An Open-Label, Phase II, Randomized, Controlled Study of Danvatirsen Plus Pembrolizumab Compared to Pembrolizumab Alone in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC)
Phase: PHASE2
Conditions: HNSCC
Sponsor: Flamingo Therapeutics NV

Protocol Title: 
An Open-Label, Phase II, Randomized, Controlled Study of 
Danvatirsen Plus Pembrolizumab Compared to Pembrolizumab 
Alone in Recurrent or Metastatic Head and Neck Squamous Cell 
Carcinoma (HNSCC) 
 
 
Brief Title: 
Activity and Safety of Danvatirsen and Pembrolizumab in 
HNSCC 
Acronym: 
PEMDA-HN 
Protocol Number: 
FLM-6774-201 
Name of Investigational 
Product: 
Danvatirsen 
NCT Number: 
05814666 
Sponsor: 
Flamingo Therapeutics 
Gaston Geenslaan 3, Building 4 
3001 Leuven 
Belgium 
 
 
Amendment 4 
Document Date: 
 
8 May 2025 
 
 
 

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
1
CONFIDENTIAL
CLINICAL STUDY PROTOCOL 
Protocol Title:
An Open-Label, Phase II, Randomized, Controlled Study of 
Danvatirsen Plus Pembrolizumab Compared to Pembrolizumab 
Alone in Recurrent or Metastatic Head and Neck Squamous 
Cell Carcinoma (HNSCC)
Short Protocol Title:
Activity and Safety of Danvatirsen and Pembrolizumab in 
HNSCC
Acronym:
PEMDA-HN
Protocol Number:
FLM-6774-201
Amendment:
4
Name of 
Investigational 
Product:
Danvatirsen
IND Number:
113825
IND Holder:
Flamingo Therapeutics
Sponsor:
Flamingo Therapeutics
Gaston Geenslaan 3, Building 4
3001 Leuven
Belgium
Original Protocol
Date:
21 December 2022
Amendment 4 Date:
8 May 2025
Confidentiality 
Statement:
This document contains information that is the confidential and 
proprietary property of Flamingo Therapeutics. Any use, 
distribution, or disclosure without the prior written consent of 
Flamingo Therapeutics is strictly prohibited except to the extent 
required under applicable laws or regulations.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
2
CONFIDENTIAL
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE
Protocol Title:
An Open-Label, Phase II, Randomized, Controlled Study of 
Danvatirsen Plus Pembrolizumab Compared to 
Pembrolizumab Alone in Recurrent or Metastatic Head and 
Neck Squamous Cell Carcinoma (HNSCC)
Protocol Number:
FLM-6774-201
Date of Original 
Protocol:
21 December 2022
Amendment 4 Date:
8 May 2025
APPROVAL STATEMENT
The undersigned has reviewed the format and content of the above protocol and approved for 
issuance.
Approved by:
Andrew Denker, MD; PhD
Chief Medical Officer
DATE
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PhD
h

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
3
CONFIDENTIAL
INVESTIGATOR ACCEPTANCE PAGE 
I have read this protocol entitled:
An Open-Label, Phase II, Randomized, Controlled Study of Danvatirsen Plus 
Pembrolizumab Compared to Pembrolizumab Alone in Recurrent or Metastatic 
Head and Neck Squamous Cell Carcinoma (HNSCC)
By signing below, the Investigator acknowledges that he/she has read and understands this 
protocol and will comply with the requirements for obtaining informed consent from all 
study participants prior to initiating any protocol-specific procedures, obtaining written initial 
and ongoing Institutional Review Board protocol review and approval, understands and 
abides by the requirements for maintenance of source documentation, and provides assurance 
that this study will be conducted according to all requirements as defined in this protocol,
trial specific manuals, Clinical Trial Agreement, ICH GCP guidelines, and all applicable 
national and local regulatory requirements.
Investigator Name (print)
Investigator Signature
Date
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
4
CONFIDENTIAL
SYNOPSIS 
Protocol Title
An Open-Label, Phase II, Randomized, Controlled Study of Danvatirsen Plus 
Pembrolizumab Compared to Pembrolizumab Alone in Recurrent or Metastatic 
Head and Neck Squamous Cell Carcinoma (HNSCC)
Study Phase
Phase II
Objectives and 
Endpoints
Primary Objective
Primary Endpoint
To determine the objective response 
rate (ORR) by Response Evaluation 
Criteria in Solid Tumors version 1.1 
(RECIST v1.1) as determined by the 
Investigator for the combination of 
danvatirsen and pembrolizumab 
compared with pembrolizumab alone as 
first-line treatment of patients with 
metastatic or unresectable, recurrent 
HNSCC whose tumors express 
programmed death-ligand 1 (PD-L1) by 
Combined Positive Score (CPS) ≥1
Confirmed ORR (partial response 
[PR] + complete response [CR]
defined according to RECIST v1.1) 
(Eisenhauer et al 2009)
Secondary Objectives
Secondary Endpoints
To characterize the safety and 
tolerability of the combination of 
danvatirsen and pembrolizumab
Adverse events (AEs), serious 
adverse events, physical 
examinations, clinical laboratory 
values, and tolerability (dose 
interruptions/reductions)
To evaluate additional efficacy 
parameters for the combination of 
danvatirsen and pembrolizumab 
compared with pembrolizumab alone
x
Duration of response (DOR) by 
RECIST v1.1
x
Disease control rate (DCR) and 
CR rate by RECIST v1.1
x
ORR and DOR by RECIST v1.1 
in tumors with CPS ≥20 and 
CPS ≥50
x
Progression-free survival (PFS)
by RECIST v1.1, defined as the 
time from randomization to the 
first documentation of 
progressive disease (PD) or death 
from any cause, whichever comes 
first
x
Overall survival (OS), defined as 
time from randomization to death 
from any cause
To characterize the pharmacokinetics 
(PK) of danvatirsen
PK parameters derived from plasma 
concentrations of danvatirsen at 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
5
CONFIDENTIAL
defined timepoints in the combination 
regimen
To determine the immunogenicity of 
danvatirsen
Anti-danvatirsen antibody titers at 
defined timepoints in the combination 
regimen 
Exploratory Objectives
Exploratory Endpoints
x
To determine the pharmacodynamic 
activity of danvatirsen in pre- and
on-treatment tumor and blood 
specimens
x
To determine the relationship
between clinical activity and human 
papillomavirus (HPV) and other 
biomarkers in pre- and on-treatment 
specimens
x
STAT3 levels in pre- and on-
treatment samples 
x
Gene expression changes (RNA 
and/or protein) in pre- and on-
treatment samples 
x
Determination of HPV positivity
Study Design
Open-label, Phase II, randomized, controlled study evaluating the efficacy and 
safety of danvatirsen in combination with pembrolizumab compared with 
pembrolizumab alone as first-line treatment of patients with recurrent/metastatic 
(R/M) HNSCC. Two-thirds of patients will be randomized to receive danvatirsen 
and pembrolizumab and one-third will be randomized to receive pembrolizumab 
alone. 
Patients will be stratified by CPS (CPS ≥1 and <20 vs. CPS ≥20).  An early
assessment of response in patients with CPS ≥1 and <20 will be performed and 
should the response rate in this subgroup not pass the minimum desired efficacy 
level, eligibility will be restricted to patients with CPS ≥20.
Study Visit 
Schedule and 
Procedures
The study consists of a screening period, treatment period, safety follow-up, and 
survival follow-up.
After the screening period (Day -28 to Day -1), eligible patients will be 
randomized in a 2:1 ratio to receive either danvatirsen + pembrolizumab or 
pembrolizumab monotherapy, respectively. The treatment period consists of 
sequential 21-day treatment cycles. Patients will receive study treatment until 
PD, unacceptable toxicity, or voluntary withdrawal.
Patients with an initial assessment of PD may remain on treatment until a 
confirmatory scan is performed at least 4 weeks later to confirm PD prior to 
removing the patient from study treatment, as long as the progression does not 
represent a safety risk in the Investigator’s judgment.
Patients who discontinue study treatment for any reason will have a safety 
follow-up visit 30 days (+7 days) after the last dose of study treatment and a
follow-up for AEs 90 days (+7 days) after the last dose of pembrolizumab.
Survival information, including survival status and initiation of new anticancer 
treatment(s), will be collected every 12 weeks (±7 days) during the survival
follow-up period. The patients may be contacted remotely, and the information 
collected will be recorded in an electronic case report form.
Number of 
Sites
Approximately 35 sites globally
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
6
CONFIDENTIAL
Number of 
Patients
Approximately 81 patients
Study 
Population
To be eligible to participate in this study, candidates with R/M HNSCC must 
meet all of the following eligibility criteria within 28 days of Cycle 1 Day 1 or at 
the timepoint specified in the individual eligibility criterion. 
Inclusion Criteria
1.
Must have given written informed consent (signed and dated).
2.
Patient is ≥18 years old or age of majority in the country in which they 
reside, whichever is higher.
3.
Recurrent/metastatic histologically or cytologically proven squamous cell 
carcinoma of the head and neck that is considered incurable by local therapy. 
Eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, 
and larynx.
4.
Presence of measurable tumor per RECIST v1.1 criteria.
5.
Detectable PD-L1 expression in tumor, defined as CPS ≥1 determined by a 
test approved by US FDA or national regulatory agency of the country in 
which the patient resides.
x
A Tumor Proportion Score (TPS) value ≥30 may be used for initial 
eligibility however a CPS value must be obtained and reported utilizing a 
tissue sample obtained prior to the start of study treatment.
Examples of approved tests include PD-L1 IHC 22C3 pharmDx (Dako 
North America, Inc.); PD-L1 IHC 28-8 pharmDx (Dako North America, 
Inc.); Ventana PD-L1 (SP142) Assay (Ventana Medical Systems, Inc.);
Ventana PD-LI (SP263) Assay (Ventana Medical Systems, Inc)
6.
Baseline fresh tumor biopsy or archival specimen. A fresh biopsy is 
preferred if safe and feasible to obtain and consented to by the patient
(details provided in section on Tissue Samples).
7.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8.
Adequate organ function within 10 days of study treatment, including the 
following:
x
Absolute neutrophil count ≥1,500/μL
x
Platelet count ≥100,000/μL
x
Hemoglobin ≥9 g/dL (may be with transfusion)
x
Serum creatinine within normal limits or for patients with serum 
creatinine above institutional normal:
−
Creatinine clearance ≥45 mL/min
−
Creatine clearance can be calculated using an appropriate 
standard formula (e.g. Modification of Diet in Renal 
Disease equation [MDRD], Cockcroft-Gault formula or 
another formula that is typically used at the institution), or 
can be obtained from a 24-hour urine collection.
x
Total bilirubin ≤1.5× upper limit of normal (ULN) 
x Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
and alanine aminotransferase (serum glutamic pyruvic transaminase) 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
7
CONFIDENTIAL
≤2.5× ULN in the absence of liver metastases or ≤5× ULN in the 
presence of liver metastases
x International normalized ratio or prothrombin time (PT) and activated 
partial thromboplastin time or partial thromboplastin time (PTT) ≤1.5× 
ULN unless patient is receiving anticoagulant therapy as long as PT or 
PTT is within therapeutic range of intended use of anticoagulants
9.
Oxygen saturation on room air ≥92% by pulse oximetry.
10. Patients must satisfy the following criteria:
x
Females: must be non-pregnant and non-lactating and either:
i.
Surgically sterile (e.g., hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy)
ii.
Postmenopausal (defined as 12 months of spontaneous amenorrhea 
in females >55 years of age or, in females ≤55 years, 12 months of 
spontaneous amenorrhea without an alternative medical cause and
follicle-stimulating hormone levels in the postmenopausal range for 
the laboratory involved)
iii.
Abstinent* or
iv.
If engaged in sexual relations and of childbearing potential, agree to 
use highly effective contraceptive methods (Appendix 3) from the 
time of signing the informed consent form (ICF) until at least 4
months after the last dose of study treatment
x
Males, if engaged in sexual relations with a female of childbearing 
potential, must use an acceptable method of birth control (i.e. condom in 
line with the Clinical Trials Facilitation Group guidance) from the time 
of signing the ICF until at least 4 months after the last dose of study 
treatment.
*Abstinence is only acceptable as true abstinence, i.e., when this is in line 
with the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception.
11. Has an estimated life expectancy of at least 3 months.
12. Has recovered from all complications or surgery and all toxicities of prior 
therapy to ≤Grade 1 (or baseline) by National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE
v5.0) (exceptions: peripheral neuropathy ≤Grade 2 and any toxicities that in 
the view of the Investigator are not a clinically significant safety risk for 
further therapy administration, such as but not limited to: alopecia, fatigue, 
erectile dysfunction, hot flashes, cough, and urinary incontinence).
Exclusion Criteria
1.
Prior therapy for metastatic HNSCC. 
Systemic therapy for locoregionally recurrent HNSCC that was completed 
more than 3 months prior to signing consent is allowed if given as part of 
multimodal treatment for locally advanced disease.
2.
Has disease suitable for local therapy with curative intent.
3.
Primary tumor of the nasopharynx.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
8
CONFIDENTIAL
4.
Has received prior therapy with an anti-programmed death 1 (PD-1),
anti-PD-L1, or anti-programmed death-ligand-2 (PD-L2).
5.
Radiation therapy (or other non-systemic therapy) within 2 weeks of Day 1
of study treatment.
6.
Known autoimmune disease that has required systemic treatment (i.e., use of 
disease modifying agents, corticosteroids, or immunosuppressive drugs) in 
the past year. Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroids for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
7.
Known immunodeficiency or receiving systemic steroid therapy that would 
be the equivalent of >10 mg prednisone daily or any other form of 
immunosuppressive therapy within 7 days prior to Day 1 of study treatment.
x
Patients with known immunodeficiency conditions in which the number 
of immune cells is not impacted may be enrolled.
8.
Prior allogeneic tissue/solid organ transplant.
9.
Has any of the following cardiac criteria:
a.
Any abnormalities in rhythm, conduction, or morphology of resting 
12-lead electrocardiogram (ECG) that in the opinion of the Investigator 
render the patient unsuitable for participation in the study
b.
Mean resting corrected QT interval (QTc) calculated using Fridericia’s 
formula >450 msec for males and >470 msec for females according to 
local assessment and obtained from 3 ECGs performed approximately 
2 minutes apart (exception: patients stable on pacemaker with higher 
QTc)
c.
Any factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as heart failure, hypokalemia, congenital long 
QT syndrome, any concomitant medication known to prolong the QT
interval, or family history of long QT syndrome or unexplained sudden 
death under 40 years of age
10. Has received a live vaccine within 30 days of planned start of study 
treatment.
11. Active infection requiring systemic antiviral or antimicrobial therapy that 
will not be completed prior to Day 1 of study treatment.
12. History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
13. History of other malignancies, except the following:
a.
Malignancy treated with curative intent and with no known active 
disease present for ≥3 years before the first dose of study treatment and
felt to be at low risk for recurrence by treating physician. 
b.
Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease. 
c.
Adequately treated carcinoma in situ without evidence of disease.
14. Pregnant or breastfeeding; a negative pregnancy test is required within 
14 days of randomization for all women of childbearing potential. 
15. Active infection with human immunodeficiency virus (HIV) except patients 
who are currently stable on antiretroviral therapy (ART) for at least 4 weeks 
and agree to adhere to ART during study treatment, have HIV viral load of 
<400 copies per milliliter at screening (or undetectable per local criteria), 
and have cluster of differentiation 4 (CD4) T-cell counts ≥200/μL.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
9
CONFIDENTIAL
16. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. For 
patients with evidence of HBV infection, the HBV viral load must be 
undetectable on suppressive therapy, if indicated. For patients with HCV, 
infection must have been treated and cured or patients must be currently on 
treatment and have an undetectable HCV viral load.
17. Treated or untreated parenchymal brain metastases or leptomeningeal 
disease. Current active malignant epidural disease is also excluded.
Previously treated epidural disease does not exclude the patient from study 
as long as disease is inactive. (Note: Computed tomography or magnetic 
resonance imaging of brain is not needed to rule these out unless the patient 
has clinical symptoms suggestive of central nervous system metastases.)
18. Treatment with another investigational drug, biological agent, or device 
within 1 month of screening, or 5 half-lives of investigational agent (if 
known), whichever is longer.
19. As judged by the Investigator, any evidence of severe or uncontrolled 
systemic disease (e.g., unstable or uncompensated respiratory, cardiac, 
hepatic, or renal disease or impairment), laboratory finding or history of 
substance abuse or psychiatric disorder that makes it undesirable for the 
patient to participate in the study and/or comply with study procedures.
20. Hypersensitivity to any component of danvatirsen or pembrolizumab.
Study Drug 
Dosage and 
Administration
Treatment cycles are based on the schedule of administration of pembrolizumab. 
Each cycle is considered 21 days in length. The maximum duration of treatment
with pembrolizumab is 24 months. There will be no limit on the duration of 
treatment with danvatirsen. 
Danvatirsen dosing
Week 1: Danvatirsen 3 mg/kg intravenously (IV) on Days 1, 3, and 5 (±1 day) 
over 1 hour (±10 minutes)
Week 2 and subsequent weeks: Danvatirsen 3 mg/kg IV weekly (±2 days) over 
1 hour (±10 minutes)
Pembrolizumab dosing
Pembrolizumab 200 mg IV every 3 weeks (±7 days) over 30 minutes
(-5 min/+10 min)
Infusion of danvatirsen should be completed at least 60 minutes (Cycle 1) or at 
least 30 minutes (in subsequent cycles if no infusion reaction in first cycle) 
before the start of the pembrolizumab infusion on days that both drugs are 
administered.
Adjustment of 
Dose and/or 
Treatment 
Schedule
See section on Dose Modification Guidelines and Toxicity Management for 
specific toxicities. 
Safety Plan
Safety and toxicity will be continuously monitored in the study under the 
guidance from the Safety Review Committee. In addition, the committee will 
evaluate the safety data from the first 9 patients randomized who have completed
at least one cycle of study treatment for any unexpected toxicities, 
discontinuations due to study drug-related toxicities, or other signals that may 
raise safety concerns. Accrual to the study will be suspended if this analysis is 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
10
CONFIDENTIAL
not completed by the time the 20th patient is randomized to the study. If the 
combination is deemed intolerable, further accrual will be halted.
Statistical 
Considerations
Sample Size
Sample size considerations were based on monitoring the primary efficacy 
endpoint, ORR, using a 2-arm Bayesian optimal phase 2 (BOP2) design.
The primary efficacy evaluation will be the magnitude of ORR in each of the 
treatment arms and the probability that the combination arm ORR is superior to 
that of the control (monotherapy) arm, that is Pr(ORRcomb > ORRcon│data).
The design is optimized to maximize the power under H0:ORRcon = 0.15 and 
ORRcomb = 0.43, while controlling the type I error rate at 1-sided 0.05.
An interim futility analysis is planned when ORR can be assessed for the first 
39 patients, and the final ORR analysis is planned after 81 patients are followed 
for a minimum of 3 months (2 radiologic scans). A 2:1 combination:control 
randomization will be used for the 2 arms and will yield 83% power at the 
1-sided 5% alpha based on the decision rule to reject the null hypothesis and 
conclude that the combination arm is superior compared to the control.
Analysis Populations
x
Full Analysis Set (FAS): All patients who receive at least 1 dose of study 
treatment based on the treatment assigned at randomization; this will be the 
primary analysis set for efficacy analyses.
x
Safety Analysis Set: All patients who receive at least 1 dose of study 
treatment based on the actual treatment received; this will be the primary 
analysis set for safety analyses.
x
PK Evaluable Set: All FAS patients with evaluable PK data.
x
Biomarker Evaluable Set: All FAS patients with evaluable biomarker data.
Safety Analysis
The analysis of safety will focus on AEs with summaries of treatment-emergent 
adverse events (TEAEs, i.e., AEs that start or increase in severity after the first 
dose of study treatment). AEs will be coded according to the latest Medical 
Dictionary for Regulatory Activities (MedDRA) version available at the time of 
database creation. The severity of AEs will be graded according to NCI CTCAE 
v5.0. 
Safety summaries will also be provided for laboratory tests, vital signs, ECOG 
performance status, ECG, and weight parameters.
Efficacy Analysis
The primary efficacy analysis for ORR, as well as the interim analysis for PFS
and OS, will be conducted once all patients are treated and followed for a
minimum of 3 months (2 radiologic scans). The final analysis for PFS and OS 
will be conducted after all patients have been followed for a minimum of 
15 months, unless the study is deemed futile at the interim or primary analysis 
stage. 
ORR and DCR will be reported along with the corresponding 2-sided 90% and 
95% Clopper-Pearson exact confidence interval, and a comparison between the 
2 treatment groups will be performed based on Fisher’s exact test.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
11
CONFIDENTIAL
DOR, PFS, and OS will be summarized using Kaplan-Meier methods. PFS and 
OS comparisons between the 2 groups will be performed using the stratified log 
rank test. 
Interim Analyses
Safety Analysis
The Safety Review Committee will meet regularly to monitor the safety of the 
combination regimen throughout this study. Cumulative safety data from the first 
9 patients randomized who have completed at least one cycle of study treatment 
will be reviewed. Accrual to the study will be suspended if this analysis is not 
completed by the time the 20th patient is randomized to the study.
Futility Analysis
The BOP2 suggested futility monitoring criteria for the entire study population, 
as well as the CPS ≥1 and <20 subgroup, are non-binding. At the primary 
analysis, a lower ORR for advancement may also suffice by taking into 
consideration the CR rate that suggests superiority with regard to deep responses 
over that observed with pembrolizumab alone.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
12
CONFIDENTIAL
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL.........................................................................................1
SPONSOR PROTOCOL APPROVAL SIGNATURE PAGE.............................................2
INVESTIGATOR ACCEPTANCE PAGE ...........................................................................3
SYNOPSIS................................................................................................................................4
TABLE OF CONTENTS ......................................................................................................12
LIST OF TABLES.................................................................................................................15
LIST OF FIGURES ...............................................................................................................16
LIST OF ABBREVIATIONS ...............................................................................................17
1
INTRODUCTION......................................................................................................22
1.1
Background......................................................................................................22
1.1.1
Head and Neck Cancer......................................................................22
1.1.2
Danvatirsen .......................................................................................22
1.2
Rationale for Study Design and Dose Regimen ..............................................24
1.3
Benefits and Risks............................................................................................25
2
STUDY OBJECTIVES AND ENDPOINTS............................................................26
3
STUDY DESIGN........................................................................................................28
3.1
Overall Study Design.......................................................................................28
3.2
Definition of End of Study...............................................................................29
3.3
Duration of Study Participation .......................................................................29
3.4
Randomization and Blinding ...........................................................................29
4
STUDY POPULATION ............................................................................................31
4.1
Inclusion Criteria .............................................................................................31
4.2
Exclusion Criteria ............................................................................................33
5
STUDY TREATMENTS AND CONCOMITANT THERAPY ............................35
5.1
Study Treatments .............................................................................................35
5.2
Preparation, Storage, Handling, and Accountability .......................................36
5.2.1
Danvatirsen .......................................................................................36
5.2.2
Pembrolizumab .................................................................................36
5.2.3
General Study Drug Administration.................................................36
5.3
Study Treatment Compliance ..........................................................................37
5.4
Dose Modification Guidelines and Toxicity Management..............................37
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
13
CONFIDENTIAL
5.4.1
Purpose and Approach ......................................................................37
5.4.2
Dose Modifications for Danvatirsen.................................................38
5.4.3
Dose Holds for Pembrolizumab........................................................39
5.4.4
Management of Other Toxicities ......................................................39
5.5
Concomitant Medications................................................................................39
5.5.1
Hematopoietic Growth Factors.........................................................39
5.5.2
Concomitant Surgery ........................................................................39
5.5.3
Concomitant Radiotherapy ...............................................................40
5.5.4
Supportive Care ................................................................................40
5.6
Prohibited Medications....................................................................................40
5.6.1
Precautionary Medications................................................................40
6
DISCONTINUATION AND WITHDRAWAL CRITERIA..................................41
6.1
Discontinuation of Study Treatment................................................................41
6.2
Patient Withdrawal from the Study..................................................................41
6.3
Lost to Follow-up.............................................................................................42
7
STUDY ASSESSMENTS AND PROCEDURES....................................................43
7.1
Informed Consent Form...................................................................................43
7.2
Screening..........................................................................................................43
7.3
Screen Failures.................................................................................................44
7.4
Prior, Concomitant, and Post-Treatment Medication Reviews .......................44
7.5
Treatment Period..............................................................................................44
7.6
End-of-Treatment Visits ..................................................................................44
7.6.1
30-Day Safety Follow-up..................................................................44
7.6.2
90-Day Safety Follow-up..................................................................45
7.6.3
Survival Follow-up ...........................................................................45
7.7
Imaging Assessments.......................................................................................45
7.8
Safety Assessments..........................................................................................46
7.8.1
Physical Examination........................................................................46
7.8.2
Clinical Laboratory Parameters ........................................................46
7.8.3
Vital Signs, Height, and Weight .......................................................47
7.8.4
Electrocardiogram.............................................................................47
7.8.5
ECOG Performance Status ...............................................................48
7.9
Adverse Events ................................................................................................48
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
7.9.1
Definition of an Adverse Event ........................................................48
7.9.2
Definition of a Serious Adverse Event .............................................48
7.9.3
Severity of Adverse Events...............................................................49
7.9.4
Relationship of Adverse Events to Study Treatment........................49
7.9.5
Clinical Laboratory Adverse Events.................................................50
7.9.6
Reporting of Adverse Events and Serious Adverse Events..............51
7.9.7
Regulatory Aspects of Adverse Event Reporting.............................52
7.9.8
Pregnancy..........................................................................................52
7.9.9
Overdose ...........................................................................................52
7.10
Pharmacokinetic Assessments .........................................................................53
7.11
Immunogenicity Assessments..........................................................................53
7.12
Pharmacodynamic and Biomarker Assessments .............................................53
7.12.1
Tissue Samples..................................................................................53
7.12.2
Biomarker Blood Samples................................................................54
7.12.3
Storage and Destruction of Biological Samples ...............................55
8
ASSESSMENTS AND PROCEDURES BY STUDY VISIT..................................56
8.1
Schedule of Activities......................................................................................57
8.2
Pharmacokinetic, Immunogenicity, and Biomarker Sampling........................61
9
STATISTICAL CONSIDERATIONS .....................................................................62
9.1
Statistical Hypotheses ......................................................................................62
9.2
Sample Size......................................................................................................62
9.3
Analysis Populations........................................................................................64
9.3.1
Full Analysis Set...............................................................................64
9.3.2
Safety Analysis Set ...........................................................................64
9.3.3
PK Evaluable Set ..............................................................................64
9.3.4
Biomarker Evaluable Set ..................................................................65
9.4
General Considerations....................................................................................65
9.5
Disposition, Demographic and Baseline Characteristics, and Exposure.........65
9.6
Analysis of Safety............................................................................................65
9.7
Analysis of Efficacy.........................................................................................66
9.8
Plasma Pharmacokinetic Analysis ...................................................................67
9.9
Biomarker and Immunogenicity Analysis .......................................................67
9.10
Interim Analyses ..............................................................................................67
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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CONFIDENTIAL
9.10.1
Safety Analysis .................................................................................67
9.10.2
Futility Analysis................................................................................67
10
ETHICAL AND LEGAL CONSIDERATIONS.....................................................69
10.1
Compliance Statement .....................................................................................69
10.2
Ethics Committee and Regulatory Authorities ................................................69
10.3
Financial Disclosure.........................................................................................70
10.4
Informed Consent Process ...............................................................................70
10.5
Patient Data Protection ....................................................................................70
10.6
Dissemination of Clinical Study Data..............................................................70
10.7
Source Documents ...........................................................................................71
10.7.1
Electronic Case Report Form............................................................71
10.7.2
Clinical Study Report........................................................................71
10.8
Quality Control and Quality Assurance...........................................................71
10.8.1
Data Quality Assurance ....................................................................71
10.8.2
Quality Assurance Audits .................................................................72
10.9
Study and Site Closure.....................................................................................73
10.10 Publication Policy............................................................................................73
11
REFERENCES...........................................................................................................74
12
APPENDICES............................................................................................................76
Appendix 1.
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS................................................................76
Appendix 2.
eGFR Formulas....................................................................................77
Appendix 3.
BIRTH CONTROL METHODS CONSIDERED HIGHLY 
EFFECTIVE ........................................................................................78
Appendix 4.
TOXICITY GRADING AND DOSE MODIFICATION 
GUIDELINES FOR PEMBROLIZUMAB .........................................79
Appendix 5.
RECIST V. 1.1...................................................................................106
LIST OF TABLES 
Table 1:
Doses and Schedule of Administration..................................................................35
Table 2:
Dose Modifications for Elevations in Liver Function Tests..................................38
Table 3:
Dose Holds for All Other Adverse Events.............................................................38
Table 4:
Clinical Laboratory Tests.......................................................................................48
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
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CONFIDENTIAL
Table 5:
CTCAE AE Grading..............................................................................................50
Table 6:
Schedule of Activities............................................................................................58
Table 7:
Pharmacokinetic Sampling ....................................................................................62
Table 8:
Immunogenicity and Biomarker Sampling............................................................62
Table 9:
Optimized Stopping Boundaries............................................................................64
Table 10: Operating Characteristics.......................................................................................65
LIST OF FIGURES 
Figure 1:
Study Scheme.........................................................................................................29
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
16mer ASO
16-nucleotide antisense oligonucleotide
ACC
American College of Cardiology
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody
ADEM
acute disseminated encephalomyelitis
ADL(s)
activity(ies) of daily living
AE
adverse event
AHA
American Heart Association
AI
adrenal insufficiency
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ART
antiretroviral therapy
ASCO
American Society of Clinical Oncology
ASO
antisense oligonucleotide
AST
aspartate aminotransferase
ATG
antithymocyte globulin
AUCtau
area under the plasma concentration-time curve over the dosing interval
BAL
bronchoalveolar lavage
BOP2
Bayesian optimal phase 2
BOR
best overall response
BSA
body surface area
BU
Bethesda units
BUN
blood urea nitrogen
C
cycle
c/w
coupled with
CAD
coronary artery disease
CD4
cluster of differentiation 4
CD52
cluster of differentiation 52
cEt
constrained ethyl
CFR
Code of Federal Regulations
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
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CONFIDENTIAL
Abbreviation 
Definition 
CHEST
American College of Chest Physicians
CI
confidence interval
CIADM
checkpoint inhibitor–associated autoimmune diabetes
CK
creatine kinase
Cmax
maximum concentration recorded
CMV
cytomegalovirus
CNS
central nervous system
CPS
Combined Positive Score
CRI
chronic renal insufficiency
CRO
contract research organization
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXR
chest X-ray
CYP
cytochrome P450
D
day
DCR
disease control rate
DI
diabetes insipidus
DIHS
drug-induced hypersensitivity syndrome
DKA
diabetic ketoacidosis
DLCO
diffusing capacity of lung for carbon monoxide
DMARD
disease-modifying anti-rheumatic drug
DOR
duration of response
DRESS
drug reaction with eosinophilia and systemic symptoms
DVT
deep vein thrombosis
EBV
Epstein-Barr virus
EC
Ethics Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ED
emergency department
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
Abbreviation 
Definition 
EDC
electronic data capture
EGD
esophagogastroduodenoscopy
EMG
electromyography
EOT
end of treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEIBA
factor eight inhibitor bypassing activity
FFPE
formalin-fixed paraffin-embedded
FT4
free thyroxine
GBS
Guillain-Barre syndrome
GCP
Good Clinical Practice
GI
gastrointestinal
Gx
grade, where x is a number
HBV
hepatitis B virus
HCV
hepatitis C virus
Hgb
hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HNSCC
head and neck squamous cell carcinoma
HPV
human papillomavirus
HUS
hemolytic-uremic syndrome
ICF
informed consent form
ICH
International Council for Harmonisation
ICU
intensive care unit
IEC
Independent Ethics Committees
IgG
immunoglobulin G
IL-6
interleukin-6
INR
international normalized ratio
irAE
immune-related adverse event
IRB
Institutional Review Board
IRR
infusion-related reaction
IRT
Interactive Response Technology
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
Abbreviation 
Definition 
ITP
idiopathic thrombocytopenic purpura
IV
intravenous(ly)
IVIG
intravenous immunoglobulin
LDH
lactate dehydrogenase
LLN
lower limit of normal
LMWH
low-molecular-weight heparin
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MGFA
Myasthenia Gravis Foundation of America
MMF
mycophenolate mofetil
MRI
magnetic resonance imaging
mRNA
messenger RNA
NA
not applicable
NASH
nonalcoholic steatohepatitis
NCI
National Cancer Institute
NMO
neuromyelitis optica
NSAID
non-steroidal anti-inflammatory drug
ON
optic neuritis
ORR
objective response rate
OS
overall survival
PB
peripheral blood
PBMC
peripheral blood mononuclear cell
PCP
primary care practitioner
PCR
polymerase chain reaction 
PD
progressive disease
PD-1
programmed death 1
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PEX
plasma exchange
PFS
progression-free survival
PK
pharmacokinetic
PMN
polymorphonuclear cell
PR
partial response
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
Abbreviation 
Definition 
PT
prothrombin time
PTT
partial thromboplastin time
QTc
corrected QT interval
QW
weekly
QxW
every x weeks
R/M
recurrent/metastatic
RBC
red blood cell
RECIST v1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
ROW
Rest of World
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Safety Analysis Set
SCAR
severe cutaneous adverse reaction
SJS
Stevens-Johnson syndrome
SoA
Schedule of Activities
SSKI
potassium iodide
SUSAR
suspected unexpected serious adverse reaction
T2DM
Type 2 diabetes mellitus
TEAE
treatment-emergent adverse event
TEN
toxic epidermal necrolysis
Tmax
time to maximum plasma concentration
TNFα
tumor necrosis factor alpha
TPS
Tumor Proportion Score
TSH
thyroid-stimulating hormone
TTP
thrombotic thrombocytopenic purpura
ULN
upper limit of normal
US
United States
UTI
urinary tract infection
VKA
vitamin K antagonist
WBC
white blood cell 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
22
CONFIDENTIAL
1
INTRODUCTION 
1.1
Background 
1.1.1
Head and Neck Cancer 
Head and neck cancer is the sixth most common cancer worldwide, with the predominant 
histology being head and neck squamous cell carcinoma (HNSCC) (Sung et al 2020). In the 
United States (US), HNSCC accounts for 3% of all cancers diagnosed annually and 2% of 
cancer-related deaths. The majority of patients with HNSCC initially present with locally 
advanced disease. Despite aggressive, combined modality treatment, a significant proportion 
of patients will develop recurrent or metastatic (R/M) disease that is no longer amenable to 
curative therapy. Existing treatment options include platinum-based doublets, epidermal 
growth factor receptor inhibition, and immunotherapy. However, outcomes are generally 
poor, and most patients die within a year of diagnosis of R/M HNSCC (NCCN 2022).
Targeted immunotherapy promoting anti-tumor T-cell activity initially demonstrated 
improved survival and durable objective responses in many different cancers (Galon and 
Bruni 2019). As programmed death-ligand 1 (PD-L1) expression is observed in close to 68% 
of patients with HNSCC regardless of human papillomavirus (HPV) status, targeting 
programmed death 1 (PD-1)/PD-L1 in HNSCC was a rational approach for study 
(NCCN 2022). Initially, pembrolizumab was studied in a Phase Ib study in patients with R/M
disease and demonstrated an objective response rate (ORR) of 18%, and later the benefit was 
confirmed in the second-line setting (Ferris et al 2016). The benefit was comparable between 
HPV-positive and HPV-negative groups. 
Pembrolizumab is also approved for use in R/M disease. Indeed, the data from the
KEYNOTE-048 study reshaped the current standard of care in the frontline R/M HNSCC 
setting (Burtness et al 2019). Both single-agent pembrolizumab and pembrolizumab in 
combination with chemotherapy were evaluated against the existing standard-of-care 
regimen in this setting. Single-agent pembrolizumab demonstrated a 19% ORR 
(5% complete response [CR]) and 23% ORR (8% CR) in the subsets of Combined Positive 
Score (CPS) ≥1 and CPS ≥20 populations, respectively. There was also improvement on 
overall survival (OS) but not in progression-free survival (PFS). The totality of the data led to 
the approval of Keytruda® (pembrolizumab) in combination with platinum and fluorouracil
for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC 
and as a single agent for the first-line treatment of patients whose tumors express PD-L1 
(CPS ≥1) as determined by a Food and Drug Administration (FDA)-approved test.
1.1.2
Danvatirsen  
Danvatirsen (AZD9150, ISIS 481464) is a 16-nucleotide antisense oligonucleotide (16mer 
ASO) designed to target and down-regulate expression of human STAT3 messenger RNA 
(mRNA). It is a phosphorothioate-modified chimeric antisense oligonucleotide (ASO) with a 
10-base central oligonucleotide core that supports mediated metabolism, flanked by
3 constrained ethyl (cEt)-modified nucleosides on both the 5′ and 3′ ends (Seth et al 2009).
The novel cEt chemical modification incorporated into danvatirsen is anticipated, based on
extensive preclinical studies, to confer properties similar to second generation 
2′ methoxyethyl chemical modifications, but with a potential for enhanced potency.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
The target of danvatirsen, STAT3, is generally regarded as undruggable by more traditional 
approaches. STAT3 belongs to the STAT family of transcription factors and is a promising 
cancer drug target because of its pleiotropic involvement in tumorigenesis. STAT3 regulates 
the expression of many genes directly important to the survival of tumor cells (Alvarez et al 
2005). In addition, it plays an important role in non-tumor cells of the tumor 
microenvironment involved in immune evasion of tumor cells, angiogenesis, and metastasis 
(Kortylewski et al 2009).
Preclinical studies of danvatirsen administered intravenously (IV) led to a rapid initial 
clearance from plasma, followed by a much slower elimination phase due to extensive tissue 
distribution (most notably in the kidneys). Anti-drug antibodies (ADAs) were detected in the 
plasma of some animals.
In vitro cytochrome P450 (CYP) drug interaction studies demonstrated that danvatirsen 
drug-drug interaction is not expected to be a risk through inhibition of CYP activity, 
particularly at clinically appropriate concentrations. However, this potential effect cannot be 
completely excluded. 
Preclinical toxicity studies showed that danvatirsen is generally well tolerated. 
Proinflammatory effects were noted in several organs, including liver, along with minor 
elevations in liver function tests. Overall, the toxicology findings were similar to those noted 
with similar ASOs.
To date, well over 500 patients with hematologic malignancies or solid tumors have been 
exposed to danvatirsen, and several doses, schedules, and infusion times have been 
evaluated. Both monotherapy and combination therapy with other anticancer agents have 
been studied. Consistent with the preclinical data, a bi-phasic pharmacokinetic (PK) profile 
was noted with an initial fast distribution phase (half-life of 2 to 3 hours) followed by a 
slower elimination phase. With regard to adverse events (AEs), risks included 
thrombocytopenia, liver enzyme elevations, anemia, and neutropenia. Overall, danvatirsen 
demonstrated a tolerable safety profile, and toxicities were well managed with standard 
guidelines.
The most relevant study of danvatirsen with regard to HNSCC is the SCORES study, which 
evaluated the addition of danvatirsen to checkpoint blockade. This study included both 
first-line and second-line patients with R/M HNSCC. The ORR was assessed in 66 evaluable 
patients treated with danvatirsen at a dose of 3 mg/kg weekly in combination with 
durvalumab in the first-line setting. In this patient population that was not selected for PD-L1 
expression, ORR was 23% (CR 9.1%). The duration of response (DOR) was 42 weeks,
indicating a clinically meaningful benefit. Considering that danvatirsen monotherapy in this 
anti-PD-L1 naïve HNSCC patient population showed no responses, and the historical ORR 
with durvalumab as monotherapy is also generally regarded as negligible, the combination of 
danvatirsen and durvalumab appeared to be active and well tolerated. Moreover, additional 
analyses showed an intriguing relationship between PD-L1 levels and ORR and CRs. In 
patients with CPS ≥1 or CPS t20, the combination of danvatirsen and durvalumab led to an 
ORR of 31% to 37%, and 33% to 43%, respectively (note that the range is due to lack of CPS 
measures in some patients) and to a CR rate of 11% to 13% in the CPS≥1 subgroup and 19% 
to 22% in the CPS t20 subgroup. These outcomes are numerically superior to 
pembrolizumab historical data in this population.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
24
CONFIDENTIAL
For the most up-to-date clinical information regarding danvatirsen, refer to the latest version 
of the Investigator’s Brochure.
1.1.3
Pembrolizumab 
Binding of the PD-1 ligands, PD-L1 and programmed death-ligand 2 (PD-L2), to the PD-1
receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation 
of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to 
inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal 
antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, 
releasing PD-1 pathway-mediated inhibition of the immune response, including the 
anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity 
resulted in decreased tumor growth. Other checkpoint inhibitors, including the PD-1 inhibitor 
nivolumab and the PD-L1 inhibitor durvalumab, have also been studied in head and neck 
cancer. Pembrolizumab and nivolumab have shown activity in large studies and have been 
FDA approved for use in R/M HNSCC.
For the most up-to-date clinical information regarding pembrolizumab, refer to the latest 
version of the KEYTRUDA product insert.
1.2
Rationale for Study Design and Dose Regimen 
The SCORES study combined danvatirsen and durvalumab in different cohorts of patients 
with R/M HNSCC. The dose and schedule of administration of danvatirsen that will be used 
in this study are derived primarily from the SCORES study where they were shown to be safe 
and effective in a similar patient population when combined with a full dose of durvalumab. 
However, SCORES used a 1-week run-in period in which patients were treated with 
danvatirsen alone 3 times weekly for 1 week as a loading strategy prior to the addition of 
durvalumab for the combination phase. As the standard of care has evolved and 
pembrolizumab is now approved, the dosing and loading strategy for danvatirsen has been 
modified such that both danvatirsen and pembrolizumab dosing commence on the first day of 
the first cycle. The two additional doses of danvatirsen in the first week of dosing are likely 
to be tolerable in view of the relatively short circulation time of danvatirsen. The longer 
tissue half-life of danvatirsen is expected to take more time and ultimately be comparable to 
the steady-state phase of dosing with both drugs after 1 or more weeks.
The dose and schedule of administration of pembrolizumab chosen for this study are already 
approved for the frontline treatment of HNSCC and are described further in the KEYTRUDA 
product insert. Two schedules of administration for pembrolizumab are currently approved in 
the HNSCC setting: every 3 weeks (Q3W) and every 6 weeks. Among those two schedules, 
the Q3W schedule has been chosen as it was the schedule used in the KEYNOTE-048 study.
The benchmark efficacy data for this study are derived primarily from KEYNOTE-048 and 
informed by the data from the SCORES study. This study is designed to test the hypothesis 
that the data from the SCORES study evaluating the combination of danvatirsen and an 
anti-PD-L1, durvalumab, can be replicated with an anti-PD-1, pembrolizumab, in HNSCC. 
This is an important objective as durvalumab has not achieved approval while 
pembrolizumab is approved in frontline HNSCC and has been widely adopted as the standard
of care in appropriate patients. The study will enroll patients with a CPS ≥1 because these 
patients are hypothesized to derive greater benefit from the combination of danvatirsen and 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
25
CONFIDENTIAL
pembrolizumab. Stratification will occur based on CPS to determine if higher PD-L1 
expression predicts a higher response rate. Finally, the randomized design is chosen to 
rigorously assess the anticipated improvement of the dual regimen of danvatirsen and 
pembrolizumab versus pembrolizumab alone. The primary endpoint of ORR will be assessed 
by the Investigator. It is anticipated that this design will yield robust efficacy data to inform 
additional studies that may be pivotal in intent.
1.3
Benefits and Risks 
This study is intended to generate new information about the efficacy and safety of the
investigational agent danvatirsen when combined with pembrolizumab, which is approved 
for frontline R/M HNSCC. Patients who choose to participate generally cannot expect to 
receive direct additional benefit from the combination regimen than that provided by 
pembrolizumab alone. However, based on the preceding SCORES study, which evaluated 
danvatirsen in combination with durvalumab, an antibody that is mechanistically similar to 
pembrolizumab, the benefit:risk profile of this novel combination should be favorable and 
allow for a detailed and thorough characterization of the efficacy and safety of the 
combination regimen in a biomarker-selected patient population that is likely to derive
greater benefit than the patient population that was included in SCORES. Nevertheless, the 
tolerability of the experimental combination regimen is currently unknown. Every attempt 
will be made to scrutinize the qualitative and quantitative nature of drug-related toxicities 
continuously and at a formal analysis early in the course of the study to ensure that the safety 
of the combination is acceptable.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
26
CONFIDENTIAL
2
STUDY OBJECTIVES AND ENDPOINTS 
Objectives and Endpoints 
Objective
Endpoint
Primary
To determine the ORR by Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 
v1.1) as determined by the Investigator for the 
combination of danvatirsen and pembrolizumab 
compared with pembrolizumab alone as 
first-line treatment of patients with metastatic or 
unresectable, recurrent HNSCC whose tumors 
express PD-L1 by CPS ≥1
Confirmed ORR (partial response [PR] + CR 
defined according to RECIST v1.1) (Eisenhauer 
et al 2009)
Secondary
To characterize the safety and tolerability of the 
combination of danvatirsen and pembrolizumab
AEs, serious adverse events (SAEs), physical 
examinations, clinical laboratory values, and 
tolerability (dose interruptions/reductions)
To evaluate additional efficacy parameters for
the combination of danvatirsen and 
pembrolizumab compared with pembrolizumab 
alone
x DOR by RECIST v1.1
x Disease control rate (DCR) and CR rate by 
RECIST v1.1
x ORR and DOR by RECIST v1.1 in tumors 
with CPS ≥20 and ≥50
x PFS by RECIST v1.1, defined as the time 
from randomization to the first 
documentation of progressive disease (PD) 
or death from any cause, whichever comes 
first
x OS, defined as time from randomization to 
death from any cause
To characterize the PK of danvatirsen 
PK parameters derived from plasma 
concentrations of danvatirsen at defined 
timepoints in the combination regimen
To determine the immunogenicity of 
danvatirsen
Anti-danvatirsen antibody titers at defined 
timepoints in the combination regimen 
Exploratory
x
To determine the pharmacodynamic activity 
of danvatirsen in pre- and on-treatment 
tumor and blood specimens 
x
To determine the relationship between 
clinical activity and HPV and other 
x
STAT3 levels in pre- and on-treatment 
samples 
x
Gene expression changes (RNA and/or 
protein) in pre- and on-treatment samples 
x
Determination of HPV positivity
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
27
CONFIDENTIAL
biomarkers in pre- and on-treatment 
specimens
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
28
CONFIDENTIAL
3
STUDY DESIGN 
3.1
Overall Study Design  
This is a multicenter, open-label, Phase II, randomized, controlled study to determine the 
efficacy, safety, and other indicators of clinical and biological activity of the combination of
danvatirsen and pembrolizumab as first-line treatment for R/M HNSCC. 
After providing informed consent, patients will be assessed for eligibility during the
screening phase of the study. All patients must be willing and able to provide a 
formalin-fixed paraffin-embedded (FFPE) archival or fresh tumor sample collected during 
the screening period; a fresh biopsy is preferred if safe and feasible to obtain and consented 
to by the patient. Following the screening period, eligible patients will be randomized in a 
2:1 ratio to danvatirsen + pembrolizumab or pembrolizumab monotherapy, respectively.
Patients will be stratified by CPS (CPS ≥1 and <20 vs. CPS ≥20).  An early assessment of 
response in patients with CPS ≥1 and <20 will be performed and should the response rate in 
this subgroup not pass the minimum desired efficacy level, eligibility will be restricted to 
patients with CPS ≥20.
Patients will receive treatment in 21-day cycles. Patients assigned to the pembrolizumab
monotherapy arm will receive treatment until a criterion for discontinuation is met or a 
maximum of 24 months/34 cycles of treatment. Patients assigned to combination therapy will 
receive both treatments until a criterion for discontinuation is met or the patient has received 
a maximum of 24 months/34 cycles of pembrolizumab, after which they may remain on
danvatirsen monotherapy.
As the combination of danvatirsen and pembrolizumab has not been evaluated previously, 
safety will be assessed on a continuous basis. A formal review of safety will be performed by 
the Safety Review Committee after the first 9 patients randomized have completed at least 
one cycle of the assigned study treatment. If accrual reaches 20 patients prior to availability 
of the safety results, accrual will be suspended. If the combination is deemed intolerable, 
further accrual will be halted.
A futility analysis will be conducted when ORR can be assessed for the first 39 patients, as 
described in more detail in Section 9.2.
Patients in both treatment arms will have radiologic tumor assessments every 6 weeks 
(±1 week), regardless of treatment delays, until objective disease progression, initiation of 
new anticancer treatment, death, withdrawal of consent, or end of study, whichever occurs 
first.
All patients who discontinue study treatment for any reason will have a safety follow-up visit
30 days (+7 days) after the last dose of study treatment and a follow-up for AEs 90 days 
(+7 days) after the last dose of pembrolizumab. Patients will be followed for survival at 
12-week (±7 days) intervals until death or withdrawal of consent, whichever occurs first. 
Survival follow-up will continue until at least 15 months after the last patient is randomized 
in the study.
The study design is depicted in Figure 1.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
29
CONFIDENTIAL
Figure 1: Study Scheme  
Note: Maximum duration of pembrolizumab treatment is 24 months; there is no limit to the duration of 
danvatirsen treatment.
Abbreviations: PD = progressive disease; Q3W = every 3 weeks; QW = weekly; SFU = safety follow-up &
survival follow-up
3.2
Definition of End of Study 
A patient is considered to have completed the study upon completion of the last scheduled 
procedure shown in the Schedule of Activities (SoA) (Section 8.1), including the survival 
follow-up.
End of study is defined as the date of the last visit of the last patient. 
3.3
Duration of Study Participation
Study participation includes the screening, treatment, and follow-up periods. The screening 
period is 28 days. After randomization, patients receive treatment in 21-day cycles. The 
maximum duration of treatment with pembrolizumab is 24 months; there will be no limit of 
the duration of treatment with danvatirsen. 
The follow-up period includes safety follow-up until 30 days (+7 days) after the last dose of
study treatment, follow-up for AEs until 90 days (+7 days) after the last dose of
pembrolizumab, and survival follow-up every 12 weeks (±7 days) until death or withdrawal 
of consent, whichever occurs first. Survival follow-up will continue until at least 15 months 
after the last patient is randomized in the study.
3.4
Randomization and Blinding
Randomization will be managed centrally through an Interactive Response Technology (IRT)
system. Patients will be randomized in a 2:1 ratio to either danvatirsen + pembrolizumab or 
pembrolizumab monotherapy. Randomization will be stratified by Eastern Cooperative 
Oncology Group (ECOG) performance status (0 vs. 1 [Appendix 1]) for patients enrolled 
under the original protocol or Amendment 1.
For patients enrolled following this amendment, randomization will be stratified by the CPS 
(CPS ≥1 and <20 vs. CPS ≥20) obtained during screening, instead of ECOG performance 
status. Considering the addition of the new subgroup of subjects (CPS ≥1 and <20) as of this 
amendment, the change in stratification variables will not impact the intended randomization
balance. Removing ECOG performance status as a potential second stratification variable in
addition to CPS is necessary considering the limited size of the study and the 2:1 
randomization ratio.
Screening
Randomization 2:1
Pembrolizumab (200 mg Q3W)
Danvatirsen (Week 1: 3 mg/kg Day 1, 
3, and 5; Week ≥2: 3 mg/kg QW)
+
Pembrolizumab (200 mg Q3W)
SFU
PD
Eligible 
participants
SFU
PD
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
30
CONFIDENTIAL
Sites will receive the randomized treatment assignment for all patients by logging into the 
IRT system and entering the required data. 
Patients who are randomized in the IRT but do not receive study treatment will not be 
replaced.
Blinding is not applicable for this open-label study.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
31
CONFIDENTIAL
4
STUDY POPULATION 
To be eligible to participate in the study, candidates with R/M HNSCC must meet all of the 
eligibility criteria within 28 days of Cycle 1 Day 1 or at the timepoint specified in the 
individual eligibility criterion.
4.1
Inclusion Criteria  
To be eligible for study participation, all of the following inclusion criteria must be met:
1. Must have given written informed consent (signed and dated).
2. Patient is ≥18 years old or age of majority in the country in which they reside, 
whichever is higher.
3. Recurrent/metastatic histologically or cytologically proven squamous cell carcinoma 
of the head and neck that is considered incurable by local therapy. Eligible primary 
tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.
4. Presence of measurable tumor per RECIST v1.1 criteria.
5. Detectable PD-L1 expression in tumor, defined as CPS ≥1 determined by a test
approved by US FDA or national regulatory agency of the country in which the 
patient resides. A TPS value ≥30 may be used for initial eligibility however a CPS 
value must be obtained and reported utilizing a tissue sample obtained prior to the 
start of study treatment.
x
Examples of approved tests include PD-L1 IHC 22C3 pharmDx (Dako North 
America, Inc.); PD-L1 IHC 28-8 pharmDx (Dako North America, Inc.); Ventana 
PD-L1 (SP142) Assay (Ventana Medical Systems, Inc.); Ventana PD-LI (SP263) 
Assay (Ventana Medical Systems, Inc)
6. Baseline fresh tumor biopsy or archival specimen. A fresh biopsy is preferred if safe 
and feasible to obtain and consented to by the patient (details provided in section on 
Tissue Samples [Section 7.12.1]).
7. ECOG performance status of 0 or 1.
8. Adequate organ function within 10 days of study treatment, including the following:
a.
Absolute neutrophil count ≥1,500/μL
b.
Platelet count ≥100,000/μL
c.
Hemoglobin ≥9 g/dL (may be with transfusion)
d.
Serum creatinine within normal limits or, for patients with serum creatinine 
above institutional normal:
x
Creatinine clearance ≥45 mL/min
x
Creatine clearance can be calculated using an appropriate standard 
formula (e.g. Modification of Diet in Renal Disease equation [MDRD],
Cockcroft-Gault formula, or another formula that is typically used at the 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
32
CONFIDENTIAL
institution) or can be obtained from a 24-hour urine 
collection.(Appendix 2)
e.
Total bilirubin ≤1.5× upper limit of normal (ULN)
f.
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase)
and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase)
≤2.5× ULN in the absence of liver metastases or ≤5× ULN in the presence of 
liver metastases
g.
International normalized ratio (INR) or prothrombin time (PT) and activated 
partial thromboplastin time or partial thromboplastin time (PTT) ≤1.5× ULN 
unless patient is receiving anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of anticoagulants
9. Oxygen saturation on room air ≥92% by pulse oximetry.
10. Patients must satisfy the following criteria:
a.
Females: must be non-pregnant and non-lactating and either:
i.
Surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy)
ii.
Postmenopausal (defined as 12 months of spontaneous amenorrhea in females 
>55 years of age or, in females ≤55 years, 12 months of spontaneous 
amenorrhea without an alternative medical cause and follicle-stimulating 
hormone levels in the postmenopausal range for the laboratory involved)
iii.
Abstinent* or
iv.
If engaged in sexual relations and of childbearing potential, agree to use 
highly effective contraceptive methods (Appendix 3) from the time of signing 
the informed consent form (ICF) until at least 4 months after the last dose of 
study treatment
b. Males, if engaged in sexual relations with a female of childbearing potential, must 
use an acceptable method of birth control (i.e. condom in line with the Clinical 
Trials Facilitation Group guidance) from the time of signing the ICF until at least 
4 months after the last dose of study treatment.
*
Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a study, and withdrawal are not acceptable methods of contraception.
11. Has an estimated life expectancy of at least 3 months.
12. Has recovered from all complications or surgery and all toxicities of prior therapy to 
≤Grade 1 (or baseline) by National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events Version 5.0 (CTCAE v5.0) (exceptions: peripheral 
neuropathy ≤Grade 2 and any toxicities that in the view of the Investigator are not a 
clinically significant safety risk for further therapy administration, such as but not 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
33
CONFIDENTIAL
limited to: alopecia, fatigue, erectile dysfunction, hot flashes, cough, and urinary 
incontinence).
4.2
Exclusion Criteria 
A patient will be ineligible for study participation if any of the following exclusion criteria 
are met:
1. Prior therapy for metastatic HNSCC. 
Systemic therapy for locoregionally recurrent HNSCC that was completed more than 
3 months prior to signing consent is allowed if given as part of multimodal treatment 
for locally advanced disease.
2. Has disease suitable for local therapy with curative intent.
3. Primary tumor of the nasopharynx.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2.
5. Radiation therapy (or other non-systemic therapy) within 2 weeks of Day 1 of study 
treatment.
6. Known autoimmune disease that has required systemic treatment (i.e., use of disease 
modifying agents, corticosteroids, or immunosuppressive drugs) in the past year. 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroids for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
7. Known immunodeficiency or receiving systemic steroid therapy that would be the 
equivalent of >10 mg prednisone daily or any other form of immunosuppressive 
therapy within 7 days prior to Day 1 of study treatment. 
x
Patients with known immunodeficiency conditions in which the number of 
immune cells is not impacted may be enrolled.
8. Prior allogeneic tissue/solid organ transplant.
9. Has any of the following cardiac criteria:
a.
Any abnormalities in rhythm, conduction, or morphology of resting 12-lead 
electrocardiogram (ECG) that in the opinion of the Investigator render the patient 
unsuitable for participation in the study
b. Mean resting corrected QT interval (QTc) calculated using Fridericia’s formula
>450 msec for males and >470 msec for females according to local assessment 
and obtained from 3 ECGs performed approximately 2 minutes apart (exception: 
patients stable on pacemaker with higher QTc)
c.
Any factors that increase the risk of QTc prolongation or risk of arrhythmic 
events such as heart failure, hypokalemia, congenital long QT syndrome, any 
concomitant medication known to prolong the QT interval, or family history of 
long QT syndrome or unexplained sudden death under 40 years of age
10. Has received a live vaccine within 30 days of planned start of study treatment.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
11. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Day 1 of study treatment.
12. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
13. History of other malignancies, except the following:
a.
Malignancy treated with curative intent and with no known active disease present 
for ≥3 years before the first dose of study treatment and felt to be at low risk for 
recurrence by treating physician. 
b. Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
c.
Adequately treated carcinoma in situ without evidence of disease.
14. Pregnant or breastfeeding; a negative pregnancy test is required within 14 days of 
randomization for all women of childbearing potential. 
15. Active infection with human immunodeficiency virus (HIV) except patients who are 
currently stable on antiretroviral therapy (ART) for at least 4 weeks and agree to 
adhere to ART during study treatment, have HIV viral load of <400 copies per 
milliliter at screening (or undetectable per local criteria), and have cluster of 
differentiation 4 (CD4) T-cell counts ≥200/μL.
16. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. For patients with 
evidence of HBV infection, the HBV viral load must be undetectable on suppressive 
therapy, if indicated. For patients with HCV, infection must have been treated and 
cured or patients must be currently on treatment and have an undetectable HCV viral 
load.
17. Treated or untreated parenchymal brain metastases or leptomeningeal disease. 
Current active malignant epidural disease is also excluded. Previously treated 
epidural disease does not exclude the patient from study as long as disease is inactive. 
(Note: Computed tomography [CT] or magnetic resonance imaging (MRI) of brain is 
not needed to rule these out unless the patient has clinical symptoms suggestive of 
central nervous system metastases).
18. Treatment with another investigational drug, biological agent, or device within 
1 month of screening, or 5 half-lives of investigational agent (if known), whichever is 
longer.
19. As judged by the Investigator, any evidence of severe or uncontrolled systemic 
disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease 
or impairment), laboratory finding or history of substance abuse or psychiatric 
disorder that makes it undesirable for the patient to participate in the study and/or 
comply with study procedures.
20. Hypersensitivity to any component of danvatirsen or pembrolizumab.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
35
CONFIDENTIAL
5
STUDY TREATMENTS AND CONCOMITANT THERAPY 
5.1
Study Treatments 
Danvatirsen is the investigational medicinal product (IMP). Pembrolizumab is the standard of 
care. Collectively, these 2 drugs are referred to as the “study treatments” in this protocol.
Information on dose and schedule of administration is provided in Table 1.
Table 1: Doses and Schedule of Administration 
Study Treatment Name 
Danvatirsen 
Pembrolizumab 
Unit dose strength
Danvatirsen 50 mg/mL
Pembrolizumab 25 mg/mL
Dosage level
3 mg/kg
200 mg fixed dose
Dose formulation
Concentrate for solution for 
infusion
Concentrate for solution for 
infusion
Route of administration
IV infusion
IV infusion
IMP 
IMP
Standard of care
Sourcing
Sponsor
Study center
Packaging and labeling
IMP will be provided in glass vials. 
Each vial will be labeled per FDA 
requirements.
Commercial package 
Abbreviations: FDA = Food and Drug Administration; IMP = investigational medicinal product; 
IV = intravenous
Danvatirsen will be administered via an IV infusion at 3 mg/kg on Days 1, 3, and 5 of 
Cycle 1 Week 1 with a ±1 day dosing window and ensuring there is at least 1 day between 
each danvatirsen dose, i.e. danvatirsen should not be dosed on consecutive days. Note: The 
visit windows on D1, D3 and D5 do not apply to patients that are participating in the intense 
PK subset. Danvatirsen is dosed weekly thereafter beginning on Days 8 and 15 of Cycle 1 
and on Days 1, 8, and 15 of each subsequent 3-week cycle. Starting at Cycle 1 Week 2, 
danvatirsen has a ±2-day dosing window.
Pembrolizumab will be administered via an IV infusion on Day 1 of each 3-week treatment 
cycle after all procedures and assessments have been completed. Pembrolizumab has a 
±7-day dosing window.
On days when both danvatirsen and pembrolizumab are administered, danvatirsen will be 
administered first. After a window of at least 60 minutes, pembrolizumab will be 
administered. In the absence of Grade 2 or greater hypersensitivity reactions, the window of
time between the two infusions may be reduced to 30 minutes after the first cycle.
Danvatirsen may be held to allow for recovery of toxicities (See Section 5.4.2 for further
guidance on dose modifications). Doses missed during the hold will be considered skipped,
and the patient should receive their next dose at the scheduled time.
Pembrolizumab may be delayed to allow for recovery of toxicities (See Section 5.4.3 for 
further guidance on dose modifications). Doses missed during the hold will be considered 
skipped, and the patient should receive their next dose at the scheduled time.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
36
CONFIDENTIAL
5.2
Preparation, Storage, Handling, and Accountability 
5.2.1
Danvatirsen 
Danvatirsen will be administered as a dose of 3 mg/kg over 1 hour (±10 minutes, the infusion 
may be extended beyond the 10 minute window as medically indicated). The patient’s weight 
within 14 days of Cycle 1 Day 1 dosing should be used to calculate the dose. The dose is not 
recalculated if the patient’s weight changes during the study.
Danvatirsen vials are to be stored at the study center in a secured facility with limited access 
and controlled temperature following the labeled storage conditions. The temperature should 
be monitored on a daily basis and documented on the temperature monitoring log or
equivalent. Should a temperature excursion occur, the vials should be quarantined in a 
secure, temperature controlled (2°C to 8°C/36°F to 46°F) area and the Sponsor notified.
In accordance with International Council for Harmonisation (ICH) and local regulatory 
requirements, the Investigator and/or the person responsible for dispensing study treatment 
must be able to account for all study treatment provided to the site and patient at all times.
The IMP must be dispensed only at the study site, and no study medication is to be used 
outside of this study. At the conclusion of the study, all used and unused study medication 
shipped to the Investigator should be destroyed on site after reconciliation procedures with 
the study monitor are complete. A destruction certificate will be required.
Further guidance and information on preparation, handling, storage, accountability, and final 
disposition of unused danvatirsen are provided in the Pharmacy Manual.
5.2.2
Pembrolizumab 
Pembrolizumab vials should not be used beyond the expiration date provided by the 
manufacturer.
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes 
[-5 min/+10 min]). The infusion time may be extended beyond the 10min window if 
medically indicated.
Pembrolizumab should be stored according to the package insert.
Refer to the package insert for further instructions.
5.2.3
General Study Drug Administration 
Do not co-administer other drugs through the same IV line.
Do not administer as an IV push or bolus.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
37
CONFIDENTIAL
5.3
Study Treatment Compliance 
Study treatment will be administered IV at the study center. The administration of study 
treatment will be documented in the appropriate section of the electronic case report form
(eCRF).
5.4
Dose Modification Guidelines and Toxicity Management 
5.4.1
Purpose and Approach 
If a patient experiences a clinically significant and/or unacceptable toxicity with the study 
treatment, dosing will be interrupted or the dose reduced. Supportive therapy will be 
administered as required. 
If the toxicity resolves or improves to at least Grade 1 or pretreatment baseline (refer to 
specific toxicity criteria in Section 5.4.2 for danvatirsen and Section 5.4.3 for 
pembrolizumab) by day 21 for danvatirsen and day 42 for pembrolizumab, dosing may 
resume.
If the toxicity does not resolve (refer to specific toxicity criteria in Section 5.4.2 for 
danvatirsen and Section 5.4.3 for pembrolizumab) or at least improve after 21 days for 
danvatirsen or 42 days for pembrolizumab, dosing may still be resumed after discussion and 
agreement with the medical monitor.
Dose modification should only be applied if the toxicity is at least possibly related to study 
treatment and in the absence of alternative etiologies.
x
When more than one toxicity is noted simultaneously with different grades of 
severity, the highest grade should be used to guide dose modification decisions.
x
As one arm of this study is a combination regimen and some side effects of 
danvatirsen and pembrolizumab can be overlapping (e.g., possible ALT/AST 
elevations, thrombocytopenia, and neutropenia), every effort should be made to 
attribute the toxicity to the component part of the study treatment regimen, and 
only the dose of the component part should be modified. If the Investigator has 
any questions with regard to such an AE, the Investigator should immediately contact 
the Medical Monitor.
x
In the absence of clear alternative etiology, all events of an inflammatory nature 
should be considered immune related. 
x
The reasons for dose modifications, actions taken, and outcomes will be recorded. 
x
For concomitant medications, dose modifications will be at the discretion of the 
Investigator in accordance with the severity of the toxicity.
x
For temporary delays in study treatment due to toxicity, the cycle structure should
remain and not be regarded as delayed. Following the resolution of toxicity, the 
treatment regimen will resume as previously scheduled. This plan will potentially 
result in skipped doses and is intended to keep the treatment cycles synchronized with 
study assessments.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
38
CONFIDENTIAL
5.4.2
Dose Modifications for Danvatirsen 
One dose reduction of danvatirsen will be allowed for an individual patient, to 
2 mg/kg weekly. Dose reductions are required for elevations in liver function tests and are 
also permitted, at Investigator’s discretion, for other toxicities/AEs after they have resolved 
to grade 1 or pretreatment baseline, following discussion with the medical monitor and 
approval. If the dose reduction is not tolerated, study treatment should be permanently 
discontinued, and the patient should be followed up for safety. Once the dose of danvatirsen 
is reduced, it cannot be re-escalated.
If danvatirsen is held at Day 1 of a cycle, pembrolizumab should be continued and 
danvatirsen resumed at the next opportunity (i.e., according to the cycle schedule).
Dose modifications for elevations in liver function tests are shown in Table 2, and dose 
modifications for all other AEs are shown in Table 3.
Table 2: Dose Modifications for Elevations in Liver Function Tests 
Severity of Event 
Dose Adjustment for Danvatirsen 
Grade 1
No change.
Grade 2
No change.
Grade 3
1st occurrence: Hold administration of danvatirsen until the AE recovers to 
Grade 0-1 or to pretreatment baseline AE level, then re-start at the lower dose 
upon resolution.
2nd occurrence: Discontinue.
Grade 4
Discontinue.
Abbreviation: AE = adverse event
Table 3: Dose Holds for All Other Adverse Events 
Severity of Event 
Dose Adjustment for Danvatirsen 
Grade 1
Maintain danvatirsen dose level and provide treatment to control symptoms, 
if applicable.
Grade 2 
(tolerable)
Maintain danvatirsen dose level and provide treatment to control symptoms, 
if applicable.
Grade 2 
(intolerable or 
recurrent)
Hold administration of danvatirsen until the AE recovers to Grade 0-1 or to 
pretreatment baseline AE level, whichever is more abnormal. Then, resume 
treatment.
Grade 3
Hold administration of danvatirsen until the AE recovers to Grade 0-1 or to 
pretreatment baseline AE level, whichever is more abnormal. Then re-start at 
the same dose or lower dose at the discretion of the Investigator and approval 
by the medical monitor
Grade 4
Discontinue.
Abbreviation: AE = adverse event
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5.4.3
Dose Holds for Pembrolizumab 
Dose delays are allowed for pembrolizumab; dose reductions are not allowed.
American Society of Clinical Oncology (ASCO) guidelines for the workup and management 
of immune-related toxicities should be followed (Schneider et al 2021
https://ascopubs.org/doi/pdf/10.1200/JCO.21.01440).
Appendix 4 presents a summary of those guidelines adapted for pembrolizumab for a rapid 
reference but is not a substitute for the complete guidelines.
5.4.4
Management of Other Toxicities 
All other hematologic and non-hematologic toxicities should be managed according to 
standard medical practice and should adhere to commonly accepted guidelines. For example, 
while the prophylactic use of colony-stimulating factors is not allowed during the first 
administration of study treatment for any patient, for subsequent administrations, ASCO 
guidelines should be followed for the therapeutic use of granulocyte colony-stimulating 
factor in patients with Grade 3-4 febrile neutropenia in addition to appropriate workup for 
sepsis, antibiotics and/or other anti-infectives, and other supportive care.
Patients should also receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent 
medical conditions. All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records.
5.5
Concomitant Medications 
A concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. Every effort should be made to optimize the well-being 
of a patient through appropriate supportive care. All prior and concomitant medications taken 
from 30 days prior to enrollment in the study until 30 days after the patient’s last dose of 
study treatment must be recorded on the eCRF.
5.5.1
Hematopoietic Growth Factors 
Primary prophylactic use of granulocyte colony-stimulating factors is not permitted during 
Cycle 1 of treatment, but they may be used to treat treatment-emergent neutropenia as 
indicated by the current ASCO guidelines.
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines. Patients who enter the study on stable doses 
of erythropoietin or darbepoietin may continue this treatment, and patients may start either 
drug during the study at the discretion of the treating physician.
5.5.2
Concomitant Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. The 
appropriate interval of time between surgery and administration of IMPs to minimize the risk 
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of impaired wound healing and bleeding has not been determined. In case of a surgical 
procedure, IMPs should be delayed. Postoperatively, the decision to reinitiate IMPs should 
be discussed with the Sponsor. 
5.5.3
Concomitant Radiotherapy 
Palliative radiotherapy is not permitted during study treatment.
5.5.4
Supportive Care 
x
Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice. Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 
x
Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice. 
x
Anti-inflammatory or narcotic analgesics may be offered as needed. 
x
Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin. If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Factor Xa inhibitors) may be allowed; however, appropriate 
monitoring of PT/INR should be performed.
5.6
Prohibited Medications 
The concomitant use of the following therapies is prohibited while on study except as noted 
below: 
x
Immunosuppressive agents, unless used to treat drug-related AEs.
x
Immunosuppressive doses of systemic corticosteroids. 
o
Steroid use at prednisone dose (or dose equivalent) ≤10 mg/day is allowed but 
must be kept to a minimum.
o
Corticosteroids as premedication for allergic reactions (e.g., IV contrast) or as a 
management of AEs are allowed. 
x
Any live, attenuated vaccine within 30 days prior to Day 1 of study treatment or at 
any time during the study. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines and are not allowed. Note: Authorized 
COVID-19 vaccines are allowed. 
x
Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy other than study treatment, palliative radiation therapy, or standard or 
investigational anticancer agents).
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5.6.1
Precautionary Medications 
Drugs that are metabolized by CYP should be used with caution.
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6
DISCONTINUATION AND WITHDRAWAL CRITERIA 
6.1
Discontinuation of Study Treatment 
After consultation with the medical monitor, patients in the combination arm that are 
discontinued from one of the study treatments may remain in the study and continue to 
receive the other study treatment until a discontinuation criterion for the remaining treatment
has been met.
Treatment with danvatirsen and pembrolizumab should be permanently discontinued for any 
of the following: 
x
Consent withdrawal
x
Intolerable AE or an AE that meets the criteria for discontinuation 
x
Confirmed PD 
o
Clinically stable patients who experience radiographic PD by RECIST v1.1 may 
continue to receive study treatment if patients are otherwise tolerating study 
treatment in the opinion of the Investigator and there are no signs of rapid, 
radiographic progression of disease or progression at critical anatomical sites 
(e.g., cord compression or tumor impinging on a major blood vessel) requiring 
urgent alternative interventions. Confirmatory imaging should be performed at 
least 4 weeks later for patients with PD who remain on study treatment. If PD is 
confirmed, the patient will withdraw from study treatment.
x
Clinical progression, in absence of radiographic progression by RECIST v1.1,
including intolerable signs or symptoms consistent with disease progression, rapidly
worsening laboratory values or relevant tumor markers, rapid decline in ECOG 
performance status, or impingement of the tumor at critical anatomic sites requiring 
urgent interventions. Whenever possible, discontinuation due to clinical progression 
should be discussed with the Medical Monitor
x
Pregnancy
x
Significant patient non-compliance with the protocol or major protocol deviation
x
Investigator decision
x
Sponsor decision to end the study.
Patients who discontinue study treatment will complete end-of-treatment (EOT) procedures,
safety follow-up, and will enter the survival follow-up phase, as specified in the SoA
(Section 8.1). See Section 7.6 for more information.
6.2
Patient Withdrawal from the Study 
Any patient may voluntarily withdraw consent at any time and for any reason. In addition, 
the Investigator may withdraw a patient due to clinical and compliance considerations, and 
the Sponsor may withdraw a patient due to safety, administrative, or compliance reasons.
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Withdrawal may be from the study treatment phase only or from the entire study, including 
the requisite follow-up visits.
If such withdrawal occurs, or if the patient fails to return for visits, the Investigator must 
determine the primary reason for a patient’s withdrawal from the study and record the 
information on the eCRF. If the reason for withdrawal is an AE, monitoring should continue 
until the outcome is evident. The specific event or test result(s) must be recorded in the 
eCRF. 
It should be clearly documented in the source data whether patients withdrew their consent 
from all study procedures and will not enter the follow-up phase, or if the patient withdrew 
their consent for study treatment and procedures but will continue participation in the 
follow-up phase.
If a patient withdraws consent for the survival follow-up phase, the study site is still 
obligated to follow the patient’s survival status through publicly available forms of 
information (i.e., death registries) .
The Sponsor may retain and continue to use any data collected before such a withdrawal of 
consent.
6.3
Lost to Follow-up 
A patient will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits, and the study site is unable to make contact. Before a patient is deemed lost to 
follow-up, the Investigator or designee must make every effort to regain contact with the 
patient. These contact attempts (e.g., 3 phone calls followed by a certified letter) should be 
documented in the patient’s medical record. Should the patient continue to be unreachable, 
they will be considered to have withdrawn from the study. 
If a patient is lost to follow-up, the study site is still obligated to follow the patient’s survival 
status through publicly available forms of information (i.e., death registries).
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7
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures are described in the SoA (Section 8.1).
The Investigator and Sponsor will conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and local regulations. Adherence to the study design requirements, including 
those specified in the SoA, is essential and required for study conduct, and the Investigator
must ensure that study procedures are performed as described in the protocol. During the 
study, procedures and observations will be monitored to confirm that study requirements are 
being followed as outlined in the SoA.
7.1
Informed Consent Form 
Informed consent may be obtained any time prior to screening procedures, no visit window 
applies. ICFs for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
The anticipated consents to be used in the study are listed below; however, individual 
Institutional Review Boards (IRBs)/Ethics Committees (ECs) may require additional consent.
1. General Informed Consent: Consents patients for all required study procedures.
2. Optional Tissue Study Informed Consent (US patients only): Consented patients who 
are able and willing to provide fresh tumor tissue at C2D1, and EOT. As noted in the 
eligibility criteria, a fresh biopsy at screening is also preferred if safe and feasible to 
obtain and consented to by the patient.
7.2
Screening  
All screening procedures must be performed within 28 days prior to the first treatment 
(Cycle 1 Day 1), unless otherwise stated in the SoA (Section 8.1). Procedures conducted as 
part of the patient’s routine clinical management (e.g., blood count) and obtained before 
signing the ICF may be used for screening or baseline purposes provided the procedures meet 
the protocol-specified criteria and were performed within the time frame defined in the SoA.
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee 
to ensure that the patient qualifies for the study. Eligibility will also be reviewed by the
Sponsor or designee. In the event of borderline laboratory results or other factors that are 
deemed clinically insignificant, procedures may be repeated to meet eligibility requirements 
fully and/or discussed with the Medical Monitor for potential inclusion.
Demographic data, baseline characteristics, and medical and surgical history will be obtained 
during screening. 
History of the cancer under study will be recorded separately. This will include, but is not 
limited to, data on histopathological diagnosis, grading, staging, sites of metastases, prior 
treatments, prior best response, and diagnostic and biomarker data.
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7.3
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are 
not subsequently assigned to study treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure patients to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria not met, and any SAEs related to study procedures that occur after the ICF 
was signed.
Individuals who do not meet the criteria for participation in the study may rescreen by 
repeating the individual assessment(s) for which they failed.
7.4
Prior, Concomitant, and Post-Treatment Medication Reviews 
Prior medications: Prior medications taken by the patient within 30 days of enrollment into
the study and all ongoing medications will be recorded. Prior treatments for the current 
cancer will be recorded separately and not listed among prior medications.
Concomitant medications: Medications taken by the patient during the study will be 
recorded from the date of consent through the 30-day safety follow-up.
Concomitant cancer-related procedures: Cancer-related procedures during the study will 
be recorded from the date of consent through the 30-day safety follow-up.
Post-treatment anticancer therapy: The Investigator or qualified designee will review all 
new anticancer therapy initiated after the last dose of study treatment. If a patient initiates a 
new anticancer therapy within 4 weeks after the last dose of study treatment, the 30-day 
safety follow-up visit must occur before the first dose of the new therapy. Once new 
anticancer therapy has been initiated, patients will move into survival follow-up.
7.5
Treatment Period 
Patients should continue to receive study treatments and assessments as defined in the SoA
(Section 8.1) until treatment discontinuation criteria are met (Section 6.1).
7.6
End-of-Treatment Visits 
EOT visit requirements are described in the SoA (Section 8.1).
The EOT visit should occur as soon as possible at the time both study treatments are 
discontinued. If the EOT visit occurs approximately 30 days from the last dose of study 
treatment, the procedures performed at the EOT visit can serve as the 30-day safety 
follow-up and do not need to be repeated. 
7.6.1
30-Day Safety Follow-up 
The 30-day safety follow-up visit is required for all patients 30 days (+7 days) after the last 
dose of study treatment or before initiation of new anticancer treatment, whichever comes 
first. Patients with an AE of Grade ≥2 will be further followed until the resolution of the AE 
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to Grade 0-1 or until initiation of new anticancer therapy, whichever occurs first. Patients 
with an ongoing treatment-related AE must be followed until it resolves, becomes stable, or 
is considered not clinically significant by the Investigator.
7.6.2
90-Day Safety Follow-up 
All patients who discontinue pembrolizumab will be contacted (telephone communication or
clinic visit, at the Investigator’s discretion) for the follow-up of AEs 90 days (+7 days) after 
the last dose of pembrolizumab or before initiation of new anticancer treatment, whichever 
comes first.
7.6.3
Survival Follow-up 
All patients who have discontinued the study treatment will continue to be followed for 
survival information, including survival status and initiation of new anticancer treatment(s). 
Survival information will be collected every 12 weeks (±7 days) (telephone communication 
or in clinic visit) until the study ends. Survival data will be obtained from public records for 
patients who have been lost to follow-up.
Patients who discontinue study treatment for reasons other than PD will continue to have 
tumor assessments performed every 6 weeks until PD or the initiation of new anticancer 
therapy.
7.7
Imaging Assessments 
For all patients, tumor response assessment will be obtained by radiographic imaging with 
contrast-enhanced CT (preferred) or MRI evaluation. Optimal anatomic coverage for most
solid tumors include the chest, abdomen, and pelvis. Coverage should encompass all areas of 
known predilection for metastases in the disease under evaluation and should additionally 
investigate areas that may be involved based on signs and symptoms of individual patients.
In general, lesions present at baseline should be followed using the same imaging 
methodology and imaging equipment at subsequent assessments.
Tumor response assessments will be based on evaluation of response of target, non-target, 
and new lesions according to RECIST v1.1, as detailed in Appendix 5 (all measurements 
should be recorded in metric notation). Following initial objective response (PR or CR per 
RECIST v1.1), confirmatory imaging studies should be obtained 4 to 6 weeks later 
(Eisenhauer et al 2009).
Before stopping treatment, confirmation of PD should be considered by imaging no less than 
4 weeks after initial progression.
The timing of on-study imaging should follow calendar days and should not be adjusted for 
delays in treatment administration or for visits. The same imaging technique should be used 
in a patient throughout the study for consistency. 
For patients who discontinue study treatment for reasons other than PD, radiographic scans 
should continue according to the respective schedule of assessment until PD, initiation of 
new anticancer therapy, withdrawal of consent, or at least 15 months after the last patient is 
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randomized in the study, whichever comes first. Additional imaging may be performed if 
clinically indicated per the Investigator’s discretion.
Brain MRI with or without contrast is the preferred brain imaging modality; however, CT is 
acceptable if MRI is clinically contraindicated. Patients with treated or untreated 
parenchymal brain metastases, leptomeningeal disease, or current active malignant epidural 
disease are excluded from participation in the study (see Section 4.2). Patients with 
previously treated epidural disease are allowed as long as disease is inactive. Patients are not
required to have brain imaging at screening unless there are suggestive clinical 
symptoms/suspicion. 
During the study, brain CT/MRI scans should be conducted if clinically indicated by 
development of new specific symptoms.
7.8
Safety Assessments 
7.8.1
Physical Examination 
The Investigator or qualified designee will perform a complete physical examination during 
the screening period, on Day 1 of each cycle, and at the end of the treatment period as 
specified in the SoA (Section 8.1). Clinically significant abnormal findings during screening 
should be captured in the medical history. 
Patients on the danvatirsen and pembrolizumab arm will have a targeted physical 
examination as directed by disease, signs, and symptoms performed on Days 8 and 15 of 
each cycle and at the 30-day safety follow-up visit. New and clinically significant abnormal 
findings during the study should be recorded as AEs.
Patients on the pembrolizumab arm will have a targeted physical examination as directed by 
disease, signs, and symptoms performed on Days 8 and 15 of each cycle through cycle 4 and 
at the 30-day safety follow-up visit. New and clinically significant abnormal findings during 
the study should be recorded as AEs. Beginning with cycle 5, patients on the pembrolizumab
arm are only required to have an in person visit on Days 8 and 15 if clinically indicated
therefore the Investigator or qualified designee will contact the patient via a phone call on
Days 8 and 15 to evaluate their general health status and monitor for new AEs and 
concomitant medications.
7.8.2
Clinical Laboratory Parameters 
The hematology panel will consist of complete blood count (hemoglobin, hematocrit, 
erythrocytes [i.e., red blood cell count], and leukocytes [i.e., white blood cell count]) with 
differential (i.e., basophils, eosinophils, lymphocytes, monocytes, neutrophils) and platelet 
counts. 
The clinical laboratory tests are listed in Table 4; the timing and frequency of the laboratory 
tests are provided in the SoA (Section 8.1). These assessments should be performed at the 
local laboratory associated with the Investigator site.
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Table 4: Clinical Laboratory Tests 
Hematology 
Chemistry 
Coagulation Urinalysis 
Pregnancy 
Test 
Other  
Hemoglobin
ALT
INR
Urine dipstick 
for blood, 
protein, 
glucose
For female 
patients of 
childbearing 
potential, 
serum or urine 
Thyroid 
Function 
Tests: TSH, 
free T4, free 
T3
Hematocrit
AST
aPTT or 
PTT
WBC (with 
differential)
Alkaline 
phosphatase
Neutrophils
Sodium
Lymphocytes
Potassium
HBV and/or 
HCV viral 
load**
Monocytes
Magnesium
Eosinophils
Chloride
Basophils
Total calcium
Morning, 
cortisol*
RBC count
BUN or Urea
Platelets
Creatinine
ACTH*
Glucose 
(non-fasted)
HIV viral 
load**
Total bilirubin
Albumin
Phosphorous 
**(or 
phosphate)
LDH
Amylase**
Lipase**
Bicarbonate (or 
carbon dioxide)
Uric acid**
* Morning, cortisol required at screening and when clinically indicated (adrenal insufficiency suspected). Blood 
sample should be drawn with ACTH.
** To be obtained only as clinically indicated for eligibility and throughout the study.
Abbreviations: ACTH = adrenocorticotropic hormone; ALT = alanine aminotransferase; aPTT = activated 
partial thromboplastin time; AST = aspartate aminotransferase; BUN = blood urea nitrogen; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; INR = international normalized ratio;
LDH = lactate dehydrogenase; RBC=red blood cell; TSH = thyroid-stimulating hormone; WBC = white blood 
cell 
7.8.3
Vital Signs, Height, and Weight 
Vital signs include temperature, pulse, respiratory rate, blood pressure, and oxygen 
saturation. Weight should be assessed at the beginning of each cycle, per the SoA
(Section 8.1). Height will be measured at screening only.
7.8.4
Electrocardiogram 
A standard 12-lead ECG in triplicate will be performed using local standard procedures as 
specified in the SoA (Section 8.1). Three consecutive 12-lead ECGs (triplicates) will be 
performed approximately 2 minutes apart to determine mean QTc (average of triplicates). If 
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the mean QTc is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified 
person at the institution for confirmation and should be repeated as clinically indicated. 
Additional triplicate ECGs may be performed as clinically indicated. Clinically significant 
findings seen on follow-up ECGs should be recorded as AEs.
7.8.5
ECOG Performance Status 
ECOG performance status (Appendix 1) will be assessed as specified in the SoA (see 
Section 8.1).
7.9
Adverse Events 
7.9.1
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a medicinal 
product that does not necessarily have a causal relationship with this treatment. An AE can, 
therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the study (investigational) product. This 
includes an exacerbation of pre-existing conditions or events, concurrent illnesses, drug 
interactions, or the significant worsening of the indication under investigation. Anticipated 
fluctuations of pre-existing conditions, including the disease under study that does not 
represent a clinically significant exacerbation or worsening, need not be considered AEs.
Symptoms of the disease under study/lack of efficacy/cancer progression should not be 
classified as an AE if they are within the normal day-to-day fluctuation or expected 
progression of the disease.
It is the responsibility of the Investigator to document all AEs that occur during the study. 
AEs should be reported on the appropriate eCRF.
7.9.2
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence at any dose (including those occurring after the 
ICF is signed and before dosing) that:
x
Results in death
x
Is life-threatening (patient is at immediate risk of death from the event as it occurred)
x
Requires inpatient hospitalization or prolongation of existing hospitalization
x
Results in persistent or significant disability/incapacity
x
Results in a congenital anomaly/birth defect
x
Meets criteria for an important medical event, as described below
Important medical events that may not result in death, are not immediately life-threatening, 
or do not require hospitalization may be considered SAEs when, based on appropriate
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such events 
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include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.
For SAE reporting purposes, hospitalization is defined as inpatient hospital stay. 
Hospitalizations for elective surgery or other medical procedures that are not related to a 
treatment-emergent adverse event (TEAE) are not considered SAEs. Hospitalization that, in
the opinion of the Investigator, is unrelated to the study treatment(s) and due to purely 
non-medical circumstances (e.g., respite care, lack of a caretaker at home, lack of 
transportation home) is also not considered to be an SAE. 
Death should not be considered an SAE. The primary reason for a patient’s death should be 
reported as the SAE, with death reported as the outcome.
7.9.3
Severity of Adverse Events 
The severity of the AE will be graded according to the CTCAE v5.0. Only AEs not listed in 
the CTCAE should be graded as summarized in Table 5.
Table 5: CTCAE AE Grading 
CTCAE 
Grade 
Equivalent To: 
Definition 
Grade 1
Mild
Discomfort noticed but no disruption of normal daily 
activity 
Grade 2
Moderate
Discomfort sufficient to reduce or affect daily activity; no 
treatment or medical intervention is indicated, although 
this could improve the overall well-being or symptoms of 
the patient
Grade 3
Severe
Inability to work or perform normal daily activity; 
treatment or medical intervention is indicated to improve 
the overall well-being or symptoms; delaying the onset of 
treatment is not putting the survival of the patient at direct 
risk
Grade 4
Life-threatening/ 
disabling
An immediate threat to life or leading to a permanent 
mental or physical condition that prevents work or 
performing normal daily activities; treatment or medical 
intervention is required to maintain survival
Grade 5
Death
AE resulting in death 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events
7.9.4
Relationship of Adverse Events to Study Treatment 
For each AE/SAE, a causality assessment must be provided by the Investigator. The 
Investigator will use clinical judgment to determine whether or not an AE/SAE was related to 
each study treatment, as outlined below. 
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Related is defined as one of the following:
x
Definitely related: This applies when, after careful medical consideration, there is 
almost no consideration of other causation.
x
Probably related: There is a clinically plausible time sequence between onset of the 
AE and study treatment administration. The AE is unlikely to be caused by a 
concurrent or underlying illness, other drugs, or procedures. If applicable, the AE 
follows a clinically consistent resolution pattern upon withdrawal of study treatment. 
x
Possibly related: There is a clinically plausible time sequence between onset of the 
AE and study treatment administration, but the AE could also have been caused by 
the concurrent or underlying illness, other drugs, or procedures. Information 
regarding study treatment withdrawal may be lacking or unclear. “Possible” should be 
used when study treatment administration is one of several biologically plausible 
causes of the AE.
Not Related is defined as one of the following:
x
Unlikely related: The AE is most likely due to a cause not related to study treatment 
administration. However, association with the study treatment cannot be completely 
ruled out.
x
Unrelated: Another cause of the AE is most plausible, and a clinically plausible 
temporal sequence is inconsistent with the onset of the AE and study treatment 
administration and/or a causal relationship is considered biologically implausible.
For the purpose of regulatory reporting requirements, causal relationships of definite, 
probable, and possible will be considered treatment-related, while unlikely and unrelated will 
be considered not treatment-related.
7.9.5
Clinical Laboratory Adverse Events 
A clinical laboratory AE is any laboratory value that is deemed clinically significant by the 
Investigator and is accompanied by one of the following:
x
Requires a medical intervention
x
Requires a modification or interruption of study treatment
x
Is accompanied by clinical symptoms
Laboratory abnormalities that do not require medical intervention should not be recorded as 
AEs and will be captured and reported in the laboratory section of the clinical study report 
(CSR). If a medical intervention occurs, it should be recorded as a treatment with the 
abnormal laboratory finding as the AE (e.g., anemia with treatment required and blood 
transfusion recorded as a procedure, hyperglycemia with treatment required and change in 
insulin dose recorded on the concomitant medications eCRF).
The Investigator should decide, based upon the AE criteria and the clinical condition of the 
patient, whether a change in a laboratory parameter is clinically significant and therefore 
represents an AE.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
52
CONFIDENTIAL
If, at the end of the treatment phase with the study treatment, there are pathological 
laboratory values that were not present at baseline, further clinical or laboratory 
investigations should be performed until the values return to within reference range or until a 
plausible explanation (i.e., concomitant disease) is found for the pathologic laboratory 
values.
7.9.6
Reporting of Adverse Events and Serious Adverse Events 
Patients will be monitored for all AEs from the time the first dose of study treatment is 
administered through 30 days after the last dose of study treatment and 90 days after the last 
dose of pembrolizumab. All AEs/SAEs occurring through the reporting period (30 days after 
last dose of danvatirsen or 90 days after last dose of pembrolizumab, which ever is longer) or
until the time the patient begins a new anticancer treatment are reported in the CRF
irrespective of causality. All AEs and SAEs that occur from the signing of the ICF until the 
first dose of study treatment should be recorded in the eCRF only if the event was related to a 
study procedure. 
All patients with treatment-related AEs/SAEs should be observed until resolution or 
stabilization of the event. Any SAE occurring after the reporting period must be promptly 
reported if a causal relationship to the study treatment(s) is suspected. 
Elective or previously scheduled hospitalizations for pre-existing conditions that have not 
worsened after initiation of treatment should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE.
All AEs should be recorded individually unless, in the opinion of the Investigator, the AEs 
constitute components of a recognized condition, disease, or syndrome. In the latter case, the 
condition, disease, or syndrome should be reported rather than each individual sign or
symptom. If a constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded as an AE or SAE, as appropriate, on the relevant form(s) (SAE Report Form and/or 
AE form). If a diagnosis is subsequently established, it should be reported as follow-up
information becomes available. If a diagnosis is determined after the reporting of the 
constellation of symptoms, the signs/symptoms should be updated to reflect the diagnosis.
In general, disease progression should not be reported as an AE (or an SAE) or cause of 
death in this study. Instead, the AEs (or SAEs) considered as complications of disease 
progression should be reported. However, if no specific complications of disease progression 
can be identified that explain the clinical observations, “disease progression” may be 
reported as an SAE or cause of death.
Each AE will be evaluated for duration, severity according to the CTCAE v5.0, seriousness, 
and causal relationship to each study treatment. The action taken with each study treatment
and the outcome must also be recorded.
All SAEs, regardless of relationship to each study treatment, must be reported immediately 
(within 24 hours of awareness of event by Investigator) to the Sponsor and contract research 
organization (CRO) pharmacovigilance group. All SAE notifications should be made by 
completing the AE eCRF in the electronic data capture (EDC) system. Follow-up SAE 
reports must be submitted by the Investigator as new information becomes available.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
53
CONFIDENTIAL
The Medical Monitor for this study may be contacted for advice or assistance. Contact details 
will be provided separately in a study contact list.
7.9.7
Regulatory Aspects of Adverse Event Reporting 
The Sponsor and/or sponsor’s designee is responsible for submitting reports of SAEs 
associated with the use of the study treatments to the appropriate regulatory authority (e.g.,
the US FDA), Investigators, and central IRB/EC in accordance with all applicable regulations
and guidelines. 
It is the responsibility of the Investigator to notify their local IRB of SAEs that occur at his or 
her site per IRB requirements. Investigators will be notified of all suspected unexpected 
serious adverse reactions (SUSARs, i.e., via 7-/15-Day Safety Reports) that occur during any 
clinical studies of danvatirsen. Each site is responsible for notifying their local IRB of these 
additional SUSARs in accordance with local regulations.
7.9.8
Pregnancy 
Any pregnancy must be reported to the Sponsor or designee within 24 hours of the 
Investigator’s knowledge of the pregnancy using a Pregnancy Report Form.
Pregnancy is not considered an AE unless there is cause to believe that the study treatments
may have interfered with the effectiveness of a contraceptive medication or if the outcome of 
the pregnancy meets SAE criteria (miscarriage or congenital anomaly/birth defect, etc.), in 
which case it should be reported in the same manner and timelines as an SAE. In addition, 
any infant death or congenital anomaly that the Investigator suspects is related to in utero 
exposure to the study treatments should also be reported as an SAE. Hospitalization for 
normal delivery of a healthy newborn is not an SAE. 
Pregnancies occurring in patients during the study treatment period and until 30 days after 
the patient’s last dose of study treatments are considered immediately reportable events. If a 
pregnancy occurs in a patient, study treatments must be discontinued immediately. The 
pregnant woman should be referred to an obstetrician/gynecologist experienced in 
reproductive toxicity for further evaluation and counseling. The Investigator will observe the 
pregnant woman until completion of the pregnancy and must notify the Sponsor of the 
outcome within 24 hours of the Investigator’s knowledge of the pregnancy outcome. This
notification includes pregnancies resulting in live, “normal” births.
If a male patient impregnates his female partner, the study personnel at the site should be 
informed immediately and the pregnancy reported to the Sponsor.
7.9.9
Overdose 
For danvatirsen and/or pembrolizumab, administration of doses significantly exceeding those 
specified in the protocol (>10% above the specified dose) may be considered to be an 
overdose. In all cases, Investigators should be advised that any patient who receives a higher 
dose than that intended should be monitored closely, managed with appropriate supportive 
care, and followed up expectantly. There is currently no specific treatment in the event of an 
overdose of study drugs. All overdoses or medication errors should be reported to the 
Sponsor within 24 hours. 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
54
CONFIDENTIAL
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF.
7.10
Pharmacokinetic Assessments 
Venous blood samples for determination of danvatirsen concentrations in plasma will be 
taken at the times presented in Table 7. All patients in the danvatirsen + pembrolizumab arm 
will have sparse PK samples collected at Cycle 2 Day 1, Cycle 5 Day 1, and EOT. For 10 US 
patients in the danvatirsen + pembrolizumab arm who are participating in the intense PK 
subset, additional samples will be collected at Cycle 1 Day 1 and Cycle 1 Day 5. The date 
and time of collection of each sample will be recorded. 
PK parameters will be determined for danvatirsen. Possible relationships between PK and 
pharmacodynamic variables, efficacy, and/or selected toxicities will be explored, as 
appropriate.
Blood samples should be collected from the arm opposite from the investigational drug 
infusion, or from another site if collected within 24 hours of dosing. 
Retained/residual PK samples may also be used to evaluate safety or efficacy aspects related 
to concerns arising during or after the study. This includes their use in the development 
and/or validation of bioassays.
Please refer to the Laboratory Manual for details on collection and processing of blood PK 
samples.
7.11
Immunogenicity Assessments 
Venous blood samples for the assessment of ADA levels will be drawn at the timepoints 
presented in Table 8 from patients receiving danvatirsen + pembrolizumab. The date and 
time of collection of each sample will be recorded.
Blood samples should be collected from the arm opposite from the investigational drug 
infusion, or from another site if collected within 24 hours of dosing. 
Retained/residual ADA samples may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. This includes their use in the 
development and/or validation of bioassays.
Please refer to the Laboratory Manual for details on collection and processing of blood ADA 
samples.
7.12
Pharmacodynamic and Biomarker Assessments 
Whole blood samples and tissue specimens are to be collected according to the SoA 
(Section 8.1).
7.12.1
Tissue Samples 
An FFPE archival or fresh tumor sample collected during screening is required prior to 
randomization. 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
55
CONFIDENTIAL
x
Tissue samples will be used to assess pharmacodynamic activity of danvatirsen and 
exploratory biomarker assessments. 
x
Tumor tissue from a fresh biopsy (in FFPE) is preferred at screening if safe/feasible 
to obtain and consented to by the patient. If surgical resection of an accessible tumor 
is possible, then in addition to a piece of the tumor going to FFPE, 2 frozen pieces of 
the resection biopsy should be taken (1 each for RNA and protein analysis).
x
If a fresh biopsy is not safe/feasible or not consented to by the patient, an archival
sample may be provided. 
o
If an archival sample is provided, it should be from the most recent biopsy of a 
tumor lesion within the previous 24 months collected either at the time of or after 
the diagnosis of advanced or metastatic disease and from a site not previously 
irradiated. Approximately 10 to 20 slides of freshly prepared unstained 5-micron 
sections from the tumor block must be provided.
For US patients only that consented to the optional tissue study, additional fresh tumor 
samples are requested as soon as possible after Cycle 2 Day 1 (i.e., after study treatment has 
been administered) and at EOT, if safe/feasible to obtain. These tumor samples will be used 
to further define the tissue/plasma ratio of danvatirsen and evaluate the effects of danvatirsen 
on the levels of STAT3 expression (RNA and/or protein) and potentially other gene 
expression in STAT and related pathways. 
Tissue samples will be sent to a central laboratory or another facility approved by the 
Sponsor for analysis and storage. 
See the study Laboratory Manual for further guidance on tissue collection requirements and 
instructions.
7.12.2
Biomarker Blood Samples 
Whole blood samples will be collected for evaluation of exploratory biomarkers. The 
following samples for biomarker research are required:
x
Whole blood samples (All patients): Whole blood will be collected at the timepoints 
specified in Table 8 to evaluate the effects of danvatirsen on the level of STAT3 
expression and other gene expression.
x
Whole blood samples for isolation of peripheral blood mononuclear cells
(PBMCs) (US only): Whole blood will be collected at the timepoints specified in 
Table 8 to evaluate the effects of danvatirsen on the level of STAT3 expression and 
potentially other gene expression in PBMCs.
x
Whole blood samples for serum (US only) and plasma biomarkers (All patients):
Whole blood will be collected at the timepoints specified in Table 8 to evaluate the 
effects of danvatirsen on the level of circulating cytokines and other proteins.
Samples for exploratory biomarkers will be sent to a central laboratory or another facility 
approved by the Sponsor for storage and analysis. See the study Laboratory Manual for 
further guidance on blood sample collection requirements and instructions. 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
56
CONFIDENTIAL
7.12.3
Storage and Destruction of Biological Samples 
Biological samples used for PK, pharmacodynamic, ADA, and biomarker analysis may be 
retained at a central laboratory or another facility approved by the Sponsor until research and 
development of danvatirsen is completed, after which the samples will be destroyed.
Residual unused samples may be retained at a central laboratory or another facility approved 
by the Sponsor indefinitely as they may be used to support further bioassay or biomarker 
development for danvatirsen. Samples will be destroyed after use or at such time they are not 
needed for further research.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
57
CONFIDENTIAL
8
ASSESSMENTS AND PROCEDURES BY STUDY VISIT 
The timing of the study assessments and procedures are summarized in the Schedule of 
Activities (Table 6).
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
58
CONFIDENTIAL
8.1
Schedule of Activities 
Table 6: Schedule of Activities 
Assessments 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 & Cycle 
4  
Cycle 5 and 
Subsequent 
Cycles 
 
Danvatirsen+ 
Pembrolizumab 
arm 
Cycle 5 and 
Subsequent 
Cycles 
 
Pembrolizumab 
arm 
EOTa 
(+7D) 
Safety 
Follow-
upb 
30D 
(+7D) 
Safety 
Follow-
upb  
90D 
(+7D) 
Survival 
Follow-
up 
Q12W 
(±7D) 
-28 to 0 
D1 
D3r& 
D5 
+ 
- 
1D 
D8 
f
3D 
D15 
f3D 
D1 
f
3D 
D8 
f
3D 
D15 
f
3D 
D1 
f
3D 
D8 
f
3D 
D15 
f
3D 
D1 
±3D 
D8 
±3D 
D15 
±3D 
D1 
±3D 
D8 
±3Ds 
D15 
±3Ds 
Informed consentc
X
Demography; baseline 
characteristics;
medical, surgical, and 
cancer history
X
Tumor tissue 
collectiond
X
X
X
Randomization
following final 
confirmation of 
eligibilitye
X
Complete physical 
examinationf
X
X
X
X
X
X
X
Targeted physical 
examinationf
X
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weightf
X
X
X
X
X
X
X
12-Lead ECG in 
triplicate
X
X
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
59
CONFIDENTIAL
Assessments 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 & Cycle 
4  
Cycle 5 and 
Subsequent 
Cycles 
 
Danvatirsen+ 
Pembrolizumab 
arm 
Cycle 5 and 
Subsequent 
Cycles 
 
Pembrolizumab 
arm 
EOTa 
(+7D) 
Safety 
Follow-
upb 
30D 
(+7D) 
Safety 
Follow-
upb  
90D 
(+7D) 
Survival 
Follow-
up 
Q12W 
(±7D) 
-28 to 0 
D1 
D3r& 
D5 
+ 
- 
1D 
D8 
f
3D 
D15 
f3D 
D1 
f
3D 
D8 
f
3D 
D15 
f
3D 
D1 
f
3D 
D8 
f
3D 
D15 
f
3D 
D1 
±3D 
D8 
±3D 
D15 
±3D 
D1 
±3D 
D8 
±3Ds 
D15 
±3Ds 
Laboratory safety tests 
(hematology)f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory safety tests 
(serum chemistry)f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory safety tests 
(coagulation)f
X
X
X
X
X
X
X
X
Urinalysisf
X
X
X
X
X
X
X
X
Thyroid function testsf
X
X
X
X
X
X
X
X
Pregnancy testh
X
X
X
X
X
X
X
X
X
Concomitant 
medicationsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xs
Xs
X
X
AEi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xs
Xs
X
X
X
Tumor assessmentsj
X
X
X
X
X
Danvatirsenk
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumabl
X
X
X
X
X
Sparse 
Pharmacokineticsm
X
X
X
Intense 
Pharmacokineticsm
X
X
ADAn
X
X
X
X
US patients only whole 
blood, serum, and 
plasma biomarkerso
X
X
X
X
X
X
X
X
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
60
CONFIDENTIAL
Assessments 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 & Cycle 
4  
Cycle 5 and 
Subsequent 
Cycles 
 
Danvatirsen+ 
Pembrolizumab 
arm 
Cycle 5 and 
Subsequent 
Cycles 
 
Pembrolizumab 
arm 
EOTa 
(+7D) 
Safety 
Follow-
upb 
30D 
(+7D) 
Safety 
Follow-
upb  
90D 
(+7D) 
Survival 
Follow-
up 
Q12W 
(±7D) 
-28 to 0 
D1 
D3r& 
D5 
+ 
- 
1D 
D8 
f
3D 
D15 
f3D 
D1 
f
3D 
D8 
f
3D 
D15 
f
3D 
D1 
f
3D 
D8 
f
3D 
D15 
f
3D 
D1 
±3D 
D8 
±3D 
D15 
±3D 
D1 
±3D 
D8 
±3Ds 
D15 
±3Ds 
ROW patients only 
whole blood and 
plasma biomarkersp
X
X
X
X
X
US patients only 
PBMC biomarkersq
X
X
X
X
X
X
X
X
Survival status and
anticancer therapy
X
X
X
Abbreviations: ADA = anti-drug antibody; AE = adverse event; C = cycle; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group;
EOT = end of treatment; ICF = informed consent form; IRT = Interactive Response Technology; PBMC = peripheral blood mononuclear cell;
PD = progressive disease; PK = pharmacokinetic; Q3W = every 3 weeks; Q12W = every 12 weeks; SAE = serious adverse event
a.
EOT assessments need not be repeated if performed within the previous 14 days (or 30 days for imaging). When the last study visit is the same as the EOT
visit, default to the EOT and consider any additional procedures unscheduled.
b.
The 30-day safety follow-up visit will occur 30 days (+7 days) after the last dose of study treatment or prior to the start of new anticancer therapy, whichever 
occurs first. The 90-day safety follow-up may be a telephone communication or clinic visit, at the Investigator’s discretion, and will occur 90 days (+7 days) 
after the last dose of pembrolizumab or before initiation of new anticancer therapy, whichever occurs first.
c.
Informed consent may be obtained any time prior to screening procedures. There is no defined visit window between the date of ICF and C1D1.
d.
Fresh tumor biopsies are requested if safe/feasible at baseline before treatment, and for US patients that consented to the optional tissue study as soon after 
C2D1 treatment as possible, and at EOT, but this is not a requirement. If a fresh biopsy is not safe/feasible or not consented to by the patient, an archival 
sample must be provided during screening.
e.
Randomization via the IRT may be performed prior to C1D1 to allow for scheduling and study treatment preparation.
f.
To facilitate scheduling of predose assessments, a window of −2 days is allowed to obtain the following procedures prior to dosing a patient: physical 
examination, weight, laboratory safety tests (hematology, serum chemistry, and coagulation), urinalysis, and thyroid function tests.
g.
Vital signs include temperature, pulse, respiratory rate, blood pressure, and oxygen saturation.
h.
For female patients of childbearing potential, serum or urine. The pregnancy test at the 90 day safety follow up visit is required for all patients in the UK and 
as clinically indicated for all other patients.
i.
Patients are to be followed up for 30 days (+7 days) after the last dose of study treatment for any new reports of AEs, SAEs, and concomitant medications. 
Tracking of AEs will continue for all patients treated with pembrolizumab for 90 days (±7 days) after the last dose of pembrolizumab or until the initiation of 
subsequent anticancer therapy.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
61
CONFIDENTIAL
j.
Tumor assessments performed within 30 days of C1D1 may be used as the baseline tumor assessments. Tumor assessments will be performed every 6 weeks 
until tumor progression. Patients who discontinue treatment for reasons other than PD will continue to undergo tumor assessments every 6 weeks until PD or 
the initiation of new anticancer therapy. To facilitate scheduling of tumor assessments, a window of ±7 days is allowed.
k.
For C1 Week 1, danvatirsen will be administered on D1, D3, and D5 as a loading dose period. Starting with C1 Week 2, danvatirsen will be administered 
every week on D1, D8, and D15 of each treatment cycle; doses will have a ±2-day dosing window. 
l.
For pembrolizumab, a window of ±7 days is allowed for dosing days. Patients will receive pembrolizumab Q3W on D1 of each cycle.
m.
For C1 Week 1, intense PK sampling will be performed on D1 and D5 for 10 US patients in the danvatirsen + pembrolizumab arm. Sparse PK sampling also 
occurs on C2D1, C5D1 and EOT for all patients in the danvatirsen + pembrolizumab arm. Detailed PK sampling times are provided in Table 7.
n.
ADA will be assessed for danvatirsen + pembrolizumab patients at C1D1, C2D1, C5D1, and EOT, as shown in Table 8.
o.
Whole blood will be collected for the assessment of whole blood, serum, and plasma biomarkers in all US patients at C1D1, D8, and D15; C2D1; C3D1;
C5D1; and EOT, as shown in Table 8.
p.
Whole blood will be collected for the assessment of whole blood and plasma biomarkers in all ROW patients at C1D1; C2D1; C5D1; and EOT, as shown in 
Table 8.
q.
Whole blood will be collected for assessment of PBMC biomarkers in all US patients at C1D1, D8, and D15; C2D1; C3D1; C5D1; and EOT, as shown in 
Table 8.
r.
C1D3 and C1D5 visits are only applicable to patients on the danvatirsen + pembrolizumab arm. A minimum of one day is required between the D1, D3 and 
D5 danvatirsen doses. Note: The visit windows on D1, D3 and D5 do not apply to patients that are participating in the intense PK subset.
s.
D8 and D15 AE and concomitant medication assessments for patients on the pembrolizumab arm, may be conducted via a phone call beginning with Cycle 
5. In person visits should occur as clinically indicated.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
62
CONFIDENTIAL
8.2
Pharmacokinetic, Immunogenicity, and Biomarker Sampling 
Table 7: Pharmacokinetic Sampling 
Timepoint 
PK Sample
Cycle 
Day 
10 Danvatirsen + Pembrolizumab US
Patients
All Other Danvatirsen +
Pembrolizumab Patients
1
1
Predose and at 0.5 h (±5 min), 1 h (end of 
infusion; ±10 min), 2 h (±15 min), 
4 h (±30 min), and 6 h (±30 min) after the start 
of the danvatirsen infusion
1
5
Predose and at 0.5 h (±5 min), 1 h (end of 
infusion; ±10 min), 2 h (±15 min), 
4 h (±30 min), and 6 h (±30 min) after the start 
of the danvatirsen infusion
2
1
Predose and 2 h (±15 min) after the start of the 
danvatirsen infusion
Predose and 2 h (±15 min) 
after the start of the 
danvatirsen infusion
5
1
Predose and 2 h (±15 min) after the start of the 
danvatirsen infusion
Predose and 2 h (±15 min) 
after the start of the 
danvatirsen infusion
EOT
EOT
Any time during the EOT visit
Any time during the EOT 
visit
Abbreviation: PK = pharmacokinetic
Table 8: Immunogenicity and Biomarker Sampling 
Timepoint 
Immunogenicity 
Sample 
Whole Blood, 
Serum, and 
Plasma 
Biomarker 
Sample 
PBMC 
Biomarker 
Sample 
Whole Blood 
and Plasma 
Biomarker 
Sample 
Cycle 
Day 
All Danvatirsen + 
Pembrolizumab 
Patients 
US Patients 
US Patients 
ROW 
Patients 
1
1
X (Predose)
X (Predose)
X (Predose)
X (Predose)
1
8
X
X
1
15
X
X
2
1
X
X
X
X
3
1
X
X
5
1
X
X
X
X
End of Treatment
X
X
X
X
Abbreviation: PBMC = peripheral blood mononuclear cell
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Trial ID: FLM-6774-201
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9
STATISTICAL CONSIDERATIONS 
A summary of the study design and the planned statistical analyses for the primary and key 
secondary endpoints is presented below. A more technical and detailed description of the 
statistical methodology will be documented in the statistical analysis plan (SAP). Changes to 
the analyses will be described and justified in the CSR for the study.
9.1
Statistical Hypotheses 
The primary efficacy evaluation will be the magnitude of ORR in each of the treatment arms 
and the probability that the combination arm ORR is superior to that of the control 
(monotherapy) arm, that is Pr(ORRcomb > ORRcon│data).
9.2
Sample Size  
Sample size considerations were based on monitoring the primary efficacy endpoint, ORR, 
using a 2-arm Bayesian optimal phase 2 (BOP2) design (Zhao et al 2022).
Specifically, let ݊denote the interim sample size and ܰdenote the maximum sample size. 
Let ORRcon denote the control ORR and ORRcomb denote the combination treatment ORR. We 
define the null hypothesis H0: ORRcomb ≤ORRcon, under which the combination arm is 
deemed as unacceptable, respective to the control. We employ the following Bayesian rule to 
make a go/no-go decision:
(Futility stopping) stop enrolling patients and claim that the experimental arm is unacceptable 
if:
ܲݎ(ܱܴܴ௖௢௠௕> ܱܴܴ௖௢௡|݀ܽݐܽ) < ߣ(݊
ܰ)ఈ,
Where λ=0.96 and α=0.94 are design parameters optimized to maximize the power under 
H0:ORRcon = 0.15 and ORRcomb = 0.43, while controlling the type I error rate at 0.05 under 
ORRcon = ORRcomb = 0.15. This optimization is performed assuming a vague prior 
Beta(0.5,0.5) for ORRcon and ORRcomb.
An interim futility analysis is planned when ORR can be assessed for the first 39 patients,
and the final ORR analysis is planned after 81 patients are followed for a minimum of 
3 months (2 radiologic scans). A 2:1 combination:control randomization will be used for the 
2 arms and will yield 83% power at the 1-sided 5% alpha based on the above decision rule to 
reject the null hypothesis and conclude that the combination arm is superior compared to the 
control:
At the interim analysis: Pr(ORRcomb > ORRcon│data) > 0.5, and
At the final analysis: Pr(ORRcomb > ORRcon│data) > 0.96
The go/no-go criteria, also presented in detail in Table 9 below, are non-binding.
The operating characteristics of the design, based on 100000 simulations using the BOP2 
application, are presented in Table 10.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
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Table 9: Optimized Stopping Boundaries 
Control N 
Combination N 
# CR/PR in 
Control 
Stop for Futility if # of CR/PR in 
Combination - # of CR/PR in Control ≤ 
13
26
0
0
13
26
1~2
1
13
26
3
2
13
26
4
3
13
26
5
4
13
26
6
5
13
26
7
6
13
26
8
7
13
26
9
8
13
26
10
9
13
26
11
10
13
26
12
11
13
26
13
12
27
54
0
4
27
54
1
7
27
54
2
10
27
54
3
11
27
54
4
13
27
54
5
15
27
54
6
16
27
54
7
17
27
54
8
18
27
54
9
20
27
54
10
21
27
54
11
22
27
54
12~13
23
27
54
14
24
27
54
15
25
27
54
16~17
26
27
54
18~19
27
27
54
20~26
28
27
54
27
27
Abbreviations: CR = complete response; PR = partial response
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Flamingo Therapeutics
Trial ID: FLM-6774-201
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Table 10: Operating Characteristics 
Scenario 
% ORR 
Control 
% ORR 
Combination 
Early Futility 
Stopping (%) 
Claim 
Promising (%) 
Average Sample 
Size 
1
15
15
46.1
4.6
62
2
23
23
43.8
4.5
63
3
20
40
7.1
54.6
78
4
23
43
7.7
52.9
78
5
25
50
4.5
68.6
79
6
15
43
1.9
82.7
80
Abbreviation: ORR = objective response rate
Additional futility monitoring criteria will be taken into consideration for the subgroup of 
patients with CPS ≥1 and <20. Specifically, if no more than one patient achieves a response 
(confirmed or unconfirmed CR or PR within the first two scans) in the first 10 patients 
enrolled in the combination arm for this subgroup, there will be no further enrollment in this 
subgroup, and the study will continue to enroll in the CPS ≥20 subgroup, consistent with any 
guidance based on the monitoring criteria outlined in Table 9. Additionally, accrual in the 
CPS ≥1 and <20 subgroup will pause, if no responses have been achieved, but response data 
for the first 10 patients in that subgroup are not yet mature, defined as at least 2 scans
assessed.
Considering the limited size of the CPS ≥1 and <20 subgroup, the futility criteria were 
derived based on a single arm BOP2 design with the interim assessment after 10 patients, a 
final assessment of 27 patients (half of the intended size of the combination arm) testing a 
null hypothesis of 15% ORR (KEYNOTE-048 pembrolizumab monotherapy ORR for this 
subgroup (Burtness et al 2022)) vs. an alternative hypothesis of 29% ORR (SCORES 
combination arm for this subgroup), at 1-sided 10% level with approximately 65% power. 
9.3
Analysis Populations 
9.3.1
Full Analysis Set  
The Full Analysis Set (FAS) will include all patients who receive at least 1 dose of study 
treatment based on the treatment assigned at randomization and will be the primary analysis 
set for efficacy analyses. 
9.3.2
Safety Analysis Set 
The Safety Analysis Set (SAS) will include all patients who receive at least 1 dose of study 
treatment based on the actual treatment received and will be the primary analysis set for 
safety analyses.
9.3.3
PK Evaluable Set 
The PK Evaluable Set will include all FAS patients with evaluable PK data.
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9.3.4
Biomarker Evaluable Set 
The Biomarker Evaluable Set will include all FAS patients with evaluable biomarker data.
9.4
General Considerations 
Descriptive statistics will be used to display the results. Continuous variables, including 
baseline characteristics, will be summarized by reporting the number of observations, mean, 
standard deviation, median, minimum, and maximum. Categorical/discrete variables will be 
summarized using frequency tables showing the number and percentage of patients within a 
category. 
For time-to-event endpoints, the median, 25th and 75th percentiles (if estimable) using 
Kaplan-Meier methods along with the 90% and 95% confidence intervals (CIs) will be 
reported. Kaplan-Meier curves will also be generated for each time-to-event endpoint. 
Missing data will not be imputed except as described in the SAP. Baseline value will be 
defined as the last non-missing value before receipt of the first dose of study treatment.
9.5
Disposition, Demographic and Baseline Characteristics, and Exposure 
The number of patients in each study population and the reasons for exclusion will be 
summarized.
Patient demographics, baseline characteristics, and exposure will be listed and summarized 
for the FAS. Patient attributes will be summarized using frequency distributions for 
categorical variables or descriptive statistics for continuous endpoints, as appropriate.
Descriptive information for danvatirsen and pembrolizumab will be provided regarding the 
number of doses administered, the number of dose modifications and delays, the duration of 
treatment, and the relative dose intensity (% of treatment administered compared to targeted).
9.6
Analysis of Safety 
The analysis of safety will focus on AEs with summaries of TEAEs (i.e., AEs that start or 
increase in severity after the first dose of study treatment). AEs will be coded according to 
the latest Medical Dictionary for Regulatory Activities (MedDRA) version available at the 
time of database creation. The severity of AEs will be graded according to NCI CTCAE v5.0. 
The number and percent of patients with any AE will be tabulated by system organ class and 
preferred term using MedDRA. AEs related to danvatirsen, AEs related to pembrolizumab, 
all SAEs, related SAEs, and AEs by maximum CTCAE grade will be summarized similarly. 
Laboratory test results after the first dose of study treatment will be summarized by shift in 
CTCAE grade for laboratory parameters that can be graded. Laboratory parameters that 
cannot be graded by CTCAE will be summarized by shifts to low, normal, or high 
postbaseline. 
Vital signs will be summarized by the change from baseline at each postbaseline timepoint. 
Descriptive statistics will be provided by study visit for physical examination, ECOG
performance status, ECG, and weight parameters.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
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9.7
Analysis of Efficacy 
The primary efficacy analysis for ORR, as well as the interim analysis for PFS and OS, will 
be conducted once all patients are treated and followed for a minimum of 3 months 
(2 radiologic scans). The final analysis for PFS and OS will be conducted after all patients 
have been followed for a minimum of 15 months, unless the study is deemed futile at the 
interim or primary analysis stage. 
The overall response will be assessed by the Investigator based on the RECIST v1.1 criteria 
at each timepoint specified the SoA (Section 8.1). The best overall response (BOR) will be 
assessed from response assessments occurring after the first dose of either study treatment up
to the first documented assessment of PD that is prior to the initiation of a new anticancer 
therapy. Objective response (i.e., BOR of PR or CR) will require confirmation of the 
response (CR or PR) at least 4 weeks after the initial CR or PR.
The ORR will be defined as the proportion of patients with a confirmed objective response as 
assessed by the Investigator in the FAS. Patients who receive at least one dose of either study 
treatment but have no valid postbaseline radiographic assessment will be considered 
non-responders. The ORR will be reported along with the corresponding 2-sided 90% and 
95% Clopper-Pearson exact CI. The criteria for promising ORR at the primary analysis are 
detailed in Table 9 and, in addition, a comparison between the 2 treatment groups will be 
performed based on Fisher’s exact test.
DOR is defined as the date of the patient’s first confirmed BOR of CR or PR to the earliest 
date of documented progression or death if no prior evidence of disease progression, for all 
patients in the FAS with a confirmed objective response. A patient that starts a new 
anticancer therapy prior to disease progression will be censored at the date of last valid 
disease assessment prior to the start of the new anticancer therapy. All other patients without 
progression or death will be censored at the date of the last valid disease assessment. DOR
will be summarized using Kaplan-Meier methods.
The DCR, which includes a BOR of CR, PR, or SD, will be analyzed similar to ORR.
PFS is defined as the time from randomization to the first of either disease progression or 
death from any cause, where disease progression will be determined based on RECIST v1.1
criteria. A patient that starts a new anticancer therapy prior to disease progression will be 
censored at the date of last valid disease assessment prior to the start of the new anticancer 
therapy. Patients without documented disease progression or death will be censored at the 
last valid disease assessment date. Any patient without a valid disease assessment will be 
censored on the day of the first dose. PFS will be summarized using Kaplan-Meier methods 
and compared between the 2 groups using a stratified log rank test.
Sensitivity analyses for ORR, DOR, and PFS will be repeated with the requirement of 
confirmation of disease progression at least 4 weeks after an initial assessment of PD. Any 
unconfirmed disease progression assessment will not be counted as PD in these analyses.
OS is defined as the time from randomization to death from any cause. Patients without 
documentation of death as of the data cutoff will be censored at the last date the patient was 
known alive. OS will be summarized using Kaplan-Meier methods and compared between 
the 2 groups using a stratified log rank test.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
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All efficacy analyses will be performed for two key efficacy subgroups, which includes all 
patients with CPS ≥20 and CPS ≥50. Additional subgroups of interest will be defined in the 
SAP.
9.8
Plasma Pharmacokinetic Analysis 
A detailed PK analysis plan will be provided in the SAP.
The plasma concentrations of danvatirsen will be summarized by nominal sampling time 
using descriptive statistics. Plasma PK parameters (i.e., maximum concentration recorded 
[Cmax], trough concentration [Ctrough], area under the plasma concentration-time curve over 
the dosing interval [AUCtau], and time to maximum plasma concentration [Tmax]) after single 
and multiple doses as feasible will be listed and summarized using descriptive statistics. 
Mean plasma concentrations over time will be plotted in semi-logarithmic and linear scale as 
mean ± standard deviation. 
All available PK data may be used to conduct population PK, PK/pharmacodynamic, and 
exposure-response analyses.
9.9
Biomarker and Immunogenicity Analysis  
Descriptive analyses of ADA results may be performed based on the SAS.
Descriptive analyses, as well as correlative analyses with exposure and response, will be 
performed based on the Biomarker Evaluable Set, for the whole blood, serum, and plasma
biomarkers collected as well as the PBMC biomarkers.
9.10
Interim Analyses 
9.10.1
Safety Analysis 
An internal team of experts and a subset of site Principal Investigators will constitute the 
Safety Review Committee, which will meet regularly to monitor the safety of the 
combination regimen throughout this study. The committee will consider all available 
clinical safety and laboratory safety data. The details on membership, key responsibilities, 
and corresponding procedures are provided in the Safety Review Committee charter. 
Cumulative safety data from the first 9 patients randomized who have completed at least one 
cycle of study treatment will be reviewed for any unexpected toxicities, discontinuations due 
to study drug-related toxicities, or other signals that may raise safety concerns. Accrual to the 
study will be suspended if this analysis is not completed by the time the 20th patient is 
randomized to the study. If the combination is deemed intolerable, further accrual will be 
halted.
9.10.2
Futility Analysis 
The BOP2 suggested futility monitoring criteria that apply for the entire study population, as 
well as the CPS ≥1 and <20 subgroup, are presented in Section 9.2 and are non-binding. At 
the primary analysis, a lower ORR for advancement may also suffice by taking into 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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consideration the CR rate that suggests superiority with regard to deep responses over that 
observed with pembrolizumab alone.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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10
ETHICAL AND LEGAL CONSIDERATIONS 
10.1
Compliance Statement 
This study will be conducted in accordance with the protocol and with ICH GCP guidelines, 
as well as all applicable country and regional legal and regulatory requirements. The
Investigator is responsible for ensuring that this protocol, the site’s ICF, and any other 
information that will be presented to potential patients are reviewed and approved by the 
appropriate Independent Ethics Committee (IEC)/IRB prior to the enrollment of any study 
patients.
10.2
Ethics Committee and Regulatory Authorities 
This study will be conducted in accordance with the protocol and with the following:
x
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
x
Applicable ICH GCP Guidelines
x
Applicable laws and regulations
The Sponsor or designee will submit the study protocol plus all relevant study documents to 
applicable regulatory agencies for approval before the study start. No patient will be admitted 
to the study until appropriate regulatory approval of the study protocol has been received.
Each Investigator must complete a Form FDA 1572 or equivalent and provide the completed 
form according to written instructions to the Sponsor (or designee). 
The study will be registered at www.clinicaltrials.gov and other trial registries as required 
based on the countries in which the study is conducted.
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be approved by an IRB/EC before the study is 
initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.
The Investigator will be responsible for the following:
x
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC
x
Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures
x
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
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European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.3
Financial Disclosure 
The Investigators and sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. The 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.4
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements (where applicable), and the
IRB/IEC or study site.
The medical record must include a statement that written informed consent was obtained 
when the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF.
Patients will be reconsented to the most current version of the ICF(s) during their 
participation in the study, as necessary.
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.
10.5
Patient Data Protection 
Patients will be assigned a unique identifier during screening. Any patient records or datasets 
that are transferred to the Sponsor will contain the identifier only; patient names or any 
information that would make the patient identifiable will not be transferred.
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient who will be required to give consent for their data to be used as 
described in the informed consent.
10.6
Dissemination of Clinical Study Data 
The Sponsor will comply with current regulatory requirements for disclosure and submission 
of study results. The Sponsor’s policy on publication of study results is described in 
Section 10.10.
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Trial ID: FLM-6774-201
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10.7
Source Documents 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 
Electronic source data are data initially recorded in electronic form. Examples of source data 
include but are not limited to hospital records, clinical and office charts, laboratory notes, 
memoranda, patients’ memory aids or evaluation checklists, pharmacy dispensing records, 
audio recordings of counseling sessions, recorded data from automated instruments, copies or 
transcriptions certified after being verified as accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, and patient files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical study.
The source documents should indicate the patient’s consent to participate in the study. Data 
collection is the responsibility of the clinical study staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.
Definition of what constitutes source data can be found in ICH guidance for industry E6 
Good Clinical Practice: Consolidated Guidance.
10.7.1
Electronic Case Report Form 
Data will be collected using an EDC system and eCRFs. Sites will receive training on the 
EDC system. All users will be supplied with unique login credentials.
For each patient enrolled, eCRFs must be completed within a reasonable time period
(i.e., <2 weeks after data collection).
Full information regarding EDC and completing eCRFs is included in a study manual. All 
questions or comments related to electronic capture should be directed to the assigned 
monitor.
10.7.2
Clinical Study Report 
A CSR will be prepared under the responsibility and supervision of the Sponsor and signed 
by a Sponsor representative, thereby indicating their agreement with the analyses, results, 
and conclusions of the CSR.
10.8
Quality Control and Quality Assurance 
10.8.1
Data Quality Assurance 
All patient data relating to the study will be recorded in the electronic eCRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data). The Investigator
is responsible for verifying that data entries are accurate and correct by electronically signing 
the eCRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
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The Investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.
The monitoring plan provided describes monitoring strategy (e.g., risk-based initiatives in
operations and quality such as Risk Management and Mitigation Strategies), methods, 
responsibilities, and requirements (including handling of noncompliance issues and 
monitoring techniques [i.e., central, remote, or on-site monitoring]).
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
The Sponsor assumes accountability for actions delegated to other individuals (e.g., CROs).
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
The Sponsor will determine the minimum retention period and, upon request, will provide 
guidance to the Investigator when documents no longer need to be retained. The Sponsor also 
recognizes that documents may need to be retained for a longer period if required by local 
regulatory requirements. All study documents shall be made available if required by relevant 
regulatory authorities. The Investigator must consult with and obtain written approval by the 
Sponsor prior to destroying study and/or patient files.
No data should be destroyed without the agreement of the Sponsor. Should the Investigator
wish to assign the study records to another party or move them to another location, the 
Sponsor must be notified in writing of the new responsible person and/or the new location. 
The Sponsor will inform the Investigator, in writing, when the study-related records are no 
longer needed.
Patients’ medical records and other original data will be archived in accordance with the 
archiving regulations or facilities of the investigational site.
10.8.2
Quality Assurance Audits 
Clinical centers may be audited by the Sponsor’s quality unit qualified auditor or designee as 
required per approved schedule. The purpose of an audit, which is independent of and 
separate from routine monitoring or quality unit functions, is to evaluate study conduct and 
compliance with the protocol, standard operating procedures, ICH GCPs, and the applicable 
regulatory requirements. The Investigator and the Sponsor may also be subject to an 
inspection by US FDA, European regulatory authorities, or other applicable regulatory 
authorities at any time.
The auditor and regulatory authorities will require authority from the Investigator to have 
direct access to patients’ medical records. It is important that the Investigator(s) and their 
staff cooperate with the auditor or regulatory authorities during this audit or inspection.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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10.9
Study and Site Closure 
The Sponsor or designee reserves the right to close a study site or terminate the study at any 
time for any reason (e.g., as necessary for patient safety) at the sole discretion of the Sponsor.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study site closure visit has 
been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:
x
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor’s procedures, or GCP guidelines
x
Inadequate recruitment of patients by the Investigator
x
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/ECs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up.
10.10
Publication Policy 
The conditions regulating dissemination of the information derived from this study are 
described in the Clinical Trial Agreement.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multi-site studies only in their entirety and not as individual site data. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
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11
REFERENCES 
Alvarez JV, Febbo PG, Ramaswamy S, Loda M, Richardson A, Frank DA. Identification of a
genetic signature of activated signal transducer and activator of transcription 3 in human 
tumors. Cancer Res 2005;65:5054-62.
Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus 
cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the 
head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 
2019;394:1915–28.
Burtness B, Rischin D, Greil R, et al. Pembrolizumab Alone or With Chemotherapy for 
Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048:
Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol. 
2022;40(21):2321-2332.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41.
CTFG. Clinical Trial Facilitation Group: Recommendations related to contraception and 
pregnancy testing in clinical trials, version 1.1. 2020. 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Ver
sion_1.1_updated.pdf.
Eisenhauer EA, Therasse P, Bogaert J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell 
carcinoma of the head and neck. N Engl J Med 2016;375:1856–67.
Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with 
combination immunotherapies. Nat Rev Drug Discov 2019;18(3):197-218.
KEYTRUDA Product Insert: 
https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf.
Levey AS, Bosch JP, Lewis JB, et al.. A more accurate method to estimate glomerular 
filtration rate from serum creatinine: a new prediction equation. Modification of Diet in 
Renal Disease Study Group. Ann Intern Med. 1999;130:461-70.
Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann Intern Med. 2006;145:247-54
Kortylewski M, Xin H, Kujawski M, et al. Regulation of the IL 23 and IL-12 balance by 
Stat3 signaling in the tumor microenvironment. Cancer Cell 2009;15:114-23.
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
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CONFIDENTIAL
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines). Head and Neck Cancers, version 2. 2022 
https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf.
Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse 
events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. 
J Clin Oncol 2021;39:4073-4126. https://ascopubs.org/doi/pdf/10.1200/JCO.21.01440.
Seth PP, Siwkowski A, Allerson CR, et al. Short antisense oligonucleotides with novel 2͛-
4͛ conformationally restricted nucleoside analogues show improved potency without 
increased toxicity in animals. J Med Chem 2009;52:10-3.
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of 
incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 
2021;71:209-49.
Zhao Y, Yang B, Lee JJ, Wang L, Yuan Y. Bayesian Optimal Phase II Design for
Randomized Clinical Trials. Statistics in Biopharmaceutical Research. 2022;14:423-32.
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Trial ID: FLM-6774-201
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APPENDICES 
APPENDIX 1.
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG)
PERFORMANCE STATUS
Grade 
Performance Status  
0
Fully active, able to carry on all predisease performance without restriction 
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work 
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5
Dead 
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Trial ID: FLM-6774-201
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Appendix 2.
eGFR Formulas
Cockroft-Gault Method
Source: Cockcroft and Gault 1976
MDRD Method
GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African 
American)
Scr (standardized serum creatinine) = mg/dL
Sources: Levay et al., 1999; Levay et al., 2006
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Trial ID: FLM-6774-201
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APPENDIX 3.
BIRTH CONTROL METHODS CONSIDERED HIGHLY 
EFFECTIVE
According to the Clinical Trial Facilitation Group “Recommendations related to 
contraception and pregnancy testing in clinical trial” (CTFG 2020), methods that can achieve 
a failure rate of less than 1% per year when used consistently and correctly are considered as 
highly effective birth control methods, such as:
1. Combined (estrogen and progesterone containing) hormonal contraception associated 
with inhibition of ovulation
−
oral
−
intravaginal
−
transdermal
2. Progesterone-only hormonal contraception associated with inhibition of ovulation
−
oral
−
injectable
−
implantable
3. Intrauterine device 
4. Intrauterine hormone-releasing system
5. Bilateral tubal occlusion
6. Vasectomized partner
7. Sexual abstinence
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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APPENDIX 4.
TOXICITY GRADING AND DOSE MODIFICATION 
GUIDELINES FOR PEMBROLIZUMAB
Adapted from ASCO Guidelines for the Management of Immune-Related Adverse Events:
https://ascopubs.org/doi/pdf/10.1200/JCO.21.01440 (Schneider et al 2021)
AE and Grade by 
CTCAE v5.0
Management
Cutaneous Toxicities
Rash or Inflammatory 
Dermatitis
G1: Rash covering <10% 
BSA, which may or may 
not be associated with 
symptoms of pruritus or 
tenderness
x Continue pembrolizumab.
x Treat with topical emollients and/or mild-moderate potency topical 
corticosteroids.
x Counsel patients to avoid skin irritants.
G2: Rash covering 10%-
30% BSA with or without 
symptoms (e.g., pruritus, 
burning, tightness); 
limiting instrumental 
ADLs; rash covering 
>30% BSA with or 
without mild symptoms
x Consider holding pembrolizumab and monitor weekly for 
improvement. If skin toxicity not improved after 4 weeks, then 
regrade toxicity as G3.
x In addition, treat with topical emollients, oral antihistamines, and 
medium-to-high potency topical corticosteroids.
x Consider initiating prednisone (or equivalent) at dosing 
0.5-1 mg/kg, tapering over 4 weeks. In patients with pruritis without 
rash, consider topical anti-itch remedies (e.g., refrigerated menthol, 
pramoxine).
G3: Rash covering >30% 
BSA with moderate or 
severe symptoms; limiting 
self-care ADL
x Hold pembrolizumab therapy and consult with dermatology to 
determine appropriateness of resuming.
x Treat with topical emollients, oral antihistamines, and high-potency 
topical corticosteroids. May also consider phototherapy to treat 
severe pruritus.
x Initiate oral prednisone or equivalent (1 mg/kg/d) tapering over at 
least 4 weeks.
x Once downgraded to ≤G1 and prednisone (or equivalent) below 
10 mg/d, clinicians may consider resuming pembrolizumab therapy 
with close monitoring and follow-up with dermatology in certain 
cases such as psoriasis.
x In patients with pruritis without rash, may treat with gabapentin, 
pregabalin, aprepitant, or dupilumab.
G4: Severe consequences 
requiring hospitalization 
or urgent intervention 
indicated or 
life-threatening 
consequences
x Immediate hold pembrolizumab.
x May admit patient immediately with direct oncology involvement 
and with an urgent consult by dermatology.
x Systemic steroids: IV methylprednisolone (or equivalent) dosed at 
1-2 mg/kg with slow tapering when the toxicity resolves.
x Monitor closely for progression to SCAR.
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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AE and Grade by 
CTCAE v5.0
Management
x Consider alternative antineoplastic therapy over resuming 
pembrolizumab if the skin irAE does not resolve to ≤G1. 
Bullous Dermatoses
G1: Asymptomatic or 
blisters covering <10% 
BSA and no associated 
erythema
x If blisters are <10% BSA, are asymptomatic and non-inflammatory 
(such as the case with friction blisters or pressure blisters), cessation 
of pembrolizumab is not necessary and only observation/local 
wound care is warranted.
x When symptomatic bullae or erosions, which are “deroofed” 
vesicles or bullae, are noted on the skin or mucosal surfaces, the 
cutaneous irAE is considered at least G2.
x See G2 management recommendations.
G2: Blistering that affects 
quality of life and require 
intervention based on 
diagnosis not meeting 
criteria for >G2. Blisters 
covering 10%-30% BSA
x Hold pembrolizumab and consult with dermatology for steroid-
sparing options, work up, and to determine appropriateness of 
resuming.
x Attention given to general local wound care, which includes plain 
petrolatum ointment and bandages or plain petrolatum ointment 
gauze and bandage over any open erosions, which are left on the 
skin after the blister has “popped” or if the roof of the blister easily 
sloughs off.
x Initiate class 1 high potency topical steroid, e.g., clobetasol, 
betamethasone, or equivalent and reassess every 3 days for 
progression or improvement.
x Low threshold to initiate treatment with prednisone (or equivalent) 
at 0.5-1 mg/kg/d dosing and taper over at least 4 weeks.
x Monitor patients closely for progression to greater BSA
involvement and/or mucous membrane involvement. Consider 
following patients closely using serial photography.
G3: Skin sloughing 
covering >30% BSA with 
associated pain and 
limiting self-care ADL
x Hold pembrolizumab and consider admitting patient.
x Administer IV methylprednisolone (or equivalent) 1-2 mg/kg and 
when appropriate convert to oral steroids, tapering over at least 
4 weeks.
x If bullous pemphigoid is diagnosed, it may be possible to avoid 
long-term use of systemic steroids and transition to steroid-sparing 
options (e.g., IVIG and rituximab), as an alternative approach to 
treating the irAE.
x Consult with dermatology to determine appropriateness of resuming 
pembrolizumab once symptoms improve.
G4: Blisters covering 
>30% BSA with 
associated fluid or 
electrolyte abnormalities
x Permanently discontinue pembrolizumab.
x Admit patient immediately and place under supervision of a 
dermatologist.
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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AE and Grade by 
CTCAE v5.0
Management
x Administer IV methylprednisolone (or equivalent) 1–2 mg/kg and 
when appropriate convert to oral steroids, with tapering over at least 
4 weeks.
x If bullous pemphigoid is diagnosed, it may be possible to avoid 
long-term use of systemic steroids and treat with steroid-sparing 
options as an alternative approach to treating the irAE (e.g., IVIG 
and rituximab).
SCAR
All Grades
x In cases of suspected SJS or any mucous membrane involvement 
(not including isolated stomatitis), discontinue pembrolizumab 
treatment and consult dermatology. Monitor closely for 
improvement regardless of grade.
G1 and G2: NA
x For the SCAR adverse reactions, there are no G1 or G2 categories. 
If limited BSA is involved with bullae or erosions, there should 
remain high concern that this reaction will progress to G3 or G4.
G3: Skin sloughing 
covering <10% BSA with 
mucosal involvement-
associated signs (e.g., 
erythema, purpura, 
epidermal detachment, and 
mucous membrane 
detachment)
x Hold pembrolizumab therapy and consult with dermatology.
x Admit to burn unit and/or consult wound services with attention to 
supportive care including fluid and electrolyte balance, minimizing 
insensible water losses, and preventing infection.
x Treat skin with topical emollients and other petrolatum emollients, 
oral antihistamines, and high strength topical corticosteroids. 
Dimethicone may also be offered as an alternative to petrolatum.
x Administer IV methylprednisolone (or equivalent) 0.5-1 mg/kg and 
convert to oral corticosteroids on response, wean over at least 
4 weeks.
x Given the immune mechanism of action of these medicines, use of 
immune suppression is warranted and should be offered. The usual 
prohibition of corticosteroids for SJS is not relevant here, as the 
underlying mechanism is a T-cell immune-directed toxicity. 
Adequate suppression is necessary with corticosteroids or other 
agents and may be prolonged in cases of DRESS or drug 
hypersensitivity syndrome.
x For mucous membrane involvement of SJS or TEN, appropriate 
consulting services should be offered to guide management in 
preventing sequelae from scarring (e.g., ophthalmology, 
otolaryngology, urology, or gynecology, as appropriate).
G4: Skin erythema and 
blistering/sloughing 
covering ≥10% BSA with 
associated signs (e.g., 
erythema, purpura, 
epidermal detachment, 
mucous membrane 
detachment) and/or 
x Permanently discontinue pembrolizumab.
x Admit patient immediately to a burn unit or ICU with consulted 
dermatology and wound care services. Consider further 
consultations based on management of mucosal surfaces (e.g.,
ophthalmology, urology, gynecology, otolaryngology, etc.).
x Initiate IV methylprednisolone (or equivalent) 1-2 mg/kg, tapering 
when toxicity resolves to normal.
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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AE and Grade by 
CTCAE v5.0
Management
systemic symptoms and 
concerning associated 
blood work abnormalities 
(e.g., liver function test 
elevations in the setting of 
DRESS or DIHS)
x IVIG or cyclosporine may also be considered in severe or steroid-
unresponsive cases.
x Consider pain/palliative consultation and/or admission in patients 
presenting with DRESS manifestations.
Colitis
G1: Increase of <4 stools 
per day over baseline; 
mild increase in ostomy 
output compared to 
baseline
x Continue pembrolizumab. Alternatively, pembrolizumab may be 
held temporarily and resumed if toxicity does not exceed G1 or 
resolves.
x May also include supportive care with medications such as 
loperamide if infection has been ruled out in patients with diarrhea 
only and not colitis-related symptoms as a temporary measure.
x Monitor for dehydration and recommend dietary changes.
x Patient should be closely monitored by phone or electronic medical 
system for symptoms changes by clinical providers every 3 days or 
more frequently if needed until stabilized.
x May obtain gastroenterology consult for prolonged G1 cases and 
consider endoscopy with biopsies.
G2: Increase of 4-6 stools 
per day over baseline; 
moderate increase in 
ostomy output compared 
to baseline
x Hold pembrolizumab at least until recovery to G1 – see last bullets.
x May also include supportive care with medications such as 
loperamide if infection has been ruled out in patients with diarrhea 
only and not colitis-related symptoms as a temporary measure.
x Consider consult with gastroenterology for ≥G2.
x Administer corticosteroids, unless diarrhea is transient, starting with 
initial dose of 1 mg/kg/d prednisone or equivalent until symptoms 
improve to G1, and then start taper over 4-6 weeks.
x Consider adding narrower-spectrum/more potent agents, including 
anti-TNF (infliximab) or anti-integrin (vedolizumab) antibody to 
patients whose colitis is corticosteroid-refractory (i.e., no decrease 
by one grade in 72 hours) or dependent or with high-risk 
endoscopic features on initial endoscopy exam.
x When symptoms improve to ≤G1, taper corticosteroids over 
4-6 weeks; may consider shorter tapers in patients also treated with 
biologics.
x Endoscopic evaluation with EGD/colonoscopy is highly 
recommended for cases ≥G2 to stratify patients for early treatment 
of biologics based on the endoscopic findings.
x Resuming pembrolizumab after symptoms improve to <G1 may be 
considered when steroid taper is completed, risks/benefits are 
reviewed if maintained on biologics, and/or if endoscopic and 
histologic remission are achieved. Fecal calprotectin <116 μg/g may 
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
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AE and Grade by 
CTCAE v5.0
Management
be considered as a surrogate for endoscopic and histologic 
remission.
G3: Increase of ≥7 stools 
per day over baseline; 
incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to 
baseline; limiting self-care 
ADL
x Follow G2 recommendations as listed, with the following additions 
for G3:
x Administer corticosteroids (initial dose of 1-2 mg/kg/d prednisone 
or equivalent) until symptoms improve to G1, and then start taper 
over 4-6 weeks. Consider IV methylprednisolone, especially if 
concern for concurrent upper GI inflammation.
x Consider early introduction of infliximab or vedolizumab in 
addition to steroids in patients with high-risk endoscopic features on 
initial endoscopy exam or inadequate response to steroids 
(persistent symptoms after 3 days).
x Consider hospitalization for patients with dehydration or electrolyte 
imbalance.
x Consider repeat colonoscopy in patients who are 
immunosuppression-refractory.
G4: Life-threatening 
consequences; urgent 
intervention indicated
x Follow G2-G3 recommendations as listed, with the following 
additions for G4:
x Permanently discontinue treatment.
x Should provide inpatient care.
x Administer 1-2 mg/kg/d methylprednisolone or equivalent until 
symptoms improve to G1, and then start taper over 4-6 weeks.
x Consider early biologics (infliximab or vedolizumab) if inadequate 
response to steroids after 3 days.
x Consider lower GI endoscopy if symptoms are refractory despite 
treatment or there is concern of new infections.
Hepatitis
G1: Asymptomatic (AST 
or ALT >ULN to 3.0× 
ULN and/or total bilirubin 
>ULN to 1.5× ULN)
x Continue pembrolizumab with close monitoring; consider alternate 
etiologies.
x Consider monitoring labs 1-2 times weekly.
x Manage with supportive care for symptom control.
G2: Asymptomatic (AST 
or ALT >3.0 to ≤5× ULN 
and/or total bilirubin >1.5 
to ≤3× ULN)
x Hold pembrolizumab temporarily.
x Patients should be advised to stop unnecessary medications and any 
known hepatotoxic drugs. Temporarily hold other potentially 
hepatotoxic oncologic agents.
x For G2 hepatic toxicity, may administer steroid (0.5-1 mg/kg/day 
prednisone) or equivalent if no improvement is seen after 3-5 days.
x Increase frequency of monitoring to every 3 days.
x If inadequate improvement after 3 days, consider adding MMF.
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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AE and Grade by 
CTCAE v5.0
Management
x May initiate steroid taper when symptoms improve to ≤G1 and may 
resume pembrolizumab when steroid ≤10 mg/d. Taper over at least 
1 month.
x Consider hepatology consult for G2 and above.
x May resume if recover to ≤G1 on prednisone ≤10 mg/d.
G3: AST or ALT 5-20×
ULN and/or total bilirubin 
3-10× ULN, OR 
symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis; reactivation of 
chronic hepatitis
x Follow G2 recommendations as listed, with the following additions 
for G3:
x Consider permanently discontinuing pembrolizumab if
asymptomatic; permanently discontinue if symptomatic. 
Immediately start steroid 1-2 mg/kg methylprednisolone or 
equivalents.
x If steroid refractory, consider liver biopsy to rule out NASH, tumor, 
cholestatic variants, other drug-related hepatic inflammation, 
infection, or other autoimmune entity and consider adding 
azathioprine or mycophenolate if infectious cause is ruled out.
x Labs daily or every other day; consider inpatient monitoring for 
patients with AST/ALT >8× ULN and/or elevated total bilirubin 
3× >ULN.
x If no improvement is achieved with steroid or for patients on 
pembrolizumab combined with a novel agent, with standard 
chemotherapy, or with targeted therapy, refer to hepatologist for 
further pathologic evaluation of hepatitis.
x Steroid taper can be attempted around 4-6 weeks when ≤G1, 
re-escalate if needed, optimal duration unclear.
x Consider transfer to tertiary care facility if necessary.
G4: AST or ALT >20× 
ULN and/or total bilirubin 
>10× ULN OR 
decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma)
x Follow G3 recommendations as listed, with the following additions 
for G4:
x Administer 2 mg/kg/d methylprednisolone equivalents.
Lung Toxicities
Pneumonitis
G1: Asymptomatic; 
confined to one lobe of the 
lung or <25% of lung 
parenchyma; clinical or 
diagnostic observations 
only
• Hold pembrolizumab or proceed with close monitoring.
• Monitor patients weekly with history and physical examination, 
pulse oximetry; may also offer chest imaging (CXR, CT) if 
uncertain diagnosis and/or to follow progress.
• Repeat chest imaging in 3-4 weeks or sooner if patient becomes 
symptomatic.
• In patients who have had baseline testing, may offer a repeat 
spirometry or DLCO in 3-4 weeks.
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Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
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AE and Grade by 
CTCAE v5.0
Management
• May resume pembrolizumab with radiographic evidence of 
improvement or resolution if held. If no improvement, should treat 
as G2.
G2: Symptomatic; 
Involves more than one 
lobe of the lung or 25%-
50% of lung parenchyma; 
medical intervention 
indicated; limiting 
instrumental ADL
x Hold pembrolizumab until clinical improvement to ≤G1.
x Prednisone 1-2 mg/kg/d and taper over 4-6 weeks.
x Consider bronchoscopy with BAL ± transbronchial biopsy.
x Consider empiric antibiotics if infection remains in the differential 
diagnosis after workup.
x Monitor at least once per week with history and physical 
examination, pulse oximetry, consider radiological imaging; if no 
clinical improvement after 48-72 hours of prednisone, treat as G3.
x Pulmonary and infectious disease consults if necessary.
G3: Severe symptoms; 
Hospitalization required: 
Involves all lung lobes or 
>50% of lung 
parenchyma; limiting self-
care ADL; oxygen 
indicated. 
G4: Life-threatening 
respiratory compromise; 
urgent intervention 
indicated (intubation)
x Permanently discontinue pembrolizumab.
x Empiric antibiotics may be considered.
x Methylprednisolone IV 1-2 mg/kg/d.
x If no improvement after 48 hours, may add immunosuppressive 
agent. Options include infliximab or MMF IV or IVIG or 
cyclophosphamide. Taper corticosteroids over 4-6 weeks.
x Pulmonary and infectious disease consults if necessary.
x May consider bronchoscopy with BAL ± transbronchial biopsy if 
patient can tolerate.
Endocrine Toxicities
Thyroid
Primary 
Hypothyroidism
G1: TSH >4.5 and 
<10 mIU/L and 
asymptomatic
Should continue pembrolizumab with monitoring of TSH (option for 
FT4) every 4-6 weeks as part of routine care.
G2: Moderate symptoms, 
able to perform ADL;
TSH persistently 
>10 mIU/L
x May continue or hold pembrolizumab until symptoms resolve to 
baseline.
x Consider endocrine consultation for unusual clinical presentations, 
concern for central hypothyroidism, or difficulty titrating hormone 
therapy.
x Prescribe thyroid hormone supplementation in symptomatic patients 
with any degree of TSH elevation or in asymptomatic patients with 
TSH levels that persist over 10 mIU/L (measured 4 weeks apart).
x Monitor TSH every 6-8 weeks while titrating hormone replacement 
to goal of TSH within the reference range.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
87
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
x FT4 can be used to help interpret ongoing abnormal TSH levels on
therapy, as TSH may take longer to normalize.
x Once adequately treated, repeat testing every 6-12 months or as 
indicated for a change in symptoms.
G3-4: Severe symptoms, 
medically significant or 
life-threatening 
consequences, unable to 
perform ADL
x Hold pembrolizumab until symptoms resolve to baseline with 
appropriate supplementation
x Endocrine consultation to assist with rapid hormone replacement.
x Hospital admission for developing myxedema (bradycardia, 
hypothermia, altered mental status).
x Inpatient endocrinology consultation can assist with IV 
levothyroxine dosing, steroids, and supportive care.
x If there is uncertainty about whether primary or central 
hypothyroidism is present, hydrocortisone should be given before 
thyroid hormone is initiated.
x Myxedema coma is a life-threatening emergency requiring 
admission and a high level of care.
x Thyroid supplementation and reassessment as in G2.
Thyrotoxicosis
G1: Asymptomatic or mild 
symptoms
x Can continue pembrolizumab.
x Beta-blocker (e.g., atenolol or propranolol) for symptomatic relief.
x Close monitoring of thyroid function every 2-3 weeks after 
diagnosis to catch the transition to hypothyroidism, the most 
common outcome for transient subacute thyroiditis.
x Treat transition to elevated TSH and low FT4 as for primary 
hypothyroidism.
x For persistent thyrotoxicosis (>6 weeks) consider endocrine 
consultation for additional work up.
G2: Moderate symptoms, 
able to perform ADL
x Consider holding pembrolizumab until symptoms return to baseline.
x Consider endocrine consultation.
x Beta-blocker (e.g., atenolol or propranolol) for symptomatic relief.
x Hydration and supportive care.
x For persistent thyrotoxicosis (>6 weeks) refer to endocrinology for 
additional workup and possible medical thyroid suppression.
G3-4: Severe symptoms, 
medically significant or 
life-threatening 
consequences, unable to 
perform ADL
x Hold pembrolizumab until symptoms resolve to baseline with 
appropriate therapy.
x Endocrine consultation for all patients.
x Beta-blocker (e.g., atenolol or propranolol).
x Hydration and supportive care.
x Consider hospitalizing patients in severe cases as in-patient 
endocrine consultation can guide the use of additional medical 
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		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
88
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
therapies including steroids, potassium iodide (SSKI), or 
thionamide (methimazole or propylthiouracil) and possible surgery.
Adrenal
Primary AI
G1: Asymptomatic or mild 
symptoms
x Consider holding pembrolizumab until patient is stabilized on 
replacement hormone.
x Endocrine consultation.
x Initiate replacement therapy with hydrocortisone (15-20 mg in 
divided dose).
x Titrate hydrocortisone to maximum of 30 mg daily total dose for 
residual symptoms of AI.
x Reduce maintenance dosing for symptoms of iatrogenic Cushing’s 
syndrome (e.g., bruising, thin skin, edema, weight gain, 
hypertension, and hyperglycemia).
x Most primary AI will also require fludrocortisone (starting dose 
0.5-0.1 mg/d). Adjust based on volume status, sodium level, and 
renin response (target upper half of the reference range).
G2: Moderate symptoms, 
able to perform ADL
x Consider holding pembrolizumab until patient is stabilized on 
replacement hormone.
x Endocrine consultation.
x See in clinic to assess need for hydration, supportive care, and 
hospitalization.
x Initiate outpatient corticosteroid treatment at 2-3 times maintenance 
(e.g., hydrocortisone 30-50 mg total dose or prednisone 20 mg 
daily) to manage acute symptoms.
x Initiate fludrocortisone (0.5-0.1 mg/d).
x Decrease stress dose corticosteroids down to maintenance doses 
after 2 days.
x Maintenance therapy as in G1.
G3-4: Severe symptoms, 
medically significant or 
life-threatening 
consequences, unable to 
perform ADL
x Hold pembrolizumab until patient is stabilized on replacement 
hormone.
x Endocrine consultation.
x Inpatient management may be needed to provide:
x Normal saline (at least 2 L).
x IV Stress dose steroids: Hydrocortisone 50-100 mg Q6-8 hours 
initial dosing.
x Taper stress dose corticosteroids down to oral maintenance doses 
over 5-7 days.
x Maintenance therapy as in G1.
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		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
89
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
Pituitary
Hypophysitis
G1: Asymptomatic or mild 
symptoms
x Consider holding pembrolizumab until patient is stabilized on 
replacement hormones.
x Endocrine consultation.
x Corticosteroid replacement for AI with preference for 
hydrocortisone (15-20 mg in divided doses).
x Initiate other hormone replacement only after any needed adrenal 
replacement to avoid precipitating adrenal crisis.
x Thyroid hormone replacement if needed using dosing as above for 
primary hypothyroidism, with a goal FT4 in the upper half of the 
reference range (TSH is not accurate in central hypothyroidism).
x Testosterone or estrogen therapy if needed in those without 
contraindications (e.g., prostate cancer, breast cancer, or history of 
DVT).
x Recommend education on stress dosing, emergency injectable, and 
a medical alert or necklace accessory or system
G2: Moderate symptoms, 
able to perform ADL
x Consider holding pembrolizumab until patient is stabilized on 
replacement hormones
x Endocrine consultation.
x Clinic evaluation to assess need for steroids and volume repletion.
x Consider oral pulse dose therapy in patients with MRI findings of 
swelling or threatened optic chiasm compression (prednisone 
1 mg/kg/d [or equivalent]). Taper over 1-2 weeks and transition to 
physiologic maintenance therapy once down to 5 mg prednisone 
equivalent.
x Hormonal supplementation as in G1.
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		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
90
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G3-4: Severe symptoms, 
medically significant or 
life-threatening 
consequences, unable to 
perform ADL
x Hold pembrolizumab until patient is stabilized on replacement 
hormones.
x Endocrine consultation.
x Hospitalize or make an ED referral for:
x Normal saline (at least 2 L) or monitored free water replacement 
if DI.
x IV Stress dose steroids: Hydrocortisone 50-100 mg Q6-8 hours 
initial dosing.
x Oral pulse dose therapy with prednisone 1-2 mg/kg daily (or 
equivalent) tapered over at least 1-2 weeks to physiologic 
maintenance in patients with significant swelling on MRI, optic 
chiasm compression, severe headache, or visual changes.
x Taper stress dose corticosteroids down to oral maintenance doses 
over 5-7 days.
x Maintenance therapy as in G1.
Diabetes
G1: Asymptomatic or mild 
symptoms; T2DM with 
fasting glucose value 
> ULN to 160 mg/dL 
(> ULN to 8.9 mmol/L).
No evidence of CIADM 
such as ketoacidosis or 
laboratory evidence of 
pancreatic autoimmunity
x Can continue pembrolizumab with close clinical follow-up and
laboratory evaluation.
x Refer to PCP for additional management or:
x May initiate oral therapy for those with new onset T2DM.
x Intensify medical therapy for those with worsening T2DM.
G2: Moderate symptoms, 
able to perform ADL; 
T2DM with fasting 
glucose value >160 to 
250 mg/dL (>8.9 to 
13.9 mmol/L). No 
ketoacidosis or metabolic 
derangements but other 
evidence of CIADM at 
any glucose level.
x May hold pembrolizumab until glucose control is obtained.
x Urgent endocrine consultation for any patient with new-onset 
CIADM.
x Initiate insulin for CIADM (or as default therapy if there is any 
question about the diagnosis).
x Referral to ED or hospital admission if unable to initiate therapy, 
urgent outpatient specialist evaluation is not available, developing 
ketoacidosis or other concern for CIADM.
G3-4: Severe symptoms, 
medically significant or 
life-threatening 
consequences, unable to 
perform ADL; 
G3: >250-500 mg/dL 
(>13.9-27.8 mmol/L); 
G4: >500 mg/dL 
(>27.8 mmol/L). 
x Hold pembrolizumab until glucose control is obtained with 
reduction of toxicity to ≤G1.
x Admit for inpatient management of DKA, volume and electrolyte 
resuscitation, and insulin initiation.
x Endocrine consultation for all patients.
x Insulin therapy appropriate for all patients.
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		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
91
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
Ketoacidosis or other 
metabolic abnormality.
Musculoskeletal 
Toxicities
Inflammatory Arthritis
G1: Mild pain with 
inflammation, erythema, 
or joint swelling
x Continue pembrolizumab.
x Initiate analgesia with acetaminophen and/or NSAIDs.
G2: Moderate pain 
associated with signs of 
inflammation, erythema, 
or joint swelling; limiting 
instrumental ADL
x Consider holding pembrolizumab.
x Escalate analgesia and consider higher doses of NSAIDs as needed.
x If inadequately controlled, initiate prednisone 10-20 mg/d or 
equivalent.
x If improvement, slow taper according to response during the next 
4-6 weeks. If no improvement after initial 4 weeks, treat as G3.
x If unable to lower corticosteroid dose to below 10 mg/d after 
6-8 weeks, consider DMARD.
x Consider intra-articular steroid injections for large joints.
x Referral to rheumatology.
G3-4: Severe pain 
associated with signs of 
inflammation, erythema, 
or joint swelling; 
irreversible joint damage; 
disabling; limiting 
self-care ADL
x Hold pembrolizumab temporarily and may resume in consultation 
with rheumatology, if recover to ≤G1.
x Initiate oral prednisone 0.5-1 mg/kg.
x If failure of improvement after 2 weeks or worsening in meantime, 
consider synthetic or biologic DMARD.
x Synthetic: methotrexate, leflunomide, hydroxychloroquine, 
sulfasalazine alone or in combination.
x Biologic: Consider anti-cytokine therapy such as TNFα or IL-6
antagonists. Note: As a caution, IL-6 inhibition can cause intestinal 
perforation. While this is extremely rare, it should not be used in 
patients with concomitant immune-related colitis.
x Referral to rheumatology.
Myositis
G1: Mild weakness with 
or without pain
x Continue pembrolizumab.
x If CK and/or aldolase are elevated and patient has muscle weakness 
may offer oral corticosteroids, starting prednisone at 0.5 mg/kg/d. 
Offer analgesia with acetaminophen or NSAIDs for myalgia if there 
are no contraindications.
x Consider holding statins.
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		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
92
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G2: Moderate weakness 
with or without pain 
limiting age-appropriate 
instrumental ADL
x Hold pembrolizumab temporarily and may resume upon symptom 
control, if CK is normal and prednisone dose <10 mg; if worsens, 
treat as per G3.
x NSAIDs as needed.
x Referral to rheumatologist or neurologist.
x If CK is elevated (×3 ULN or more), initiate prednisone or 
equivalent at 0.5-1 mg/kg/d
x May require permanent discontinuation of pembrolizumab in cases 
with G2 symptoms if patient had other objective findings of severe 
muscle involvement such as very elevated enzymes, or extensive 
involvement as determined by EMG, MRI, or histology
x Pembrolizumab should not be restarted until CK is normal and 
clinical manifestations of myositis are resolved.
G3-4: Severe weakness 
with or without pain; 
limiting self-care ADL
x Hold pembrolizumab.
x Consider hospitalization for patients with severe weakness severely 
limiting mobility, respiratory, dysphagia, or rhabdomyolysis.
x Urgent referral to rheumatologist and/or neurologist.
x Initiate prednisone 1 mg/kg/d or equivalent.
x For patients with severe compromise, start 1-2 mg/kg of 
methylprednisolone IV or higher dose bolus.
x Consider plasmapheresis in patients with acute/severe disease as 
guided by rheumatology/neurology.
x Consider IVIG therapy, noting onset of action is slower. Note: 
Plasmapheresis immediately after IVIG will remove 
immunoglobulin.
x Consider other immunosuppressant therapy including biologics 
(e.g., rituximab), TNFα, or IL-6 antagonists if symptoms worsen or 
if no improvement after 2 weeks. Other synthetic 
immunosuppressants such as methotrexate, azathioprine, or MMF
could be considered for maintenance, or if symptoms and CK levels 
do not resolve entirely after 4 weeks. Rituximab is used in primary 
myositis.
x Consider permanent discontinuation of pembrolizumab.
Polymyalgia-Like 
Syndrome
G1: Mild stiffness and 
pain
x Continue pembrolizumab.
x Initiate analgesia with acetaminophen and/or NSAIDs if there are 
no contraindications.
G2: Moderate stiffness and 
pain; limiting age 
x Consider holding pembrolizumab and resuming upon symptom 
control, prednisone <10 mg; if worsens, treat as per G3.
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		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
93
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
appropriate instrumental 
ADL
x Initiate prednisone 20 mg/d or equivalent. If symptoms improve, 
start to taper dose after 3-4 weeks.
x If no improvement or need for higher dosages after 4 weeks, 
escalate to G3.
x Consider referral to rheumatology.
G3-4: Severe stiffness and 
pain; limiting self-care 
ADL
x Hold pembrolizumab and may resume, in consultation with 
rheumatology, if recover to ≤G2. However, note that cases of 
toxicity returning upon rechallenge have been reported.
x Referral to rheumatology.
x Should initiate prednisone 40 mg/d or equivalent. If no 
improvement or need for higher dosages for prolonged time, may 
offer a steroid sparing agent such as synthetic drugs (e.g.,
methotrexate) or biologic agents (e.g., IL-6 antagonists). Note: As 
caution, IL-6 inhibition can cause intestinal perforation. While this 
is extremely rare, it should not be used in patients with immune-
related colitis.
x Consider admission of patients with severe symptoms.
Renal Toxicities
Nephritis or Acute 
Kidney Injury
G1: Creatinine level 
increase of >0.3 mg/dL; 
creatinine 1.5-2.0× above 
baseline
Consider temporarily holding pembrolizumab and/or other potential 
contributing agents in combination regimens, pending consideration 
of potential alternative etiologies (recent IV contrast, medications, 
fluid status, UTI) and baseline renal function. A change that is still 
<1.5 ULN could be meaningful.
G2: Creatinine 2-3× above 
baseline
x Hold pembrolizumab temporarily.
x Consult nephrology.
x Evaluate for other causes (recent IV contrast, medications, fluid 
status, etc.) If other etiologies are ruled out, administer 
0.5-1 mg/kg/d prednisone equivalents.
x If worsening or no improvement after 1 week, increase to 
1-2 mg/kg/d prednisone equivalents and permanently discontinue 
pembrolizumab.
x If improved to ≤G1, taper steroids over at least 4 weeks.
x If no recurrence of CRI, discuss resumption of pembrolizumab with 
patient after taking into account the risks and benefits. Resumption 
of pembrolizumab can be considered once steroids have been 
successfully tapered to ≤10 mg/d or discontinued.
G3: Creatinine >3× 
baseline or >4.0 mg/dL; 
hospitalization indicated
x Permanently discontinue pembrolizumab if it is directly implicated 
in renal toxicity.
x Consult nephrology.
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		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
94
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G4: Life-threatening 
consequences; dialysis 
indicated; creatinine 6× 
above baseline
x Evaluate for other causes (recent IV contrast, medications, fluid 
status, UTI, etc.).
x Administer corticosteroids (initial dose of 1-2 mg/kg/d prednisone 
or equivalent).
Nephritis or Acute 
Kidney Injury –
Follow-up
G1: Creatinine level 
increase of >0.3 mg/dL; 
creatinine 1.5-2.0× above 
baseline
x If improved to baseline:
x Resume routine creatinine monitoring.
G2: Creatinine 2-3× above 
baseline
x If improved to G1:
x Taper corticosteroids over at least 4 weeks before resuming 
treatment with routine creatinine monitoring.
x If elevations persist >7 days or worsen and no other cause found, 
treat as G3.
G3: Creatinine >3× 
baseline or >4.0 mg/dL; 
hospitalization indicated
x If improved to G1:
x Taper corticosteroids over at least 4 weeks.
x If elevations persist >3-5 days or worsen, consider additional 
immunosuppression (e.g., infliximab, azathioprine, 
cyclophosphamide [monthly], cyclosporine, mycophenolate).
G4: Life-threatening 
consequences; dialysis 
indicated; creatinine 6× 
above baseline
x If improved to G1:
x Taper corticosteroids over at least 4 weeks.
x If elevations persist >2-3 days or worsen, consider additional 
immunosuppression (e.g., infliximab, azathioprine, 
cyclophosphamide [monthly], cyclosporine, mycophenolate).

		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
95
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
Nervous System 
Toxicities
Myasthenia Gravis
No G1
NA
G2: Some symptoms 
interfering with ADLs. 
MGFA severity class I 
(ocular symptoms and 
findings only) and MGFA 
severity class II (mild 
generalized weakness).
x Hold pembrolizumab and may resume in G2 patients (MGFA 1 and 
2) only if symptoms resolve and steroid taper completed.
x Neurology consultation.
x Strongly consider in-patient care as patients can deteriorate quickly.
x Pyridostigmine starting at 30 mg oral three times a day and 
gradually increase to maximum of 120 mg oral four times a day as 
tolerated and based on symptoms and wean based on improvement. 
These procedures should be done in close collaboration with the 
neurologist.
x Administer corticosteroids (prednisone 0.5 mg/kg orally daily). 
Wean based on symptom improvement.
G3-4: Limiting self-care 
and aids warranted, 
weakness limiting 
walking, ANY dysphagia, 
facial weakness, 
respiratory muscle 
weakness, or rapidly 
progressive symptoms or 
MGFA severity class III-V
(moderate to severe 
generalized weakness to 
myasthenic crisis)
x Follow G2 recommendations as listed, with the following additions 
for G3-4:
x Permanently discontinue pembrolizumab.
x Admit patient, may need ICU-level monitoring.
x Continue steroids, taper should begin 3-4 weeks after initiation then 
wean based on symptom improvement.
x Initiate IVIG 2 g/kg IV over 5 days (0.4 g/kg/d) or plasmapheresis × 
5 days.
x Consider adding rituximab if refractory to IVIG or plasmapheresis.
x Frequent pulmonary function assessment.
x Daily neurologic review.
GBS
No G1
NA
G2: Moderate: some 
interference with ADLs, 
symptoms concerning to 
patient. 
G3-4: Severe: limiting 
self-care and aids 
warranted, weakness 
limiting walking, ANY 
dysphagia, facial 
weakness, respiratory 
muscle weakness, or 
x Discontinue pembrolizumab.
x Neurology consultation.
x Admission to inpatient unit with capability of rapid transfer to 
ICU-level monitoring.
x Start IVIG (0.4 g/kg/d for 5 days for a total dose of 2 g/kg) or 
plasmapheresis. Note: plasmapheresis immediately after IVIG will 
remove immunoglobulin.
x Corticosteroids are usually not recommended for idiopathic GBS;
however, in pembrolizumab-related forms, a trial is reasonable 
(methylprednisolone 2-4 mg/kg/d), followed by slow steroid taper. 
Pulse steroid dosing (methylprednisolone 1 g daily for 5 days) may 

		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
96
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
rapidly progressive 
symptoms.
also be considered for G3-4 along with IVIG or plasmapheresis. 
After pulse steroids, taper steroids over 4-6 weeks.
x Frequent neuro checks and pulmonary function monitoring.
x Monitor for concurrent autonomic dysfunction.
x Non-opioid management of neuropathic pain, for example, 
pregabalin, gabapentin, or duloxetine.
x Treatment of constipation/ileus.
Peripheral Neuropathy
G1: Mild: no interference 
with function and 
symptoms not concerning 
to patient. Note: any 
cranial nerve problem 
should be managed as 
moderate
Low threshold to hold pembrolizumab and monitor symptoms for a 
week. If to continue, monitor very closely for any symptom 
progression.
G2: Moderate: some 
interference with ADLs, 
symptoms concerning to 
patient (i.e., pain but no 
weakness or gait 
limitation).
x Hold pembrolizumab and resume once return to ≤G1.
x Initial observation OR initiate prednisone 0.5-1 mg/kg/d (if 
progressing from mild).
x Gabapentin, pregabalin, or duloxetine for pain.
G3-4: Severe: limiting 
self-care and aids 
warranted, weakness 
limiting walking or 
respiratory problems (i.e.,
leg weakness, foot drop, 
rapidly ascending sensory 
changes). Severe may be 
GBS and should be 
managed as such.
x Permanently discontinue pembrolizumab.
x Admit patient.
x Neurology consultation.
x Initiate IV methylprednisolone 2-4 mg/kg/d and proceed as per 
GBS management.
Autonomic Neuropathy
G1: Mild: no interference 
with function and 
symptoms not concerning 
to patient.
Low threshold to hold pembrolizumab and monitor symptoms for a 
week. If to continue, monitor very closely for any symptom 
progression.
G2: Moderate: some 
interference with ADLs, 
symptoms concerning to 
patient.
x Hold pembrolizumab and resume once return to ≤G1 and off 
prednisone if used.
x Initial observation OR initiate prednisone 0.5-1 mg/kg/d (if 
progressing from mild).
x Neurology consultation.

		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
97
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G3-4: Severe: limiting 
self-care and aids 
warranted.
x Permanently discontinue pembrolizumab.
x Admit patient.
x Initiate methylprednisolone 1 g daily × 3 days followed by oral 
steroid taper.
x Neurology consultation.
Aseptic Meningitis
G1: Mild: no interference 
with function and 
symptoms not concerning 
to patient. Note: any 
cranial nerve problem 
should be managed as 
moderate.
G2: Moderate: some 
interference with ADLs, 
symptoms concerning to 
patient (i.e., pain but no 
weakness or gait 
limitation).
G3-4: Severe: limiting 
self-care and aids 
warranted
x Hold pembrolizumab and discuss resumption with patient only after 
taking into account the risks and benefits.
x Consider neurology consult.
x Consider empiric antiviral (IV acyclovir) and antibacterial therapy 
until CSF results.
x Once bacterial and viral infection negative, may closely monitor off 
corticosteroids or consider oral prednisone 0.5-1 mg/kg/d or IV 
methylprednisolone 1 mg/kg/d if moderate or severe symptoms.
x Steroids can be tapered after 2-4 weeks, monitoring for symptom 
recurrence.
x Consider hospitalization for G3-4.
Encephalitis
G1: Mild: No interference 
with function and 
symptoms not concerning 
to patient. Note: any 
cranial nerve problem 
should be managed as 
moderate.
G2: Moderate: Some 
interference with ADLs, 
symptoms concerning to 
patient (i.e., pain but no 
weakness or gait 
limitation).
G3-4: Severe: Limiting 
self-care and aids 
warranted.
x Hold pembrolizumab and discuss resumption with patient only after 
taking into account the risks and benefits.
x As above for aseptic meningitis suggest concurrent IV acyclovir 
until PCR results obtained and negative.
x Trial of methylprednisolone 1-2 mg/kg/d.
x Neurology consultation.
x If severe or progressing symptoms or oligoclonal bands present, 
consider pulse corticosteroids (methylprednisolone 1 g IV daily for 
3-5 days) plus IVIG 2 g/kg over 5 days (0.4 g/kg/d) or 
plasmapheresis.
x Taper steroids following acute management over at least 4-6 weeks.
x If positive for autoimmune encephalopathy or paraneoplastic 
antibody or limited or no improvement, consider rituximab in 
consultation.
x Admit patient for G3-4.

		

Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
98
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
Demyelinating Diseases, 
Including Multiple 
Sclerosis, Transverse 
Myelitis, ADEM, ON,
and NMO
G1: Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only
x Intervention not indicated.
x Continue immunotherapy unless symptoms worsen or do not 
improve.
G2: Moderate symptoms; 
minimal, limiting age-
appropriate instrumental 
ADL
x Stop pembrolizumab.
x Neurology consultation.
x Start prednisone 1 mg/kg daily and taper over 1 month.
x Rule out infection.
G3: Severe or medically 
significant symptoms but 
not immediately 
life-threatening; limiting 
self-care ADL
x Permanently discontinue pembrolizumab.
x Neurology consultation.
x Non-opioid management of neuropathic pain, for example, 
pregabalin, gabapentin, or duloxetine.
x Admit patient for methylprednisolone pulse dosing 1 g/d and 
consider IVIGa or plasmapheresis if no improvement or symptoms 
worsen after 3 days.
G4: Life-threatening 
consequences
x Permanently discontinue pembrolizumab.
x Neurology consultation.
x ICU level inpatient care.
x Start methylprednisolone pulse dosing 1 g/d and consider IVIG or 
plasmapheresis if no improvement or symptoms worsen after 
3 days.
Hematologic Toxicities
Hemolytic Anemia
G1: Hgb < LLN to 
10.0 g/dL; < LLN to 
6.2 mmol/L; < LLN to 
100 g/L
Continue pembrolizumab with close clinical follow-up and laboratory 
evaluation.
G2: Hgb <10.0 to 
8.0 g/dL; <6.2 to 
4.9 mmol/L; <100 to 
80 g/L
x Hold pembrolizumab and strongly consider permanent 
discontinuation.
x Administer 0.5-1 mg/kg/d prednisone equivalents.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
99
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G3: Hgb <8.0 g/dL; 
<4.9 mmol/L; <80 g/L; 
transfusion indicated
x Permanently discontinue pembrolizumab.
x Should use clinical judgment and consider admitting the patient.
x Hematology consult.
x Prednisone 1-2 mg/kg/d (oral or IV equivalent depending on 
symptoms/speed of development).
x Consider RBC transfusion per existing guidelines. Do not transfuse 
more than the minimum number of RBC units necessary to relieve 
symptoms of anemia or to return a patient to a safe Hgb range 
(7-8 g/dL in stable, noncardiac inpatients).
x Should offer patients supplementation with folic acid 1 mg daily.
G4: Life-threatening 
consequences; urgent 
intervention indicated
x Permanently discontinue pembrolizumab.
x Admit patient.
x Hematology consult.
x IV prednisone corticosteroids 1-2 mg/kg/d.
x If no improvement on or if worsening on corticosteroids or severe 
symptoms on presentation, initiate other immunosuppressive drugs, 
such as rituximab, IVIG, cyclosporine, infliximab, MMF, or ATG.
x RBC transfusion per existing guidelines. Discuss with blood bank 
team prior to transfusions that a patient with possible 
pembrolizumab SAE is in the hospital.
Acquired TTP
G1: Evidence of RBC 
destruction 
(schistocytosis) without 
anemia, renal 
insufficiency, or 
thrombocytopenia 
clinically
G2: Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequence with 
G2 anemia and 
thrombocytopenia
x Hold pembrolizumab and discuss resumption with patient only after 
taking into account the risks and benefits, noting that there are
currently no data to recommend restarting pembrolizumab therapy.
x Administer 0.5-1 mg/kg/d prednisone.
G3: Laboratory findings 
with clinical consequences 
(G3 thrombocytopenia, 
anemia, renal insufficiency 
>2)
G4: Life-threatening 
consequences (e.g., CNS 
hemorrhage or 
x Hold pembrolizumab and discuss resumption with patient only after 
taking into account the risks and benefits, noting that there are
currently no data to recommend restarting pembrolizumab therapy.
x In conjunction with hematology, initiate therapeutic PEX according 
to existing guidelines with further PEX dependent on clinical 
progress.
x Administer methylprednisolone 1 g IV daily for 3 days, with the 
first dose typically administered immediately after the first PEX. 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
100
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
thrombosis/embolism or 
renal failure)
For patient who has an initial platelet count response, discontinue 
PEX.
x May offer rituximab.
x Consider caplacizumab if ADAMTS13 activity level is <10 IU/dL 
or <10% of normal, with an inhibitor or elevated anti-ADAMTS13 
IgG.
x If no exacerbation within 3-5 days after stopping PEX, taper 
steroids over 2-3 weeks, complete course of rituximab (if receiving) 
and discontinue caplacizumab (if receiving).
HUS
G1-2: Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences of 
anemia, thrombocytopenia 
G2
x Continue pembrolizumab with close clinical follow-up and 
laboratory evaluation.
x Supportive care.
G3: Laboratory findings 
with clinical consequences 
(e.g., renal insufficiency 
and petechiae)
G4: Life-threatening 
consequences, (e.g., CNS 
thrombosis or embolism or 
renal failure)
x Permanently discontinue pembrolizumab.
x Hematology consult.
x Begin therapy with eculizumab (anti-C5 antibody) 900 mg weekly 
× 4 doses, 1,200 mg week 5, then 1,200 mg every 2 weeks.
x Red blood transfusion according to existing guidelines.
Aplastic Anemia
G1: Mild: >0.5 PMNs × 
109/L hypocellular 
marrow, with marrow 
cellularity <25%, 
Peripheral platelet count 
>20,000, reticulocyte 
count >20,000
x Hold pembrolizumab and provide growth factor support, close 
clinical follow-up, and laboratory evaluation.
x Supportive transfusions as per local guidelines.
G2: Moderate: 
Hypocellular marrow 
<25% and two of the 
following ANC <500,
peripheral platelet <20,000 
and reticulocyte <20,000
x Hold pembrolizumab and provide growth factor support and close 
clinical laboratory evaluations daily.
x Hematology consult.
x Administer horse ATG plus cyclosporine.
x Supportive transfusions as per local guidelines. All blood products 
should be irradiated and filtered.
x HLA typing and evaluation for bone marrow transplantation if 
patient is a candidate.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
101
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G3-4: Severe: ANC <200, 
platelet count <20,000, 
reticulocyte count of 
<20,000, plus hypocellular 
marrow <25%.
x As per G2
x Hold pembrolizumab and monitor weekly for improvement. If not 
resolved, discontinue treatment until AE has reverted to G1.
x If no response, repeat immunosuppression with rabbit ATG plus 
cyclosporine and cyclophosphamide.
x For refractory patients, consider eltrombopag plus supportive care.
Lymphopenia
All Grades
x No specific action is required for lymphopenia G1-G3 and 
pembrolizumab therapy should be continued.
x For G4 (<250 PB lymphocyte count), continue pembrolizumab and
initiate Mycobacterium avium complex prophylaxis and 
Pneumocystis jirovecii prophylaxis, CMV screening. HIV and 
hepatitis screening, if not already done.
x May consider EBV testing if evidence of lymphadenopathy or 
hepatitis, fevers, and hemolysis occur c/w lymphoproliferative 
disease occurs.
ITP
G1: Platelet count 75 to 
<100/μL
x Continue pembrolizumab with close clinical follow-up and 
laboratory evaluation.
G2: Platelet count 50 to 
<75/μL
x Hold pembrolizumab but monitor for improvement. If not resolved, 
interrupt treatment until AE has reverted to G1.
x Administer prednisone 1 mg/kg per day (dosage range: 0.5–2 mg/kg 
per day) orally for 4 weeks followed by taper over 4-6 weeks to the 
lowest effective dose.
x IVIG may be used in conjunction with corticosteroids if a more 
rapid increase in platelet count is required.
G3: Platelet count 25 to 
<50/μL
G4: Platelet count <25/μL
x As per G2.
x Hematology consult.
x Consider as alternative to prednisone, dexamethasone 40 mg daily 
for 4 days.
x If IVIG is used, the dose should initially be 1 g/kg as a one-time 
dose.
x If previous treatment with corticosteroids and/or IVIG has been 
unsuccessful, subsequent treatment may include rituximab, 
thrombopoietin receptor agonists, or more potent 
immunosuppression.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
102
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
Acquired Hemophilia A
G1: Mild: 5%-40% of 
normal factor activity in 
blood; 0.05-0.4 IU/mL of 
whole blood
x Hold pembrolizumab and discuss resumption with patient only after 
taking into account the risks and benefits.
x Administer 0.5-1 mg/kg/d prednisone.
x Transfusion support as required.
x Treatment of bleeding disorders with hematology consult.
G2: Moderate: 1%-5% of 
normal factor activity in 
blood; 0.01-0.05 IU/mL of 
whole blood
x Hold pembrolizumab and discuss resumption with patient only after 
taking into account the risks and benefits.
x Administration of factor replacement (choice based on BU of titer).
x Administer 1 mg/kg/d prednisone ± rituximab (dose 375 mg/m2
weekly × 4 weeks) and/or cyclophosphamide (dose 1-2 mg/kg/d). 
Choice of rituximab versus cyclophosphamide is patient specific 
and should be done with assistance of hematology consult. 
Prednisone, rituximab, and cyclophosphamide should be given for 
at least 5 weeks.
x Factors should be provided to increase level during bleeding 
episodes, with choice of factor based on presence or absence of 
inhibitor.
x Transfusion support as required for bleeding.
G3-4: Severe: <1% of 
normal factor activity in 
blood; <0.01 IU/mL of 
whole blood
x Permanently discontinue pembrolizumab.
x Admit patient.
x Administration of factor replacement, choice based on BU level of 
inhibitor.
x Bypassing agents may be used (Factor VII FEIBA). Caution should 
be taken in elderly patients and those with CAD.
x Prednisone corticosteroids 1-2 mg/kg/d (oral or IV depending on 
symptoms) ± rituximab (dose 375 mg/m2 weekly × 4 weeks) and/or 
cyclophosphamide (dose 1-2 mg/kg/d).
x Transfusion support as required for bleeding.
x If worsening or no improvement add cyclosporine or 
immunosuppression or immunoadsorption.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
103
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
Cardiovascular 
Toxicities
Myocarditis, 
Pericarditis, 
Arrhythmias, Impaired 
Ventricular Function 
with Heart Failure, and 
Vasculitis
G1: Abnormal cardiac 
biomarker testing without 
symptoms and with no 
ECG abnormalities
G2: Abnormal cardiac 
biomarker testing with 
mild symptoms or new 
ECG abnormalities 
without conduction delay
G3: Abnormal cardiac 
biomarker testing with 
either moderate symptoms 
or new conduction delay
G4: Moderate to severe 
decompensation, IV 
medication or intervention 
required, life-threatening 
conditions
x All grades warrant workup and intervention given the potential for 
cardiac compromise.
x Hold pembrolizumab for G1 elevated troponin M and recheck 
troponin 6 hours later. May consider resuming once normalized or 
if believed not to be related to pembrolizumab.
x Hold pembrolizumab and discontinue for ≥G2.
x For patients with ≥G2, early (i.e., within 24 hours) initiation of 
high-dose corticosteroids (1-2 mg/kg/d of prednisone, oral or IV 
depending on symptoms) should be considered as it is likely to be
beneficial without adverse effects.
x Admit patient, cardiology consultation.
x Management of cardiac symptoms according to ACC/AHA 
guidelines and with guidance from cardiology.
x Immediate transfer to a coronary care unit should be considered for 
patients with elevated troponin or conduction abnormalities.
x For new conduction delay, consider a pacemaker.
x In patients without an immediate response to high-dose 
corticosteroids, consider early institution of cardiac transplant 
rejection doses of corticosteroids (methylprednisolone 1 g every 
day) and the addition of either mycophenolate, infliximab, or 
anti-thymocyte globulin. Consider abatacept (costimulatory 
molecule blockade) or alemtuzumab (CD52 blockade) as additional 
immunosuppression in life-threatening cases.
Venous 
Thromboembolism
G1: Venous thrombosis 
(e.g., superficial 
thrombosis)
x Continue pembrolizumab.
x Warm compress.
x Clinical surveillance.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
104
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G2: Venous thrombosis 
(e.g., uncomplicated 
DVT), medical 
intervention indicated
x Continue pembrolizumab.
x Management according to CHEST, ACC, and/or AHA guidelines 
and consider consult from cardiology or other relevant specialties.
x LMWH, VKA, dabigatran, rivaroxaban, apixaban, or edoxaban for 
initial anticoagulation treatment. For long-term anticoagulation, 
LMWH, edoxaban, rivaroxaban, or apixaban for at least 6 months 
are preferred over VKAs because of improved efficacy.
x IV heparin is an acceptable alternative for initial use and oral 
anticoagulants are acceptable for the long term.
G3: Venous thrombosis 
(e.g., uncomplicated 
pulmonary embolism), 
urgent medical 
intervention indicated
x Hold pembrolizumab and may reintroduce after risks/benefits are 
considered.
x Follow G2 anticoagulation recommendations.
G4: Life-threatening 
consequences; 
hemodynamic or 
neurologic instability; 
organ damage; loss of 
extremity(ies)
x Hold pembrolizumab and may reintroduce after risks/benefits are 
considered.
x Admit patient and management according to CHEST, ACC, and/or 
AHA guidelines and with guidance from cardiology.
x Respiratory and hemodynamic support.
x Follow G2 anticoagulation recommendations with further clinical 
management as indicated based on symptoms.
Ocular Toxicities
Uveitis or Iritis
G1: Anterior uveitis with 
trace cells
x Continue pembrolizumab.
x Prompt referral to ophthalmology (usually within 1 week).
x Artificial tears.
G2: Anterior uveitis with 
1+ or 2+ cells
x Hold pembrolizumab temporarily until after ophthalmology consult.
x Urgent ophthalmology referral.
x Topical corticosteroids (e.g., 1% prednisolone acetate suspension), 
cycloplegic agents (e.g., atropine), systemic corticosteroids.
x May resume pembrolizumab treatment once off systemic steroids if 
patient has only ocular irAE, once corticosteroids are reduced to 
≤10 mg prednisone equivalent. Continued topical/ocular steroids are 
permitted when resuming therapy to manage and minimize local 
toxicity.
x Retreat after return to ≤G1.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
105
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
G3: Anterior uveitis with 
3+ or greater cells; 
intermediate posterior or 
panuveitis
x Permanently discontinue pembrolizumab.
x Urgent ophthalmology referral.
x Systemic corticosteroids and intravitreal or periocular or topical 
corticosteroids.
x Methotrexate may be used in patients who respond poorly to 
systemic corticosteroids or those with severe sight- threatening 
inflammation.
G4: Best corrected visual 
acuity of 20/200 or worse 
in the affected eye
x Permanently discontinue pembrolizumab.
x Emergent ophthalmology referral.
x Systemic corticosteroids - prednisone 1-2 mg/kg/d or 
methylprednisolone 0.8-1.6 mg/kg/d and intravitreal or periocular 
or topical corticosteroids per ophthalmologist opinion.
Episcleritis
G1: Asymptomatic
x Continue pembrolizumab.
x Prompt ophthalmology referral (usually within 1 week).
x Artificial tears.
G2: Vision 20/40 or better
x Hold pembrolizumab temporarily until after ophthalmology consult.
x Urgent ophthalmology referral.
x Topical corticosteroids (e.g., 1% prednisolone acetate suspension), 
cycloplegic agents (e.g., atropine), systemic corticosteroids.
G3: Symptomatic and 
vision worse than 20/40
x Permanently discontinue pembrolizumab.
x Urgent ophthalmology referral.
x Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents.
G4: 20/200 or worse
x Permanently discontinue pembrolizumab.
x Emergent ophthalmology referral.
x Systemic corticosteroids and topical corticosteroids with 
cycloplegic agents.
Systemic Toxicities
IRRs
G1: Mild transient 
reaction; infusion 
interruption not indicated; 
intervention not indicated
x Continue pembrolizumab.
x May consider premedication with acetaminophen and an 
antihistamine for subsequent infusions.
G2: Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment; 
x Consider holding pembrolizumab temporarily and/or reducing the 
rate of infusion to 50% (or per institutional guidelines).
x Offer symptomatic treatment with antihistamines, NSAIDs, opioids, 
and IV fluids as clinically appropriate.
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
106
CONFIDENTIAL
AE and Grade by 
CTCAE v5.0
Management
prophylactic medication 
indicated for ≤24 hours
x Offer prophylactic acetaminophen and an antihistamine per
institution guidelines for subsequent infusions.
G3: Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae
x Hold pembrolizumab temporarily and consider resuming, at an 
infusion rate of 50% (or per institutional guidelines), once return to 
≤G1.
x Offer symptomatic treatment with antihistamines, NSAIDs, opioids, 
and IV fluids as clinically appropriate.
x Consider antihistamines and corticosteroid medications 
intravenously.
x Hospitalization for other clinical sequelae.
G4: Life-threatening 
consequences; urgent 
intervention indicated
x Permanently discontinue pembrolizumab.
x ICU level inpatient care.
a
IVIG 2 g/kg, administered in divided doses per package insert.
Abbreviations: ACC = American College of Cardiology; ADEM = acute disseminated encephalomyelitis;
ADL(s) = activity(ies) of daily living; AE = adverse event; AHA = American Heart Association; AI = adrenal 
insufficiency; ALT = alanine aminotransferase; ANC = absolute neutrophil count; ASCO = American Society 
of Clinical Oncology; AST = aspartate aminotransferase; ATG = antithymocyte globulin;
BAL = bronchoalveolar lavage; BSA = body surface area; BU = Bethesda units; c/w = coupled with;
CAD = coronary artery disease; CD52 = cluster of differentiation 52; CHEST = American College of Chest 
Physicians; CIADM = checkpoint inhibitor–associated autoimmune diabetes; CK = creatine kinase; 
CMV = cytomegalovirus; CNS = central nervous system; CRI = chronic renal insufficiency; 
CSF = cerebrospinal fluid; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; CXR = chest X-ray; DI = diabetes insipidus; DIHS = drug-induced hypersensitivity syndrome; 
DKA = diabetic ketoacidosis; DLCO = diffusing capacity of lung for carbon monoxide;
DMARD = disease-modifying anti-rheumatic drug; DRESS = drug reaction with eosinophilia and systemic 
symptoms; DVT = deep vein thrombosis; EBV = Epstein-Barr virus; ECG = electrocardiogram; 
ED = emergency department; EGD = esophagogastroduodenoscopy; EMG = electromyography; 
FEIBA = factor eight inhibitor bypassing activity; FT4 = free thyroxine; GBS = Guillain-Barre syndrome; 
GI = gastrointestinal; Gx = grade, where x is a number; Hgb = hemoglobin; HIV = human immunodeficiency 
virus; HLA = human leukocyte antigen; HUS = hemolytic-uremic syndrome; ICU = intensive care unit; 
IgG = immunoglobulin G; IL-6 = interleukin-6; irAE = immune-related adverse event; IRR = infusion-related 
reaction; ITP = idiopathic thrombocytopenic purpura; IV = intravenous; IVIG = intravenous immunoglobulin; 
LLN = lower limit of normal; LMWH = low-molecular-weight heparin; MGFA = Myasthenia Gravis 
Foundation of America; MMF = mycophenolate mofetil; MRI = magnetic resonance imaging; NA = not 
applicable; NASH = nonalcoholic steatohepatitis; NMO = neuromyelitis optica; NSAID = non-steroidal anti-
inflammatory drug; ON = optic neuritis; PB = peripheral blood; PCP = primary care practitioner;
PCR = polymerase chain reaction; PEX = plasma exchange; PMN = polymorphonuclear cell; Q = every; 
RBC = red blood cell; SAE = serious adverse event; SCAR = severe cutaneous adverse reaction; SJS = Stevens-
Johnson syndrome; SSKI = potassium iodide; T2DM = Type 2 diabetes mellitus; TEN = toxic epidermal 
necrolysis; TNFα = tumor necrosis factor alpha; TSH = thyroid-stimulating hormone; TTP = thrombotic 
thrombocytopenic purpura; ULN = upper limit of normal; UTI = urinary tract infection; VKA = vitamin K 
antagonist
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
107
CONFIDENTIAL
APPENDIX 5.
RECIST V. 1.1
Measurable Disease. Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, 
solid organ metastases) are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as ≥20 mm with chest X-ray and as ≥10 mm
with computed tomography (CT) scan or clinical examination. Bone lesions are considered 
measurable only if assessed by CT scan and have an identifiable soft tissue component that 
meets these requirements (soft tissue component ≥10 mm by CT scan). Malignant lymph 
nodes must be ≥15 mm in the short axis to be considered measurable; only the short axis will 
be measured and followed. All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). Previously irradiated lesions are not considered measurable 
unless progression has been documented in the lesion.
Non-Measurable Disease. All other lesions (or sites of disease), including small lesions are 
considered non-measurable disease. Bone lesions without a measurable soft tissue 
component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin, and 
abdominal masses followed by clinical examination are all non-measurable. Lesions in 
previously irradiated areas are non-measurable, unless progression has been demonstrated.
Target Lesions. When more than one measurable tumor lesion is present at baseline all 
lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. Note that 
pathological nodes must meet the criterion of a short axis of ≥15 mm by CT scan and only 
the short axis of these nodes will contribute to the baseline sum. All other pathological nodes 
(those with short axis ≥10 mm but <15 mm) should be considered non-target lesions. Nodes 
that have a short axis <10 mm are considered non-pathological and should not be recorded or 
followed. At baseline, the sum of the target lesions (longest diameter of tumor lesions plus 
short axis of lymph nodes: overall maximum of 5) is to be recorded. After baseline, a value 
should be provided on the case report form for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are 
too small to measure and indeed are believed to be absent, a default value of 0 mm may be 
used.
Non-Target Lesions. All non-measurable lesions (or sites of disease) plus any measurable 
lesions over and above those listed as target lesions are considered non-target lesions.
Measurements are not required but these lesions should be noted at baseline and should be 
followed as “present” or “absent.”
Response.
All patients will have their BEST OBJECTIVE RESPONSE from the start of study 
treatment until the end of treatment classified as outlined below:
Complete Response (CR): disappearance of target and non-target lesions and 
normalization of tumor markers. Pathological lymph nodes must have short axis 
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
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CONFIDENTIAL
measures <10 mm (note: continue to record the measurement even if <10 mm and 
considered CR). Residual lesions (other than nodes <10 mm) thought to be 
non-malignant should be further investigated by cytology specialized imaging or other 
techniques as appropriate for individual cases before CR can be accepted. Confirmation 
of response is required and should occur no less than 4 weeks after the initial response.
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter 
for tumor lesions and short axis measure for nodes) of target lesions, taking as reference 
the baseline sum of diameters. Non-target lesions must be non-PD. Confirmation of 
response should occur no less than 4 weeks after the initial response.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD taking as reference the smallest sum of diameters on study. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of ≥5 mm. Appearance of new lesions will also 
constitute PD (including lesions in previously unassessed areas). In exceptional 
circumstances, unequivocal progression of non-target disease may be accepted as 
evidence of disease progression, where the overall tumor burden has increased 
sufficiently to merit discontinuation of treatment or where the tumor burden appears to 
have increased by at least 73% in volume. Modest increases in the size of one or more 
non-target lesions are NOT considered unequivocal progression. If the evidence of PD is 
equivocal (target or non-target), treatment may continue until the next assessment, but if 
confirmed, the earlier date must be used.
Integration of Target, Non-Target, and New Lesions into Response Assessment
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for This Category 
Also Requires 
Target lesions ± non-target lesions 
CR
CR
No
CR
Normalization of tumor markers, 
tumor nodes <10 mm 
CR
Non-CR/Non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD/not all 
evaluated 
No
PR
SD
Non-PD/not all 
evaluated 
No
SD
Documented at least once ≥4 wks. 
from baseline
Not all 
evaluated 
Non-PD
No
NE
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
Non-target lesions ONLY
No target 
CR
No
CR
Normalization of tumor markers, 
tumor nodes <10 mm 
No target 
Non-CR/non-PD 
No
Non-
CR/non-
PD 
No target 
Not all evaluated 
No
NE
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Flamingo Therapeutics
Trial ID: FLM-6774-201
Activity and Safety of Danvatirsen and Pembrolizumab in HNSCC
Amendment 4
8 May 2025
109
CONFIDENTIAL
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for This Category 
Also Requires 
No target 
Unequivocal PD 
Any
PD
No target 
Any
Yes*
PD
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.” This is 
a reason for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
*Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may be 
continued pending further assessments.
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease.
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