the tumor. Local induction of OX40L within the tumor milieu via 
intratumoral injection may restrict the immune response to the tumor. A resulting 
T-memory effect might then have anti-tumor effects at sites distant to the tumor 
lesion directly injected. Agents such as talimogene laherparepvec (Imlygic™, 
T-VEC) have demonstrated that intralesional injections can lead to durable 
responses (Andtbacka et al 2015). 
mRNA-2416 is a novel messenger ribonucleic acid (mRNA)-based immuno- 
oncological treatment for solid tumors that encodes the wild type human OX40L 
(hOX40L), a transmembrane T-cell costimulatory protein normally expressed on 
antigen presenting cells upon immune stimulation. 
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G 
(IgG) 1, kappa (IgG1, kappa) subclass that blocks the interaction of PD-L1 (but not 
programmed cell death - ligand 2 [PD-L2]) with programmed cell death protein 1 
(PD-1) on T-cells and cluster of differentiation (CD) 80 proteins on immune cells. 
Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of 
immune responses, including those that may result in tumor elimination. In vitro 
studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on 
primary human T cells resulting in the restored proliferation of IFN-γ (Stewart et al 
2015). In vivo studies have shown that durvalumab inhibits tumor growth in 
xenograft models via a T cell dependent mechanism (Stewart et al 2015). Based on 
these data, durvalumab is expected to stimulate the patient’s antitumor immune 
response by binding to PD L1 and shifting the balance toward an antitumor response. 
Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity 
and complement-dependent cytotoxicity. 
The population for Dose Escalation was selected as those patients with locally 
advanced, recurrent or metastatic incurable solid malignancy or lymphoma that has 
progressed after standard therapy or for which standard therapy has proven to be 
ineffective or intolerable or is considered inappropriate and are therefore considered 
to be appropriate candidates for clinical trials exploring new forms of treatment. In 
the Dose Expansion period, patients with ovarian cancer of epithelial origin will be 
enrolled at the MTD and/or RDE. 
Planned Number of 
Patients 
The planned study enrollment is approximately 117 patients. Approximately 
57 patients will be enrolled during the Dose Escalation and Dose Confirmation 
Periods of the study. During the Expansion Period of the study, approximately 60 
patients will be enrolled at the maximum tolerated dose/recommended dose for 
expansion (MTD/RDE). 
Planned Number of 
Sites 
Approximately 15 sites in the United States 

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Study Objectives 
Primary: 
Phase I 
• 
To determine safety and tolerability of escalating intratumoral doses of 
mRNA-2416 alone and in combination with durvalumab in patients with 
relapsed/refractory solid tumor malignancies or lymphoma 
• 
To define the MTD and recommended dose for expansion (RDE) and 
schedule for intratumoral injections of mRNA-2416 alone and in 
combination with durvalumab in patients with relapsed/refractory solid 
tumor malignancies or lymphoma 
Phase II 
• 
To assess objective response rate of mRNA-2416 alone and in 
combination with durvalumab in ovarian cancer based on Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 
Secondary: 
• 
To assess mRNA pharmacokinetics (PK) of mRNA-2416 alone and in 
combination with durvalumab 
• 
To assess emergence of antibodies against the drug product as well as 
OX40L, the protein translated by the drug product 
• 
To assess anti-tumor effects of mRNA-2416 alone and in combination 
with durvalumab 
• 
Phase I only: To assess objective response rate and duration of response of 
mRNA-2416 monotherapy based on Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 or Cheson 2014 criteria (lymphomas) 
• 
Phase II only: To assess disease control rate and duration of response of 
mRNA-2416 alone and in combination with durvalumab based on 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
Exploratory: 
• 
To assess objective response rate of mRNA-2416 alone and in 
combination with durvalumab based on Immune-related Response Criteria 
(irRC) or lymphoma response to immunomodulatory therapy criteria 
(LYRIC). 
• 
To assess the correlation of other investigational serum-based proteins (eg, 
anti-drug antibodies) with PK, efficacy, and safety endpoints. 
• 
To assess biomarkers of immunological response in tumor and blood of 
mRNA-2416 alone and in combination with durvalumab. 
• 
To assess pharmacokinetics (PK) of durvalumab in combination with 
mRNA-2416 
Study Outcome 
Measures 
Primary: 
Phase I 
• 
Incidence and nature of dose-limiting toxicities (DLTs) with mRNA-2416 
alone and in combination with durvalumab 

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• 
Incidence, nature, and severity of AEs/serious AEs, graded according to 
the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03 for mRNA-2416 alone and in 
combination with durvalumab 
Phase II 
• 
Assessment of objective response rate of mRNA-2416 alone and in 
combination with durvalumab in patients with ovarian cancer based on 
RECIST v1.1 
Secondary: 
• 
Presence and/or concentration of antibodies against the drug product as 
well as OX40L, the protein translated by the drug product 
• 
PK parameters for mRNA-2416 alone and in combination with 
durvalumab: maximum observed concentration and area under the 
concentration-time curve 
• 
Phase I only: Assessment of objective response rate and duration of 
response (progression-free survival) of mRNA-2416 monotherapy and 
combination with durvalumab based on RECIST v1.1 or Cheson 2014 
criteria (lymphomas) 
• 
Phase II only: Assessment of disease control rate and duration of response 
of mRNA-2416 alone and in combination with durvalumab in patients 
with ovarian cancer based on Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 
Exploratory: 
• Assessment of objective response rate of mRNA-2416 alone and in 
combination with durvalumab based on irRC or LYRIC 
• Assessment of the correlation of other investigational serum-based proteins 
(eg, anti-drug antibodies with PK, efficacy, and safety) 
• 
Evaluation of plasma will include assessment of pro-inflammatory cytokines 
and interferons 
• 
Evaluations of tumor tissue will include: 
o Expression of OX40 and OX40L and change in expression over the 
treatment period 
o Expression of other immune-related markers, including PD-1 and PD- 
L1 
o Infiltration of tumor with immune effector cells, including T-cells 
• 
PK parameters for durvalumab in combination with mRNA-2416: 
maximum observed concentration and area under the concentration-time 
curve 
Study Design 
This is an open-label, multicenter, Phase I/II Dose Escalation study of repeated 
intratumoral injections of mRNA-2416 alone (Arm A) and in combination with 
intravenously administered durvalumab (Arm B) in patients with advanced 
relapsed/refractory solid tumor malignancies or lymphoma, followed by Expansion 
periods in patients with ovarian cancer in each treatment arm. The study includes 
the following 2 treatment arms: 

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• 
Arm A: mRNA-2416 alone 
• 
Arm B: mRNA-2416 in combination with durvalumab (PD-L1 inhibitor) 
Each arm of the study consists of a Dose Escalation and Dose Confirmation part 
followed by a Dose Expansion part in ovarian cancer. Each dose level in the Dose 
Escalation period will be conducted using a standard 3+3 study design in order to 
determine the safety and tolerability of each dose. For Arm A Dose Escalation, once 
a dose level has been cleared for safety, that dose level is open to enrollment of up 
to 9 additional patients who are willing and eligible to undergo tumor biopsy. 
Once the expected MTD/RDE has been cleared in Dose Escalation for Arm A, Dose 
Escalation in Arm B will begin with mRNA-2416 at 1 dose level lower than the Arm 
A MTD/RDE according to Table 1. 
For both Arms, once the expected MTD/RDE has been cleared in Dose Escalation, 
Dose Confirmation of the MTD/RDE will be conducted in at least 3 patients with 
visceral lesions injectable with ultrasound or CT guidance. Dose Confirmation will 
be conducted in the same fashion as Dose Escalation, as described in Section 8.2.1 
and Section 8.4. 
For both Arms, once the MTD and/or RDE has been determined in Dose 
Escalation/Confirmation, patients will be enrolled in an Expansion cohort in order 
to assess the preliminary anti-tumor activity of mRNA-2416 in ovarian cancer of 
epithelial origin 
The Dose Expansion will consist of 2 investigational groups across the treatment 
arms summarized as follows and shown in Figure 1: 
Arm A: mRNA-2416 alone 
• 
Group 1: Ovarian cancer 
Arm B: mRNA-2416 in combination with durvalumab 
• 
Group 2: Ovarian cancer 
Prior to enrollment, all patients will undergo screening to determine study eligibility. 
All patients completing study therapy with an overall tumor assessment of stable 
disease (SD) or better will be followed for 6 months or until disease progression, 
whichever occurs first. 
Study Duration 
Approximately 3.5 years 
Study Population 
Inclusion Criteria 
All patients must meet all of the following inclusion criteria: 
1. Males or females ≥18 years of age who have provided written informed 
consent prior to completing any study-specific procedure 
2. Disease state and prior therapies: 
a. Dose Escalation and Dose Confirmation Periods: Histologically- or 
cytologically-confirmed advanced/metastatic solid tumor or 
lymphoma by pathology report and who has received, or been 
intolerant to, all approved therapies. Advanced solid tumors (i.e. 
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squamous cell) and lymphomas (i.e. including by not limited to diffuse 
large B cell lymphoma) of any type are eligible for enrollment. 
b. Dose Expansion Period: Histologically or cytologically confirmed 
diagnosis of: epithelial cancer of the ovary, fallopian tube, or 
peritoneum which is platinum resistant or platinum refractory. Patients 
must have received at least 2 prior lines of therapy. Patients with 
known BRCA mutation positive must have been treated with and 
progressed on at least 1 prior PARPi (poly(ADP-ribose) polymerase 
inhibitor). 
3. No limit to the number of prior therapies 
a. Patients who refuse standard treatments may also be considered 
provided that he/she has been made aware of all therapeutic options 
and it is documented in the study records. 
4. Lesions for intratumoral injection and biopsies: 
a. Dose Escalation: A minimum of one non-visceral lesion that is easily 
accessible for injection where easily accessible is defined as a 
cutaneous or subcutaneous mass that is palpable and/or visualizable by 
ultrasound 
b.  Dose Confirmation: A minimum of one visceral lesion injectable with 
ultrasound or computer tomography (CT) guidance and that is not 
encasing or abutting major vascular structures or are in a location that 
are considered high risk for AEs by the enrolling physician 
c. Dose Expansion: A minimum of one lesion amenable to injection 
(either non-visceral or visceral). Patients must have a tumor lesion 
amenable to biopsy and consent to a pre-treatment and an on-treatment 
biopsy. For patients with only one lesion amenable to injection, 
biopsy, and RECIST assessment, the lesion must be ≥ 2 cm. 
d. Biopsy Cohort Enrichment: Patients must have a tumor lesion 
amenable to biopsy and consent to a pre-treatment and an on-treatment 
biopsy 
5. All lesion(s) targeted for the initial injection must be ≥ 0.5 cm on longest 
diameter, be at least 5 mm thick, and have distinct borders based on exam or 
imaging, not close to critical structures such as major vessels, nerves, or 
airways 
6. Patients must have measurable disease as determined by RECIST v1.1 (solid 
tumors) or Cheson 2014 criteria (lymphomas). 
a. Dose Expansion: Patients must have at least 1 measurable lesion per 
RECIST v1.1 which has not been previously irradiated. 
7. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 
8. Adequate hematological and biological function, confirmed by the following 
laboratory values: 
Bone marrow function 

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a. Absolute neutrophil count ≥1.5 × 109/L 
b. Hemoglobin ≥9 g/dL or ≥6.2 mmol/L 
c. Platelets ≥100 × 109/L without transfusion support 
Hepatic function 
d. Aspartate aminotransferase and alanine aminotransferase ≤2.5 × upper 
limit of normal (ULN) (≤5 × ULN, if hepatic involvement of tumor) 
e. Bilirubin ≤1.5 × ULN (<3.0 mg/dL if patient has Gilbert’s disease) 
Renal function 
f. Serum creatinine ≤1.5 × ULN or creatinine clearance of >50 mL/min 
(using Cockcroft-Gault formula) 
(140−𝐴𝐴𝐴𝐴𝐴𝐴 [𝑦𝑦𝑦𝑦𝑦𝑦]) × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 [𝑘𝑘𝑘𝑘] × [0.85 𝑖𝑖𝑖𝑖 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹] 
𝑒𝑒𝑒𝑒𝐶𝐶𝐶𝐶[𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚𝑚𝑚] = 
72 × 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 [𝑚𝑚𝑚𝑚⁄𝑑𝑑𝑑𝑑] 
Coagulation function 
g. Protime/international 
normalized 
ratio 
and 
activated 
partial 
thromboplastin time ≤1.5 × ULN 
Thyroid function 
h. Thyroid-stimulating hormone within normal range 
9. Female patients of childbearing potential must have a negative serum 
pregnancy test during screening. Male and female patients must agree to use a 
highly reliable method of birth control (expected failure rate less than 1% per 
year) from the Screening visit through 120 days after the last dose of study 
drug. Patients must consent to following the contraception requirements in 
Section 10.14.1 and 10.14.2 
10. Must have a life expectancy of at least 12 weeks 
11. Body weight >30 kg. 
Exclusion Criteria 
Any of the following criteria will exclude patients from study participation: 
1. Active central nervous system tumors or metastases 
2. Treatment with chemotherapy, radiation (local radiation for palliative care is 
permitted), hormonal anti-cancer treatment, or biologic therapy <14 days prior 
to the first day of study treatment (Cycle 1 Day 1 [C1D1]) 
a. Treatment with any other investigational agent or treatment with any 
anti-cancer monoclonal antibody, immunostimulant, or vaccine <28 
days prior to C1D1. 
3. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer 
therapy with the exception of alopecia, vitiligo, and the laboratory values 
defined in the inclusion criteria 
• 
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case 
basis after consultation with the Study Physician. 
• 
Patients with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab may be included only after 
consultation with the Study Physician. 

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4. History of severe allergic reactions to any of the study drug components 
5. Has active or prior documented autoimmune or inflammatory disorders 
(including inflammatory bowel disease [eg, colitis or Crohn’s disease], 
diverticulitis [with the exception of diverticulosis], systemic lupus 
erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis 
with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, 
etc]). The following are exceptions to this criterion: 
• 
Patients with vitiligo or alopecia 
• 
Patients with hypothyroidism (eg, following Hashimoto syndrome) stable 
on hormone replacement 
• 
Patients with any chronic skin condition that does not require systemic 
therapy 
• 
Patients without active disease in the last 5 years may be included but only 
after consultation with the Moderna medical monitor 
• 
Patients with celiac disease controlled by diet alone. 
6. Has a history of primary immunodeficiency, allogenic solid organ 
transplantation, or tuberculosis. 
7. Immunosuppressive doses of systemic steroids or absorbed topical steroids 
(doses >10 mg prednisone daily equivalent) within 2 weeks before study drug 
administration 
8. Local infection at site of a tumor lesion amenable to injection requiring anti- 
infective therapy within 2 weeks of the first dose of study drug 
9. Receipt of live attenuated vaccine within 30 days prior to the first dose of 
study treatment. Note: Patients, if enrolled, should not receive live vaccine 
whilst receiving study treatment and up to 30 days after the last dose of study 
treatment. 
10. History of human immunodeficiency virus infection 
11. Active/chronic hepatitis B or C 
12. Major surgical procedures ≤28 days or non-study-related minor procedures 
≤7 days prior to C1D1. In all cases, the patient must be sufficiently recovered 
and stable before treatment administration. 
13. Any of the following cardiac abnormalities: 
a. Medically uncontrolled hypertension 
b. New York Heart Association Class III or IV cardiac disease 
c. Myocardial infarction within prior 6 months 
d. Unstable angina 
e. Unstable arrhythmias or mean QT interval corrected for heart rate 
using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs 
(within 15 minutes at 5 minutes apart) 
14. History of another primary malignancy except for: 
• 
Malignancy treated with curative intent and with no known active disease 
≥5 years before the first dose of IP and of low potential risk for recurrence 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 

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• 
Adequately treated carcinoma in situ without evidence of disease 
15. Patients requiring active systemic anticoagulation at the time of intratumoral 
injection or biopsy 
16. Active GI bleeding 
17. Females who are pregnant or breastfeeding 
18. Any other unstable or clinically significant concurrent medical condition (eg, 
substance abuse, psychiatric illness/social situations, uncontrolled intercurrent 
illness including active infection, arterial thrombosis, symptomatic pulmonary 
embolism, active interstitial lung disease, serious chronic gastrointestinal 
conditions associated with diarrhea etc) that would, in the opinion of the 
investigator, jeopardize the safety of a patient, impact their expected survival 
through the end of the study participation, and/or impact their ability to give 
written informed consent or comply with the protocol. 
19. For patients who have received prior anti-PD-1 or anti PD-L1 therapy, a 
patient must not have experienced any of the following: 
a. Must not have experienced a toxicity that led to permanent 
discontinuation of prior immunotherapy. 
b. All AEs while receiving prior immunotherapy must have completely 
resolved or resolved to baseline prior to screening for this study. 
20. Must not have experienced a ≥ Grade 3 immune-related AE or an 
immune-related neurologic or ocular AE of any grade while receiving prior 
immunotherapy. Note: Patients with endocrine AEs of ≤ Grade 2 are permitted 
to enroll if they are stable while maintained on appropriate replacement 
therapy and are asymptomatic. 
21. Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE, not have experienced recurrence 
of an AE if re-challenged, and not currently require maintenance doses of > 10 
mg prednisone or equivalent per day. 
22. Has an active infection including tuberculosis (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and 
tuberculosis testing in line with local practice), hepatitis B (known positive 
HBV surface antigen [HBsAg] result), hepatitis C, or human 
immunodeficiency virus (positive HIV-1/2 antibodies). Patients with a past or 
resolved HBV infection (defined as the presence of hepatitis B core antibody 
[anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis 
C (HCV) antibody are eligible only if polymerase chain reaction is negative 
for HCV RNA. 
23. Has a history of (non-infectious) pneumonitis that required steroids or has 
current pneumonitis. 
24. Has a history of leptomeningeal carcinomatosis. 
25. Has involvement in the planning and/or conduct of the study. 
Study Drug, 
Dosage and Route 
of Administration 
mRNA-2416 will be administered to patients as intratumoral injections on Days 1 
and 15 of each 28-day cycle (±2 days). All patients in Arm B and Arm A patients 
that are to receive intratumoral injections to visceral lesions will reduce dosing 
frequency to every 4 weeks after completing 1 cycle of therapy (Day 1 and Day 15 
for Cycle 1, then Day 1 only for Cycles 2-6). 

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The starting dose is 1.0 mg mRNA-2416 for Arm A and 4.0mg mRNA-2416 in 
combination with 1500mg of durvalumab for Arm B; other dose levels may be 
evaluated during this trial. 
Randomization 
Not applicable 
Efficacy 
Assessments 
Best response will be determined for each patient in accordance with 
RECIST/Cheson and irRC/LYRIC guidelines. 
Safety Assessments 
Safety measures will include: 
• 
AEs (including imAEs and AESIs) 
• 
Hematology, clinical chemistry, and liver function tests 
• 
12-Lead electrocardiograms 
• 
Physical examination 
• 
Vital signs and body weight 
• 
Concomitant medications/procedures 
• 
ECOG performance status 
• 
Antibodies against OX40L, the protein translated by the drug product, will 
be reviewed with investigators as data are available 
Where applicable, AEs will be classified according to the NCI CTCAE 
Version 4.03. 
Biomarker & 
Pharmacodynamic 
Assessments 
The biomarker analysis will be used to investigate the effect of mRNA-2416 alone 
and in combination with durvalumab, as well as to determine how the markers are 
associated with clinical outcome. Immune responses will be studied in the peripheral 
circulation and in tumor biopsy specimens. Tumor biopsies will be examined using 
methods such as immunohistochemistry, quantitative immunofluorescence, RNA 
sequencing, and/or electrochemiluminescence (ECL) assays to evaluate changes in 
key immune pathway axes, such as PD-L1/PD-1 and OX40L/OX40, as well as 
characterization (eg, phenotype, distribution, and activation) of tumor infiltrating 
lymphocyte and myeloid populations. Cytokines will also be examined in both 
tumor and blood tissues using methods such as RNA sequencing and enzyme-linked 
immunosorbent assay (ELISA)/ ECLassays respectively. 
Patient Reported 
Outcome 
Assessments 
None 
Statistical 
Procedures 
Described in Section 13 and in the Statistical Analysis Plan 

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3 
SCHEDULE OF EVENTS 
 
Study Procedure 
Screening 
Cycle 1 
Cycle 2 - 
Cycle 6 
End of 
Treatment 
Follow-up 
Study Days 
-14 to -1 
1 
2 
8 
15 
1 
15 
Within 14 days 
of Treatment 
Discontinuation 
30 and 90 Day 
Safety F/U 
90 and 180 
Day Disease 
Progression 
F/U Period 
Visit Window 
- 
- 
+1 day 
±2 
days 
±2 days 
±2 days 
-2/+7 days 
±30 days 
Clinical Assessments 
Informed Consent 
X 
Inclusion/exclusion criteria 
X 
Demographics1 
X 
Medical/Surgical/Cancer Histories2 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Body Weight 
X 
X 
X 
X 
X 
Physical Exam4 
X 
X 
Symptom-directed Physical Exam 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
Concomitant Medications5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Assessments 
Full Blood Count6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation6 
X 
X 
X 
Serum Chemistry Panel6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid Function 12 
X 
X 
X 
X 
X 
X 
Urinalysis6 
X 
X 
Pregnancy Test 10 
X 
X 
X 
X 
X 
12-Lead Electrocardiogram 
X 
X 
X 
HIV, Hepatitis B & C Tests6,11 
X 
Study Drug Administration 

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Study Procedure 
Screening 
Cycle 1 
Cycle 2 - 
Cycle 6 
End of 
Treatment 
Follow-up 
Study Days 
-14 to -1 
1 
2 
8 
15 
1 
15 
Within 14 days 
of Treatment 
Discontinuation 
30 and 90 Day 
Safety F/U 
90 and 180 
Day Disease 
Progression 
F/U Period 
Visit Window 
- 
- 
+1 day 
±2 
days 
±2 days 
±2 days 
-2/+7 days 
±30 days 
mRNA-2416 intratumoral injection7 
X 
X 
X 
X7 
Durvalumab infusion 
X 
X 
Tumor Assessments 
Tumor assessment8 
X 
C3 & 
C5 
X 
X 
PK/Pharmacodynamic Assessments 
PK Sampling9 
X 
X 
X 
C2 
Cytokine Profile Sampling9 
X 
X 
X 
C2 
Serum Immunogenicity Sample9 
X 
X 
X 
C3 & 
C6 
X 
Tumor Biopsy 
X 
Refer to Section 10.5 
1. 
Demographics include age, sex, race, and ethnicity. 
2. 
Prior cancer history includes (i) date of diagnosis, (ii) staging, (iii) all previous therapies (ie, chemotherapy, immunotherapy, biologic or targeted agents, experimental therapies, 
radiotherapy, and surgery), (iv) previous therapy details (ie, regimen, start and stop dates), and (v) best response for each regimen. 
3. 
Vital signs include temperature, blood pressure, preferably in seated position, and pulse rate. Pre-dose and as clinically indicated before every infusion or administration. 
4. 
Complete physical examination should include evaluation of the HEENT and neck and dermatologic, cardiovascular, respiratory, gastrointestinal (including assessments of liver and 
spleen), musculoskeletal, neurological, and lymphatic systems. 
5. 
Please refer to Section 10.8 for additional detail regarding prior and concomitant medications 
6. 
Please reference Appendix B Safety Laboratory Tests and Hepatitis Serology 
7. 
Only for Arm A patients receiving treatment to superficial lesions. All patients in Arm B and patients in Arm A receiving treatment to visceral lesions are to receive intratumoral injections 
on Day 1 and Day 15 for Cycle 1, and on Day 1 only for Cycles 2-6. Please refer to Section 8.2 Study Design and Section 10.1 Intratumoral Injections for mRNA-2416 dosing requirements. 
8. 
Please refer to Section 10.2 and 10.3 for tumor assessment imaging requirements 
9. 
Please refer to Table 6 for PK, Cytokine Profile, and Serum Immunogenicity sampling details. 
10. Females of child bearing potential only. 
11. Testing for HIV and Hepatitis B or C is to be done locally. It is not required if a documented negative test within 6 months is available. 
12. TSH and reflex free T3 or free T4g. If measured within 14 days prior to C1D1, it does not need to be repeated at C1D1. 

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TABLE OF CONTENTS 
1 
SPONSOR SIGNATURE PAGE ............................................................................................ 2 
2 
TABULATED PROTOCOL SUMMARY ........................................................................... 12 
3 
SCHEDULE OF EVENTS ..................................................................................................... 22 
4 
LIST OF ABBREVIATIONS ............................................................................................... 28 
5 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .......................... 31 
6 
BACKGROUND AND RATIONALE.................................................................................. 32 
6.1 
INDICATION BACKGROUND ............................................................................................................................ 33 
6.2 
MRNA-2416 BACKGROUND .......................................................................................................................... 33 
6.3 
DURVALUMAB BACKGROUND ....................................................................................................................... 35 
6.4 
MRNA-2416 DOSING RATIONALE ............................................................................................................... 36 
6.5 
DURVALUMAB DOSING RATIONALE ............................................................................................................. 37 
6.6 
PATIENT POPULATION ....................................................................................................................................... 38 
6.7 
STATEMENT OF COMPLIANCE ........................................................................................................................ 38 
7 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 39 
7.1 
PRIMARY OBJECTIVES ....................................................................................................................................... 39 
7.2 
PRIMARY ENDPOINTS ....................................................................................................................................... 39 
7.3 
SECONDARY OBJECTIVES................................................................................................................................ 39 
7.4 
SECONDARY ENDPOINTS ................................................................................................................................. 40 
7.5 
EXPLORATORY OBJECTIVES ........................................................................................................................... 40 
7.6 
EXPLORATORY ENDPOINTS ............................................................................................................................ 40 
7.7 
SAFETY PARAMETERS ...................................................................................................................................... 41 
8 
STUDY DESIGN .................................................................................................................... 42 
8.1 
NUMBER OF PATIENTS ..................................................................................................................................... 42 
8.2 
STUDY DESIGN ................................................................................................................................................... 42 
8.2.1 
ARM A DOSE ESCALATION PERIOD ............................................................................................................. 43 
8.2.2 
ARM A DOSE ESCALATION BIOPSY COHORT ENRICHMENT ................................................................ 44 
8.2.3 
ARM B DOSE ESCALATION PERIOD ............................................................................................................. 44 
8.2.4 
DOSE CONFIRMATION IN VISCERAL LESIONS ........................................................................................... 45 
8.2.5 
ARM A PHASE II DOSE EXPANSION PERIOD ............................................................................................ 45 
8.2.6 
ARM B PHASE II DOSE EXPANSION PERIOD .............................................................................................. 45 
8.2.7 
PHASE II DOSE EXPANSION PERIOD STOPPING RULES .......................................................................... 45 
8.3 
STUDY FLOW AND EXPECTED DURATION OF PATIENT PARTICIPATION ........................................... 46 
8.4 
DOSE ESCALATION PROCEDURES .................................................................................................................. 46 
8.4.1 
SAFETY REVIEW COMMITTEE (SRC) ....................................................................................... 46 
8.4.2 
DEFINITION OF DOSE-LIMITING TOXICITIES .............................................................................................. 47 
8.4.3 
DEFINITION OF MTD ................................................................................................................ 48 
8.4.4 
DOSE ESCALATION PROCEDURE .................................................................................................................... 48 
9 
SELECTION OF PATIENTS ............................................................................................... 49 
9.1 
INCLUSION CRITERIA ........................................................................................................................................ 49 
9.2 
EXCLUSION CRITERIA ...................................................................................................................................... 50 

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10 
STUDY PROCEDURES ....................................................................................................... 52 
10.1 
INTRATUMORAL INJECTIONS ......................................................................................................................... 52 
10.2 
DURVALUMAB ADMINISTRATION ................................................................................................................ 54 
10.3 
MRNA-2416 DOSE MODIFICATION ............................................................................................................. 55 
10.4 
DURVALUMAB DOSE MODIFICATION AND TOXICITY MANAGEMENT 
GUIDELINES ......................................................................................................................................................... 55 
10.5 
DOSE OMISSIONS AND DISCONTINUATION OF STUDY DRUG ADMINISTRATION ........................... 55 
10.6 
DISCONTINUATION FROM THE STUDY ......................................................................................................... 57 
10.6.1 
HANDLING OF WITHDRAWALS OF CONSENT ............................................................................................ 57 
10.7 
ANCILLARY TREATMENTS .............................................................................................................................. 57 
10.8 
CONCOMITANT THERAPY................................................................................................................................ 58 
10.9 
MANAGEMENT OF CLINICAL SUPPLIES ....................................................................................................... 60 
10.10 
RADIOLOGIC ASSESSMENTS ........................................................................................................................... 60 
10.11 
OPTIONAL DIGITAL PHOTOGRAPHY ............................................................................................................ 62 
10.12 
PHARMACOKINETICS AND IMMUNOGENICITY .......................................................................................... 62 
10.12.1 
DURVALUMAB PHARMACOKINETICS........................................................................................................... 62 
10.13 
BIOMARKERS ...................................................................................................................................................... 62 
10.13.1 
TUMOR BIOPSIES ............................................................................................................................................... 63 
10.13.2 
DOSE ESCALATION BIOPSY COLLECTION PLAN ...................................................................................... 64 
10.13.3 
DOSE EXPANSION BIOPSY COLLECTION PLAN ......................................................................................... 65 
10.13.4 
ADDITIONAL BIOMARKER ASSESSMENTS .................................................................................................. 67 
10.14 
PREGNANCY CONSIDERATIONS ..................................................................................................................... 67 
10.14.1 
INSTRUCTIONS FOR MALE PATIENTS........................................................................................................... 68 
10.14.2 
INSTRUCTIONS FOR FEMALE PATIENTS ....................................................................................................... 68 
10.14.3 
PREGNANCY REPORTING .................................................................................................................................. 69 
10.14.3.1 
FOLLOW-UP IN THE EVENT OF A PREGNANCY .......................................................................................... 69 
10.15 
OVERDOSE MANAGEMENT ............................................................................................................................. 69 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................... 70 
11.1 
QUALITY CONTROL ........................................................................................................................................... 70 
11.1.1 
MONITORING ...................................................................................................................................................... 70 
11.2 
QUALITY ASSURANCE ...................................................................................................................................... 70 
12 
ASSESSMENT OF SAFETY ................................................................................................ 70 
12.1 
DEFINITIONS........................................................................................................................................................ 70 
12.1.1 
ADVERSE EVENT ............................................................................................................................................... 70 
12.1.2 
ADVERSE DRUG REACTION ............................................................................................................................ 71 
12.1.3 
SERIOUS ADVERSE EVENT .............................................................................................................................. 71 
12.1.4 
UNEXPECTED ADVERSE REACTIONS ........................................................................................................... 72 
12.1.5 
DURVALUMAB ADVERSE EVENTS OF SPECIAL INTEREST ..................................................................... 72 
12.2 
AE COLLECTING AND REPORTING ................................................................................................................ 73 
12.3 
RELATIONSHIP TO STUDY DRUG................................................................................................................... 74 
12.4 
LABORATORY TEST ABNORMALITIES ......................................................................................................... 75 
12.5 
FOLLOW-UP OF AES .......................................................................................................................................... 75 
13 
STATISTICAL METHODS ................................................................................................. 76 
13.1 
DATA COLLECTION AND PROCESSING ........................................................................................................ 76 
13.2 
SAMPLE SIZE CONSIDERATIONS ..................................................................................................................... 76 
13.3 
HANDLING OF MISSING DATA ....................................................................................................................... 76 
13.4 
STATISTICAL METHODOLOGY ....................................................................................................................... 76 
13.4.1 
ANALYSIS POPULATIONS ................................................................................................................................ 77 

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13.4.2 
SAFETY ANALYSES ........................................................................................................................................... 77 
13.4.3 
EFFICACY ANALYSES ....................................................................................................................................... 77 
13.4.4 
PK AND PHARMACODYNAMIC ANALYSES................................................................................................. 78 
13.4.5 
INTERIM ANALYSIS ........................................................................................................................................... 78 
14 
STUDY DRUG MATERIALS .............................................................................................. 78 
14.1 
INVESTIGATIONAL PRODUCT .......................................................................................................................... 78 
14.2 
STUDY DRUG PREPARATION .......................................................................................................................... 78 
14.3 
STUDY DRUG STORAGE ................................................................................................................................... 79 
14.4 
STUDY DRUG PACKAGING AND LABELING ............................................................................................... 79 
14.5 
STUDY DRUG ACCOUNTABILITY .................................................................................................................. 79 
14.6 
STUDY DRUG HANDLING AND DISPOSAL .................................................................................................. 79 
15 
INVESTIGATOR REQUIREMENTS ................................................................................. 79 
15.1 
AE COLLECTION AND REPORTING ............................................................................................................... 79 
15.2 
PROTOCOL ADHERENCE .................................................................................................................................. 80 
15.3 
CASE REPORT FORMS....................................................................................................................................... 80 
15.4 
SOURCE DOCUMENT MAINTENANCE .......................................................................................................... 80 
15.5 
STUDY MONITORING REQUIREMENTS ........................................................................................................ 80 
15.6 
STUDY COMPLETION ........................................................................................................................................ 81 
16 
PROTECTION OF HUMAN PATIENTS AND GENERAL STUDY 
ADMINISTRATION ............................................................................................................. 81 
16.1 
INFORMED CONSENT ........................................................................................................................................ 81 
16.2 
IRB APPROVAL .................................................................................................................................................. 81 
16.3 
PATIENT DATA PROTECTION ......................................................................................................................... 81 
17 
DATA MANAGEMENT AND MONITORING ................................................................. 82 
17.1 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................................................... 82 
17.2 
RETENTION OF RECORDS ................................................................................................................................ 82 
18 
FINANCING AND INSURANCE ........................................................................................ 82 
19 
PUBLICATION POLICY ..................................................................................................... 82 
20 
REFERENCES ...................................................................................................................... 83 
APPENDIX A: 
ECOG PERFORMANCE STATUS........................................................................... 85 
APPENDIX B: 
SAFETY LABORATORY TESTS AND HEPATITIS SEROLOGY ..................... 86 
APPENDIX C: 
SUMMARY OF TUMOR ASSESSMENT CRITERIA ........................................... 87 
APPENDIX D: 
SUMMARY OF RECIST 1.1 CRITERIA ................................................................. 93 
APPENDIX E: DOSE MODIFICATION AND TOXICITY MANAGEMENT 
GUIDELINES FOR IMMUNE-MEDIATED, INFUSION RELATED, 
AND NON IMMUNE-MEDIATED REACTIONS ............................................................. 95 

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LIST OF TABLES 
Table 1: 
Arm A Provisional Dose Levels ................................................................................ 43 
Table 2: 
Arm B Provisional Dose Levels ................................................................................ 44 
Table 3: 
Maximum Injection Volume per Lesion Size ......................................................... 53 
Table 4: 
Prohibited concomitant medications ....................................................................... 58 
Table 5: 
Supportive medications ............................................................................................ 60 
Table 6: 
Sampling schedule for Pharmacokinetics, Immunogenicity, and 
Cytokine Profiling ..................................................................................................... 63 
Table 7: 
Dose Escalation Tumor Biopsy Analyses by Group .............................................. 64 
Table 8: 
Arm A Dose Expansion Tumor Biopsy Analyses by Group ................................. 66 
Table 9: 
Arm B Dose Expansion Tumor Biopsy Analyses by Group .................................. 67 
Table 10 
Highly effective methods of contraception (<1% failure rate) .............................. 69 
 
 
LIST OF FIGURES 
Figure 1: 
mRNA-2416-P101 Study Schema ............................................................................ 43 

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4 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Definitions 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT/GPT 
Alanine aminotransferase 
AST/GOT 
Aspartate aminotransferase 
ATA 
Anti-therapeutic antibody 
AUC 
area under the concentration-time curve 
BUN 
blood urea nitrogen 
CXDX 
Cycle X Day X 
CD 
cluster of differentiation 
CD4 
cluster of differentiation 4: a glycoprotein that is found primarily on the surface of 
helper T-cells 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed concentration 
CR 
complete response 
CRF 
case report form 
CRO 
Contract Research Organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T lymphocyte-associated antigen 4 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
ECL 
electrochemiluminescence 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
F/U 
Follow Up 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 

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Abbreviation 
Definitions 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C antibody 
hrs 
hours 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IND 
Investigational New Drug 
IR 
Immune response 
IRB 
Institutional Review Board 
irRC 
Immune-related Response Criteria 
IV 
intravenous(ly) 
kg 
kilogram 
L 
liter 
LDH 
lactic dehydrogenase 
LNP 
lipid nanoparticle 
LYRIC 
lymphoma response to immunomodulatory therapy criteria 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minute(s) 
mg 
milligram 
mL 
milliliter 
mmol 
millimoles 
mM 
millimolar 
mRNA 
messenger ribonucleic acid 
MTD 
maximum tolerated dose 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NIH 
National Institute of Health 
NK 
natural killer 
OX40L 
OX40 ligand 
PARPi 
poly(ADP-ribose) polymerase inhibitor 
PD 
progressive disease 

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Abbreviation 
Definitions 
PD-1 
programmed death 1 
PD-L1 
programmed death ligand 1 
PI 
Principal Investigator 
PK 
pharmacokinetics 
PR 
partial response 
QIF 
quantitative immunofluorescence 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RDE 
recommended dose for expansion 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SD 
Stable Disease 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
US / USA 
United States of America 
WBC 
white blood cell 

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5 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
SPONSOR 
ModernaTX, Inc. 
 
200 Technology Square 
Cambridge, MA 02139 
USA 
Phone:+1-617-714-6500 
 
Phone:
Email: 
 
 
 
CONTRACT RESEARCH ORGANIZATION 
PPD, Inc 
929 N. Front Street 
Wilmington, NC 28401 
USA 
 
 
 
Phone:
Email: 
PPD
PPD
PPD
PPD
PPD

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6 
BACKGROUND AND RATIONALE 
 
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of immune-oncology 
for both solid tumors and hematologic malignancies. The cytotoxic T lymphocyte-associated antigen 4 
(CTLA-4) and programmed death 1 (PD-1) receptor and its ligand (programmed death ligand 1 [PD-L1]) 
are important cellular targets that play complementary roles in regulating adaptive immunity. Checkpoint 
inhibitors have induced regressions and improved survival in melanoma and non-small cell lung cancer 
(Robert et al 2015; Borghaei et al 2015). However, checkpoint inhibitors alone are not sufficient to induce 
significant tumor regressions in the majority of patients. 
 
Generating optimal T-cell responses also requires T-cell receptor activation and co-stimulation, which can 
be provided via ligation of tumor necrosis factor (TNF) receptor family members, such as OX40. The OX40 
receptor (TNFRSF4, cluster of differentiation [CD]134) is expressed on activated immune effector cells 
such as T-cells and natural killer (NK) cells (Mallett et al 1990). The ligand for OX40, OX40L, is a homo- 
trimeric protein expressed on antigen-presenting cells (Compaan and Hymowitz 2006); binding of OX40 
by OX40L in the presence of a recognized antigen, such as a tumor neoantigen, enhances the expansion of 
CD4+ and CD8+ T-cells and increases T-cell memory effects while inhibiting T regulatory cells. OX40 
ligation with agonist antibodies boosts cytokine production and enhances anti-tumor immunity (Sugamura 
et al 2004). As a result, induction of expression of OX40L by tumor cells, or other cells presenting tumor 
antigens to immune effector cells, is an attractive method of enhancing local anti-tumor immunity and may 
trigger a specific cell-mediated immune response with systemic anti-tumor effects. Durable tumor 
regressions have been observed in murine mouse models treated with single-agent anti-OX40. 
 
Several agonists of OX40 have entered early-phase clinical trials. Preliminary results demonstrate only low- 
grade adverse events (AEs) coupled with minimal activity as a single agent. In a Phase 1 study, the 
preliminary safety and efficacy of PF04518600 was assessed with doses ranging from 0.01 to 3.0 mg/kg 
administered intravenously (IV) every 2 weeks. Treatment-emergent AEs (TEAEs) were Grades 1 to 2 and 
were observed in 67.7% of patients; fatigue and decreased appetite were the most common TEAEs. One 
partial response was observed at 0.1 mg/kg, and 14 patients experienced stable disease across the dose 
ranges (Diab et al 2016). Similar effects were seen in the Phase 1 trial of MOXR0916 (0.2 to 1200 mg IV 
every 3 weeks) in which only Grade 1 and 2 TEAEs were observed; the most common TEAEs included 
fatigue, gastrointestinal (GI) symptoms, and infusion reactions. Minimal activity was demonstrated, but 
initial reports indicate that increased immune activation and efficacy may be seen in combination with a 
PD-L1 inhibitor (Infante et al 2016). 
 
However, most agents currently being tested are administered systemically and can activate immune 
effector cells at sites of active inflammation or immune reactivity outside the tumor. Local induction of 
OX40L within the tumor milieu via intratumoral injection may restrict the immune response to the tumor. 
A resulting T-memory effect might then have anti-tumor effects at sites distant to the tumor lesion directly 
injected. This can improve outcomes from systemically delivered antibodies, such as CPIs, and have an 
improved tolerability profile compared to systemic therapy alone. Intratumoral administration of 
immune-mediated therapies have primarily included oncolytic viruses, DNA-based gene delivery, small 
molecules, and antibodies (Aznar et al 2017; Van Lint et al 2016). More recently, mRNA-based therapies 
have been studied in this setting. Moderna’s platform enables the local delivery of several mRNAs 
formulated in LNPs that can encode various proteins that have distinct functions yet work synergistically 
in mediating anti-cancer responses. 
 
Based on the afore-mentioned research, ModernaTX, Inc. is proposing to conduct a clinical study using 
mRNA-2416 encoding for OX40L as a monotherapy and in combination with an anti-PD-L1 antibody. 

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6.1 
INDICATION BACKGROUND 
 
Cancer immunotherapy attempts to stimulate the immune system to recognize and destroy tumor cells. To 
date, a variety of methods have been utilized. Most recently, the advent of checkpoint inhibitors has 
demonstrated activity in a multitude of tumor types. Although ipilimumab has been approved for melanoma 
only (metastatic and adjuvant treatment), PD-1/PD-L1 inhibitors have expanded use into additional tumor 
types including non-small cell lung cancer, renal cell carcinoma, Hodgkin’s disease, and urothelial 
carcinoma. In addition, a multitude of tumor types are currently under investigation including both solid 
tumors and hematologic malignancies. Likewise, use of an immunostimulatory molecule such as an OX40L 
should have activity in a wide variety of tumors. 
 
Ovarian cancer is the leading cause of death from gynecological malignancies in the United States with an 
incidence rate of approximately 22,000 and 14,000 deaths per year (Meehan et al 2016). The five-year 
survival rate remains dismal especially for later stage disease. While great strides have been made with 
immunotherapy, ovarian carcinoma hasn’t seen much benefit from these advances. Recent phase I and II 
studies demonstrate limited monotherapy activity of PD-1/PD-L1 pathway inhibition in recurrent ovarian 
cancer, yielding 11% to 17% response rates, with a few durable complete responses in a subset of heavily 
pretreated patients (Bourla et al 2016). During the dose escalation period of this trial, 2 epithelial ovarian 
cancer patients were enrolled and had stable disease per RECIST1.1 with noted response in injected lesions 
(SITC annual meeting 2018 poster P295). 
 
6.2 
mRNA-2416 BACKGROUND 
 
mRNA-2416 is a novel mRNA-based therapeutic agent containing 2 mg/mL of CX-000006, mRNA Drug 
Substance, that encodes the wild type human OX40 ligand (OX40L), a transmembrane protein normally 
expressed on antigen presenting cells upon immune stimulation. mRNA-2416 is intended for intratumoral 
injection. 
 
Modified mRNA is less immunogenic than unmodified mRNA and results in increased protein translation. 
Both the murine and human OX40L mRNA constructs that have been tested encode the wild type 
transmembrane OX40L protein. Each construct also contains a miR-122 recognition site in the 
3’ untranslated region, which significantly reduces protein expression by normal hepatocytes, a potentially 
undesirable location for immune activation. The mRNA is then encapsulated in lipid nanoparticles and may 
be used for direct injection. 
 
Transfection of mRNA encoding both murine and human OX40L has been shown to induce functionally 
active surface-bound OX40L protein both in vitro and in vivo. Expression is stable in vitro for up to 5 days. 
After injection of the murine analog of OX40L mRNA to murine tumors, expression of OX40L protein 
peaks at around 24 hours and is still detectable at 7 days. Pharmacodynamic studies demonstrate rapid 
increase of NK cells within the tumor following injection of OX40L mRNA, followed at 7 to 14 days by 
an increase in CD8+ T-cells. Non-translated mRNA has no effect. 
 
The efficacy of murine OX40L mRNA has been tested in subcutaneous murine models of cancer in 
immunocompetent mice. Injection of OX40L mRNA encapsulated in a lipid nanoparticle (LNP) directly 
into established tumors induces tumor regressions and tumor growth delay. Mice in whom tumors 
completely regress did not grow tumors when challenged with re-implantation, suggesting an immune 
memory response was induced, which resulted in tumor rejection. Weekly injection of OX40L mRNA for 
6 to 8 doses resulted in efficacy, which appears to be superior to 2 doses. There was also a dose-dependent 
effect; 12.5 µg of mRNA weekly was more efficacious than 6.25 µg or 3.25 µg. 

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The efficacy of murine OX40L mRNA in combination with anti-PD-L1 checkpoint inhibitor has been tested 
in the syngeneic MC38S colon carcinoma tumor model. Weekly injection of OX40LmRNA encapsulated 
in LNP combined with αPD-L1 antibody administered via IP injection twice weekly resulted in 8/15 
complete responders (CRs) (53%) at the end of the study period. In contrast, treatment with OX40L mRNA 
combined with Isotype control antibody resulted in 1/15 CRs (7%). Treatment with a nontranslated control 
mRNA in combination with αPD-L1 resulted in 1/15 CRs (7%). As with OX40L mRNA monotherapy 
therapy, mice treated with the combination that were complete responders, did not grow tumors when 
challenged with re-implantation suggesting an immune memory response. 
 
Biodistribution studies have been performed in tumor-bearing mice. Twenty-four hours following a single 
intratumoral injection of OX40L mRNA, the highest concentration of mRNA was detected in the injected 
tumor. Substantially lower and nearly equal concentrations of mRNA were detected in the liver, heart, 
proximal lymph node, lung, kidney, and brain. Considering the very high sensitivity of the branched DNA 
assay used to quantify mRNA levels, it was stipulated that these results are possibly due to incomplete PBS 
perfusion to clear blood from tissues before collection or other artifacts of the method. 
 
OX40L protein levels in the liver, spleen, and MC38 tumor tissue were determined by an OX40L-specific 
enzyme-linked immunosorbent assay. Although the highest concentration of OX40L protein was observed 
in the liver, a lack of dose response and similarly high levels of OX40L in animals administered a 
nontranslating construct, suggest that it is an endogenous protein. Hence, it was concluded that dose-related 
OX40L was reliably detected only in tumor and spleen samples. 
 
The safety and tolerability of mRNA-2416 were evaluated in repeat-dose toxicity studies in 
Sprague-Dawley rats and cynomolgus monkeys. In two 1-month, Good Laboratory Practice (GLP) 
compliant, repeat-dose toxicity studies with a 14-day post-study recovery period, mRNA-2416 was 
administered subcutaneously (SC), using lipid nanoparticle containing mRNA encoding wild type human 
OX40L, once per week for a total of 5 doses in the outbred Sprague-Dawley rat and cynomolgus monkey. 
 
Results of the repeat-dose toxicity study in rats via the SC route demonstrated no mRNA-2416-related 
effects on survival, ocular findings and urinalysis parameters. All animals survived until the scheduled 
necropsy. Weekly administration of mRNA-2416 to Sprague-Dawley rats at dose levels of 0.1, 0.3, and 1.0 
mg/kg was associated with dose-dependent injection site lesions that were considered adverse at 1.0 mg/kg. 
Histology indicated minimal to mild hepatocellular single cell necrosis with subcapsular localization in 
females at ≥0.1 mg/kg. Secondary to injection site inflammatory changes, systemic inflammation changes 
were observed at ≥0.1 mg/kg. Possible stress-related findings were observed at ≥0.3 mg/kg. All changes 
were either totally or partially resolved following a 14-day recovery period. 
 
Results of the repeat-dose toxicity study in monkeys via the SC route appear to support the safe delivery of 
mRNA-2416 in monkeys. Following 5 repeated SC doses of up to 0.6 mg/kg, no significant systemic 
toxicity was observed and there were no deaths. Treatment-related findings were generally limited to the 
SC injection site where a dose-related inflammatory reaction was noted at all doses. Moderate edema of the 
SC tissue was only observed in a single 0.6 mg/kg male, and mild arterial necrosis was only observed in a 
single 0.6 mg/kg female. Systemic inflammation and changes in endocrine organs were also observed and 
considered consistent with a secondary response to inflammation associated with the administration sites. 
Decreased body weights, decreased red blood cell count, and increased liver weights were also observed in 
some animals at the 0.6 mg/kg dose but all changes were partially resolved (microscopic changes at the 
injection site and in the spleen) or fully resolved following a 14-day recovery period. The monkey was 
determined to be the most sensitive species, and the highest non-severely toxic dose was judged to be 
0.3mg/kg. 

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In the rat and monkey, ATA analysis indicated a dose-dependent increase in antibodies (IgM and IgG) 
directed against human OX40L on Day 29 in all groups dosed with mRNA-2416. Since all animals treated 
with mRNA-2416 developed anti-hOX40L response (and homology of cyno and human OX40L is 
considered high = 99%), seroconversion may occur in patients. Published studies in knock-out animals have 
indicated that there is no or only minor contribution of this protein to immunity since it is part of a redundant 
signaling system (Boettler et al 2012, Kopf et al 1999, Murata et al 2000, Salek-Ardakani et al 2008). 
Therefore, seroconversion in patients is not anticipated to cause significant risk. 
 
The safety of mRNA-2416 was evaluated in an in vivo genotoxicity study in Sprague Dawley rats using 
the bone marrow micronucleus test. In addition, the concentrations of mRNA-2416 in the plasma were 
determined. Refer to the Investigator’s Brochure for study details. 
 
Results showed mRNA-2416 induced chromosome damage in rat bone marrow immature erythrocytes, 
when administered intravenously at up to 2 and 3 mg/kg, the estimated maximum tolerated doses for male 
and female Sprague Dawley rats, respectively. These results were considered weakly positive. Based on 
the relative lack of response in females at the higher dose (3 mg/kg), the mild nature of response (˂ 3-fold), 
the high doses administered by the IV route, and the lack of in vitro response of SM-86, the risk of 
genotoxicity in patients is considered low. 
 
The safety of SM-86, a novel lipid excipient of the mRNA-2416, was evaluated in 2 in vitro genotoxicity 
studies. SM-86 did not show any evidence of genotoxic activity in either assay. 
 
This study represents the first-in-human clinical study for mRNA-2416. As of 08-Feb-2019, 32 patients 
with advanced relapsed/refractory malignancies have been enrolled. General adverse reactions, reported in 
3 or more subjects, included site pain, injection site reaction (erythema, edema, itching), pyrexia, flushing, 
fatigue, chills, and nausea with all the events being mild to moderate in severity except for one Grade 3 
injection-related reaction. Refer to the current mRNA-2416 and durvalumab investigator’s brochures (IB) 
for a complete summary of pre-clinical and clinical information. 
 
6.3 
Durvalumab BACKGROUND 
 
Durvalumab (MEDI4736) is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1, kappa 
(IgG1, kappa) subclass that blocks the interaction of PD-L1 (but not programmed cell death - ligand 2 [PD- 
L2]) with programmed cell death protein 1 (PD 1) on T-cells and cluster of differentiation (CD) 80 proteins 
on immune cells. Durvalumab is being developed by AstraZeneca/MedImmune for use in the treatment of 
cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be 
referred to as AstraZeneca throughout this document). The proposed mechanism of action for durvalumab 
is interference in the interaction of PD L1 with PD 1 and CD80. Blockade of PD-L1/PD-1 and PD L1/CD80 
interactions releases the inhibition of immune responses, including those that may result in tumor 
elimination. In vitro studies demonstrated that durvalumab antagonizes the inhibitory effect of PD-L1 on 
primary human T-cells resulting in the restored proliferation of interferon-gamma ([IFN γ] Stewart et al 
2015). In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T cell 
dependent mechanism (Stewart et al 2015). Based on these data, durvalumab is expected to stimulate the 
patient’s anti-tumor immune response by binding to PD L1 and shifting the balance toward an anti-tumor 
response. Durvalumab has been engineered to reduce antibody dependent cellular cytotoxicity and 
complement-dependent cytotoxicity. 
 
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies either as 
monotherapy or in combination with other anti-cancer agents. Risks with durvalumab include, but are not 
limited to, diarrhea/colitis, pneumonitis/ILD, endocrinopathies (ie, events of hypophysitis, adrenal 
insufficiency, hypo- and hyper thyroidism, and type I diabetes mellitus), hepatitis/increases in 

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transaminases, nephritis/increases in creatinine, pancreatitis/increases in serum amylase and lipase, 
rash/dermatitis, myocarditis, myositis/polymyositis, other rare or less frequent inflammatory events 
including neurotoxicities, infusion-related reactions, hypersensitivity reactions, and infections/serious 
infections. 
 
In monotherapy clinical studies, very commonly AEs reported included events such as fatigue, diarrhea, 
nausea and vomiting, decreased appetite, and muscle and joint pain. A total of 5% to 10% of patients 
discontinued the drug due to an AE. Refer to the current version of the IB for a detailed summary of the 
monotherapy data including AEs, SAEs, and Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 3 to 5 events reported across the durvalumab program. 
 
The majority of treatment-related AEs were manageable, with dose delays, symptomatic treatment, and in 
the case of events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity (see Appendix E). 
 
For information on all identified and potential risks with durvalumab, please refer to the current version of 
the durvalumab IB. 
 
6.4 
MRNA-2416 DOSING RATIONALE 
 
The planned starting dose is 1.0 mg (0.5 mL) of mRNA-2416 on Day 1 and Day 15 of 28-day cycles. 
 
Antibody agonists of OX40 have been tested in Phase 1 trials in cancer patients. Preliminary results 
demonstrate only low-grade AEs. In a Phase 1 study, the preliminary safety and efficacy of PF04518600 
was assessed with doses ranging from 0.01 to 3.0 mg/kg administered IV every 2 weeks. TEAEs were 
Grades 1 to 2 and were observed in 67.7% of patients; fatigue and decreased appetite were the most common 
TEAEs (Diab et al 2016). Similar effects were seen in the Phase 1 trial of MOXR0916 (0.2 to 1200 mg IV 
every 3 weeks) in which only Grade 1 and 2 TEAEs were observed; the most common TEAEs included 
fatigue, GI symptoms, and infusion reactions. 
 
The dose of mRNA injected may be limited by either local or systemic tolerability or by the maximum 
volume of mRNA that can be injected. mRNA-2416 has been formulated at 2 mg/mL. Experience with 
intratumoral injection of the oncolytic viral product talimogene laherparepvec (Imlygic™, T-VEC) 
suggests that 5 mL is the maximal intratumoral volume per injection. Toxicology studies in non-human 
primates suggest that a safe starting dose for mRNA-2416, including a 6 times margin of error, is 0.017 
mg/kg, or approximately 1 mg in a 70 kg patient. 
 
In the first clinical study of mRNA-2416 it is proposed that the study drug is administered by intratumoral 
injection on Days 1 and 15 of a 28-day cycle, repeated for a maximum of 6 cycles. The selection of a 14-day 
dosing regimen is based upon the following: 
 
• 
The observed pharmacodynamic effects of OX40L may extend to 14 days given that there was an 
increase in T-cells in tumors 14 days after injection of mRNA encoding murine OX40L (Section 6.2). 
• 
Any local toxicity observed in the GLP toxicology studies after subcutaneous injection of mRNA-2416 
was either partially resolved (microscopic changes at the injection site and in the spleen) or fully 
resolved 14 days after injection (Section 6.2). 
• 
This dosing regimen enables convenient combination in future studies of mRNA-2416 with an anti-PD- 
1 or anti-programmed death ligand 1 (PD-L1) antibody in accordance with their approved dosing 
regimens (Planchard et al 2016). 

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The proposal to repeat administration of mRNA-2416 is justified by the nonclinical efficacy data 
demonstrating that repeated doses of murine OX40L into tumor-bearing mice are more efficacious than a 
single administration. Patients who do not experience dose-limiting or other unacceptable toxicity after the 
first cycle of therapy, and who are otherwise adjudged to benefit from study therapy at the end of Cycle 2 
tumor assessment, may continue on study treatment. Repeated dosing for up to 6 cycles (approximately 6 
months) is justified on the basis that other immune therapies for cancer, such as PD-1 inhibitors, may not 
show clinical efficacy immediately. Median time to first response for patients with melanoma treated with 
the PD-1 inhibitor pembrolizumab was 3 months, with some patients fulfilling the definition of tumor 
response for the first time after 6 months of therapy (Robert et al 2016). 
 
All patients in Arm B and patients that are to receive intratumoral injections to visceral lesions will reduce 
dosing frequency to every 4 weeks after completing 1 cycle of therapy (Day 1 and Day 15 for Cycle 1, then 
Day 1 only for Cycles 2-6). The choice for this regimen is a balance between the dosing rationale described 
above and consideration for the clinical feasibility of repeat injections in patients with visceral lesions that 
require additional utilization of limited institutional resources such as imaging and procedural time by 
interventional radiology. 
 
6.5 
DURVALUMAB DOSING RATIONALE 
 
The planned dose of durvalumab for this study is 1500 mg every 4 weeks (Q4W). A durvalumab dose of 
20 mg/kg Q4W is supported by in vitro data, pre-clinical activity, clinical PK/pharmacodynamics, 
biomarkers, and activity data from Study CD-ON-MEDI4736-1108 (hereafter referred to as Study 1108) in 
patients with advanced solid tumors and from a Phase I study performed in Japanese patients with advanced 
solid tumor (Study D4190C00002). A fixed dose of 1500 mg Q4W is supported by results of a population 
PK analysis. 
 
Pharmacokinetic/Pharmacodynamic data 
 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with doses ranging from 0.1 to 
10 mg/kg Q2W or 15 mg/kg every 3 weeks (Q3W), durvalumab exhibited non-linear (dose dependent) PK 
consistent with target-mediated drug disposition. The PK approached linearity at ≥3 mg/kg Q2W, 
suggesting near complete target saturation (membrane-bound and sPD L1), and further shows that the 
durvalumab dosing frequency can be adapted to a particular regimen given the linearity seen at doses higher 
than 3 mg/kg. The expected half-life with doses ≥3 mg/kg Q2W is approximately 21 days. A dose- 
dependent suppression in peripheral sPD-L1 was observed over the dose range studied, consistent with 
engagement of durvalumab with PD L1. A low level of immunogenicity has been observed. No patients 
have experienced immune-complex disease following exposure to durvalumab. (For further information on 
immunogenicity, refer to the current durvalumab IB.) 
 
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg Q2W or 15 
mg/kg Q3W; Fairman et al 2014). Multiple simulations indicate that a similar overall exposure is expected 
following both 10 mg/kg Q2W and 20 mg/kg Q4W regimens, as represented by AUC at steady state 
(AUCss) (calculated over 4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg Q4W 
(approximately 1.5-fold) and median Ctrough,ss is expected to be higher with 10 mg/kg Q2W 
(approximately 1.25-fold). Clinical activity with the 20 mg/kg Q4W dosing regimen is anticipated to be 
consistent with 10 mg/kg Q2W and is expected to (a) achieve complete target saturation in majority of 
patients; (b) account for anticipated variability in PK, pharmacodynamics, and clinical activity in diverse 
cancer populations; (c) maintain sufficient PK exposure in case of ADA impact; and (d) achieve PK 
exposure that yielded maximal anti-tumor activity in animal models. 

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Given the similar area under the serum drug concentration-time curve (AUC) and modest differences in 
median peak and trough levels at steady state, the observation that both regimens maintain complete sPD 
L1 suppression at trough, and the available clinical data, the 20 mg/kg Q4W and 10 mg/kg Q2W regimens 
are expected to have similar efficacy and safety profiles, supporting the use of 20 mg/kg Q4W. 
 
Clinical data 
 
Refer to the current durvalumab IB for a complete summary of clinical information including safety, 
efficacy, and PK for the 20 mg/kg Q4W regimen. 
 
Rationale for fixed dosing 
 
A population PK model was developed for durvalumab using monotherapy data Study 1108 (N=292; doses 
= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). Population PK analysis indicated only minor 
impact of body weight on the PK of durvalumab (coefficient of ≤ 0.5). The impact of body weight-based 
(10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations (5th, median, and 95th percentiles) using the population PK model. A fixed 
dose of 750 mg was selected to approximate 10 mg/kg (based on median body weight of ~75 kg). A total 
of 1000 patients were simulated using body weight distribution of 40 to 120 kg. Simulation results 
demonstrate that body weight-based and fixed dosing regimens yield similar median steady state PK 
concentrations with slightly less overall between-patient variability with fixed dosing regimen. 
 
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing 
errors. Given the expectation of similar PK exposure and variability, AstraZeneca considered it feasible to 
switch to fixed dosing regimens for durvalumab. Based on an average body weight of 75 kg, a fixed dose 
of 1500 mg Q4W durvalumab (for a body weight-based dose of 20 mg/kg Q4W) is included in the current 
study. 
 
6.6 
PATIENT POPULATION 
 
The population for Dose Escalation was selected as those patients with locally advanced, recurrent or 
metastatic incurable solid malignancy or lymphoma that has progressed after standard therapy or for which 
standard therapy has proven to be ineffective or intolerable or is considered inappropriate and are therefore 
considered to be appropriate candidates for clinical trials exploring new forms of treatment. In the Dose 
Expansion periods, patients with ovarian cancer of epithelial origin will be enrolled at the MTD and/or 
RDE. 
 
6.7 
STATEMENT OF COMPLIANCE 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and applicable 
regulatory and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements. 

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7 
STUDY OBJECTIVES AND ENDPOINTS 
 
7.1 
PRIMARY OBJECTIVES 
 
The primary objectives of the study are as follows: 
 
Phase 1 
• 
To determine safety and tolerability of escalating intratumoral doses of mRNA-2416 alone and in 
combination with durvalumab in patients with relapsed/refractory solid tumor malignancies or 
lymphoma 
• 
To define the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and 
schedule for intratumoral injections of mRNA-2416 alone and in combination with durvalumab in 
patients with relapsed/refractory solid tumor malignancies or lymphoma 
Phase II 
• 
To assess objective response rate of mRNA-2416 alone and in combination with durvalumab in ovarian 
cancer based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
 
7.2 
PRIMARY ENDPOINTS 
 
The primary endpoints of the study are as follows: 
 
Phase 1 
• 
Incidence and nature of dose-limiting toxicities (DLTs) with mRNA-2416 alone and in combination 
with durvalumab 
• 
Incidence, nature, and severity of AEs/serious adverse events (SAEs), graded according to the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for 
mRNA-2416 alone and in combination with durvalumab 
Phase II 
• 
Assessment of objective response rate of mRNA-2416 alone and in combination with durvalumab in 
patients with ovarian cancer based on RECIST v1.1 
 
 
7.3 
SECONDARY OBJECTIVES 
 
The secondary objectives of the study are as follows: 
 
• 
To assess emergence of antibodies against the drug product as well as OX40L, the protein translated 
by the drug product 
• 
To assess mRNA pharmacokinetics (PK) alone and in combination with durvalumab 
• 
To assess anti-tumor effects of mRNA-2416 alone and in combination with durvalumab 
• 
Phase I only: To assess objective response rate and duration of response of mRNA-2416 monotherapy 
based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 / or Cheson 2014 criteria 
(lymphomas) 

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• 
Phase II only: To assess disease control rate and duration of response of mRNA-2416 alone and in 
combination with durvalumab based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
 
7.4 
SECONDARY ENDPOINTS 
 
The secondary endpoints of the study are as follows: 
 
• 
Presence and/or concentration of antibodies against the drug product as well as OX40L, the protein 
translated by the drug product 
• 
Phase I only: Assessment of objective response rate and duration of response (progression-free 
survival) of mRNA-2416 monotherapy based on RECIST v1.1 or Cheson 2014 criteria (lymphomas); 
See Appendix C and Appendix D 
• 
Phase II only: Assessment of disease control rate and duration of response of mRNA-2416 alone and 
in combination with durvalumab in patients with ovarian cancer based on Response Evaluation Criteria 
in Solid Tumors (RECIST) v1.1 
• 
PK parameters for mRNA-2416 alone and in combination with durvalumab: maximum observed 
concentration (Cmax) and area under the concentration-time curve (AUC) 
 
7.5 
EXPLORATORY OBJECTIVES 
 
The exploratory objectives of the study are as follows: 
 
• 
To assess objective response rate of mRNA-2416 alone and in combination with durvalumab based on 
Immune-related Response Criteria (irRC) or lymphoma response to immunomodulatory therapy 
criteria (LYRIC) 
• 
To assess the correlation of other investigational serum-based proteins (eg, anti-drug antibodies) with 
PK, efficacy, and safety endpoints 
• 
To assess biomarkers of immunological response in tumor and blood of mRNA-2416 alone and in 
combination with durvalumab. 
• 
To assess pharmacokinetics (PK) of durvalumab in combination with mRNA-2416. 
 
7.6 
EXPLORATORY ENDPOINTS 
The exploratory endpoints of the study are as follows: 
• 
Assessment of objective response rate of mRNA-2416 alone and in combination with durvalumab 
based on irRC or LYRIC 
• 
Assessment of the correlation of other investigational serum-based proteins (eg, anti-drug antibodies) 
with PK, efficacy, and safety 
• 
Evaluation of plasma will include assessment of pro-inflammatory cytokines and interferons 
• 
Evaluations of tumor tissue will include: 
o 
Expression of OX40 and OX40L and change in expression over the treatment period 
o 
Expression of other immune-related markers, including PD-1 and PD-L1 
o 
Infiltration of tumor with immune effector cells, including T cells 

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• 
PK parameters for durvalumab in combination with mRNA-2416: maximum observed concentration 
and area under the concentration-time curve 
 
The on-treatment biopsy timing may be adjusted based on emerging data. 
 
Where possible, outcome measures will be correlated with clinical characteristics such as tumor histotype, 
dose of mRNA administered, and clinical outcomes. 
 
7.7 
SAFETY PARAMETERS 
 
The parameters that will be used to assess safety in this study include the following: 
 
• 
AEs 
• 
Hematology, clinical chemistry, and liver function tests 
• 
12-Lead electrocardiogram (ECG) 
• 
Physical examination 
• 
Vital signs and body weight 
• 
Concomitant medications/procedures 
• 
Eastern Cooperative Oncology Group (ECOG) performance status 
• 
Antibodies against OX40L, the protein translated by the drug product, will be reviewed with 
investigators as data are available. 
 
Where applicable, AEs will be classified according to the NCI CTCAE Version 4.03. 

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8 
STUDY DESIGN 
 
8.1 
NUMBER OF PATIENTS 
 
The planned study enrollment is approximately 117 patients. Approximately 57 patients will be enrolled in 
the Dose Escalation and Dose Confirmation Periods of the study. During the Expansion Period of the study, 
approximately 60 patients will be enrolled at the MTD/RDE. 
 
8.2 
STUDY DESIGN 
This is an open-label, multicenter, Phase I/II Dose Escalation study of repeated intratumoral injections of 
mRNA-2416 alone (Arm A) and in combination with intravenously administered durvalumab (Arm B) in 
patients with advanced relapsed/refractory solid tumor malignancies or lymphoma, followed by Expansion 
periods in patients with ovarian cancer in each treatment arm. The study includes the following 2 treatment 
arms: 
• 
Arm A: mRNA-2416 alone 
• 
Arm B: mRNA-2416 in combination with durvalumab (PD-L1 inhibitor) 
Each arm of the study consists of a Dose Escalation and Dose Confirmation part followed by a Dose 
Expansion part in ovarian cancer. Each dose level in the Dose Escalation period will be conducted using a 
standard 3+3 study design in order to determine the safety and tolerability of each dose. For Arm A Dose 
Escalation, once a dose level has been cleared for safety, that dose level is open to enrollment of up to 9 
additional patients who are willing and eligible to undergo tumor biopsy. 
Once the expected MTD/RDE has been cleared in Dose Escalation for Arm A, Dose Escalation in Arm B 
will begin with a dose of 4mg mRNA-2416, 1 dose level lower than the Arm A MTD/RDE according to 
Table 1. 
For both Arms, once the expected MTD/RDE has been cleared in Dose Escalation, Dose Confirmation of 
the MTD/RDE will be conducted in at least 3 patients with visceral lesions injectable with ultrasound or 
CT guidance. The purpose of the Dose Confirmation part is to confirm that the dose level determined for 
patients with accessible lesions is also appropriate for patients with visceral lesions. Dose Confirmation 
will be conducted in the same fashion as Dose Escalation, as described in Section 8.2.1 and Section 8.4. 
For both Arms, once the MTD and/or RDE has been determined in Dose Escalation/Confirmation, patients 
will be enrolled in an Expansion cohort in order to assess the preliminary anti-tumor activity of mRNA- 
2416 in ovarian cancer of epithelial origin 
The Dose Expansion will consist of 2 investigational groups across the treatment arms summarized as 
follows and shown in Figure 1: 
 
Arm A: mRNA-2416 alone 
• 
Group 1: Ovarian cancer 
Arm B: mRNA-2416 in combination with durvalumab 
• 
Group 2: Ovarian cancer 
 
The study schema is presented in Figure 1. 

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Figure 1:    mRNA-2416-P101 Study Schema 
 
 
8.2.1 
ARM A DOSE ESCALATION PERIOD 
 
Dose escalation will be conducted using a standard 3+3 study design in order to determine safety and 
tolerability of the study therapy (see Section 8.4 for further details). The planned mRNA-2416 starting dose 
is 1.0 mg (0.5 mL) on Day 1 and Day 15 of 28-day cycles. Patients will be evaluated at the end of the first 
28-day period (Cycle 1). A sentinel patient will receive their initial dose of mRNA-2416 1.0 mg 
intratumoral injection per intratumoral injection criteria (Section 10.1). Following a 7-day observation 
period, additional patients may be enrolled in the 1.0 mg cohort. Table 1 describes the 1.0 mg starting dose 
and other dose levels that may be evaluated during this trial. Subsequent dose cohorts may enroll up to 3 
patients at a time. No intra-patient dose escalations may occur. 
 
Table 1: 
Arm A Provisional Dose Levels 
 
Dose level 
Proposed mRNA-2416 Q2W dose 
-1 
0.5 mg (0.25 mL) 
1 (starting dose) 
1.0 mg (0.5 mL) 
2 
2.0 mg (1.0 mL) 
3 
4.0 mg (2.0 mL) 
4 
8.0 mg (4.0 mL) 

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Once a dose level has been cleared for safety, the dose level is open to enrollment of up to an additional 9 
patients who are willing and eligible to undergo tumor biopsy for analysis (see details in Section 8.2.2). 
Any adverse events among patients in the biopsy enrichment cohorts would be considered in determining 
an appropriate RDE but will not affect the determination of the MTD. These cohorts are only opened at 
doses cleared for safety and are separate from the 3 + 3 escalation model described in Section 8.4.4. 
 
Patients must have a superficial tumor lesion amenable to injection. A tumor lesion amenable to injection 
during the Dose Escalation Period is defined as a superficial tumor lesion that is 
 
• 
clearly visible or palpable 
• 
can be easily injected without the use of imaging guidance, and 
• 
All lesion(s) targeted for the initial injection must be ≥ 0.5 cm on longest diameter, be at least 5 mm 
thick, and have distinct borders based on exam or imaging, not close to critical structures such as major 
vessels, nerves, or airways. 
 
8.2.2 
ARM A DOSE ESCALATION BIOPSY COHORT ENRICHMENT 
 
For Arm A Dose Escalation, once a dose level has been cleared for safety, the dose level is open to 
enrollment of additional patients who are willing and eligible to undergo tumor biopsy. Eligible patients 
should be enrolled into the highest dose level that has been cleared for safety, providing their injectable 
tumor volume permits the necessary dose of mRNA-2416 according to Section 10.1 Table 3. For patients 
whose tumor volume does not support dosing at the highest cleared dose level, participation in a lower dose 
level is acceptable. 
 
Up to 9 patients can be enrolled into the biopsy cohort at each dose level: 3 patients in Group A, 3 in Group 
B and 3 in Group C. Enrollment in the Biopsy Cohort Enrichment will continue throughout the conduct of 
the study until all slots are filled or it is determined additional enrollment is not required. Refer to Section 
10.12 for further details on the enrollment in Biopsy Cohort Enrichment. 
 
8.2.3 
ARM B DOSE ESCALATION PERIOD 
 
Dose escalation will be conducted using a standard 3+3 study design in order to determine safety and 
tolerability of the study therapy (see Section 8.4 for further details). In combination with a fixed dose of 
1500 mg durvalumab every 4 weeks, the planned mRNA-2416 dose is 4.0 mg (2 mL) on Day 1 and Day 
15 of 28-day cycles for Cycle 1, and on Day 1 only for Cycles 2-6. Patients will be evaluated at the end of 
the first 28-day period (Cycle 1). A sentinel patient will receive their initial dose of mRNA-2416 in 
combination with durvalumab. Following a 7-day observation period, additional patients may be enrolled 
in the 4.0 mg cohort. Table 2 describes the 4.0 mg starting dose and other dose levels that may be evaluated 
during this trial. Subsequent dose cohorts may enroll up to 3 patients at a time. No intra-patient dose 
escalations may occur. 
 
Table 2: 
Arm B Provisional Dose Levels 
 
Dose level 
Proposed mRNA-2416 dose 
Durvalumab dose level 
-1 
2.0 mg (1.0 mL) 
1500 mg 
1 (starting dose) 
4.0 mg (2.0 mL) 
1500 mg 
2 
8.0 mg (4.0 mL) 
1500 mg 

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8.2.4 
DOSE CONFIRMATION IN VISCERAL LESIONS 
For both Arms, once the expected MTD/RDE has been cleared in Dose Escalation, Dose Confirmation of 
the MTD/RDE will be conducted in at least 3 patients with visceral lesions injectable with ultrasound or 
CT guidance. The purpose of the Dose Confirmation part is to confirm that the dose level determined for 
patients with accessible lesions is also appropriate for patients with visceral lesions. Dose Confirmation 
will be will be conducted in the same fashion as Dose Escalation as described in Section 8.2.1 and Section 
8.4. A sentinel patient will receive their initial dose of mRNA-2416 intratumoral injection per intratumoral 
injection criteria (Section 10.1). Following a 7-day observation period, additional patients may be enrolled 
in the Dose Confirmation cohort. 
 
8.2.5 
ARM A PHASE II DOSE EXPANSION PERIOD 
Once the MTD and/or RDE has been determined in Dose Escalation/Confirmation, patients will be enrolled 
in the Expansion period in order to assess the preliminary anti-tumor activity of mRNA-2416 in ovarian 
cancer of epithelial origin. The Expansion period will initially enroll 13 evaluable patients, unless enrolling 
13 patients is not logistically feasible, in which case enrollment may be stopped before 13 patients are 
enrolled. If at least 1 patient has an objective response (partial response [PR] or complete response [CR]) 
per RECIST v1.1 or iRECIST, the sample size may be expanded to 27 evaluable patients. Details of the 
sample size calculations leading to the patient numbers are provided in Section 13.2. 
 
 
8.2.6 
ARM B PHASE II DOSE EXPANSION PERIOD 
Once the MTD and/or RDE has been determined in Dose Escalation/Confirmation, patients will be enrolled 
in the Expansion period in order to assess the preliminary anti-tumor activity of mRNA-2416 in 
combination with durvalumab in ovarian cancer of epithelial origin. The Expansion period will initially 
enroll 15 evaluable patients, unless enrolling 15 patients is not logistically feasible, in which case 
enrollment may be stopped before 15 patients are enrolled. If at least 2 patients have an objective response 
(partial response [PR] or complete response [CR]) per RECIST v1.1 or iRECIST, the sample size may be 
expanded to 41 evaluable patients. Details of the sample size calculations leading to the patient numbers 
are provided in Section 13.2. 
 
8.2.7 
PHASE II DOSE EXPANSION PERIOD STOPPING RULES 
 
Further computations of the DLT rate will be performed during the Expansion Period in order to incorporate 
study stopping rules. During the Expansion Period, the DLT rate will be calculated as events occur. The 
DLT rate will be defined as the ratio of the total number of patients with a DLT at the MTD/RDE divided 
by the total number of patients enrolled at that dose level who are evaluable for DLT (for evaluability see 
Section 8.4.4). 
 
If the DLT rate is ≥33%, a temporary study suspension of enrollment at the MTD/RDE will be required in 
order to perform a thorough and in-depth review of the available safety information to determine whether 
additional patients should be enrolled at that dose level. The SRC may decide to enroll 3 more patients at 
the MTD/RDE and review the DLT rate again once those patients become evaluable for DLT. 
Alternatively, if the SRC determines that there is a reasonable probability that the DLT rate will remain 
higher than 33% with further enrollment of patients at that dose level, then the SRC may decide to stop 
enrollment at the MTD/RDE and permit expansion of a dose level lower than the MTD/RDE. Enrollment 
at the new RDE will be subject to the same enrollment and stopping rules as expansion at the MTD/RDE. 

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In addition, any Grade 4 toxicity related to mRNA-2416 during the Expansion Period will require a 
temporary suspension of expansion and review by the SRC. A drug-related death at any time during the 
study would result in study pause and expedited notification to FDA per 21 CFR 312.32 
 
8.3 
STUDY FLOW AND EXPECTED DURATION OF PATIENT PARTICIPATION 
 
All patients will participate in a Screening Phase, Treatment Phase, and Follow-up Phase. 
 
Screening Phase: 
• 
A 14-day screening period before enrollment (≤ 28 days for baseline biopsy and imaging) 
• 
Patients will be evaluated against study inclusion and exclusion criteria. Patients must meet all 
inclusion criteria and none of the exclusion criteria at screening in order to be eligible for the study. 
Assessments required on C1D1 that are performed as part of the screening evaluations and within 
72 hours prior to the first dose of study treatment, do not need to be repeated on C1D1. 
Treatment Phase: 
• 
Arm A: mRNA-2416 administered for 6 cycles 
• 
Arm B: Combination dosing of mRNA-2416 with durvalumab for 6 cycles. Following completion 
of 6 cycles of combination dosing, patients may continue with durvalumab as a single-agent until 
disease progression, unacceptable toxicity, or 24 months of treatment (total), whichever is sooner. 
Safety Follow-up: 
• 
Patients will be followed up for safety evaluation 30 and 90 days after their last dose of study 
treatment. 
Disease Progression Follow-up: 
Patients who complete study treatment with an overall tumor assessment of stable disease (SD) or better 
will be followed for tumor assessment 60 and 180 days after their last dose of study treatment, or until 
disease progression, whichever occurs first. 
 
8.4 
DOSE ESCALATION PROCEDURES 
 
8.4.1 
SAFETY REVIEW COMMITTEE (SRC) 
 
A SRC composed of the study Medical Monitor, Sponsor representatives, and enrolling Principal 
Investigators (PIs) will hold teleconferences at the completion of each dose cohort in the Dose Escalation 
Period and during the Expansion Period, as needed, to review and assess all available safety data and the 
treatment status of all patients. 
 
A written summary documenting the results, and recommendations of each review, including SRC 
consensus regarding recommended dose escalations or MTD/RDE, will be provided to the investigator(s) 
and maintained on file with the Sponsor. Additional personnel may participate in reviews as indicated. 
 
Following a cohort review, the mRNA-2416 SRC may recommend proceeding with enrollment in the next 
dose cohort, enrolling additional patients in the current cohort, dropping back to a lower cohort, or not 
enrolling any additional patients. The dose escalation guidelines outlined in Section 8.4.4, as well as the 
study stopping rules outlined in Section 8.2.6, will be used as the basis for all SRC decisions. 
 
While the SRC is expected to reach a consensus opinion regarding any premature discontinuation or 
significant modification of the study, the Sponsor may independently stop the study. 

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8.4.2 
DEFINITION OF DOSE-LIMITING TOXICITIES 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as 
unrelated to disease, disease progression, inter-current illness, or concomitant medications and at least 
possibly related to the study therapy and that occurs within the first 28 days of study therapy. The 
investigator must notify the Sponsor immediately of any DLTs. 
For patients in Arm A receiving mRNA-2416, the following toxicities will be considered a DLT: 
• 
All Grade 3 AEs with the exception of the following: 
o Grade 3 thrombocytopenia lasting <7 days 
o Grade 3 neutropenia without fever or lasting <7 days 
• 
Any Grade 4 or Grade 5 toxicity. Death due to disease progression is not considered a DLT. 
For patients in Arm B receiving mRNA-2416 in combination with durvalumab, the following toxicities will 
be considered a DLT: 
 
Adverse Event (AE)+C2:F16 
DLT Criteria 
Grade 2 Events 
Grade 3 Events 
Grade 4 events 
Diarrhea/colitis 
none 
Events that do not resolve to Grade 1 or baseline within 
14 d (whether or not it is immune-mediated) 
DLT 
Pneumonitis 
Non-infectious pneumonitis that does not 
resolve to Grade ≤1 within 10 days 
Non-infectious pneumonitis is a DLT 
DLT 
Hepatitis 
none 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >8×ULN or total bilirubin (TBL) 
>5×ULN OR events meeting Hy's Law (AST or ALT ≥3×ULN 
with concurrent increase in TBL ≥2×ULN without evidence 
of cholestasis or alternative explanations) 
DLT 
Rash 
Any grade rash with bullous formation. 
Rash not resolving to Grade 1 or baseline within 30d. Any 
rash with bullous formation. 
DLT 
Peripheral neuromotor 
syndromes such as Guillain- 
Barre or myasthenia gravis 
Events not resolving to Grade 1 within 30d. 
Events with any signs of respiratory insufficiency 
or autonomic instability. 
Events that do not resolve to Grade 1 within 30d. Events 
with any signs of respiratory insufficiency or autonomic 
instability. 
DLT 
Myocarditis 
Events that do not resolve to Grade 1 within 3d 
OR a biopsy confirms immune-mediated 
myocarditis. 
All Grade 3 myocarditis. 
DLT 
Myositis/polymyositis 
Events that do not resolve to Grade 1 within 30d 
OR exhibit signs of respiratory insufficiency 
regardless of optimal medical management 
Events that do not resolve to Grade 1 within 30d OR 
exhibit signs of respiratory insufficiency regardless of 
optimal medical management 
DLT 
Endocrinopathies involving 
thyroid or pituitary glands or 
adrenal insufficiency 
none 
Excludes events that are managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy and the patient is 
asymptomatic 
Type I diabetes mellitus 
none 
Events that are not managed with appropriate diabetic therapy 
Nephritis 
none 
Any immune-mediated increase in creatinine >3×ULN, or 
>3×baseline for patients with a baseline creatinine 
elevated above ULN 
DLT 
Elevated amylase or lipase/ 
pancreatitis 
none 
Elevations in amylase or lipase >2.0×ULN with signs or symptoms of 
pancreatic inflammation 
All other imAEs OR non-imAEs
none 
Events that do not resolve to Grade 1 or baseline within 
30d 
DLT 
Infusion-related reactions 
none 
Events that do not resolve within 6h despite appropriate 
medical management. 
DLT 

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• 
Any Grade ≥3 immune or non-immune adverse event (AE) that is at least possibly related to the 
investigational product (IP) or investigational regimen (IR) with two exceptions: Any grade of vitiligo 
or alopecia 
• 
Hematologic toxicity: 
o Grade ≥3 neutropenia complicated by fever >38.3°C 
o Grade 4 neutropenia (lasting more than 7 days) 
o Grade ≥3 thrombocytopenia with significant bleeding 
o Grade 4 thrombocytopenia (regardless of duration) 
o Grade 4 anemia (regardless of duration) 
8.4.3 
DEFINITION OF MTD 
 
The MTDs will be defined as the highest dose of mRNA-2416 alone and in combination with durvalumab 
at which a DLT has been seen in less than 2 of 6 patients (<33%) during the first 28-days of study therapy. 
 
If 2 or more adverse events that meet the definition of a DLT as defined in Section 8.4.2, are observed 
beyond the first 28 days of study therapy within a dose escalation cohort, further enrollment may be held, 
pending safety analysis of the events by the SRC. These events will not affect the determination of the 
MTD but will be used in determining the appropriate RDE. 
 
8.4.4 
DOSE ESCALATION PROCEDURE 
 
In order to be evaluable for dose determination, a patient must have received ≥50% of the planned mRNA- 
2416 dose and ≥75% of the planned durvalumab dose (Arm B) for Cycle 1 and must either have been 
followed ≥ 28 days following the first dose or have experienced a DLT within 28 days of the first dose. 
Patients who are not evaluable for dose determination may be replaced. 
 
Dose escalation determination will not occur until the third patient in a cohort has completed their first 28- 
day study therapy. 
 
• 
If no patient (0 of 3) in a dose cohort experiences a DLT during the first 28 days, then the next dose 
cohort of 3 patients will be enrolled at the next dose level per Table 1 following consensus of the SRC. 
• 
If 1 of 3 patients in a dose cohort experiences a DLT, an additional 3 patients will be enrolled in that 
dose cohort. 
o Provided that no more than 1 of 6 patients in the expanded dose cohort experiences a DLT 
within 28 days of the first dose, then a dose cohort of 3 patients will be enrolled at the next 
dose level per Table 1 following consensus of the SRC. 
• 
If ≥ 2 patients in a dose cohort experience a DLT within 28 days of the first dose, that cohort will have 
exceeded the MTD. No additional patients will be dosed at that level, and 3 patients will be enrolled 
in the preceding dose cohort, unless 6 patients have already been treated at that dose level. Using the 
same criteria, lower dose cohorts will be explored as the MTD until ≤ 1 of 6 patients experiences a 
DLT. 
 
In the event that ≥ 2 of the first 6 DLT-evaluable patients in the 1.0 mg cohort experience a DLT, then the 
next cohort will be dosed with 0.5 mg mRNA-2416. 

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In the event that ≥ 2 of the first 6 DLT-evaluable patients in the 8.0 mg cohort experience a DLT, an 
intermediate dose cohort may be opened at 6.0 mg mRNA-2416. 
 
9 
SELECTION OF PATIENTS 
 
9.1 
INCLUSION CRITERIA 
 
All patients must meet all of the following inclusion criteria: 
 
1. Males or females ≥18 years of age who have provided written informed consent prior to completing 
any study-specific procedure 
2. Disease state and prior therapies: 
a. Dose Escalation and Dose Confirmation Periods: Histologically- or cytologically-confirmed 
advanced/metastatic solid tumor or lymphoma by pathology report and who has received, or 
been intolerant to, all approved therapies. Advanced solid tumors (i.e. including but not limited 
to melanoma, breast, head and neck squamous cell) and lymphomas (i.e. including by not 
limited to diffuse large B cell lymphoma) of any type are eligible for enrollment. 
b. Dose Expansion Period: Histologically or cytologically confirmed diagnosis of: epithelial 
cancer of the ovary, fallopian tube, or peritoneum which is platinum resistant or platinum 
refractory. Patients must have received at least 2 prior lines of therapy. Patients with known 
BRCA mutation positive must have been treated with and progressed on at least 1 prior PARPi 
(poly(ADP-ribose) polymerase inhibitor) 
3. No limit to the number of prior therapies 
a. Patients who refuse standard treatments may also be considered provided that he/she has been 
made aware of all therapeutic options and it is documented in the study records. 
4. 
Lesions for intratumoral injection and biopsies: 
a. Dose Escalation: A minimum of one lesion that is easily accessible for injection where easily 
accessible is defined as a cutaneous or subcutaneous mass that is palpable and/or visualizable 
by ultrasound 
b. Dose Confirmation: A minimum of one visceral lesion injectable with ultrasound or computer 
tomography (CT) guidance and that is not encasing or abutting major vascular structures or are 
in a location that are considered high risk for AEs by the enrolling physician 
 
c. Dose Expansion: A minimum of one lesion amenable to injection (either non-visceral or 
visceral). Patients must have a tumor lesion amenable to biopsy and consent to a pre-treatment 
and an on-treatment biopsy. For patients with only one lesion amenable to injection, biopsy, 
and RECIST assessment, the lesion must be ≥ 2 cm. 
 
d. Biopsy Cohort Enrichment: Patients must have a tumor lesion amenable to biopsy and consent 
to a pre-treatment and an on-treatment biopsy 
5. All lesion(s) targeted for the initial injection must be ≥ 0.5 cm on longest diameter, be at least 5 mm 
thick, and have distinct borders based on exam or imaging, not close to critical structures such as major 
vessels, nerves, or airways 
6. Patients must have measurable disease as determined by RECIST v1.1 (solid tumors) or Cheson 2014 
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a. Dose Expansion: Patients must have at least 1 measurable lesion per RECIST v1.1 which has 
not been previously irradiated. 
7. Easter Cooperative Oncology Group (ECOG) performance status of ≤1 
8. Adequate hematological and biological function, confirmed by the following laboratory values: 
Bone marrow function 
a. Absolute neutrophil count ≥1.5 × 109/L 
b. Hemoglobin ≥9 g/dL or ≥6.2 mmol/L 
c. Platelets ≥100 × 109/L without transfusion support 
Hepatic function 
d. Aspartate aminotransferase and alanine aminotransferase ≤2.5 × upper limit of normal (ULN) 
(≤5 × ULN, if hepatic involvement of tumor) 
e. Bilirubin ≤1.5 × ULN (<3.0 mg/dL if patient has Gilbert’s disease) 
Renal function 
f. Serum creatinine ≤1.5 × ULN or creatinine clearance of >50 mL/min (using Cockcroft-Gault 
formula) 
𝑒𝑒𝑒𝑒𝐶𝐶𝐶𝐶[𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚𝑚𝑚] = 
 
Coagulation function 
(140 − 𝐴𝐴𝐴𝐴𝐴𝐴 [𝑦𝑦𝑦𝑦𝑦𝑦]) × 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡 [𝑘𝑘𝑘𝑘] × [0.85 𝑖𝑖𝑖𝑖 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹] 
 
 
72 × 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 [𝑚𝑚𝑚𝑚⁄𝑑𝑑𝑑𝑑] 
g. Protime/international normalized ratio and activated partial thromboplastin time ≤1.5 × ULN 
Thyroid function 
h. Thyroid-stimulating hormone within normal range. 
9. Female patients of childbearing potential must have a negative serum pregnancy test during screening. 
Male and female patients must agree to use a highly reliable method of birth control (expected failure 
rate less than 1% per year) from the Screening visit through 120 days after the last dose of study drug. 
Patients must consent to following the contraception requirements in Section 10.14.1 and 10.14.2. 
 
10. Must have a life expectancy of at least 12 weeks 
11. Body weight > 30 kg 
 
9.2 
EXCLUSION CRITERIA 
 
Any of the following criteria will exclude patients from study participation: 
 
1. Active central nervous system tumors or metastases 
2. Treatment with chemotherapy, radiation (local radiation for palliative care is permitted), hormonal anti- 
cancer treatment, or biologic therapy <14 days prior to the first day of study treatment (Cycle 1 Day 1 
[C1D1]). 
b. Treatment with any other investigational agent or treatment with any anti-cancer monoclonal 
antibody, immunostimulant, or vaccine <28 days prior to C1D1. 
3. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception 
of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria 

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o Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation 
with the Study Physician. 
o Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with 
durvalumab may be included only after consultation with the Study Physician. 
4. History of severe allergic reactions to any of the study drug components 
5. Has active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel 
disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic 
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, 
Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this 
criterion: 
o Patients with vitiligo or alopecia 
o Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone 
replacement 
o Patients with any chronic skin condition that does not require systemic therapy 
o Patients without active disease in the last 5 years may be included but only after consultation with 
the Moderna medical monitor 
o Patients with celiac disease controlled by diet alone. 
6. Has a history of primary immunodeficiency, allogenic solid organ transplantation, or tuberculosis. 
7. Immunosuppressive doses of systemic steroids or absorbed topical steroids (doses >10 mg prednisone 
daily equivalent) within 2 weeks before study drug administration 
8. Local infection at site of a tumor lesion amenable to injection requiring anti-infective therapy within 
2 weeks of the first dose of study drug 
9. Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving study treatment and up to 30 days 
after the last dose of study treatment. 
10. History of human immunodeficiency virus infection 
11. Active/chronic hepatitis B or C 
12. Major surgical procedures ≤28 days or non-study-related minor procedures ≤7 days prior to C1D1. In 
all cases, the patient must be sufficiently recovered and stable before treatment administration. 
13. Any of the following cardiac abnormalities: 
a. Medically uncontrolled hypertension 
b. New York Heart Association Class III or IV cardiac disease 
c. Myocardial infarction within prior 6 months 
d. Unstable angina 
e. Unstable arrhythmias or mean QT interval corrected for heart rate using Fridericia's formula 
(QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) 
14. History of another primary malignancy except for: 
o Malignancy treated with curative intent and with no known active disease ≥5 years before the first 
dose of IP and of low potential risk for recurrence 

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o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 
o Adequately treated carcinoma in situ without evidence of disease 
15. Patients requiring active systemic anticoagulation at the time of intratumoral injection or biopsy 
16. Active GI bleeding 
17. Females who are pregnant or breastfeeding 
18. Any other unstable or clinically significant concurrent medical condition (eg, substance abuse, 
psychiatric illness/social situations, uncontrolled intercurrent illness including active infection, arterial 
thrombosis, symptomatic pulmonary embolism, active interstitial lung disease, serious chronic 
gastrointestinal conditions associated with diarrhea, etc.) that would, in the opinion of the investigator, 
jeopardize the safety of a patient, impact their expected survival through the end of the study 
participation, and/or impact their ability to give written informed consent or comply with the protocol. 
19. For patients who have received prior anti-PD-1 or anti PD-L1 therapy, a patient must not have 
experienced any of the following: 
a. Must not have experienced a toxicity that led to permanent discontinuation of prior 
immunotherapy. 
b. All AEs while receiving prior immunotherapy must have completely resolved or resolved to 
baseline prior to screening for this study. 
20. Must not have experienced a ≥ Grade 3 immune-related AE or an immune-related neurologic or ocular 
AE of any grade while receiving prior immunotherapy. Note: Patients with endocrine AEs of ≤ Grade 
2 are permitted to enroll if they are stable while maintained on appropriate replacement therapy and are 
asymptomatic. 
21. Must not have required the use of additional immunosuppression other than corticosteroids for the 
management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently 
require maintenance doses of > 10 mg prednisone or equivalent per day. 
22. Has an active infection including tuberculosis (clinical evaluation that includes clinical history, physical 
examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B 
(known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus 
(positive HIV-1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence 
of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for 
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. 
23. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 
24. Has a history of leptomeningeal carcinomatosis. 
25. Has involvement in the planning and/or conduct of the study. 
26. Must not plan to donate blood or blood components while participating in this study and through 
90 days after the last dose of study treatment. 
 
10 
STUDY PROCEDURES 
 
10.1 
INTRATUMORAL INJECTIONS 
 
Patients in the Dose Escalation period of the study must have a superficial tumor lesion amenable to 
injection. A tumor lesion amenable to injection during the Dose Escalation period of the study is defined 
as a superficial tumor lesion which is: 

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• 
Clearly visible or palpable, 
• 
Can be easily injected without the use of imaging guidance, and 
• 
All lesion(s) targeted for the initial injection must be ≥ 0.5 cm on longest diameter, be at least 5 mm 
thick, and have distinct borders based on exam or imaging, not close to critical structures such as major 
vessels, nerves, or airways. 
Patients in the Dose Confirmation part of the study must have a visceral tumor lesion amenable to injection 
which is defined as: 
• 
Visceral lesion injectable with ultrasound or computer tomography (CT) guidance 
• 
Must not be encasing or abutting major vascular structures or are in a location that are considered high 
risk for AEs by the enrolling physician 
 
Patients in the Dose Expansion part of the study must have an injectable lesion which may be either a 
superficial lesion or a visceral lesion which is not encasing or abutting major vascular structures or is in a 
location that is considered high risk for AEs by the enrolling physician. 
 
Patients in Arm A receiving treatment to superficial lesions are to receive intratumoral injections on Day 1 
and Day 15 of 28-day cycles for up to 6 cycles. All patients in Arm B and patients receiving treatment to 
visceral lesions are to receive intratumoral injections on Day 1 and Day 15 of 28-day cycles for Cycle 1, 
and on Day 1 only for Cycles 2-6. 
 
mRNA-2416 is injected directly into the tumor. A single injection is preferred, however, the prescribed 
dose of mRNA-2416 may be administered as several injections into different sites within the same lesion 
or split across several lesions if no single lesion is large enough to receive the entire dose per the maximum 
injection volume per lesion size (see Table 3). All patients must have tumor(s) of sufficient size to support 
injection of the first planned dose of mRNA-2416. No intra-patient dose escalations may occur. If the 
tumor at subsequent doses has regressed or shrunk and the size of the accessible tumor burden cannot 
support the planned dose, then the next lowest dose supported by the tumor size may be administered 
following documented approval of Moderna. Lesions displaying signs of local infection should not be 
injected. 
 
After insertion of the needle into the tumor it is important that the syringe plunger is gently withdrawn a 
short distance to ensure that the needle tip is within tumor parenchyma and not in a blood vessel. There is 
no safety data to support administration of mRNA-2416 directly into a vein or artery. Formal toxicology 
studies have deployed subcutaneous dosing in rats and non-human primates. If mRNA-2416 appears to 
extravasate from the tumor injection site into surrounding subcutaneous tissue patients should be followed 
for adverse reactions according to the protocol but no additional immediate action needs to be taken. 
 
For patients receiving mRNA-2416 in combination with durvalumab, the ITu injection of mRNA-2416 
should be administered first with at least a 30 minute break between the two study treatments. 
 
Table 3:    Maximum Injection Volume per Lesion Size 
 
Lesion Size (Longest Dimension) 
Injection Volume 
≤0.5 cm 
up to 0.1 mL 
>0.5 cm to 1.5 cm 
up to 0.5 mL 
>1.5 cm to 2.5 cm 
up to 1.0 mL 
>2.5 cm to 5 cm 
up to 2.0 mL 
>5 cm 
up to 4.0 mL 

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Each patient should be carefully monitored for possible injection related reactions. It is recommended that 
investigators observe all patients for a minimum of 1 hour after administration of each mRNA-2416 
injection, with continuous monitoring of pulse oximetry and vital sign assessment every 10 minutes for the 
first 30 minutes followed by every 15 minutes for the first hour. If an injection related reaction occurs, 
patients should be treated symptomatically as per standard of care and the Moderna Medical Monitor should 
be notified. Additionally, blood samples for complement activation of tryptase within 2 hours of the reaction 
are requested if feasible. The patient should be instructed to call the clinical site if any such reactions 
develop or don’t resolve within 24 to 48 hours. All reactions will be recorded as an adverse event. 
 
10.2 
DURVALUMAB ADMINISTRATION 
Durvalumab will be supplied by the Sponsor as a 500-mg vial solution for infusion after dilution. The 
solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine-hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. 
The nominal fill volume is 10.0 mL. Investigational product vials are to be stored at 2°C to 8°C (36°F to 
46°F) and must not be frozen. Drug product should be kept in original packaging until use to prevent 
prolonged light exposure. 
Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab for administration must be prepared by the investigator’s or site’s designated 
investigational product (IP) manager using aseptic technique. Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed the following: 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
 
A dose of 1500 mg (for patients > 30 kg in weight) will be administered using an IV bag containing 0.9% 
(w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter. Add 30.0 mL of durvalumab (ie, 
1500 mg of durvalumab) to the IV bag. The IV bag size should be selected such that the final concentration 
is within 1 to 15 mg/mL. Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 
 
If a patient’s weight falls to ≤ 30 kg, weight-based dosing at 20 mg/kg will be administered using an IV bag 
containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab concentration ranging from 
1 to 15 mg/mL, and delivered through an IV administration set with a 0.2- or 0.22-μm filter. 
 
Standard infusion time is 1 hour; however, if there are interruptions during infusion, the total allowed 
infusion time should not exceed 8 hours at room temperature. 
 
Do not co-administer other drugs through the same infusion line. 
 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the infusion set 
used after the contents of the IV bag are fully administered, or complete the infusion according to 
institutional policy to ensure the full dose is administered. 
If either preparation time or infusion time exceeds the time limits a new dose must be prepared from new 
vials. Durvalumab does not contain preservatives, and any unused portion must be discarded. 
 
Vital Sign Monitoring 

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Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated according to 
the Schedule of Events. Body weight is also recorded at each visit along with vital signs. 
 
First infusion 
On the first infusion day, patients will be monitored and vital signs collected/recorded in eCRF prior to, 
during, and after infusion of IP as presented in the bulleted list below. 
BP and pulse will be collected from patients in the IO arms before, during, and after each infusion at the 
following times (based on a 60-minute infusion): 
• 
Prior to the beginning of the infusion (measured once from approximately 30 minutes before up to 
0 minutes [ie, the beginning of the infusion]) 
• 
Approximately 30 minutes during the infusion (halfway through infusion) 
• 
At the end of the infusion ( approximately 60 minutes ±5 minutes) 
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the principles 
as described above or be taken more frequently if clinically indicated. A 1-hour observation period is 
recommended after the first infusion of durvalumab. 
Subsequent infusions 
BP, pulse, and other vital signs should be measured, collected/recorded in eCRF prior to the start of the 
infusion. Patients should be carefully monitored and BP and other vital signs should be measured during 
and post infusion as per institution standard and as clinically indicated. Any clinically significant changes 
in vital signs should be entered onto an unscheduled vital signs CRF page 
 
10.3 
mRNA-2416 DOSE MODIFICATION 
 
Patients who experience study treatment-related toxicity that leads to a dose interruption, following 
recovery to at least Grade 1 or to baseline, continue to receive injections at 50% of the planned dose based 
on investigator discretion. Patients may not be rechallenged at the planned dose. 
 
Patients with a lesion that has become inaccessible or has decreased in tumor volume during the study 
treatment period, such that the planned dose is no longer able to be administered, may continue with study 
therapy at a lower dose following documented approval from Moderna. 
 
For patients who do not tolerate the protocol-specified dosing schedule of mRNA-2416, dose reductions 
may be permitted in order to allow the patient to continue study therapy. If a patient experiences an AE 
meeting the criteria for DLT as defined in Section 8.4.2, study therapy should be withheld. Following 
resolution of the toxicity to grade 1 or to the patient’s baseline value, the patient may resume study therapy 
at 50% of the planned dose. 
 
10.4 
DURVALUMAB DOSE MODIFICATION AND TOXICITY MANAGEMENT 
GUIDELINES 
 
Dose delays are permitted for durvalumab (please see Appendix E for dose modification and toxicity 
management guidelines), however dose reductions are not permitted for durvalumab. 
 
10.5 
Dose Omissions and Discontinuation of Study Drug Administration 
 
Study treatment may be interrupted for situations other than treatment-related AEs such as medical and/or 
surgical events or logistical reasons not related to study treatment. Patients should be placed back on study 

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treatment within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The 
reason for interruption should be documented in the patient's study record. 
 
Patients who have permanently discontinued study therapy will be scheduled for an End of Treatment visit 
within 14 days (±2 days) of the decision to permanently discontinue study therapy and assessments will be 
performed per the Schedule of Events table (Section 3). Patients who have permanently discontinued study 
therapy should not be considered withdrawn from the study. They should return for the 30-day and 90-day 
safety follow-up visit from last dose and the tumor assessment follow-up visits per the Schedule of Events 
table. If the patient fails to return for these assessments for unknown reasons, every effort (e.g. telephone, 
email, letter) should be made to contact them. 
 
The following are reasons for discontinuing study therapy without necessarily requiring withdrawal from 
the study: 
 
• 
Patients who have completed 6 cycles of study therapy and have an overall tumor assessment of 
SD or better 
• 
Patients who have experienced a Grade 4 treatment-related AE at any time during study treatment 
must discontinue from study treatment 
• 
Patients who, in the opinion of the investigator, have incurred a Grade 3 drug-related DLT that has 
not recovered to Grade 1 or less within 14 days, or has recurred following restarting study therapy 
at a modified dose level. 
• 
Patients who, in the opinion of the investigator, have incurred unacceptable toxicity that does not 
meet the pre-determined criteria for DLT (eg, late-onset, treatment-emergent toxicity after the DLT 
assessment window, or Grade 2 toxicities that are sufficiently durable or unresponsive to supportive 
intervention as to render them unacceptable in the opinion of the investigator) which has not 
recovered to Grade 1 or less within 28 days, or has recurred following restarting study therapy at a 
modified dose level. 
• 
Patients who experience a Grade 3 hypersensitivity reaction or autoimmune events must 
discontinue from study treatment 
• 
Patients who no longer have lesions that meet criteria for injection 
• 
Pregnancy 
• 
Physician’s decision 
• 
Patient/guardian decision 
• 
Patients will be withdrawn from study due to progressive disease per irRC/LYRIC. Due to the 
possibility of pseudoprogression; patients should not be withdrawn from the study due to 
progressive disease per RECIST v1.1 or Cheson 2014 criteria. 
• 
Patient has received alternative anti-cancer therapy 
• 
Patient has symptomatic progression of disease, or other clinical conditions which, in the opinion 
of the investigator, render it in the interests of the patient to withdraw from the study. 
 
The reason for discontinuation of study therapy should be recorded on the appropriate page(s) of the 
electronic case report form (eCRF). 

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10.6 
DISCONTINUATION FROM THE STUDY 
 
Patients will be permanently discontinued from the study following completion of the EOT, 30-day and 
90-day safety follow-up visits. Additional reasons for discontinuation from the study include the following: 
 
• 
Patient withdraws consent 
• 
Unwillingness to comply with study requirements 
 
10.6.1 
HANDLING OF WITHDRAWALS OF CONSENT 
 
Patients may withdraw consent to participate in this study at any time without penalty or loss of benefits to 
which the patient is otherwise entitled. When a patient wishes to withdraw consent, it is important to 
distinguish between withdrawing their consent for a particular study procedure or visit versus withdrawing 
their consent from the study entirely. The Investigator should discuss with the Medical Monitor whether 
selective withdrawal of consent for specific procedures should disqualify the patient from further 
participation in the study. 
 
10.7 
ANCILLARY TREATMENTS 
 
The use of premedications prior to administration of mRNA-2416 is at the discretion of the treating 
investigator. If the treating physician decides to premedicate their patients, it is recommended to do so prior 
to the second and subsequent injections, and to follow local institutional guidelines for premedication with 
montelukast, H-1 and H-2 antagonists. Per exclusion criteria 7, immunosuppressive doses of systemic 
steroids or absorbed topical steroids (doses >10 mg prednisone daily equivalent) are not allowed within 2 
weeks before the start of study treatment. 
 
If any patient develops an injection related reaction (IRR) despite premedication with montelukast, H-1 and 
H-2 antagonists, please contact the Moderna Medical Monitor regarding continued treatment with 
mRNA-2416. If treatment is to be continued, it is recommended to escalate the pretreatment regimen as per 
institutional guidelines. 
 
If any patient develops a Grade 3 or above IRR, then that patient must be discontinued from further 
injections with mRNA-2416. If ≥ 2 patients experience Grade 3 or above IRR, then a mandatory primary 
prophylaxis premedication regimen including montelukast, H-1 and H-2 antagonists will be instituted after 
discussion and agreement among principal investigators and Moderna Medical Monitor. 
 
Rescue Medications and Supportive Care 
 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined, along with the dose modification guidelines, in Section 10.3 and Appendix E. Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased. As a result of immune-mediated AEs that could potentially be experienced by patients 
on durvalumab, steroids and other immunosuppressant rescue medication has to be made available to this 
patient population. 

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10.8 
CONCOMITANT THERAPY 
 
The investigator must be informed as soon as possible about any medication taken from the time of 
screening until the end of the clinical treatment phase of the study including the 90-day Safety Follow-up 
Period following the last dose of study drug. 
 
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, pro-biotics, 
and/or herbal supplements that the patient is receiving at the time of enrollment or receives during the study 
must be recorded along with the following: 
 
• 
Reason for use 
 
• 
Dates of administration including start and end dates 
 
• 
Dosage information including dose, unit and frequency 
 
Patients must be instructed not to take any medications, including over-the-counter products, without first 
consulting with the investigator. 
 
Restricted, prohibited, and permitted concomitant medications are described in Table 4 and Table 5. Refer 
also to the Dose Modification and Toxicity Management Guidelines (see Section 10.4). 
 
Table 4:    Prohibited concomitant medications 
 
Prohibited medication/class of drug: 
Usage: 
For all treatment arms 
Any investigational anti-cancer therapy other 
than those under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment 
mAb against PD-1, or PD-L1 other than those 
under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study 
Should not be given concomitantly whilst the patient 
is on study treatment. (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes 
and hormone replacement therapy] is acceptable. 
Local treatment of isolated lesions, excluding target 
lesions, for palliative intent is acceptable [eg, by local 
surgery or radiotherapy]) 
Live attenuated vaccines 
Should not be given through 30 days after the last dose 
of IP 

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Prohibited medication/class of drug: 
Usage: 
Any substrates to CYP3A4, CYP2C19, and 
CYP1A2. 
Should be used with caution through to 90 days after 
the last dose of study treatment 
For the durvalumab treatment arm only 
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers 
Should not be given concomitantly or used for 
premedication prior to the infusions. The following are 
allowed exceptions: 
Use of immunosuppressive medications for the 
management of IP-related AEs, 
Use in patients with contrast allergies. 
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted. 
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non-immunotherapy related events 
experienced by the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea). 
EGFR TKIs 
Should not be given concomitantly. 
Should be used with caution in the 90 days post last 
dose of durvalumab. 
Increased incidences of pneumonitis (with third 
generation EGFR TKIs) and increased incidence of 
transaminase increases (with 1st generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly. 
Herbal and natural remedies which may have 
immune-modulating effects 
Should not be given concomitantly unless agreed by 
the Sponsor 
Abbreviations: AE, adverse event; CYP, cytochrome P450; EGFR, epidermal growth factor receptor; IP, investigational product; mAb, monoclonal 
antibody; PD-1, programmed cell death protein 1; PD-L1, programmed death - ligand 1; TKI, tyrosine kinase inhibitor 

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Table 5:    Supportive medications 
 
Supportive medication/class of drug: 
Usage: 
Concomitant 
medications 
or 
treatments 
(eg, acetaminophen 
or 
diphenhydramine) 
deemed 
necessary 
to 
provide 
adequate 
prophylactic or supportive care, except for those 
medications identified as “prohibited,” as listed 
above 
To be administered as prescribed by the investigator 
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy 
to non-target lesions, etc]) 
Should be used, when necessary, for all patients 
Inactivated viruses, such as those in the 
influenza vaccine 
Permitted 
 
10.9 
MANAGEMENT OF CLINICAL SUPPLIES 
mRNA-2416 will be supplied by the Sponsor as solution for intratumoral injection in 2-mL glass vials. 
mRNA-2416 must be stored at -20°C. Detailed information regarding the storage and preparation of the 
mRNA-2416 will be provided in the Pharmacy Manual. 
 
Durvalumab will be supplied by the Sponsor as a 500-mg vial solution for infusion after dilution (50 
mg/mL). Durvalumab vials are to be stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug 
product should be kept in original packaging until use to prevent prolonged light exposure. A temperature 
log will be used to record the temperature of the storage area. Temperature excursions outside the 
permissible range listed in the clinical supply packaging are to be reported to the monitor upon detection. 
A calibrated temperature monitoring device will be used to record the temperature conditions in the drug 
storage facility. Storage conditions stated in the IB may be superseded by the label storage. 
 
mRNA-2416 and durvalumab must be stored in a restricted access area under the storage conditions 
indicated in the Pharmacy Manual. 
 
10.10 
RADIOLOGIC ASSESSMENTS 
 
For the purpose of this clinical trial, the following imaging will be acquired at Screening for a baseline 
tumor assessment and on study: 
 
• 
CT (with contrast) or magnetic resonance imaging (MRI) of the chest, abdomen and pelvis 
• 
CT (with contrast) or MRI of the neck, if clinically indicated 
• 
Bone scan if clinically indicated 

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• 
PET-CT (for lymphoma) 
 
All patients will have tumor assessments performed within 28 days prior to C1D1, every 56 days from 
C1D1 (± 7 days), and during Disease Progression Follow-up Period at 90 and 180 days following the end 
of treatment (± 30 days). 
 
At screening, all patients will undergo CT with IV contrast of the chest, abdomen and pelvis. MRI should 
only be used to evaluate sites of disease that are not adequately imaged by CT. If a patient is intolerant of 
iodine-based contrast agents, CTs may be performed without contrast. MRI may be used to evaluate sites 
of disease where a CT without IV contrast is not adequate. Visible skin lesions and easily palpable 
subcutaneous tumors may be measured by physical examination using a ruler or calipers. Bone scans should 
be performed within past 60 days prior to Cycle 1 Day 1. If the baseline bone scan is positive, scans should 
be repeated at Cycle 3 Day 1, Cycle 5 Day 1, at the end of Cycle 6, and during Disease Progression Follow- 
up Period at 90 and 180 days following the end of treatment (± 30 days). 
 
For optimal evaluation of patients, the same methods of assessment and technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. Target lesions should be 
selected and measured as per RECIST guidelines (see Appendix C and Appendix D). 
 
At the investigator’s discretion, imaging studies may be repeated at any time if disease progression is 
suspected. Due to the possibility of pseudoprogression, patients will be permitted to continue with treatment 
beyond initial RECIST 1.1 or Cheson defined disease progression as long as they meet the following 
criteria: 
• 
If, in the opinion of the investigator, he/she is continuing to receive clinical benefit as defined by: 
o Absence of clinical symptoms and signs (including worsening of laboratory values) 
indicating disease progression 
o No decline in ECOG performance status 
o Absence of rapid progression of disease or of progressive tumor at critical anatomical sites 
(e.g., cord compression) requiring urgent alternative medical intervention. 
o Subject is tolerating study drug 
 
All decisions to continue treatment beyond disease progression must be discussed with the Sponsor/Medical 
Monitor and documented in the study records. Disease progression will be confirmed after at least 4 weeks 
per irRC/LYRIC. If disease progression is confirmed per irRC/LYRIC, the patient will discontinue study 
therapy. The local investigator’s assessment will be used for the analysis of response according to both 
RECIST 1.1 and irRC/Lyric, and for treatment decision making (study discontinuation due to PD as per 
irRC). Patients experiencing progressive disease per RECIST v. 1.1 criteria may continue to be treated 
according to irRC guidelines until progression is documented via irRC. Imaging data may be centrally 
collected and checked for quality by an imaging Contract Research Organization (CRO) designated by 
Moderna. The local investigator’s assessment will be used for the data analysis and for treatment decision 
making. Central review of the imaging data may be performed if deemed necessary. 

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10.11 
OPTIONAL DIGITAL PHOTOGRAPHY 
 
In addition to radiological imaging techniques, photographs of visible cutaneous lesions are recommended. 
Optional digital photograph(s) will be taken of all visible injected tumor(s) and non-injected tumors and of 
any remaining visible local reactions in or around the injected lesion(s) for exploratory analysis. 
 
10.12 
PHARMACOKINETICS AND IMMUNOGENICITY 
 
Blood samples will be collected from all enrolled patients for the determination of serum mRNA-2416 
concentrations at the time points indicated in Table 6. Blood samples will also be collected to assess the 
potential for immunogenicity in each treatment cycle in the peripheral circulation at the time points 
indicated in Table 6. Immunogenicity to the study treatment will be assessed by monitoring the formation 
of anti-PEG and anti-OX40L antibodies. Antibodies may be further characterized and/or evaluated for their 
ability to neutralize the activity of the study treatment. 
 
10.12.1 
DURVALUMAB PHARMACOKINETICS 
Blood samples will be collected at the time points indicated in Table 6 and may be used to assess 
durvalumab serum concentration. 
 
If emerging data from this study are consistent with the existing data from other durvalumab clinical trials, 
durvalumab PK sampling may be reduced or discontinued. 
 
10.13 
BIOMARKERS 
 
In this study, biomarker samples will be collected per Tables 6, 7,8 and 9. The biomarker analysis will be 
used to investigate the effect of mRNA-2416, as well as to determine how the markers are associated with 
clinical outcome. Immune responses will be studied in the peripheral circulation and in tumor biopsy 
specimens. Tumor biopsies will be examined using methods such as immunohistochemistry, quantitative 
immunofluorescence, RNA sequencing and/or electrochemiluminescence (ECL) assays to evaluate changes 
in key immune pathway axes, such as PD-L1/PD-1 and OX40L/OX40, as well as characterization (eg, 
phenotype, distribution, and activation) of tumor infiltrating lymphocyte and myeloid populations. 
Cytokines may also be examined in both tumor and blood tissues using methods such as RNA sequencing 
and enzyme-linked immunosorbent assay (ELISA)/ ECL assays, respectively. 
 
The goal of the biomarker assessments is to provide supportive data for the clinical study; however, there 
may be circumstances when a decision is made to stop a collection or not perform or discontinue an 
assessment (eg, inadequate sample number, sample quality or assay issues that preclude analysis, or 
impossibility to perform correlative analyses). Therefore, sample collection and/or assessment may be 
omitted at the discretion of the Sponsor. 
 
The sample collection information must be entered on the appropriate sample collection log eCRF page(s). 
Sample details including volume and instructions for the collection, handling, and shipment of samples are 
outlined in the laboratory manual for the study. 

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Table 6: 
Sampling schedule for Pharmacokinetics, Immunogenicity, and Cytokine 
Profiling 
 
Cycle 
Day 
Scheduled Time (Sampling Window) 
Purposea 
1 
1 
Pre-dose of Cycle 1 Day 1 
PK, Cytokines, IG 
1 
1 
3 h from start of injection (± 10 min) 
PK, Cytokines 
1 
1 
6 h from start of injection (± 30 min) 
PK, Cytokines 
1 
2 
24 h from start of injection (± 60 min) 
PK, Cytokines 
1 
8 
168 h from start of injection (± 24 h) 
PK, Cytokines 
1 
15 
Pre-dose of Cycle 1 Day 15 
IG 
2 
1 
Pre-dose of Cycle 2 Day 1 
PK, Cytokines, IG, mAb PK 
3 
1 
Pre-dose of Cycle 3 Day 1 
IG 
3 
15 
Pre-dose of Cycle 3 Day 15 
IG 
4 
1 
Pre-dose of Cycle 4 Day 1 
IG 
5 
1 
Pre-dose of Cycle 5 Day 1 
IG 
6 
1 
Pre-dose of Cycle 6 Day 1 
IG 
6 
15 
Pre-dose of C1D15 
IG 
EOT 
Anytime 
IG 
Unscheduled 
Anytime when needed 
PK, Cytokines, IG, mAb PK 
Abbreviations: EOT, end of treatment; FU, follow-up; IG, immunoglobulin; PEG, polyethylene glycol, mAb, monoclonal antibody 
(durvalumab). 
a. IG analyte is anti- PEG and -OX40L anti-drug antibody 
 
10.13.1 
TUMOR BIOPSIES 
 
Patients enrolled in the Biopsy Cohort Enrichment (Section 8.2.2) and all patients in the Dose Expansion 
period must consent to pre-treatment and on-treatment tumor biopsies. For all patients, every attempt to 
biopsy the same lesion pre- and post-dose should be made to minimize inter-lesion variability. If, for any 
reason, a lesion that has been biopsied pre-dose is not amenable to intratumoral injection with study drug, 
a different lesion or lesions may be injected, providing that the lesion can be biopsied post-dose. 
 
For all biopsies of tumors that have received intratumoral injections, the biopsy site should be the same as, 
or as close as possible to, the site of injection of mRNA-2416. 
 
Biopsies of superficial lesions may be performed by punch biopsy or by excision biopsy, at the discretion 
of the investigator. For visceral lesions, a core biopsy may be obtained under imaging guidance preferably 
using an 18-gauge biopsy needle. For optimal results, 4 to 6 passes are requested, if feasible. Fine needle 

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aspiration of cells from tumors will not be suitable for analysis. Institutional standard operating procedures 
and safety procedures should be used for each biopsy procedure. Biopsied tissue samples should be placed 
immediately into formalin fixative, and labeled, processed, and shipped as outlined in the mRNA-2416- 
P101 Laboratory Manual. 
 
10.13.2 
DOSE ESCALATION BIOPSY COLLECTION PLAN 
For patients in the dose escalation biopsy cohorts, collection of newly obtained tumor samples during 
screening and at 1 of the time points as specified below is required unless not medically feasible and agreed 
by the Sponsor. Up to 9 patients may be enrolled into the Biopsy Cohort Enrichment at each dose level, 3 
patients in Group A, 3 in Group B and 3 in Group C. 
Escalation Biopsy Group A: 
Patients will undergo a baseline biopsy of a lesion distinct from the planned site of intratumoral injection 
up to 14 days pre-dose Cycle 1 Day 1 and a biopsy within Cycle 1 Day 22 - 28. The primary analysis of the 
biopsies from biopsy Group A will focus on infiltration of immune effector cells into tumor lesions distal 
from the tumor lesion(s) that are injected with mRNA-2416 (eg, an abscopal anti-tumor effect). 
Escalation Biopsy Group B: 
Patients will undergo a baseline tumor biopsy of a lesion that is planned for intratumoral injection up to 14 
days pre-dose Cycle 1 Day 1 and a biopsy of the injected tumor lesion 24 to 48 hours post-dose Cycle 1 
Day 1. The biopsy site should be the same as, or as close as possible to, the site of injection of mRNA- 
2416. 
Escalation Biopsy Group C: 
Patients will undergo a baseline tumor biopsy of a lesion that is planned for intratumoral injection up to 14 
days pre-dose Cycle 1 Day 1 and a biopsy of the injected tumor lesion 24 to 48 hours post-dose Cycle 2 
Day 1. The biopsy site should be the same as, or as close as possible to, the site of injection of mRNA- 
2416. 
The primary analysis of the biopsies from biopsy Groups B and C will focus on expression of OX40L 
protein immediately after injection of mRNA. 
Table 7:    Dose Escalation Tumor Biopsy Analyses by Group 
 
Group 
Biopsy Timing 
Biopsy Site 
Analyses 
OX40/OX40L 
Expression 
Additional Tumor 
Microenvironment 
Characterization by 
IHC/ QIF and/or 
RNAseq 
A 
First biopsy: 
Within 14 days pre-study 
(C1D1) 
Any lesion NOT planned for injection 
of study drug 
X 
X 
Second biopsy: Between 
Cycle 1 Day 22-28 
Lesion that has NOT been injected with 
study drug (same lesion as baseline) 
X 
X 
B 
First biopsy: 
Within 14 days pre-study 
(C1D1) 
Any lesion planned for injection of 
study drug 
X 
X 
Second biopsy: 
24-48 hrs after C1D1 
injection 
Lesion injected with study drug *biopsy 
should be at the injection site if possible 
(same lesion as baseline) 
X 
X 

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Group 
Biopsy Timing 
Biopsy Site 
Analyses 
OX40/OX40L 
Expression 
Additional Tumor 
Microenvironment 
Characterization by 
IHC/ QIF and/or 
RNAseq 
C 
First biopsy: 
Within 14 days pre-study 
(C1D1) 
Any lesion planned for injection of 
study drug 
X 
X 
Second biopsy: 
24-48 hrs after C2D1 
injection 
Lesion injected with study drug *biopsy 
should be at the injection site if possible 
(same lesion as baseline) 
X 
X 
OX40L=OX40 ligand; QIF= quantitative immunofluorescence; RNAseq= RNA sequencing 
 
10.13.3 
DOSE EXPANSION BIOPSY COLLECTION PLAN 
 
For all patients in dose expansion, collection of newly obtained tumor samples during screening and at 1 of 
the time points as specified below is required unless not medically feasible and agreed by the Sponsor. An 
additional optional biopsy at the time of treatment response or disease progression is also requested if 
medically feasible. 
 
For all patients in dose expansion, biopsies at screening should be performed on a lesion which is planned 
for injection of study treatment, as well as a distal non-visceral lesion which is not planned for injection of 
study treatment if medically feasible. Similarly, the on-treatment biopsies should be performed on a lesion 
which has been injected with study treatment, as well as on a distal non-visceral lesion which has not been 
injected with study treatment if medically feasible. Every attempt should be made to biopsy the same 
injected and distal lesions at all time points. 
 
Patients in dose expansion will be assigned to biopsy groups which each have a different timepoint for the 
on-treatment biopsies, as specified below. 
 
Arm A Expansion Biopsy Group D: 
 
Within 14 days pre-dose Cycle 1 Day 1: A baseline tumor biopsy of a lesion that is planned for intratumoral 
injection, as well as a distal non-visceral lesion which is not planned for injection if medically feasible. 
 
24 to 48 hours post-dose Cycle 1 Day 1: Tumor biopsy of the injected tumor lesion, as well as a distal non- 
visceral lesion which has not been injected with study treatment if medically feasible. The biopsy of the 
injected lesion should include or be as close as possible to the injection site. 
 
Arm A Expansion Biopsy Group E: 
 
Within 14 days pre-dose Cycle 1 Day 1: A baseline tumor biopsy of a lesion that is planned for intratumoral 
injection, as well as a distal non-visceral lesion which is not planned for injection if medically feasible 
 
Pre-dose Cycle 2 Day 1: Tumor biopsy of the injected tumor lesion, as well as a distal non-visceral lesion 
which has not been injected with study treatment if medically feasible The biopsy of the injected lesion 
should include or be as close as possible to the injection site. 

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Arm B Expansion Biopsy Group F: 
 
Within 14 days pre-dose Cycle 1 Day 1: A baseline tumor biopsy of a lesion that is planned for intratumoral 
injection, as well as a distal non-visceral lesion which is not planned for injection if medically feasible. 
 
24 to 48 hours post-dose Cycle 1 Day 1: Tumor biopsy of the injected tumor lesion, as well as a distal non- 
visceral lesion which has not been injected with study treatment if medically feasible. The biopsy of the 
injected lesion should include or be as close as possible to the injection site. 
 
Arm B Expansion Biopsy Group G: 
 
Within 14 days pre-dose Cycle 1 Day 1: A baseline tumor biopsy of a lesion that is planned for intratumoral 
injection, as well as a distal non-visceral lesion which is not planned for injection if medically feasible 
 
Pre-dose C1D15: Tumor biopsy of the injected tumor lesion, as well as a distal non-visceral lesion which 
has not been injected with study treatment if medically feasible. The biopsy of the injected lesion should 
include or be as close as possible to the injection site. 
 
Arm B Expansion Biopsy Group H: 
 
Within 14 days pre-dose Cycle 1 Day 1: A baseline tumor biopsy of a lesion that is planned for intratumoral 
injection, as well as a distal non-visceral lesion which is not planned for injection if medically feasible 
 
Pre-dose Cycle 2 Day 1: Tumor biopsy of the injected tumor lesion, as well as a distal non-visceral lesion 
which has not been injected with study treatment if medically feasible. The biopsy of the injected lesion 
should include or be as close as possible to the injection site. 
 
Table 8:    Arm A Dose Expansion Tumor Biopsy Analyses by Group 
 
Group 
Biopsy Timing 
Biopsy Sites 
Analyses 
OX40/OX40L 
Expression 
Additional Tumor 
Microenvironment 
Characterization by 
IHC/ QIF and/or 
RNAseq 
D 
First biopsies: 
Within 14 days pre- 
study (C1D1) 
1) Lesion planned for injection of study 
drug 
2) Lesion NOT planned for injection of 
study drug 
X 
X 
Second biopsies: 
24-48 hrs after 
C1D1 injection 
1) Lesion injected with study drug 
2) Lesion NOT injected with study drug 
X 
X 
E 
First biopsies: 
Within 14 days pre- 
study (C1D1) 
1) Lesion planned for injection of study 
drug 
2) Lesion NOT planned for injection of 
study drug 
X 
X 
Second biopsies: 
Pre-dose C2D1 
injection 
1) Lesion injected with study drug 
2) Lesion NOT injected with study drug 
X 
X 
OX40L=OX40 ligand; QIF= quantitative immunofluorescence; RNAseq= RNA sequencing 

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Table 9:    Arm B Dose Expansion Tumor Biopsy Analyses by Group 
 
Group 
Biopsy Timing 
Biopsy Sites 
Analyses 
OX40/OX40L 
Expression 
Additional Tumor 
Microenvironment 
Characterization by 
IHC/ QIF and/or 
RNAseq 
F 
First biopsies: 
Within 14 days pre- 
study (C1D1) 
1) Lesion planned for injection of study 
drug 
2) Lesion NOT planned for injection of 
study drug 
X 
X 
Second biopsies: 
24-48 hrs after 
C1D1 injection 
1) Lesion injected with study drug 
2) Lesion NOT injected with study drug 
X 
X 
G 
First biopsies: 
Within 14 days pre- 
study (C1D1) 
1) Lesion planned for injection of study 
drug 
2) Lesion NOT planned for injection of 
study drug 
X 
X 
Second biopsies: 
Pre-dose C1D15 
injection 
1) Lesion injected with study drug 
2) Lesion NOT injected with study drug 
X 
X 
H 
First biopsies: 
Within 14 days pre- 
study (C1D1) 
1) Any lesion planned for injection of 
study drug 
2) Any lesion NOT planned for injection 
of study drug 
X 
X 
Second biopsies: 
Pre-dose C2D1 
injection 
1) Lesion injected with study drug 
(same lesion as baseline) 
2) Lesion NOT injected with study drug 
(same lesion as baseline) 
X 
X 
OX40L=OX40 ligand; QIF= quantitative immunofluorescence; RNAseq= RNA sequencing 
 
10.13.4 
ADDITIONAL BIOMARKER ASSESSMENTS 
During the trial, in addition to the biomarkers outlined in the study endpoints, exploratory biomarker 
analysis may be conducted on any remaining tumor and/or blood samples (including PK samples). These 
studies would extend the search for other potential relevant biomarkers to investigate the effect of mRNA- 
2416 as well as to determine how changes in the markers may relate to exposure and clinical outcomes. In 
addition, other methodologies for assessing biomarkers of immunologic response, such as (DNA 
sequencing or quantitation) or other methods may be employed. These additional investigations 
would be dependent upon clinical outcome, reagent and sample availability. 
After the study is completed, with patient consent, any remaining biological samples may be stored for up 
to 15 years to address further scientific questions related to mRNA-2416 or cancer. A decision to perform 
such exploratory research may arise from new scientific findings related to the drug class or disease, as well 
as reagent and assay availability. 
 
10.14 
PREGNANCY CONSIDERATIONS 
 
There is no information on the effects of the study medication on fetal development in humans. Patients 
should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) 
if pregnancy were to occur during the study. 

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10.14.1 
INSTRUCTIONS FOR MALE PATIENTS 
 
Non-sterilized male patients who are not abstinent and intend to be sexually active with a female partner of 
childbearing potential must use a male condom plus spermicide from the time of screening throughout the 
total duration of the drug treatment and the drug washout period (90 days after the last dose of study 
treatment). Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods 
of contraception. Male patients should refrain from sperm donation throughout this period. 
 
Female partners (of childbearing potential) of male patients must also use a highly effective method of 
contraception throughout this period (Table 5). 
 
10.14.2 
INSTRUCTIONS FOR FEMALE PATIENTS 
 
Female patients of childbearing potential who are not abstinent and intend to be sexually active with a non- 
sterilized male partner must use at least 1 highly effective method of contraception (Table 5) from the time 
of screening throughout the total duration of the drug treatment and the drug washout period (90 days after 
the last dose of durvalumab monotherapy). Non-sterilized male partners of a female patient of childbearing 
potential must use a male condom plus spermicide throughout this period. Cessation of birth control after 
this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and 
the withdrawal method are not acceptable methods of contraception. Female patients should refrain from 
breastfeeding throughout this period. 
 
Please note, females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
 
Women will be considered post-menopausal if they have been amenorrheic for 12 months without an 
alternative medical cause. The following age-specific requirements apply: 
 
• 
Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 
12 months or more following cessation of exogenous hormonal treatments and if they have 
luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the 
institution. 
 
• 
Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 
12 months or more following cessation of all exogenous hormonal treatments, had radiation- 
induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last 
menses >1 year ago. 
 
• 
Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy, or complete 
hysterectomy) are eligible. 
 
Highly effective methods of contraception, defined as one that results in a low failure rate (ie, less than 1% 
per year) when used consistently and correctly are described in Table 10. Note that some contraception 
methods are not considered highly effective (eg, male or female condom with or without spermicide; female 
cap, diaphragm, or sponge with or without spermicide; non copper containing intrauterine device; 
progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode 
of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined 
oral contraceptive pills). 

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Table 10 
Highly effective methods of contraception (<1% failure rate) 
 
Barrier/intrauterine methods 
Hormonal methods 
• 
Copper T intrauterine device 
• 
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®)a 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
This is also considered a hormonal method 
 
10.14.3 
PREGNANCY REPORTING 
• 
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®) 
• 
Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 
• 
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®) 
• 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
• 
Patch: Norelgestromin/ethinylestradiol- 
releasing transdermal system (eg, Ortho 
Evra®) 
• 
Minipill: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone-based pill 
 
Pregnancy is considered an immediately reportable event (but not an AE), and the investigator will record 
information concerning the pregnancy on the appropriate form and submit it to the Medical Monitor, 
Moderna pharmacovigilance at drugsafety@modernatx.com, and contract research organization (CRO) 
within 24 hours of learning of a patient’s pregnancy. Study drug administration will be stopped in any 
female patient who becomes pregnant while participating in the study, and the patient will be followed to 
determine the outcome of the pregnancy. 
 
10.14.3.1 
FOLLOW-UP IN THE EVENT OF A PREGNANCY 
 
The IRB and the Sponsor will be informed of all pregnancies in study patients. 
 
The patient will be asked to provide information on the outcome of the pregnancy, including premature 
termination should the case arise. Spontaneous miscarriages and congenital abnormalities will be reported 
as SAEs. Information on the status of the mother and child will be forwarded to the Medical Monitor or 
designee. Generally, follow-up will be in accordance with regulatory guidance and at least 6 to 8 weeks 
after the estimated delivery date. Any premature termination of the pregnancy will be reported. 
 
10.15 
OVERDOSE MANAGEMENT 
 
For this study, any dose of mRNA-2416 or durvalumab greater than the patient’s assigned dose level will 
be considered an overdose. No specific information is available regarding treatment for overdose of mRNA- 
2416 or durvalumab. 
 
In the event of a suspected overdose, the investigator must do the following: 
 
1. Contact the Medical Monitor and PPD pharmacovigilance/ SAE hotline immediately. 

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2. Closely monitor the patient for AEs/SAEs and laboratory abnormalities until last safety 
follow-up visit. 
3. Report any signs or symptoms associated with the overdose as an AE and record details in 
the relevant AE/SAE sections in the electronic case report form (eCRF). 
4. Document the quantity of the excess dose in the eCRF. 
 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
11.1 
QUALITY CONTROL 
 
11.1.1 
MONITORING 
 
The Sponsor, or designee(s), will monitor the study for compliance to the protocol, applicable laws and 
regulations, and GCP. The monitor(s) will verify data on the eCRF versus source data. The monitor is also 
responsible for ensuring that the proper records are maintained. Monitoring reports will be issued for each 
monitoring visit. 
 
11.2 
QUALITY ASSURANCE 
 
Quality assurance personnel may audit the clinical trial sites and/or study-related materials at any time 
during the study. 
 
12 
ASSESSMENT OF SAFETY 
 
Safety will be assessed through AEs, laboratory data (eg, hematology, chemistry, and liver function tests), 
ECGs, physical examinations, vital signs, weight, concomitant medications and procedures, and ECOG 
performance status. 
 
The PI and designated study staff are responsible for detecting, documenting, and reporting events that meet 
the definition of an AE or SAE. 
 
All SAEs/SUSARs will be reported to Health Authorities and investigators per 21 CFR 312.32. 
 
12.1 
DEFINITIONS 
 
12.1.1 
ADVERSE EVENT 
 
An AE is any adverse experience in a patient administered a pharmaceutical product, whether or not it is 
considered drug related, that occurs during a patient’s study participation (defined as after a patient signs 
the ICF through the patient’s last Safety follow-up visit or study discontinuation, whichever is later). This 
would include any side effect, injury, toxicity, sensitivity reaction, intercurrent illness, or sudden death. A 
pre-existing condition is one that is present at study entry and is reported as part of the patient’s medical 
history. It should be reported as an AE if the frequency, intensity, or character of the condition worsens 
during study drug treatment. 
 
The development of new or progression of existing metastasis from the primary cancer under study should 
be considered as disease progression and not an AE. Events that are unequivocally due to disease 
progression should not be reported as an AE during the study unless they meet serious criteria as defined 
in Section 12.1.3. 

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Patients should be instructed to report all AEs to the investigator or study staff. AEs must be appropriately 
documented in the patient’s original source documents and entered into the eCRF. Investigators should 
report syndromes rather than list symptoms. The severity of each AE will be categorized using NCI CTCAE 
Version 4.03. 
 
12.1.2 
ADVERSE DRUG REACTION 
 
An adverse drug reaction (ADR) is any untoward and unintended response in a patient to an investigational 
medicinal product, which is related to any dose administered to that patient. 
 
12.1.3 
SERIOUS ADVERSE EVENT 
 
An SAE is any AE (undesirable experience associated with the use of a medical product in a patient) where 
the patient outcome is: 
 
• 
Death 
o Report if suspected that the death was an outcome of the adverse event and include the date if 
known. 
• 
Life-threatening 
o Report if suspected that the patient was at substantial risk of dying at the time of the adverse event 
or use or continued use of the device or other medical product might have resulted in the death of 
the patient. 
• 
Hospitalization (initial or prolonged) 
o Report if admission to the hospital or prolongation of hospitalization was as a result of the adverse 
event. 
o Emergency room visits that do not result in admission to the hospital should be evaluated for one 
of the other serious outcomes (eg, life-threatening; required intervention to prevent permanent 
impairment or damage; other serious medically important event). 
• 
Disability or Permanent Damage 
o Report if the adverse event resulted in a substantial disruption of a person's ability to conduct 
normal life functions, that is, the adverse event resulted in a significant, persistent, or permanent 
change or impairment, damage, or disruption in the patient's body function/structure, physical 
activities, and/or quality of life. 
• 
Congenital Anomaly/Birth Defect 
o Report if suspected that exposure to a medical product prior to conception or during pregnancy may 
have resulted in an adverse outcome in the child. 
• 
Other Serious (Important Medical Events) 
o Report when the event does not fit the other outcomes, but the event may jeopardize the patient and 
may require medical or surgical intervention (treatment) to prevent one of the other outcomes. 
Examples include allergic bronchospasm (a serious problem with breathing) requiring treatment in 
an emergency room, serious blood dyscrasias (blood disorders), or seizures/convulsions that do not 
result in hospitalization. The development of drug dependence or drug abuse would also be 
examples of important medical events. 

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Clarification should be made between the terms “serious” and “severe” because the terms are not 
synonymous. The term “severe” is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as a severe 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 functioning. A severe AE does not necessarily need to be considered serious. For 
example, persistent nausea of several hours duration may be considered severe nausea but not an SAE. On 
the other hand, a stroke resulting in only a minor degree of disability may be considered mild but would be 
defined as an SAE based on the above noted criteria. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
 
12.1.4 
UNEXPECTED ADVERSE REACTIONS 
 
For expedited reporting purposes, expectedness of AEs will be assessed against the investigational 
treatment regimen the patient is receiving at the time of the event. AE terms not listed as an expected event 
in the Investigator’s Brochure(s) for mRNA-2416 alone (Arm A) or mRNA-2416 and/or durvalumab, (Arm 
B) will be considered as unexpected. 
 
12.1.5 
DURVALUMAB ADVERSE EVENTS OF SPECIAL INTEREST 
An AE of special interest (AESI) is one of scientific and medical interest specific to understanding of the 
IP and may require close monitoring and rapid communication by the investigator to the Sponsor. An AESI 
may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of these events 
in order to characterize and understand them in association with the use of this IP. 
AESIs for durvalumab include, but are not limited to, events with a potential inflammatory or immune- 
mediated mechanism and which may require more frequent monitoring and/or interventions such as 
steroids, immunosuppressants, and/or hormone replacement therapy. These AESIs are being closely 
monitored in clinical studies with durvalumab monotherapy and combination therapy. An imAE is defined 
as an AESI that is associated with drug exposure and is consistent with an immune-mediated mechanism 
of action and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) 
data, as appropriate, should be used to support an imAE diagnosis. Appropriate efforts should be made to 
rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. 
If the investigator has any questions with regards to an event being an imAE, the investigator should 
promptly contact the Study Physician. 
AESIs observed with durvalumab include the following: 
• 
Diarrhea/colitis and intestinal perforation 
• 
Pneumonitis/ILD 
• 
hepatitis/transaminase increases 
• 
Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypothyroidism and type I diabetes mellitus) 
• 
Rash/dermatitis 
• 
Nephritis/blood creatinine increases 
• 
Pancreatitis/serum lipase and amylase increases 
• 
Myocarditis 
• 
Myositis/polymyositis 
• 
Neuropathy/neuromuscular toxicity (eg, Guillain-Barré syndrome, and myasthenia gravis) 

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• 
Other inflammatory responses that are rare and/or less frequent with a potential immune-mediated 
etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis and other events involving 
the eye, skin, hematological, and rheumatological events. 
In addition, infusion-related reactions, and hypersensitivity and/or anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current version of the 
durvalumab IB. More specific guidelines for their evaluation and treatment are described in detail in the 
Dosing Modification and Toxicity Management Guidelines (please see Appendix E). These guidelines have 
been prepared by the Sponsor to assist the investigator in the exercise of his/her clinical judgment in treating 
these types of toxicities. These guidelines apply to AEs considered causally related to the study drug and/or 
study regimen by the reporting investigator. 
 
12.2 
AE COLLECTING AND REPORTING 
 
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 starting from the time of ICF signing through the patient’s last safety follow- 
up visit or study discontinuation, whichever is later (ie, the “AE reporting period”). From the time of ICF 
signing to first dose of mRNA-2146, only AEs related to study procedures will be collected. Also, once a 
patient has ended study treatment and has initiated any new post-treatment antineoplastic therapy, only AEs 
suspected to be related to study treatment will be collected. 
 
Any clinically relevant deterioration in laboratory assessments or other clinical findings is considered an 
AE and must be recorded on the appropriate pages of the eCRF. When possible, signs and symptoms 
indicating a common underlying pathology should be noted as 1 comprehensive event. 
 
All SAEs that occur during the AE reporting period, as defined by the protocol, must be reported by the 
investigator to the contract research organization (CRO), as the designee of the Sponsor, within 24 hours 
of the investigator becoming aware of the SAE. All SAEs and deaths that occur during the AE reporting 
period, whether or not considered causally related to the study drug, will be reported to the FDA per 21 
CFR 312.32. After informed consent, but prior to initiation of study treatment, only SAEs caused by a 
protocol-mandated intervention will be collected (eg, SAEs related to invasive procedures such as biopsies 
or medication washout). The information collected will include a minimum of the following: patient 
number, a narrative description of the event, and an assessment by the investigator as to the intensity of the 
event and relatedness to study drug. Follow-up information on the SAE may be requested by the Sponsor 
or its representative CRO. Detailed instructions for the collecting and reporting of SAEs will be provided 
in the Investigator Site File. 
 
If there are serious, unexpected ADRs associated with the use of the study drug, the Sponsor or its 
designated CRO will notify the appropriate regulatory agency(ies) and all participating investigators on an 
expedited basis (7 days for fatal or life-threatening, serious, unexpected ADRs; 15 days for all other serious, 
unexpected ADRs). The Sponsor has delegated the responsibility to promptly notify the IRB/IEC of all 
unexpected serious ADRs involving risk to human patients in accordance with the rules and regulations of 
the IRB/IEC to the PI. 
 
An unexpected event is one that is not reported in the IB. 
 
REPORTING OF SAES AND SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS 
 
All SAEs must be reported to the designated CRO within 24 hours of the investigational site’s knowledge 
of the occurrence. Each investigational site will submit the SAE information to the CRO. 

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The SAE information transmitted to the CRO will include the following (as available): 
 
• 
Patient ID, investigator name, and site number 
• 
SAE information: event term, onset date, severity, and causal relationship 
• 
Basic demographic information (eg, age, sex, weight, etc) 
• 
The outcomes attributable to the event (eg, death, a life-threatening adverse drug experience, 
inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, other important medical event[s]) 
• 
A summary of relevant test results, pertinent laboratory data, and any other relevant medical history 
• 
The first and last dates of study drug administration 
• 
A statement whether study drug was discontinued or study drug administration schedule was 
modified 
• 
A statement whether event recurred after reintroduction of study drug if administration had been 
discontinued or withheld 
• 
Supplemental information may include the following hospital records: laboratory results, radiology 
reports, progress notes, admission and emergency room notes, holding or observation notes, 
discharge summaries, autopsy reports, and death certificates. 
 
The SAE information should be transmitted within 24 hours with as much of the above information as 
available at the time. Supplemental information may be transmitted and should not delay the initial 
transmission. The Sponsor or CRO may contact the investigational site to solicit additional information or 
follow-up on the event. Investigational sites will be provided with detailed instructions on the procedures 
for transmitting SAEs to the CRO. 
 
For regulatory purposes, initial reports of serious ADRs should be transmitted within the prescribed time 
frame as long as the following minimum information is available: patient identification, suspect study drug, 
reporting source, and an event or outcome that can be identified as being both serious and unexpected for 
which, in the investigator’s opinion, there is a suspected causal relationship. 
 
A suspected unexpected serious adverse reaction (SUSAR) that is fatal or life-threatening must be reported 
to the competent authority and ethics committee immediately (within 7 days) after the Sponsor becomes 
aware of the event. Any additional information must be reported within 8 days of sending the first report. 
 
A SUSAR that is not fatal or life-threatening must be reported to the competent authority and ethics 
committee as soon as possible (within 15 days) after the Sponsor becomes aware of the event. 
 
12.3 
RELATIONSHIP TO STUDY DRUG 
 
For each reported AE, the investigator must make an assessment of the relationship of the event to each 
study drug using the following scale: 
 
• 
Not Related: An event that is not associated with study drug administration and is judged clearly due 
to causes other than the study drug. 
• 
Related: An event that is or may be associated with study drug administration. 

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o 
The terms Possibly Related and Probably Related will not be used. Any event that is 
possibly or probably related to study drug should be recorded as Related by the 
Investigator. 
 
In the event of death, the cause of death should be recorded as the AE and the relationship to study drug 
assessed as above. “Death” is an outcome and is NOT the AE. The only exception is “sudden death” when 
the cause is unknown. 
 
12.4 
LABORATORY TEST ABNORMALITIES 
 
Clinically significant abnormal laboratory findings that are detected during the study or are present at 
baseline and significantly worsen will be reported as AEs or SAEs. The investigator will exercise his or her 
medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. 
 
Clinical significance is at the discretion of the investigator and may be defined as those findings which: 
 
• 
Are directly responsible for discontinuation from the study, 
• 
Require treatment or other therapeutic intervention, 
• 
Require further monitoring, or 
• 
Require further diagnostic evaluation (other than repeat of the same test to confirm the abnormality). 
 
All abnormal laboratory values considered to be clinically significant will be recorded on the AE page of 
the eCRF. Significant abnormal laboratory values occurring during the clinical study should be followed 
until repeat tests return to normal, stabilize, or are no longer clinically significant. 
 
12.5 
FOLLOW-UP OF AES 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to resolution or 
stabilization. During the post-treatment follow-up period, all SAEs and related non-serious AEs should be 
followed until resolution or stabilization, which is defined as grade 1 or less. Patients will be referred to 
their primary care doctor for further follow-up as needed post-study. 
 
The severity of ongoing AEs at last visit will be recorded. Any additional clinical sequelae emerging from 
the AE should be recorded as a separate AE. 

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13 
STATISTICAL METHODS 
 
A detailed Statistical Analysis Plan (SAP) will be used to guide the analysis and reporting of data collected 
in this study. 
 
13.1 
DATA COLLECTION AND PROCESSING 
 
Creation and validation of the clinical database, data entry, data management, and transfer of central 
laboratory data will be conducted in accordance with 21 Code of Federal Regulations (CFR) Part 11 and 
the Guidance for Industry on Computerized Systems Used in Clinical Trials. 
 
eCRFs will be completed for all enrolled patients. Please refer to the case report form (CRF) Completion 
Guidelines for instructions on which eCRFs will be completed for patients who are enrolled but not treated. 
 
13.2 
SAMPLE SIZE CONSIDERATIONS 
 
No formal sample-size estimation will be performed. The choice of the number of patients will be based on 
a standard, Phase 1, 3+3 dose escalation design in which 3 to 6 patients are enrolled into each dose cohort. 
 
For the Arm A dose expansion period, the sample size estimation is based on Simon’s minimax two-stage 
design (Richard S, 1989). The null hypothesis that the true overall response rate is 0.05 will be tested, and 
this design with the sample size of 13 and 14 for the first and second stage, respectively, will provide an 
overall one-sided alpha value of 0.05 and statistical power of 0.80 when the true overall response rate is 
0.20. If there is 1 or more response observed from the 13 subjects in first stage, the study will proceed to 
the second stage. To account for potential patient drop-out, a total of approximately 30 patients will be 
enrolled in order to obtain evaluable data from 27 patients. If four or more responses are observed in the 27 
evaluable patients, mRNA-2416 will be considered active in ovarian cancer patients, and may warrant 
further development. 
 
For the Arm B dose expansion period, the sample size estimation is based on Simon’s two-stage design 
(Richard S, 1989). The null hypothesis that the true overall response rate is 0.1 will be tested, and this 
design with the sample size of 15 and 26 for the first and second stage, respectively, will provide an overall 
one-sided alpha value of 0.05 and statistical power of 0.80 when the true overall response rate is 0.25. If 
there is 2 or more responses observed from the 15 patients in first stage, the study will proceed to the second 
stage. To account for potential patient drop-out, a total of approximately 45 patients will be enrolled in 
order to obtain evaluable data from 41 patients. If eight or more responses are observed in the 41 evaluable 
patients, mRNA-2416 in combination with durvalumab will be considered active in ovarian cancer patients, 
and may warrant further development. 
 
13.3 
HANDLING OF MISSING DATA 
 
Details of the handling of missing data will be provided in the SAP. 
 
13.4 
STATISTICAL METHODOLOGY 
 
All data collected in this study will be presented in data listings and, where indicated, tabulated in summary 
tables. Data will be presented and summarized using the SAS System (SAS Institute Inc, Cary, NC). 
 
Continuous variables will be summarized with the number of observations, mean, standard deviation, 
median, minimum, and maximum. 

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Categorical variables will be summarized with frequencies and percentages. Percentages will be based on 
non-missing data unless specified otherwise. 
 
Except where indicated in the SAP, “baseline” is defined as the closest value prior to the start of treatment 
with study drug. 
 
13.4.1 
ANALYSIS POPULATIONS 
 
The following definitions will be used in assigning patients into analysis populations: 
 
• 
Intent-to-Treat Population – All patients who are enrolled (ie, assigned a patient number). 
• 
Safety Population – All enrolled patients who received any amount of study drug. 
• 
Activity Evaluable Population – All enrolled patient who received any amount of study drug and 
have at least 1 tumor response evaluation. 
 
13.4.2 
SAFETY ANALYSES 
 
All safety analyses will be conducted in the Safety Population. 
 
Verbatim descriptions of AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). Summary tables will be provided for all TEAEs. A TEAE is defined as any AE that newly 
appeared, increased in frequency, or worsened in severity following initiation of study drug. The number 
and percentage of patients reporting a TEAE in each dose cohort will be tabulated by system organ class 
and preferred term, severity, and relationship to study drug. The number and percentage of patients 
reporting a SAE and reporting a TEAE leading to premature discontinuation of study drug in dose cohort 
will be summarized by system organ class and preferred term. For all analyses of TEAEs, if the same AE 
(based on preferred term) is reported for the same patient more than once, the AE is counted only once for 
that preferred term and at the highest severity and strongest relationship to study drug. Clinically relevant 
abnormal physical examination results are recorded as AEs; thus, physical examination data will not be 
summarized in a table. 
 
Descriptive statistics for hematology, chemistry, and coagulation data will be summarized by dose cohort 
and time point and for the overall worst value post-baseline. Toxicity grades will be determined based on 
the CTCAE criteria version 4.03, and shift tables will be presented. The number and percentage of patients 
with at least a 2-grade increase from baseline will be summarized by dose cohort. 
 
Descriptive statistics of the change from baseline for vital signs will be summarized by dose cohort and 
time point. Abnormal values, identified by threshold values defined in the SAP, will be summarized. 
 
Descriptive statistics for ECG parameters at baseline and at the Post-treatment Safety Assessment visit and 
the change from baseline will be presented by dose cohort. 
 
13.4.3 
EFFICACY ANALYSES 
 
The Activity Evaluable Population will be used for the analyses of efficacy data based on the dose of 
mRNA-2416 received. 
 
Best response will be determined for each patient in accordance with RECIST 1.1, and Cheson guidelines 
and the objective response rate presented for each dose cohort. The overall objective response rate based 
on irRC or LYRIC will also be determined. The disease control rate based on RECIST 1.1 will also be 

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determined for Phase II patients. Progression-free survival and durability of response will be determined 
using Kaplan-Meier methodology. Please refer to Appendix C and D for a description of “Immune-related 
Response Criteria,” and RECIST 1.1 criteria. 
 
The details of Simon’s two-stage study design and analysis used for Arm A and Arm B Phase II will be 
included in the Statistical Analysis Plan (SAP). 
 
13.4.4 
PK AND PHARMACODYNAMIC ANALYSES 
 
mRNA-2416 and durvalumab PK parameters to be determined will include, but are not limited to, Cmax, 
time to maximum observed concentration, elimination half-life, and AUC. Where possible, descriptive 
statistics of the PK parameters will be provided; individual patient mRNA-2416 concentrations, actual 
sampling times, and PK parameters will be listed. 
 
This study will assess the immunological effects of each treatment cycle on the cellular and humoral 
immune responses in the peripheral circulation and in tumor biopsy specimens. Humoral immune responses 
(potential antibody production) to the study drug will be compared to baseline in serum samples. 
 
Tumor biopsies will be examined using immunohistochemistry, qualitative immunofluorescence and/or an 
orthogonal approach (i.e. ELISA) for changes in OX40L/OX40 and PD-L1/PD-1 expression levels, as well 
as characterization of tumor infiltrating lymphocyte populations (eg, phenotype, distribution, and 
activation). Plasma may be evaluated for changes in cytokine levels. 
 
13.4.5 
INTERIM ANALYSIS 
 
No interim analysis is planned for this study. 
 
14 
STUDY DRUG MATERIALS 
 
Details of the study drugs, dispensing, dosing, and accountability are summarized in the sections below. 
For detailed information, please refer to the Pharmacy Manual. 
 
14.1 
INVESTIGATIONAL PRODUCT 
 
The investigational product, mRNA-2416 injection, is a novel mRNA encoding human OX40L 
encapsulated in a lipid nanoparticle. For additional information on the investigational product, please refer 
to the IB. 
 
The investigational product, durvalumab, is a human monoclonal antibody (mAb) of the IgG 1, kappa 
subclass, that blocks the interaction of PD-L1 with programmed cell death protein 1 (PD-1) on T-cells. For 
additional information on the investigational product, please refer to the IB. 
 
14.2 
STUDY DRUG PREPARATION 
 
mRNA-2416 is formulated in 20 mM trometamol (Tris) buffer, 140 mM sodium chloride, 5% sucrose 
solution for intratumoral injection. The study drug will be administered undiluted and the administration 
volume will vary depending on the target dose of mRNA. The total volume of mRNA-2416 injected will 
not exceed 4 mL, or 8 mg mRNA. Instructions for preparation of mRNA-2416 for this clinical study will 
be detailed separately in the Pharmacy Manual. 

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Durvalumab is formulated in 26 mM histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 
0,02% weight/volume (w/v) polysorbate 80. It has a pH of 6.0 and density of 1.054 g/mL. The nominal fill 
volume is 10,0 ml. Instruction for preparation of durvalumab (MEDI4736) for this clinical study will be 
detailed separately in the Pharmacy Manual. 
 
14.3 
STUDY DRUG STORAGE 
 
mRNA-2416 must be stored at -20ºC ± 5ºC in a restricted access area. For further details, please consult 
the Pharmacy Manual. 
 
Durvalumab must be stored at 2˚C - 8˚C in a restricted access area. Product must not be frozen. For further 
details, please consult the Pharmacy Manual. 
 
14.4 
STUDY DRUG PACKAGING AND LABELING 
 
mRNA-2416 will be supplied in 2 mL glass vials containing 2 mg/mL of mRNA. Each vial contains a 1.4 
mL fill volume (2.8 mg mRNA). 
 
Durvalumab will be supplied as a 500mg vial solution for infusion after dilution (50 mg/ml). 
 
The study medication will be labeled according to the requirements of local law and legislation as well as 
current Good Manufacturing Practice and GCP guidelines. Proof labels, detailing actual label text, will be 
available in the study files of all participating countries. 
 
14.5 
STUDY DRUG ACCOUNTABILITY 
The investigational materials are to be prescribed only by the PI or the sub-investigators named on the Form 
FDA 1572 and may only be dispensed by authorized personnel at the institution(s) listed therein. Under no 
circumstances will the PI allow investigational product to be used other than as directed by the protocol. 
 
It is the responsibility of the investigator, or designee, to ensure that a current record of inventory or drug 
accountability is maintained. Inventory records must be readily available for inspection by the study 
monitor and are open to inspection by the FDA or other regulatory authorities at any time. For further 
details, please consult the Pharmacy Manual. 
 
14.6 
STUDY DRUG HANDLING AND DISPOSAL 
 
Upon the completion or termination of the study, and upon written authorization from the Sponsor or its 
representative, all unused and/or partially used study drug must be destroyed at the investigative site or 
returned to a central drug depot, as instructed by the Sponsor or its representative. It is the investigator’s 
responsibility to ensure that the Sponsor or its representative has provided written authorization for study 
drug destruction, that procedures for proper disposal of the study drug have been established, and that 
appropriate records of the disposal are documented and maintained. 
 
15 
INVESTIGATOR REQUIREMENTS 
 
15.1 
AE COLLECTION AND REPORTING 
The investigator’s responsibilities include the following: 

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• 
Monitor and record all AEs, including SAEs, regardless of the severity or relationship to study 
treatment 
• 
Determine the seriousness, relationship, and severity of each event 
• 
Determine the onset and resolution dates of each event 
• 
Monitor and record all pregnancies and follow up on the outcome of the pregnancy 
• 
Transmit SAE information to the designated CRO within 24 hours of the study site staff becoming 
aware of new information 
• 
Ensure all AE and SAE information are supported by documentation in the patients’ medical 
records 
• 
Report SAEs to local ethics committees, as required. 
 
15.2 
PROTOCOL ADHERENCE 
 
Each investigator must adhere to the protocol as detailed in this document and agree that any changes to 
the protocol must be approved by the Sponsor prior to seeking approval from the IRB/IEC. Each 
investigator will be responsible for enrolling only those patients who have met the protocol inclusion and 
exclusion criteria. The Sponsor and/or its representative reserves the right to close sites when appropriate 
(eg, in instances where the protocol is not being followed, untimely input of data into eCRFs, 
under-enrollment, etc.). 
 
15.3 
CASE REPORT FORMS 
 
eCRFs will be supplied by the Sponsor, or its representative, for the recording of all study data as specified 
in this protocol. eCRFs should be handled in accordance with instructions from the Sponsor or its 
representative. eCRFs must be completed by the designated study personnel. It is the responsibility of the 
PI to ensure that accurate eCRFs are completed in a timely manner. 
 
15.4 
SOURCE DOCUMENT MAINTENANCE 
 
Source documents are defined as the results of original observations and activities of a clinical investigation. 
Source documents may include, but are not limited to, study progress notes, email correspondences, 
computer printouts, laboratory data, and recorded data from automated instruments. All source documents 
produced in this study will be maintained by the investigator(s) and made available for inspection by 
Sponsor representatives and/or regulatory authorities. The original signed informed consent form for each 
participating patient shall be filed with records kept by the investigator(s) and a copy given to the patient. 
 
15.5 
STUDY MONITORING REQUIREMENTS 
 
Site visits will be conducted by the Sponsor or authorized Sponsor representatives to inspect study data, 
patient’s medical records, and CRFs in accordance with International Council for Harmonisation (ICH) 
guidelines, GCPs, and the respective United States (US) or foreign regulations and guidelines, as applicable. 
 
The investigator will permit representatives of the Sponsor and/or regulatory authorities the ability to 
inspect facilities and records relevant to the study. 

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15.6 
STUDY COMPLETION 
 
The Sponsor requires the following data and materials before a study can be considered complete or 
terminated: 
 
1. Laboratory findings, clinical data, and all special test results from screening through the end of the 
study follow-up period 
1. eCRFs properly completed by appropriate study personnel and signed and dated by the investigator 
2. Complete Drug Accountability records (drug inventory log and an inventory of returned or destroyed 
clinical material) 
3. Copies of protocol amendments and IRB/IEC approval or notification, if appropriate. 
 
16 
PROTECTION OF HUMAN PATIENTS AND GENERAL STUDY 
ADMINISTRATION 
 
This study will be conducted in compliance with the ICH E6 GCP (consolidated guidelines and the ethical 
principles of the Declaration of Helsinki) and any additional national or IRB/IEC-required procedures. 
 
16.1 
INFORMED CONSENT 
 
This study will be conducted in compliance with ICH E6 GCP (consolidated guidelines pertaining to 
informed consent). At the first visit, prior to initiation of any study-related procedures, patients will give 
their written consent to participate in the study after having been informed about the nature and purpose of 
the study, participation conditions, and risks and benefits. Clinical assessments and local laboratory results 
performed as part of the patient’s standard of care may be used to establish eligibility. 
 
A copy of the signed consent document or a second original must be given to the patient. The original 
signed consent document will be retained by the investigator. In case of significant changes to safety, the 
patient will be re-consented. This procedure must have prior agreement from the IEC/IRB. If applicable, 
the informed consent will be provided in a certified translation for non-English speaking patients. Signed 
consent forms must remain in the patient’s study file and be available for verification by Sponsor personnel 
or regulatory agency at any time. 
 
16.2 
IRB APPROVAL 
 
This protocol, the informed consent document, and all relevant supporting data must be submitted to the 
IRB for approval. IRB approval of the protocol, informed consent document, and any advertisement used 
to recruit study patients must be obtained before the study may be initiated. 
 
16.3 
PATIENT DATA PROTECTION 
 
Prior to any testing under this protocol, including screening tests and assessments, candidates must also 
provide all authorizations required by local law (eg, Protected Health Information authorization in North 
America). 
 
The patient will not be identified by name in the eCRF or in any study reports, and these reports will be 
used for research purposes only. The Sponsor and designee(s) and various government health agencies may 
inspect the records of this study. Every effort will be made to keep the patient’s personal medical data 
confidential. 

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17 
DATA MANAGEMENT AND MONITORING 
 
Training sessions, regular monitoring of investigators by Sponsor-designated personnel, instruction 
manuals, data verification, cross-checking, and data audits will be performed to ensure quality of all study 
data. Investigator meetings will be performed to prepare investigators and other study personnel for 
appropriate collection of study data. 
 
The Sponsor will perform internal and/or external audits of study data. 
 
It will be the responsibility of the investigator(s) to assure that essential laboratory and pharmacy manuals 
are available at the investigator/institutional site. Any or all of these documents may be subject to, and 
should be available for, audit by the Sponsor’s auditor and/or inspection by regulatory authorities. 
 
17.1 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The investigator agrees by his/her participation that the results of this study may be used for submission to 
national and/or international registration and supervising authorities. If required, these authorities will be 
provided with the names of investigators, their addresses, qualifications, and extent of involvement. It is 
understood that the investigator is required to provide the Sponsor with all study data, complete reports, 
and access to all study records. 
 
Data generated by this study must be available for inspection by any regulatory authorities, by the Sponsor, 
and the IRB/IEC, as appropriate. At a patient’s request, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare. Patient medical 
information obtained during the course of this study is confidential, and disclosure to third parties other 
than those noted above is prohibited. 
 
17.2 
RETENTION OF RECORDS 
 
US Investigational New Drug (IND) exemption regulations require that records and documents pertaining 
to the conduct of this study and the distribution of investigational products, including CRFs, consent forms, 
laboratory test results, and medication inventory records, must be kept on file by the PI for a minimum of 
2 years after notification by the Sponsor that a marketing application has been approved for the study drug 
being test (CFR Title 21, Part 312, Section 62[c]). If no application is filed or approved, these records must 
be kept for 2 years after the investigation has been discontinued and the US FDA and applicable foreign 
authorities have been notified. The Sponsor will notify the investigator of these events. No study records 
should be destroyed without prior authorization from the Sponsor. This study will be conducted under a US 
IND; for study sites outside the US, the investigator must comply with US FDA IND regulations and with 
those of the relevant national and local regulatory authorities. 
 
18 
FINANCING AND INSURANCE 
 
The financing and insurance for this study are outlined in the Clinical Trial Agreement and must comply 
with all local and national rules and regulations. 
 
19 
PUBLICATION POLICY 
 
The publication policy is outlined in the Clinical Trial Agreement. The data generated in this clinical trial 
are the exclusive property of ModernaTX, Inc. and are confidential. Written approval from Moderna is 
required prior to disclosing any information related to this clinical trial. The Sponsor will meet with the PIs 
to determine the Publication Plan. 

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20 
REFERENCES 
 
Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate 
in patients with advanced melanoma. J Clin Oncology. 2015;33(25):2780-2788. 
 
Aznar MA, Tinari N, Rullan A, et al. Intratumoral Delivery of Immunotherapy – Act Locally, Think 
Globally. J Immunol. 2017; 198(1):31-9. 
 
Boettler T, Moeckel F, Cheng Y, et al. OX40 Facilitates Control of a Persistent Virus Infection. PLOS 
Pathog 2012; 8(9): e1002913 
 
Bourla et al Immunotherapy: New Strategies for the Treatment of Gynecologic Malignancies. Oncology 
(Williston Park). 2016 Jan;30(1):59-66, 69. 
 
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous 
non-small-cell lung cancer. NEJM. 2015; 373(17):1627-1639. 
 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response 
assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014; 
32(27):3059-68. 
 
Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano Classification lymphoma response 
criteria in the era of immunomodulatory therapy. J Clin Oncol. 2014; 32(27):3059-68 
 
Compaan DM, Hymowitz SG. The crystal structure of the costimulatory OX40-OX40L complex. Structure. 
2006;14(8):1321–1330. 
 
Diab A, El-Khoueiry A, Eskens FA, et al. A first-in-human (FIH) study of PF-04518600 (PF-8600) OX40 
agonist in adult patients (pts) with select advanced malignancies. Ann of Oncol. 2016;27(suppl; abstr 
1053PD). 
 
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics of 
MEDI4376, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid tumours. 
Journal of Clinical Oncology, 2014 ASCO Annual Meeting Abstracts;32(5s): (suppl; abstr 2602). 
 
Infante JR, Hansen AR, Pishvaian MJ, et al. A Phase Ib dose escalation study of the OX40 agonist 
MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors. J Clin Oncol. 
2016;34(suppl; abstr 101). 
 
Kopf M, Ruedl C, Schmitz N, et al. OX40-Deficient Mice Are Defective in Th Cell Proliferation but Are 
Competent in Generating B Cell and CTL Responses after Virus Infection. Immunity 1999; 11: 699-708. 
 
Mallett S, Fossum S, Barclay AN. Characterization of the MRC OX40 antigen of activated CD4 positive T 
lymphocytes--a molecule related to nerve growth factor receptor. EMBO J. 1990;9(4):1063-1068. 
 
Meehan et al New treatment option for ovarian cancer: PARP inhibitors. Gynecol Oncol Res Pract. 2016 
Feb 26;3:3 
 
Murata K, Ishii N, Takano H, et al. Impairment of Antigen-Presenting Cell Function in Mice Lacking 
Expression of Ox40 Ligand. J Exp Med 2000; 191(2): 365-374. 

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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-655. 
 
Planchard D, Yokoi T, McCleod MJ, et al. A Phase III Study of Durvalumab (MEDI4736) With or Without 
Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale and Protocol Design of 
the ARCTIC Study. Clin Lung Cancer. 2016;17(3):232-236. 
 
Richard S. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical Trials 1989; 10:1- 
10 
 
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. 
NEJM. 2015; 372(4):320-330. 
 
Robert C, Ribas A, Hamid O, et al. Three-year overall survival for patients with advanced melanoma treated 
with pembrolizumab in KEYNOTE-001. 2016 ASCO Annual Meeting. 
 
Salek-Ardakani S, Moutaftsi M, Crotty S, et al. OX40 Drives Protective Vaccinia Virus-Specific CD8 T 
Cells. The Journal of Immunology 2008; 181: 7969-7976. 
 
Sugamura K, Ishii N, Weinberg AD. Therapeutic targeting of the effector T-cell co stimulatory molecule 
OX40. Nat Rev Immunol. 2004;4(6):420-431. 
 
Van Lint S, Renmans D, Broos K, et al. Intratumoral Delivery of TriMix mRNA Results in T-cell Activation 
by Cross-Presenting Dendritic Cells. Cancer Immunol Res 2016;4(2):146-156. 
 
Wolchok JD, Hoos A, O’Day S et al. Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res 2009;15(23):7412-20. 

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APPENDIX A: 
ECOG PERFORMANCE STATUS 
 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-655. 

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APPENDIX B: 
SAFETY LABORATORY TESTS AND HEPATITIS SEROLOGY 
 
Hematology 
Hemoglobin 
Monocytes 
Hematocrit 
Eosinophils 
Leukocyte count (white blood cell [WBC]) 
Basophils 
Neutrophils 
Platelets 
Lymphocytes 
Bands (if available) 
Coagulation (Screening Only) 
Prothrombin time 
Partial thromboplastin time 
Fibrinogen 
Urinalysis 
Appearance 
Blood 
pH 
Specific gravity 
Protein/Albumin 
Ketones 
Glucose 
Bilirubin 
Leukocyte esterase 
Nitrates 
Urine microscopy (red blood cell, WBC, crystals, and casts) – if clinically indicated 
Clinical Chemistry 
Magnesium 
Lactic dehydrogenase (LDH) 
Bicarbonate 
Total bilirubin 
Sodium 
Glucose 
Potassium 
Total protein 
Phosphorus 
Albumin 
Chloride 
Creatinine 
Calcium (corrected) 
Blood urea nitrogen (BUN) 
Alkaline phosphatase 
Uric acid 
Alanine aminotransferase (ALT/GPT) 
Lipase 
Aspartate aminotransferase (AST/GOT) 
Amylase 
Thyroid-stimulating hormone 
Hepatitis Serology 
Hepatitis B surface antigen (HBsAg) 
Hepatitis B core antibody (anti-HBc) 
Hepatitis B surface antibody (anti-HBs) 
Hepatitis C (HCV) antibody 

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APPENDIX C: 
SUMMARY OF TUMOR ASSESSMENT CRITERIA 
 
Table 1a: Comparison between RECIST 1.1 and irRC 
 
Criteria 
CR 
PR 
PD 
RECIST 
1.1 
Disappearance of all target 
lesions. Any pathological 
lymph nodes (whether 
target or nontarget) must 
have reduction in short axis 
to <10 mm 
At least a 30% decrease in 
the sum of diameters of 
target lesions, taking as 
reference the baseline sum 
diameters 
At least a 20% increase in the sum of 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study). In addition to the 
relative increase of 20%, the sum must 
also demonstrate an absolute increase of 
at least 5 mm 
Note: the appearance of one or more new 
lesions is also considered progression. 
irRC 
Disappearance of all lesions 
in two consecutive 
observations not less than 4 
weeks apart 
≥50% decrease in tumor 
burden compared with 
baseline in 2 observations 
at least 4 weeks apart (as 
measured bi- 
dimensionally) 
≥25% increase in tumor burden 
compared with nadir (at any single time 
point) in 2 consecutive observations at 
least 4 weeks apart, where Tumor Burden 
= SPD index lesions + SPD new, 
measurable lesions 

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Table 1b: Comparison between Cheson Criteria and LYRIC 
 
Criteria 
CR 
PR 
PD 
Cheson 
(Lugano) 
PET-CT, score 1, 2, or 
3* with or without a 
residual mass on 5PS† 
OR on CT, target 
nodes/nodal masses 
must regress to ≤1.5 
cm in LDi 
PET-CT score 4 or 5 with 
reduced uptake compared 
with baseline and residual 
mass(es) of any size. OR 
On CT ≥50% decrease in 
SPD of up to 6 target 
measurable nodes and 
extranodal sites 
PET-CT score 4 or 5 with an increase in 
intensity of uptake from baseline and/or new 
FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment. OR 
On CT, an individual node/lesion must be 
abnormal with: LDi >1.5 cm and increase by 
≥50% from PPD nadir and an increase in LDi 
or SDi from nadir 0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the splenic 
length must increase by >50% of the extent of 
its prior increase beyond baseline (eg, a 15- 
cm spleen must increase to >16 cm). If no 
prior splenomegaly, must increase by ≥2 cm 
from baseline. New or recurrent 
splenomegaly 
New or clear progression of preexisting 
nonmeasured lesions 
Regrowth of previously resolved lesions 
A new node >1.5 cm in any axis or a new 
extranodal site >1.0 cm in any axis; if <1.0 
cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma 
Assessable disease of any size unequivocally 
attributable to lymphoma 
AND/OR new or recurrent involvement of 
the bone marrow 
LYRIC 
Same as Cheson 
Same as Cheson 
As with Lugano with the following 
exceptions: 
IR 
IR(1): ≥50% increase in SPD in first 12 
weeks 
IR(2): <50% increase in SPD with 
a. New lesion(s), or 
b. ≥50% increase in PPD of a lesion or set of 
lesions at any time during treatment 
IR(3): Increase in FDG uptake without a 
concomitant increase in lesion size meeting 
criteria for PD 
 
Reference: Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano Classification lymphoma 
response criteria in the era of immunomodulatory therapy. J Clin Oncol. 2014; 32(27):3059-68 

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Table 2: Derivation of irRC overall responses 
 
Measurable response 
Nonmeasureable response 
Overall response 
Index and new, 
measureable lesions 
(tumor burden),a % 
Non-index lesions 
New, nonmeasurable 
lesions 
Using irRC 
↓100 
Absent 
Absent 
irCRb 
↓100 
Stable 
Absent 
irPRb 
↓100 
Unequivocal progression 
Absent 
irPRb 
↓≥50 
Absent/Stable 
Absent 
irPRb 
↓≥50 
Unequivocal progression 
Absent 
irPRb 
↓<50 to <25↑ 
Absent/Stable 
Absent 
irSD 
↓<50 to <25↑ 
Unequivocal progression 
Absent 
irSD 
≥25? 
Any 
Absent 
irPDb 
irCR=immune-related complete response; irPD=immune-related progressive disease; irRC=immune-related 
response criteria; irSD=immune-related stable disease 
a Decreases assessed relative to baseline, including measurable lesions only (>5 × 5 mm). 
b Assuming response (irCR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 
weeks apart. 
 
 
 
Reference: 
 
Wolchok JD, Hoos A, O’Day S et al. Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res 2009;15(23):7412-20. 

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Summary of Cheson Criteria 
 
Revised Criteria for Response Assessment 
 
Response and site 
PET-CT-based response 
CT-based response 
Complete response 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 1, 2, or 3 with or without a residual mass on 5PS 
No extralymphatic sites of disease 
Target nodes/nodal masses must regress to ≤1.5 cm in LDi 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC negative 
Partial response 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites 
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding disease 
At end of treatment, these findings indicate residual 
disease 
≥50% decrease in SPD of up to 6 target measurable nodes and 
extranodal sites 
When a lesion is too small to measure on CT, assign 5 mm x 5 mm 
as the default value 
When no longer visible, 0 x 0 mm 
For a node >5 mm x 5 mm, but smaller than normal, use actual 
measurement for calculation 
Nonmeasured lesions 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by >50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow 
but reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, 
consideration should be given to further evaluation 
with MRI or biopsy or an interval scan 
Not applicable 

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Response and site 
PET-CT-based response 
CT-based response 
No response/Stable disease 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal lesions 
Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment 
<50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for progressive 
disease are met 
Nonmeasured lesions 
Not applicable 
No increase consistent with progression 
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least 1 of the following 
Individual target 
nodes/nodal masses, 
Score 4 or 5 with an increase in intensity of uptake 
from baseline and/or 
PPD progression 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
LDi >1.5 cm and 
increase by ≥50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the splenic length must increase by 
>50% of the extent of its prior increase beyond baseline (eg, a 15- 
cm spleen must increase to >16 cm). If no prior splenomegaly, 
must increase by at least 2 cm from baseline 
New or recurrent splenomegaly 
Nonmeasured lesions 
None 
New or clear progression of preexisting nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather 
than another etiology (eg, infection, inflammation). If 
uncertain regarding etiology of new lesions, biopsy or 
interval scan may be considered 
Regrowth of previously resolved lesions 
A new node >1.5 cm in any axis 
A new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis, 
its presence must be unequivocal and must be attributable to 
lymphoma 
Assessable disease of any size unequivocally attributable to 
lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 

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5PS=5-point scale; CT=computed tomography; FDG=fluorodeoxyglucose; IHC=immunohistochemistry; LDi=longest transverse diameter of a lesion; 
MRI=magnetic resonance imaging; PET=positron emission tomography; PPD=cross product of the LDi and perpendicular diameter; SDi=shortest axis 
perpendicular to the LDi; SPD=sum of the product of the perpendicular diameters for multiple lesions. 
 
Reference: 
 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin 
lymphoma: the Lugano classification. J Clin Oncol. 2014; 32(27):3059-3068. 

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APPENDIX D: 
SUMMARY OF RECIST 1.1 CRITERIA 
 
A summary of RECIST 1.1 criteria is presented below. For a full description of RECIST 1.1, refer to 
Eisenhauer et al 2009. For a full description of Cheson criteria for lymphomas, refer to Cheson et al 2014. 
 
RECIST 1.1 
Minimum size measureable lesions 
CT: 10 mm 
Clinical: 10 mm (must be measurable with calipers) 
Chest x-ray: 20 mm 
Lymph node: 
• 
CT 
• 
≥15 mm short axis for target 
• 
≥10 - <15 mm for non-target 
• 
<10 mm is non-pathological 
Overall tumor burden 
5 lesions (2 per organ) 
Response criteria target disease 
CR 
Disappearance of all target lesions. 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
PR 
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
PD 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
Appearance of one or more new lesions is also considered progression. 
SD: 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
Response criteria non-target disease 
CR 
Disappearance of all non-target lesions and normalisation of tumour 
marker level. 
All lymph nodes must be non-pathological in size (<10mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the normal limits. 
PD 
Unequivocal progression of existing non-target lesions. 
Appearance of one or more new lesions is also considered progression. 
 
References: 

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Eisenhauer EA et al. New response criteria in solid tumours: revised RECIST guideline (version 1.1). Eur 
J of Cancer. 2009; 45(2):228-247. 

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APPENDIX E: DOSE MODIFICATION AND TOXICITY MANAGEMENT GUIDELINES FOR IMMUNE-MEDIATED, 
INFUSION RELATED, AND NON IMMUNE-MEDIATED REACTIONS 
 
 
Table 10: 
Dose modification and toxicity management guidelines for immune-mediated, infusion related, and 
non-immune-mediated reactions 
 
 
General considerations 
 
 
Dose modifications 
Toxicity management 
 
 
Drug administration modifications of study drug/study regimen will 
be made to manage potential immune-related AEs based on severity 
of treatment-emergent toxicities graded per NCI CTCAE v4.03. 
 
In addition to the criteria for permanent discontinuation of study 
drug/study regimen based on CTC grade/severity (table below), 
permanently discontinue study drug/study regimen for the following 
conditions: 
 
• 
Inability to reduce corticosteroid to a dose of ≤ 10 mg of 
prednisone per day (or equivalent) within 12 weeks after last 
dose of study drug/study regimen 
 
• 
Recurrence of a previously experienced Grade 3 treatment- 
related AE following resumption of dosing 
 
Grade 1 
No dose modification 
 
Grade 2 
Hold study drug/study regimen dose until Grade 2 
resolution to Grade ≤ 1. 
It is recommended that management of immune-mediated adverse 
events (imAEs) follows the guidelines presented in this table: 
 
− It is possible that events with an inflammatory or immune 
mediated mechanism could occur in nearly all organs, some of 
them not noted specifically in these guidelines. 
 
− Whether specific immune-mediated events (and/or laboratory 
indicators of such events) are noted in these guidelines or not, 
patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, concomitant 
medications, and infections) to a possible immune-mediated 
event. In the absence of a clear alternative etiology, all such 
events should be managed as if they were immune related. 
General recommendations follow. 
 
− Symptomatic and topical therapy should be considered for 
low-grade (Grade 1 or 2, unless otherwise specified) events. 
 
 

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General considerations 
 
 
Dose modifications 
Toxicity management 
 
 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤ 1 after completion of steroid taper. 
 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study drug/study 
regimen on the following conditions: 
 
1. The event stabilizes and is controlled. 
 
2. The patient is clinically stable as per investigator or treating 
physician’s clinical judgement. 
 
3. Doses of prednisone are at ≤ 10 mg/day or equivalent. 
 
Grade 3 
Depending on the individual toxicity, study 
drug/study regimen may be permanently discontinued. Please refer 
to guidelines below. 
 
Grade 4 
Permanently discontinue study drug/study regimen. 
 
Note: For Grade ≥ 3 asymptomatic amylase or lipase levels, hold 
study drug/study regimen, and if complete work up shows no 
evidence of pancreatitis, study drug/study regimen may be continued 
or resumed. 
 
Note: Study drug/study regimen should be permanently discontinued 
in Grade 3 events with high likelihood for morbidity and/or mortality 
– eg, myocarditis, or other similar events even if they are not 
currently noted in the guidelines. Similarly, consider whether study 
− For persistent (> 3 to 5 days) low-grade (Grade 2) or severe 
(Grade ≥ 3) events, promptly start prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
 
− Some events with high likelihood for morbidity and/or 
mortality – eg, myocarditis, or other similar events even if they 
are not currently noted in the guidelines – should progress 
rapidly to high dose IV corticosteroids (methylprednisolone at 
2 to 4 mg/kg/day) even if the event is Grade 2, and if clinical 
suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the Study Physician, 
and promptly pursue specialist consultation. 
 
− If symptoms recur or worsen during corticosteroid tapering 
(28 days of taper), increase the corticosteroid dose (prednisone 
dose [eg, up to 2 to 4 mg/kg/day PO or IV equivalent]) until 
stabilization or improvement of symptoms, then resume 
corticosteroid tapering at a slower rate (> 28 days of taper). 
 
− More potent immunosuppressives such as TNF inhibitors 
(eg, infliximab) (also refer to the individual sections of the 
imAEs for specific type of immunosuppressive) should be 
considered for events not responding to systemic steroids. 
Progression to use of more potent immunosuppressives should 
proceed more rapidly in events with high likelihood for 
morbidity and/or mortality – eg, myocarditis, or other similar 
events even if they are not currently noted in the guidelines – 
when these events are not responding to systemic steroids. 
 
− With long-term steroid and other immunosuppressive use, 
consider need for Pneumocystis jirovecii pneumonia (PJP, 
 

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General considerations 
 
 
Dose modifications 
Toxicity management 
 
 
drug/study regimen should be permanently discontinued in Grade 2 
events with high likelihood for morbidity and/or mortality – eg, 
myocarditis, or other similar events even if they are not currently 
noted in the guidelines – when they do not rapidly improve to Grade 
< 1 upon treatment with systemic steroids and following full taper 
 
Note: There are some exceptions to permanent discontinuation of 
study drug for Grade 4 events (ie, hyperthyroidism, hypothyroidism, 
Type 1 diabetes mellitus). 
formerly known as Pneumocystis carinii pneumonia) 
prophylaxis, 
gastrointestinal 
protection, 
and 
glucose 
monitoring. 
 
− Discontinuation of study drug/study regimen is not mandated 
for Grade 3/Grade 4 inflammatory reactions attributed to local 
tumor response (eg, inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study drug/study 
regimen in this situation should be based upon a benefit-risk 
analysis for that patient. 
 
 
 
Abbreviations: AE, Adverse event; CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute. 
 
 
 
Specific immune-mediated reactions 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any grade 
General guidance 
For any grade: 
 
− 
Monitor patients for signs and symptoms of pneumonitis 
or ILD (new onset or worsening shortness of breath or 
 
cough). Patients should be evaluated with imaging and  

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
pulmonary function tests, including other diagnostic 
procedures as described below. 
 
− Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry (resting 
and exertion), laboratory work-up, and high- resolution 
CT scan. 
 
 
Grade 1 
 
(asymptomatic, 
clinical 
or 
diagnostic 
observations only; 
intervention 
not 
indicated) 
No 
dose 
modifications 
required. However, consider 
holding study drug/study 
regimen dose as clinically 
appropriate 
and 
during 
diagnostic work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
 
− Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
 
− 
Consider Pulmonary and Infectious disease consult. 
 
 
 
Grade 2 
 
(symptomatic; 
medical 
intervention 
indicated; limiting 
instrumental ADL) 
Hold 
study 
drug/study 
regimen dose until Grade 2 
resolution to Grade ≤ 1. 
 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
For Grade 2 (mild to moderate new symptoms): 
 
− 
Monitor symptoms daily and consider hospitalization. 
 
− 
Promptly start systemic steroids (eg, prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
 
− 
Reimage as clinically indicated. 
 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
• 
If toxicity improves 
to Grade ≤ 1, then 
the 
decision 
to 
reinitiate 
study 
drug/study regimen 
will be based upon 
treating physician’s 
clinical 
judgment 
and 
after 
completion 
of 
steroid taper. 
− If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
 
− If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab. 
 
− Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation])a 
 
− 
Consider pulmonary and infectious disease consult. 
 
− 
Consider, 
as 
necessary, 
discussing 
with Study 
Physician. 
 
 
 
Grade 3 or 4 
 
(Grade  3:  severe 
Permanently 
discontinue 
study drug/study regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life-threatening): 
 
symptoms; limiting 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
self-care 
ADL; 
oxygen indicated) 
 
 
(Grade 
4: 
life-threatening 
respiratory 
compromise; 
urgent intervention 
indicated 
[eg, 
tracheostomy 
or 
intubation]) 
−  Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
 
− Obtain Pulmonary and Infectious disease consult; 
consider, as necessary, discussing with Study Physician. 
 
− 
Hospitalize the patient. 
 
− 
Supportive care (eg, oxygen). 
 
− If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with 
additional immunosuppressive therapy such as TNF 
inhibitors (eg, infliximab at 5 mg/kg every 2 weeks’ 
dose) started. Caution: rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab. 
 
− Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and, in particular, anti-PJP treatment (refer 
to current NCCN guidelines for treatment of cancer- 
related infections [Category 2B recommendation]).a 
 
 
 
Diarrhea/Colitis 
Any grade 
General guidance 
For any grade: 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
− Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or 
changes in bowel habits such as increased frequency 
over baseline or blood in stool) or related to bowel 
perforation (such as sepsis, peritoneal signs, and ileus). 
 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections), including testing for 
clostridium difficile toxin, etc. 
 
− Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order 
to prevent potential progression to higher grade event. 
 
− Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
 
 
Grade 1 
 
(Diarrhea: 
stool 
frequency of < 4 
over baseline per 
day) 
(Colitis: 
asymptomatic; 
clinical 
or 
No dose modifications. 
For Grade 1: 
 
− 
Monitor closely for worsening symptoms. 
 
− Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
diagnostic 
observations only) 
 
 
Grade 2 
 
(Diarrhea: 
stool 
frequency of 4 to 6 
over baseline per 
day) 
(Colitis: 
abdominal 
pain; 
mucus or blood in 
stool) 
Hold 
study 
drug/study 
regimen until resolution to 
Grade ≤ 1 
 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
 
• 
If toxicity improves 
to Grade ≤ 1, then 
study 
drug/study 
regimen 
can 
be 
resumed 
after 
completion 
 of 
steroid taper. 
For Grade 2: 
 
− Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (eg, American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
 
− Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
 
− If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, GI consult should be obtained for 
consideration of further workup, such as imaging and/or 
colonoscopy, to confirm colitis and rule out perforation, 
and prompt treatment with IV methylprednisolone 2 to 
4 mg/kg/day started. 
 
− If still no improvement within 3 to 5 days despite 2 to 4 
mg/kg 
IV 
methylprednisolone, 
promptly 
start 
immunosuppressives such as infliximab at 5 mg/kg once 
every 2 weeks a. Caution: it is important to rule out 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
bowel perforation and refer to infliximab label for 
general guidance before using infliximab. 
 
− Consider, as necessary, discussing with Study Physician 
if no resolution to Grade ≤ 1 in 3 to 4 days. 
 
− Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
Grade 3 or 4 
 
(Grade 3 diarrhea: 
stool frequency of 
≥ 7 over baseline 
per 
day; 
Grade 4 diarrhea: 
life 
 threatening 
consequences) 
(Grade 3 colitis: 
severe   abdominal 
pain,  change 
in 
bowel habits, medi- 
cal 
intervention 
indi-cated, 
Grade 
3 
Permanently 
discontinue 
study drug/study regimen 
for Grade 3 if toxicity does 
not improve to Grade ≤ 1 
within 
14 
days; 
study 
drug/study regimen can be 
resumed after completion of 
steroid taper. 
For Grade 3 or 4: 
 
−  Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
 
− Monitor stool frequency and volume and maintain 
hydration. 
 
− Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
 
− If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, 
promptly 
start 
further 
immunosuppressives 
(eg, 
infliximab at 5 mg/kg once every 2 weeks). Caution: 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
peritoneal 
 signs; 
Grade 
4 
colitis: 
life-threatening 
consequences, 
urgent intervention 
indicated) 
Grade 
4 
Permanently 
discontinue 
study drug/study regimen. 
Ensure GI consult to rule out bowel perforation and refer 
to infliximab label for general guidance before using 
infliximab. 
− Once the patient is improving, gradually taper steroids 
over ≥28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
Hepatitis 
(elevated LFTs) 
 
 
Any grade 
General guidance 
For any grade: 
 
− 
Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB. 
 
− 
Evaluate for alternative etiologies (eg, viral hepatitis, 
disease progression, concomitant medications). 
 
 
 
Grade 1 
 
(AST 
or 
ALT 
> ULN 
and 
≤ 3.0 × ULN 
and/or TB > ULN 
and ≤ 1.5 × ULN) 
• 
No 
dose 
modifications. 
 
• 
If it worsens, then 
treat as Grade 2 
event. 
For Grade 1: 
 
− 
Continue LFT monitoring per protocol. 
 
 

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PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
 
 
Grade 2 
 
(AST 
or 
ALT > 3.0 × ULN 
and 
≤ 5.0 × ULN 
and/or 
TB 
> 1.5 × ULN 
and ≤ 3.0 × ULN) 
 
• 
Hold 
study 
drug/study regimen 
dose until Grade 2 
resolution to Grade 
≤ 1. 
 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
 
• 
If toxicity improves 
to Grade ≤ 1 or 
baseline, 
resume 
study 
drug/study 
regimen 
after 
completion 
 of 
steroid taper. 
 
For Grade 2: 
 
− Regular and frequent checking of LFTs (eg, every 1 to 2 
days) until elevations of these are improving or resolved. 
 
− If no resolution to Grade ≤ 1 in 1 to 2 days, consider, as 
necessary, discussing with Study Physician. 
 
−  If event is persistent (> 3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
 
−  If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional work up and start prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day. 
 
−  If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (ie, mycophenolate mofetil).a 
Discuss with Study Physician if mycophenolate mofetil 
is not available. Infliximab should NOT be used. 
 
− 
Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
 
antifungals, and anti-PJP treatment (refer to current  

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
Grade 3 or 4 
 
(Grade 3: AST or 
ALT > 5.0 × ULN 
and ≤ 20.0 × ULN 
and/or 
TB 
> 3.0× ULN 
and ≤ 10.0 × ULN) 
 
 
(Grade 4: AST or 
ALT > 20 × ULN 
and/or 
TB > 10 × ULN) 
For Grade 3: 
 
For 
elevations 
in 
transaminases ≤ 8 × ULN, 
or  elevations  in  bilirubin 
≤ 5 × ULN: 
 
• 
Hold 
study 
drug/study regimen 
dose until resolution 
to Grade ≤ 1 or 
baseline 
 
• 
Resume  
study 
drug/study regimen 
if 
elevations 
downgrade to Grade 
≤ 1 or baseline 
within 14 days and 
after completion of 
steroid taper. 
 
• 
Permanently 
For Grade 3 or 4: 
 
− Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
 
−  If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with immunosuppressive 
therapy (ie, mycophenolate mofetil). Discuss with Study 
Physician if mycophenolate is not available. Infliximab 
should NOT be used. 
 
− Perform hepatology consult, abdominal workup, and 
imaging as appropriate. 
 
− Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
discontinue 
study 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
drug/study regimen 
if the elevations do 
not downgrade to 
Grade   ≤ 1   or 
baseline 
 
within 
14 days 
 
For 
elevations 
in 
transaminases > 8 × ULN or 
elevations   in   bilirubin 
> 5 × ULN, discontinue 
study drug/study regimen. 
 
Permanently 
discontinue 
study drug/study regimen 
for any case meeting Hy’s 
law criteria (AST and/or 
ALT > 3 × ULN + bilirubin 
> 2 × ULN without initial 
findings of cholestasis (ie, 
elevated alkaline P04) and in 
the 
absence 
of 
any 
alternative cause. b 
 
 
For Grade 4: 
 

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Hepatitis 
(elevated LFTs) 
Any grade 
General guidance 
For Any grade: 
− 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Monitor and evaluate liver function test: AST, ALT, 
ALP, and TB. 
− 
Evaluate for alternative etiologies (eg, viral hepatitis, 
disease 
progression, 
concomitant 
medications, 
worsening 
of 
liver 
cirrhosis 
[eg, 
portal 
vein 
thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral 
load, quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral 
load 
See 
instructions 
at 
bottom of shaded area 
if transaminase rise is 
not isolated but (at any 
time) occurs in setting 
− 
Consider  consulting  hepatologist/Infectious  disease 
specialist 
regarding 
change/implementation 
in/of 
antiviral medications for any patient with an elevated 
HBV viral load > 2000 IU/mL 
of 
either 
increasing 
bilirubin  or  signs  of 
− 
Consider  consulting  hepatologist/Infectious  disease 
 
specialist 
regarding 
change/implementation 
in/of  
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
Permanently 
discontinue 
study drug/study regimen. 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
DILI/liver 
decompensation 
antiviral HCV medications if HCV viral load increased 
by ≥ 2-fold 
− 
For HCV+ with HBcAB+: Evaluate for both HBV and 
HCV as above 
• 
No 
dose 
modifications. 
Grade 1 
• 
If 
ALT/AST 
(Isolated  AST  or 
elevations 
ALT  > ULN  and 
represents 
≤ 5.0 × ULN, 
significant 
whether normal or 
worsening based on 
elevated 
at 
investigator 
baseline) 
assessment, 
then 
treat  as  Grade  2 
event. 
For 
all 
grades, 
see 
instructions at bottom of 
shaded area if transaminase 
rise is not isolated but (at any 
time) occurs in setting of 
either increasing bilirubin 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
or 
signs 
of 
DILI/liver 
decompensation 
Grade 2 
•  Hold 
study  For Grade 2: 
drug/study regimen 
(Isolated AST or 
dose until Grade 2   − Regular and frequent checking of LFTs (eg, every 1 to 3 
ALT > 5.0 × ULN 
resolution to Grade 
days) until elevations of these are improving or resolved. 
and ≤ 8.0 × ULN, 
≤ 1 or baseline. 
if   normal   at 
−  Recommend consult hepatologist; consider abdominal 
baseline) 
• If toxicity worsens, 
ultrasound, including Doppler assessment of liver 
then treat as Grade 3 
perfusion. 
or Grade 4. 
−  Consider,  as  necessary,  discussing  with  Study 
(Isolated AST or 
If 
toxicity 
improves 
to 
Physician. 
ALT 
> 2.0 × Grade 
≤ 1  or 
baseline, 
baseline 
and resume 
study 
drug/study 
− 
If event is persistent (> 3 to 5 days) or worsens, and 
≤ 12.5 × ULN, 
if regimen after completion of 
investigator suspects toxicity to be immune-mediated 
elevated > ULN at 
steroid taper. 
AE, recommend to start prednisone 1 to 2 mg/kg/day PO 
baseline) 
or IV equivalent. 
−  If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup and treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
−  If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day  of  IV  methylprednisolone,  consider 
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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
additional abdominal workup (including liver biopsy) 
and imaging (ie, liver ultrasound), and consider starting 
immunosuppressives 
(ie, mycophenolate 
mofetil).a 
Discuss with Study Physician if mycophenolate mofetil 
is not available. Infliximab should NOT be used. 
Grade 3 
(Isolated AST or 
ALT > 8.0 × ULN 
and ≤ 20.0 × ULN, 
if 
normal 
at 
baseline) 
(Isolated AST or 
ALT 
> 12.5 × ULN and 
≤ 20.0 × ULN, 
if 
elevated > ULN at 
baseline) 
• 
Hold 
study  For Grade 3: 
drug/study regimen 
dose until resolution   −  Regular and frequent checking of LFTs (eg, every 1-2 
to Grade ≤ 1 or 
days) until elevations of these are improving or resolved. 
baseline 
−  Consult   hepatologist   (unless   investigator   is 
• 
Resume  
study 
hepatologist); obtain abdominal ultrasound, including 
drug/study regimen 
Doppler assessment of liver perfusion; and consider 
if 
elevations 
liver biopsy. 
downgrade to Grade 
≤ 1  or  baseline   −  Consider,  as  necessary,  discussing  with  Study 
within 14 days and 
Physician. 
after completion of 
steroid taper. 
−  If Investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
• 
Permanently 
4 mg/kg/day or equivalent. 
discontinue  study 
drug/study regimen 
−  If no improvement within 3 to 5 days despite 1 to 
if the elevations do 
 
4 mg/kg/day  methylprednisolone  IV  or  equivalent, 
obtain liver biopsy (if it has not been done already) and 
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Adverse Events 
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the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
not downgrade to 
promptly start treatment with immunosuppressive 
Grade ≤ 1 or 
therapy (mycophenolate mofetil). Discuss with Study 
baseline within 
Physician if mycophenolate is not available. Infliximab 
14 days 
should NOT be used. 
Permanently  discontinue   − Once the patient is improving, gradually taper steroids 
study drug/study regimen 
over ≥ 28 days and consider prophylactic antibiotics, 
for any case meeting Hy’s 
antifungals, and anti-PCP treatment (refer to current 
law criteria, in the absence 
NCCN guidelines for treatment of cancer-related 
of any alternative cause. b 
infections [Category 2B recommendation]).a 
Grade 4 
Permanently 
discontinue 
For 
Grade 
4: 
study drug/study regimen. 
Same 
as 
above 
(Isolated AST or 
(except would recommend obtaining liver biopsy early) 
ALT > 20 × ULN, 
whether normal or 
elevated 
at 
baseline) 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥ 1.5 × ULN, if normal at 
baseline; or 2 × baseline, if > ULN at baseline) or signs of DILI/liver decompensation (eg, fever, elevated INR): 
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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Nephritis 
or 
renal 
dysfunction 
 
(elevated 
serum 
creatinine) 
Any grade 
General guidance 
For any grade: 
 
− 
Consult with nephrologist. 
 
− Monitor for signs and symptoms that may be related to 
changes in renal function (eg, routine urinalysis, 
elevated serum BUN and creatinine, decreased 
creatinine clearance, electrolyte imbalance, decrease in 
urine output, or proteinuria). 
 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression or 
infections). 
 
− Steroids should be considered in the absence of clear 
alternative etiology even for low-grade events (Grade 2), 
in order to prevent potential progression to higher grade 
event. 
 
 
- 
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
 
 
Grade 1 
 
(Serum  creatinine 
> 1 
to 
1.5 × baseline; 
> ULN 
to 
1.5 × ULN) 
No dose modifications. 
For Grade 1: 
 
− 
Monitor 
serum 
creatinine 
weekly 
and 
any 
accompanying symptoms. 
 
• 
If creatinine returns to baseline, resume its 
regular monitoring per study protocol. 
 
• 
If creatinine worsens, depending on the severity, 
treat as Grade 2, 3, or 4. 
 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
 
 
 
Grade 2 
 
(serum 
creatinine 
> 1.5 
to 
3.0 × 
baseline; > 1.5 to 
3.0 × ULN) 
Hold 
study 
drug/study 
regimen until resolution to 
Grade ≤ 1 or baseline. 
 
• 
If toxicity worsens, 
then treat as Grade 3 
or 4. 
 
• 
If toxicity improves 
For Grade 2: 
 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
 
− 
Carefully monitor serum creatinine every 2 to 3 days and 
as clinically warranted. 
 
to Grade ≤ 1 or 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
baseline, 
then 
resume 
study 
drug/study regimen 
after completion of 
steroid taper. 
− Consult nephrologist and consider renal biopsy if 
clinically indicated. 
 
−  If event is persistent (> 3 to 5 days) or worsens, promptly 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
 
− If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone at 2 to 
4 mg/kg/day started. 
 
− Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
− When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per 
study protocol. 
 
 
 
Grade 3 or 4 
 
(Grade 3: serum 
creatinine 
Permanently 
discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
 
− 
Carefully monitor serum creatinine on daily basis. 
 
> 3.0 × baseline; 
 

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Dose modifications 
Toxicity management 
 
 
> 3 .0 
to 
6.0 × ULN; 
 
 
Grade 
4: 
serum 
creatinine 
> 6.0 × ULN) 
− Consult nephrologist and consider renal biopsy if 
clinically indicated. 
 
− Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
 
− If event is not responsive within 3 to 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, additional workup should be considered and 
prompt treatment with IV methylprednisolone 2 to 
4 mg/kg/day started. 
 
Once the patient is improving, gradually taper steroids over ≥ 28 
days and consider prophylactic antibiotics, antifungals, and anti- 
PJP treatment (refer to current NCCN guidelines for treatment 
of cancer-related infections [Category 2B recommendation]).a 
 
 
 
Rash 
 
(excluding bullous skin 
formations) 
Any grade 
 
(refer 
to 
NCI 
CTCAE v 4.03 for 
definition 
 of 
severity/grade 
depending on type 
of skin rash) 
General guidance 
For any grade: 
 
− Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
 
− IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED 
AND STUDY DRUG DISCONTINUED. 
 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 
 
− 
Consider symptomatic 
treatment, including 
oral 
anti-pruritics (eg, diphenhydramine or hydroxyzine) and 
topical therapy (eg, urea cream). 
 
 
Grade 2 
For persistent (> 1 to 2 
weeks) Grade 2 events, hold 
scheduled study drug/study 
regimen until resolution to 
Grade ≤ 1 or baseline. 
 
• 
If toxicity worsens, 
then 
treat 
as 
Grade 3. 
 
• 
If toxicity improves 
to Grade ≤ 1 or 
baseline, 
 then 
resume drug/study 
regimen 
after 
completion 
 of 
steroid taper. 
For Grade 2: 
 
− 
Obtain dermatology consult. 
 
− 
Consider 
symptomatic 
treatment, 
including 
oral 
anti-pruritics (eg, diphenhydramine or hydroxyzine) and 
topical therapy (eg, urea cream). 
 
− 
Consider moderate-strength topical steroid. 
 
− If no improvement of rash/skin lesions occurs within 3 
to 5 days or is worsening despite symptomatic treatment 
and/or use of moderate strength topical steroid, consider, 
as necessary, discussing with Study Physician and 
promptly start systemic steroids such as prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
 
−  Consider skin biopsy if the event is persistent for > 1 to 
2 weeks or recurs. 
 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Grade 3 or 4 
For Grade 3: 
 
Hold 
study 
drug/study 
regimen until resolution to 
Grade ≤ 1 or baseline. 
 
If temporarily holding the 
study drug/study regimen 
does 
not 
provide 
improvement of the Grade 3 
skin rash to Grade ≤ 1 or 
baseline within 30 days, 
then 
permanently 
discontinue 
 
study 
drug/study regimen. 
 
 
For Grade 4: 
 
Permanently 
discontinue 
study drug/study regimen. 
For Grade 3 or 4: 
 
− 
Consult dermatology. 
 
−  Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
 
− 
Consider hospitalization. 
 
− 
Monitor extent of rash [Rule of Nines]. 
 
− Consider skin biopsy (preferably more than 1) as 
clinically feasible. 
 
− Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
− 
Consider, 
as 
necessary, 
discussing 
with Study 
Physician. 
 
 
 
Endocrinopathy 
Any grade 
General guidance 
For any grade: 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
(eg, hyperthyroidism, 
hypothyroidism, Type 1 
diabetes 
  
mellitus, 
hypophysitis, 
hypopituitarism,   
and 
adrenal 
insufficiency; 
exocrine 
 event 
 of 
amylase/lipase increased 
also included  in  this 
section) 
(depending on the 
type 
of 
endocrinopathy, 
refer 
to 
NCI 
CTCAE v4.03 for 
defining the CTC 
grade/severity) 
− Consider consulting an endocrinologist for endocrine 
events. 
 
− 
Consider, 
as 
necessary, 
discussing 
with Study 
Physician. 
 
− 
Monitor 
patients for 
signs 
and 
symptoms 
of 
endocrinopathies. Non-specific symptoms include 
headache, fatigue, behavior changes, changed mental 
status, vertigo, abdominal pain, unusual bowel habits, 
polydipsia, polyuria, hypotension, and weakness. 
 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression including 
brain metastases, or infections). 
 
− Depending on the suspected endocrinopathy, monitor 
and evaluate thyroid function tests: TSH, free T3, and 
free T4 and other relevant endocrine and related labs (eg, 
blood glucose and ketone levels, HgA1c). 
 
− For modest asymptomatic elevations in serum amylase 
and lipase, corticosteroid treatment is not indicated as 
long as there are no other signs or symptoms of 
pancreatic inflammation. 
 
− If a patient experiences an AE that is thought to be 
possibly  of  autoimmune  nature  (eg,  thyroiditis, 
 

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CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
pancreatitis, hypophysitis, or diabetes insipidus), the 
investigator should send a blood sample for appropriate 
autoimmune antibody testing. 
 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH 
elevation): 
 
− Monitor patient with appropriate endocrine function 
tests. 
 
− For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment 
of early-morning ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test (though it 
may not be useful in diagnosing early secondary adrenal 
insufficiency). 
 
− If TSH < 0.5 × LLN, or TSH > 2 × ULN, or consistently 
out of range in 2 subsequent measurements, include free 
T4 at subsequent cycles as clinically indicated and 
consider consultation of an endocrinologist. 
 
 
Grade 2 
For Grade 2 endocrinopathy 
other than hypothyroidism 
For 
Grade 
2 
(including 
those 
with 
symptomatic 
endocrinopathy): 
 
and 
Type 
1 
diabetes 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
mellitus, 
hold 
study 
drug/study regimen dose 
until patient is clinically 
stable. 
 
• 
If toxicity worsens, 
then treat as Grade 3 
or Grade 4. 
 
Study drug/study regimen 
can be resumed once event 
stabilizes 
and 
after 
completion of steroid taper. 
 
Patients 
with 
endocrinopathies who may 
require 
prolonged 
or 
continued 
steroid 
replacement (eg, adrenal 
insufficiency) 
can 
be 
retreated 
with 
study 
drug/study regimen on the 
following conditions: 
 
1. The event stabilizes 
and is controlled. 
− Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. 
 
− For all patients with abnormal endocrine work up, 
except those with isolated hypothyroidism or Type 1 
DM, and as guided by an endocrinologist, consider 
short-term corticosteroids (eg, 1 to 2 mg/kg/day 
methylprednisolone or IV equivalent) and prompt 
initiation 
of 
treatment 
with 
relevant 
hormone 
replacement (eg, hydrocortisone, sex hormones). 
 
− 
Isolated 
hypothyroidism 
may 
be 
treated 
with 
replacement therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
 
− Isolated Type 1 diabetes mellitus (DM) may be treated 
with appropriate diabetic therapy, without study 
drug/study 
regimen 
interruption, 
and 
without 
corticosteroids. 
 
− Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with 
guidance of endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-PJP 
treatment  (refer  to  current  NCCN  guidelines  for 
 

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version 4.03) 
Dose modifications 
Toxicity management 
 
 
2. The 
patient 
is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
 
3. Doses of prednisone 
are ≤ 10 mg/day or 
equivalent. 
treatment of cancer-related infections [Category 2B 
recommendation]).a 
 
− For patients with normal endocrine workup (laboratory 
assessment 
or 
MRI 
scans), 
repeat 
laboratory 
assessments/MRI as clinically indicated. 
 
 
 
Grade 3 or 4 
For  Grade  3  or  4 
endocrinopathy other than 
hypothyroidism and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose 
until 
endocrinopathy 
symptom(s) are controlled. 
 
Study drug/study regimen 
can be resumed once event 
stabilizes 
and 
after 
completion of steroid taper. 
 
Patients 
with 
endocrinopathies who may 
require 
prolonged 
or 
continued 
steroid 
For Grade 3 or 4: 
 
− Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by suspected 
endocrinopathy and as clinically indicated, consider 
pituitary scan. Hospitalization recommended. 
 
− For all patients with abnormal endocrine work up, 
except those with isolated hypothyroidism or Type 1 
DM, and as guided by an endocrinologist, promptly 
initiate empiric IV methylprednisolone 1 to 2 mg/kg/day 
or equivalent, as well as relevant hormone replacement 
(eg, hydrocortisone, sex hormones). 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
replacement (eg, adrenal 
insufficiency) 
can 
be 
retreated 
with 
study 
drug/study regimen on the 
following conditions: 
 
1. The event stabilizes 
and is controlled. 
 
2. The 
patient 
is 
clinically stable as 
per investigator or 
treating physician’s 
clinical judgement. 
 
3. Doses of prednisone 
are ≤ 10 mg/day or 
equivalent. 
− For adrenal crisis, severe dehydration, hypotension, or 
shock, immediately initiate IV corticosteroids with 
mineralocorticoid activity. 
 
− 
Isolated 
hypothyroidism 
may 
be 
treated 
with 
replacement therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
 
− Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study 
regimen interruption, and without corticosteroids. 
 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections 
[Category 2B recommendation]).a 
 
 
 
Neurotoxicity 
 
(to include but not be 
limited 
to 
limbic 
encephalitis 
and 
autonomic 
neuropathy, 
excluding   Myasthenia 
Any grade 
 
(depending on the 
type 
of 
neurotoxicity, refer 
to 
NCI CTCAE 
v4.03 for defining 
General guidance 
For any grade: 
 
− Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes, or medications). 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
Gravis 
and 
Guillain- 
Barre) 
the 
CTC 
grade/severity) 
− Monitor patient for general symptoms (headache, 
nausea, vertigo, behavior change, or weakness). 
 
−  Consider   appropriate   diagnostic   testing 
(eg, 
electromyogram 
and 
nerve 
conduction 
investigations). 
 
− Perform symptomatic treatment with neurological 
consult as appropriate. 
 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 
 
− 
See “Any Grade” recommendations above. 
 
 
Grade 2 
For 
acute 
motor 
neuropathies 
 
or 
neurotoxicity, hold study 
drug/study regimen dose 
until 
 
resolution 
 
to 
Grade ≤ 1. 
 
For 
sensory 
neuropathy/neuropathic 
pain, consider holding study 
For Grade 2: 
 
− Consider, as necessary, discussing with the Study 
Physician. 
 
− 
Obtain neurology consult. 
 
− Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (eg, gabapentin or 
duloxetine). 
 
drug/study 
regimen 
dose 
 

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Severity grade of 
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version 4.03) 
Dose modifications 
Toxicity management 
 
 
until 
 
resolution 
 
to 
Grade ≤ 1. 
 
If toxicity worsens, then 
treat as Grade 3 or 4. 
 
Study drug/study regimen 
can be resumed once event 
improves to Grade ≤ 1 and 
after completion of steroid 
taper. 
−  Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
 
−  If no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day prednisone PO or IV equivalent, consider 
additional workup and promptly treat with additional 
immunosuppressive therapy (eg, IV IG). 
 
 
 
Grade 3 or 4 
For Grade 3: 
 
Hold 
study 
drug/study 
regimen 
dose 
until 
resolution to Grade ≤ 1. 
 
Permanently 
discontinue 
study drug/study regimen if 
Grade 3 imAE does not 
resolve to Grade ≤ 1 within 
30 days. 
For Grade 3 or 4: 
 
− 
Consider, 
as 
necessary, 
discussing 
with 
Study 
Physician. 
 
− 
Obtain neurology consult. 
 
− 
Consider hospitalization. 
 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, 
consider 
additional 
workup 
and 
 

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Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
For Grade 4: 
 
Permanently 
discontinue 
study drug/study regimen. 
promptly treat with additional immunosuppressants (eg, 
IV IG). 
 
− 
Once stable, gradually taper steroids over ≥ 28 days. 
 
 
 
Peripheral neuromotor 
syndromes 
 
(such as Guillain-Barre 
and myasthenia gravis) 
Any grade 
General guidance 
For any grade: 
 
− The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain 
patients 
may 
unpredictably 
experience 
acute 
decompensations that can result in substantial morbidity 
or in the worst case, death. Special care should be taken 
for certain sentinel symptoms that may predict a more 
severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory 
insufficiency or autonomic instability. 
 
− Patients should be evaluated to rule out any alternative 
etiology (eg, disease progression, infections, metabolic 
syndromes or medications). It should be noted that the 
diagnosis of immune-mediated peripheral neuromotor 
syndromes can be particularly challenging in patients 
with underlying cancer, due to the multiple potential 
confounding effects of cancer (and its treatments) 
throughout the neuraxis. Given the importance of 
 

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version 4.03) 
Dose modifications 
Toxicity management 
 
 
prompt and accurate diagnosis, it is essential to have a 
low threshold to obtain a neurological consult. 
 
− Neurophysiologic 
diagnostic 
testing 
(eg, 
electromyogram 
and 
nerve 
conduction 
investigations, 
and 
“repetitive 
stimulation” 
if 
myasthenia is suspected) are routinely indicated upon 
suspicion of such conditions and may be best facilitated 
by means of a neurology consultation. 
 
− It is important to consider that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective. Patients requiring treatment should 
be started with IV IG and followed by plasmapheresis if 
not responsive to IV IG. 
 
 
Grade 1 
No dose modifications. 
For Grade 1: 
 
− Consider, as necessary, discussing with the Study 
Physician. 
 
− Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
 
− 
Obtain a neurology consult. 
 

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Severity grade of 
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version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Grade 2 
Hold 
study 
drug/study 
regimen 
dose 
until 
resolution to Grade ≤ 1. 
 
Permanently 
discontinue 
study drug/study regimen if 
it does not resolve to 
Grade ≤ 1 within 30 days or 
if 
there 
are 
signs 
of 
respiratory insufficiency or 
autonomic instability. 
For Grade 2: 
 
− Consider, as necessary, discussing with the Study 
Physician. 
 
− Care should be taken to monitor patients for sentinel 
symptoms of a potential decompensation as described 
above. 
 
− 
Obtain a neurology consult 
 
− Sensory neuropathy/neuropathic pain may be managed 
by appropriate medications (eg, gabapentin or 
duloxetine). 
 
MYASTHENIA GRAVIS: 
 
o Steroids may be successfully used to treat 
myasthenia gravis. It is important to consider 
that steroid therapy (especially with high doses) 
may result in transient worsening of myasthenia 
and should typically be administered in a 
monitored setting under supervision of a 
consulting neurologist. 
 
o Patients unable to tolerate steroids may be 
 
candidates for treatment with plasmapheresis or  

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Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 129 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
IV IG. Such decisions are best made in 
consultation with a neurologist, taking into 
account the unique needs of each patient. 
 
o If myasthenia gravis-like neurotoxicity is 
present, consider starting AChE inhibitor 
therapy in addition to steroids. Such therapy, if 
successful, can also serve to reinforce the 
diagnosis. 
 
GUILLAIN-BARRE: 
 
o It is important to consider here that the use of 
steroids as the primary treatment of Guillain- 
Barre is not typically considered effective. 
 
o Patients requiring treatment should be started 
with IV IG and followed by plasmapheresis if 
not responsive to IV IG. 
 
 
Grade 3 or 4 
For Grade 3: 
 
Hold 
study 
drug/study 
regimen 
dose 
until 
resolution to Grade ≤ 1. 
For Grade 3 or 4 (severe or life-threatening events): 
 
− 
Consider, 
as 
necessary, 
discussing 
with 
Study 
Physician. 
 
− 
Recommend hospitalization. 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 130 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
Permanently   discontinue 
study drug/study regimen if 
Grade 3 imAE does not 
resolve to Grade ≤ 1 within 
30 days or if there are signs 
of respiratory insufficiency 
or autonomic instability. 
 
 
For Grade 4: 
 
Permanently 
discontinue 
study drug/study regimen. 
− 
Monitor symptoms and obtain neurological consult. 
 
MYASTHENIA GRAVIS: 
 
o Steroids may be successfully used to treat 
myasthenia gravis. They should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist. 
 
o Patients unable to tolerate steroids may be 
candidates for treatment with plasmapheresis or 
IV IG. 
 
o If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in 
addition to steroids. Such therapy, if successful, 
can also serve to reinforce the diagnosis. 
 
GUILLAIN-BARRE: 
 
o It is important to consider here that the use of 
steroids as the primary treatment of Guillain- 
Barre is not typically considered effective. 
 
o Patients requiring treatment should be started 
with IV IG and followed by plasmapheresis if 
not responsive to IV IG. 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 131 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Myocarditis 
Any grade 
General guidance 
 
Discontinue 
drug 
permanently 
if 
biopsy- 
proven 
immune-mediated 
myocarditis. 
For any grade: 
 
− The prompt diagnosis of immune-mediated myocarditis 
is important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function. 
 
− Consider, as necessary, discussing with the Study 
Physician. 
 
− Monitor patients for signs and symptoms of myocarditis 
(new onset or worsening chest pain, arrhythmia, 
shortness of breath, peripheral edema). As some 
symptoms 
can 
overlap 
with 
lung 
toxicities, 
simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (eg, pulmonary 
embolism, 
congestive 
heart 
failure, 
malignant 
pericardial effusion). A Cardiology consultation should 
be obtained early, with prompt assessment of whether 
and when to complete a cardiac biopsy, including any 
other diagnostic procedures. 
 
− Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), 
monitoring of oxygenation via pulse oximetry (resting 
and exertion), and additional laboratory work-up as 
 
indicated. Spiral CT or cardiac MRI can complement  

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 132 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
ECHO to assess wall motion abnormalities when 
needed. 
 
− Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other 
medications, or infections) 
 
 
Grade 1 
 
(asymptomatic 
with laboratory (eg, 
BNP) or cardiac 
imaging 
abnormalities) 
No 
dose 
modifications 
required 
unless 
clinical 
suspicion is high, in which 
case hold study drug/study 
regimen 
dose 
during 
diagnostic work-up for other 
etiologies. 
If 
study 
drug/study regimen is held, 
resume 
after 
complete 
resolution to Grade 0. 
For Grade 1 (no definitive findings): 
 
- 
Monitor and closely follow up in 2 to 4 days for 
clinical symptoms, BNP, cardiac enzymes, ECG, 
ECHO, pulse oximetry (resting and exertion), and 
laboratory work-up as clinically indicated. 
 
- 
Consider using steroids if clinical suspicion is high. 
 
 
 
Grade 2, 3 or 4 
 
(Grade 
2: 
Symptoms 
with 
mild to moderate 
activity 
or 
exertion) 
- If Grade 2 -- Hold 
study 
drug/study 
regimen dose until 
resolution 
to 
Grade 0. If toxicity 
rapidly improves to 
Grade 0, then the 
For Grade 2-4: 
 
− 
Monitor symptoms daily, hospitalize. 
 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
or equivalent after Cardiology consultation 
has 
 
decision to reinitiate 
 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 133 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
(Grade 3: Severe 
with symptoms at 
rest 
or 
with 
minimal activity or 
exertion; 
intervention 
indicated) 
 
 
(Grade 
4: 
Life- 
threatening 
consequences; 
urgent 
 
intervention 
indicated 
(eg, 
continuous 
IV 
therapy 
or 
mechanical 
hemodynamic 
support) 
study 
drug/study 
regimen   will  be 
based upon treating 
physician’s clinical 
judgment and after 
completion 
   of 
steroid 
 taper.   If 
toxicity  does  not 
rapidly 
   improve, 
permanently. 
discontinue 
study 
drug/study regimen. 
If Grade 3-4, permanently 
discontinue 
study 
drug/study regimen. 
determined whether and when to complete diagnostic 
procedures including a cardiac biopsy. 
 
− 
Supportive care (eg, oxygen). 
 
− If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(eg, infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab. 
 
− Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 134 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Myositis/Polymyositis 
(“Poly/myositis”) 
Any grade 
General guidance 
For any grade: 
 
− 
Monitor 
patients 
for 
signs 
and 
symptoms 
of 
poly/myositis. Typically, muscle weakness/pain occurs 
in proximal muscles including upper arms, thighs, 
shoulders, hips, neck and back, but rarely affects the 
extremities including hands and fingers; also difficulty 
breathing and/or trouble swallowing can occur and 
progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset 
falling, difficulty getting up from a fall, and trouble 
climbing stairs, standing up from a seated position, 
and/or reaching up. 
 
− If poly/myositis is suspected, a Neurology consultation 
should be obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may co-occur with 
poly/myositis; refer to guidance under Myocarditis. 
Given breathing complications, refer to guidance under 
Pneumonitis/ILD. 
Given possibility of an existent (but previously 
unknown) 
autoimmune 
disorder, 
consider 
Rheumatology consultation. 
 
− Consider, as necessary, discussing with the Study 
Physician. 
 
 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 135 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
− Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, LDH, BUN/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional laboratory work- 
up as indicated, including a number of possible 
rheumatological/antibody tests (ie, consider whether a 
rheumatologist consultation is indicated and could guide 
need for rheumatoid factor, antinuclear antibody, anti- 
smooth muscle, antisynthetase [such as anti-Jo-1], 
and/or 
signal-recognition 
particle 
antibodies). 
Confirmatory testing may include electromyography, 
nerve conduction studies, MRI of the muscles, and/or a 
muscle biopsy. Consider Barium swallow for evaluation 
of dysphagia or dysphonia. 
 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (eg, disease progression, other medications, 
or infections). 
 
 
Grade 1 
 
(mild pain) 
- 
No 
dose 
modifications. 
For Grade 1: 
 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
 
− 
Consider Neurology consult. 
 
 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 136 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
− 
Consider, as necessary, discussing with the Study 
Physician. 
 
 
Grade 2 
 
(moderate 
pain 
associated 
with 
weakness; 
pain 
limiting 
instrumental 
activities of daily 
living [ADLs]) 
Hold 
study 
drug/study 
regimen 
dose 
until 
resolution to Grade ≤ 1. 
 
- 
Permanently 
discontinue 
study 
drug/study regimen 
if it does not resolve 
to Grade ≤ 1 within 
30 days or if there 
are 
signs  
of 
respiratory 
insufficiency. 
For Grade 2: 
 
− 
Monitor symptoms daily and consider hospitalization. 
 
− 
Obtain Neurology consult, and initiate evaluation. 
 
− Consider, as necessary, discussing with the Study 
Physician. 
 
− If clinical course is rapidly progressive (particularly if 
difficulty 
breathing 
and/or 
trouble 
swallowing), 
promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant 
 
− If clinical course is not rapidly progressive, start 
systemic steroids (eg, prednisone 1 to 2 mg/kg/day PO 
or IV equivalent); if no improvement within 3 to 5 days, 
continue additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
 
− 
If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 days, 
 
consider start of immunosuppressive therapy such as  

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 137 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
TNF inhibitors (eg, infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance before 
using infliximab. 
 
− Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
Grade 3 or 4 
 
(pain   associated 
with 
severe 
weakness; limiting 
self-care ADLs) 
For Grade 3: 
 
Hold 
study 
drug/study 
regimen 
dose 
until 
resolution to Grade ≤ 1. 
 
Permanently 
discontinue 
study drug/study regimen if 
Grade 3 imAE does not 
resolve to Grade ≤ 1 within 
30 days or if there are signs 
of respiratory insufficiency. 
For Grade 3 or 4 (severe or life-threatening events): 
 
− 
Monitor symptoms closely; recommend hospitalization. 
 
− 
Obtain Neurology consult, and complete full evaluation. 
 
− Consider, as necessary, discussing with the Study 
Physician. 
 
− Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from 
Neurology consultant. 
 
−  If after start of IV methylprednisolone at 2 to 
4 mg/kg/day there is no improvement within 3 to 5 days, 
consider start of immunosuppressive therapy such as 
 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Specific immune-mediated reactions 
Confidential 
Page 138 of 142 
 
 
 
Adverse Events 
Severity grade of 
the Event (NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
For Grade 4: 
 
- 
Permanently 
discontinue 
study 
drug/study regimen. 
TNF inhibitors (eg, infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance before 
using infliximab. 
 
− Consider whether patient may require IV IG, 
plasmapheresis. 
 
− Once the patient is improving, gradually taper steroids 
over ≥ 28 days and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).a 
 
 
 
Abbreviations: AChE, acetylcholine esterase; ADL, activities of daily living; AE, adverse event; ALP, alkaline phosphatase test; ALT, alanine 
aminotransferase; ASTc, aspartate aminotransferase; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; CT, computed tomography; 
CTCAE, Common Terminology Criteria for Adverse Events; DM, diabetes mellitus; DILI, drug-induced liver injury; ECG, electrocardiogram; 
ECHO, echocardiogram; GI, gastrointestinal; HBcAB, hepatitis B core antibody; HBeAg, hepatitis B viral protein; HbsAg, surface antigen of the 
hepatitis B virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HgA1c, hemoglobin A1c; ILD, interstitial lung disease; imAE, immune-mediated 
adverse event; IG, immunoglobulin; IV, intravenous; LFT, liver function tests; LLN, lower limit of normal; MRI, magnetic resonance imaging; NCI, 
National Cancer Institute; NCCN, National Comprehensive Cancer Network; PJP, Pneumocystis jirovecii pneumonia (formerly known as 
Pneumocystis carinii pneumonia); PO, By mouth; T3, triiodothyronine; T4, thyroxine; TB, total bilirubin; TNF, tumor necrosis factor; TSH, thyroid- 
stimulating hormone; ULN, upper limit of normal. 
 
a 
ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
 
b 
US Food and Drug Administration Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Confidential 
Page 139 of 142 
 
 
 
Abbreviations: 
 
 
 
Infusion-related reactions 
 
 
Severity grade of 
the 
event 
(NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Any grade 
General guidance 
For any grade: 
 
− Manage per institutional standard at the discretion of 
investigator. 
 
− Monitor patients for signs and symptoms of infusion- 
related reactions (eg, fever and/or shaking chills, 
flushing and/or itching, alterations in heart rate and 
blood pressure, dyspnea or chest discomfort, or skin 
rashes) and anaphylaxis (eg, generalized urticaria, 
angioedema, wheezing, hypotension, or tachycardia). 
 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Confidential 
Page 140 of 142 
 
 
 
 
Infusion-related reactions 
 
 
Severity grade of 
the 
event 
(NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Grade 1 or 2 
For Grade 1: 
 
The infusion rate of study drug/study regimen may 
be decreased by 50% or temporarily interrupted until 
resolution of the event. 
 
 
For Grade 2: 
 
The infusion rate of study drug/study regimen may 
be decreased 50% or temporarily interrupted until 
resolution of the event. 
 
Subsequent infusions may be given at 50% of the 
initial infusion rate. 
For Grade 1 or 2: 
 
− 
Acetaminophen 
and/or 
antihistamines 
may 
be 
administered per institutional standard at the discretion 
of the investigator. 
 
− Consider premedication per institutional standard prior 
to subsequent doses. 
 
− Steroids should not be used for routine premedication 
of Grade ≤ 2 infusion reactions. 
 
 
 
Grade 3 or 4 
For Grade 3 or 4: 
 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
 
− 
Manage 
severe 
infusion-related 
reactions 
per 
institutional standards (eg, IM epinephrine, followed by 
IV 
diphenhydramine 
and 
ranitidine, 
and 
IV 
glucocorticoid). 
 
 
 
Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; IM, intramuscular; IV, intravenous; NCI, National Cancer Institute. 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Confidential 
Page 141 of 142 
 
 
 
 
 
 
Non–immune-mediated reactions 
 
 
Severity grade of the 
event 
(NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Any grade 
Note: Dose modifications are not required for AEs not 
deemed to be related to study treatment (ie, events due 
to underlying disease) or for laboratory abnormalities 
not deemed to be clinically significant. 
Treat accordingly, as per institutional standard. 
 
 
 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
 
 
Grade 2 
Hold study drug/study regimen until resolution to 
Grade ≤ 1 or baseline. 
Treat accordingly, as per institutional standard. 
 
 
 
Grade 3 
Hold study drug/study regimen until resolution to 
Grade ≤ 1 or baseline. 
 
For AEs that downgrade to ≤Grade 2 within 7 days or 
resolve to ≤Grade 1 or baseline within 14 days, resume 
study drug/study regimen administration. Otherwise, 
discontinue study drug/study regimen. 
Treat accordingly, as per institutional standard. 
 
 

ModernaTX, Inc. 
Clinical Protocol mRNA-2416-P101 
Protocol Version 7.0 
Amendment Version 6.0 
Confidential 
Page 142 of 142 
 
 
 
 
Non–immune-mediated reactions 
 
 
Severity grade of the 
event 
(NCI 
CTCAE 
version 4.03) 
Dose modifications 
Toxicity management 
 
 
 
Grade 4 
Discontinue study drug/study regimen (Note: For 
Grade 4 labs, decision to discontinue should be based 
on accompanying clinical signs/symptoms, the 
investigator’s clinical judgment, and consultation with 
the Sponsor.). 
Treat accordingly, as per institutional standard. 
 
 
 
Abbreviations: AE, Adverse event; CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute. 
 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with 
Study Physician.”