Clinical trial NCT03625323
Conditions: NSCLC HNSCC
Sponsor: Immutep S.A.S.
Start date: 2019-02-18; Completion date: 2024-11-25
Enrollment: 187 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluate the safety and efficacy of the combination of eftilagimod alpha with pembrolizumab in non-small cell lung carcinoma and head and neck carcinoma patients.

Detailed description:
Up to 187 patients will be recruited in the TACTI-002 (Two ACTive Immunotherapies) Phase II study which will take place across approximately 22 study centres in the U.S., Europe and Australia. It will evaluate the safety and efficacy of the combination of eftilagimod alpha with pembrolizumab in patients with advanced or metastatic non-small cell lung carcinoma or head and neck carcinoma. It will be a Simon's two-stage, non-comparative, open-label, single-arm, multicentre clinical study. Patients participating in the trial will be given the combination treatment for 12 months using a 30 mg s.c. eftilagimod alpha dosing every 2 or 3 weeks.

Arms: arm 1: eftilagimod alpha: 30 mg every 2 weeks for the first 8 cycles (1 cycle = 3 weeks) and every 3 weeks thereafter (starting cycle 9).

pembrolizumab (KEYTRUDA®): 200 mg every 3 weeks. arm 2: eftilagimod alpha: 30 mg every 2 weeks for the first 8 cycles (1 cycle = 3 weeks) and every 3 weeks thereafter (starting cycle 9).

pembrolizumab (KEYTRUDA®): 200 mg every 3 weeks. arm 3: eftilagimod alpha: 30 mg every 2 weeks for the first 8 cycles (1 cycle = 3 weeks) and every 3 weeks thereafter (starting cycle 9).

pembrolizumab (KEYTRUDA®): 200 mg every 3 weeks.
Interventions: intervention 1: eftilagimod alpha intervention 2: pembrolizumab (KEYTRUDA®)
Intervention descriptions: intervention 1: APC activator, MHC II agonist, LAG-3 fusion protein intervention 2: anti-PD-1 antibody

Protocol documents:
Prot_000.pdf: 
TACTI-002   
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CLINICAL TRIAL PROTOCOL 
 
Study title: 
TACTI-002 (Two ACTive Immunotherapeutics): A multicenter, open 
label, Phase II study in patients with previously untreated unresectable 
or metastatic non-small cell lung cancer (NSCLC), or recurrent PD-X 
refractory NSCLC or with recurrent or metastatic squamous head and 
neck cancer (HNSCC) receiving the soluble LAG-3 fusion protein 
eftilagimod alpha (IMP321) in combination with pembrolizumab 
(PD-1 antagonist) 
Sponsor: 
Immutep S.A.S. 
Parc Les Algorithmes  
Bâtiment 7 - Le Pythagore  
Route de l’Orme - RD 128  
91190 SAINT-AUBIN 
France 
Protocol No. 
TACTI-002 (IMP321-P015); Keynote-PN798 
Clinical Phase 
II 
Protocol date: 
Version 5.0 final, dated 18th August 2023 
IMPs 
eftilagimod alpha (efti, IMP321, LAG3-Ig; INN: eftilagimod alfa) 
pembrolizumab (Keytruda®; MK-3475) 
EudraCT: 
2018-001994-25 
IND: 
139659 
NCT: 
03625323 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
This document contains scientific and commercial information proprietary to Immutep S.A.S. that is 
privileged or confidential and is intended solely for the purpose of this clinical investigation. It should be 
kept secure and its contents should not be disclosed to any third party without the prior written consent of 
Immutep S.A.S. 


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TABLE OF REVISIONS 
Version 
Section 
Changes 
1.2 
All sections 
Editorial 
1.2 
Section 3.2.2 
Added “as assessed by investigators” to the description of several 
SAEs as requested  
1.2 
Section 5 
Corrected error in patient sample numbers according to Section 
10.1 and synopsis 
1.2 
Section 6.7.1 
Specified medical wording according to FDA requirements 
1.2.1 
Section 5.6.2 
Exclusion criterion 
20 
Deleted “a known severe ≥ grade 3” as requested by MHRA 
1.2.1 
Section 6.10 
Added wording on avoiding live vaccinations for four months 
after last IMP dose 
1.3 
Synopsis, section 5 
and; section 10 
Introduction of a confirmatory scan prior to study enrolment for 
part B, extension of the informed consent period for biopsies and 
confirmatory scans, adaptation of statistical assumptions for part 
A and additional references 
2.0 
All sections 
Editorial, clarifications, typographical corrections 
2.0 
Section 3.2.1 and 3.5 
Update on pembrolizumab’s relevant approved indication 
2.0 
Section 3.2.2 
Update of clinical data of eftilagimod alpha 
2.0 
Section 5.2 
Study Stopping Rules have been updated acc to CA comments 
2.0 
Section 5.6.1 
Inclusion criteria 
Specification of NSCLC patient population eligible for the study 
e.g. clarification on the prior use of durvalumab 
2.0 
Section 5.6.2 
Exclusion criteria 
Specification of NSCLC patient population e.g. clarification on 
the wash-out for patients receiving pembrolizumab 
Clarification on the definition/detection of hepatitis 
2.0 
Section 3.2.2 / 3.5 
 
and related risk language added 
2.0 
Section 8.1.2 vs 8.1.3 
Updating requirements on confirmation of iUPD acc to the 
guideline 
2.0 
Section 7.2. and 8.2 
Addition of minimum further 10 patients from Stage 2 (if opened) 
to the PK subset. 
2.1 
Section 6.7.1 
 
 
3.0 
Synopsis, section 5 
Clarification regarding patient selection for Part B 
3.0 
Synopsis, section 5 
Clarification of Inclusion criterion 2.2, 3.1 and Exclusion criterion 
9.1 and 18.1; Addition to Exclusion criterion 1.2 
3.0 
Synopsis, Section5, 
Section 10.1, 10.9 
and 10.13 
Concept of cohort extension and details on Part A cohort 
extension  
3.0 
Section 3.3, 3.5 
Reference to Investigator’s Brochure, Benefit and Risk Ratio 
updated  
3.0 
Section 6.7.1 and 6.8 
and 6.11 
Clarification on rules of efti treatment delay and allowed study 
treatment interruptions 
3.0 
Table 8 
Update to pembrolizumab dose modification rules 
3.0 
Section 7.1 
Elaboration on patient re-screening 
3.0 
Synopsis, Table 10 
Elaboration on pregnancy test 
3.0 
Section 7.3.3 
Replacement of patients early discontinued due to COVID-19 
3.0 
Synopsis, Section 8.2 
PK sampling window extended for late PK timepoints 
3.0 
Section 8.3.2 
Clarification on laboratory analyses used for tumour tissue 
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samples 
3.0 
Section 10.6 and 10.7 
Clarification on interim analyses and timing 
3.0 
Section 12 
Adding wording on remote monitoring under special 
circumstances (e.g. COVID pandemic) 
3.1 
Multiple sections 
Editorial, typographical clarifications 
3.1 
Synopsis 
Addition of new countries and sites 
3.1 
Section 3.5 
Update benefit and risk with details re COVID-19  
3.1 
Table 8 
Update to pembrolizumab dose modification rules 
3.1 
Section 6.10 
Clarification concomitant systemic corticosteroids and 
vaccination 
3.1 
Section 9.4 
Clarification on screening adverse events 
3.1 
Section 10.1 
Explanation on statistical considerations around clinically 
meaningful benefit in Part B  
3.1 
Section 14.2 
Clarification on protocol deviations due to COVID-19 
3.1.1./4.0 
Contact Details 
Update 
3.1.1/4.0 
Synopsis, Section 
6.1.2 and Section 6.4 
Reference to powder formulation of pembrolizumab removed 
3.1.1./4.0 
Section 10.9.2. 
Typo corrected 
4.0 
Table 8  
Update to pembrolizumab dose modification rules 
4.0 
Section 6.5 
Clarification on methods of patient assignment 
4.0 
Section 9.3 
Clarifying reporting deadline for Events of Clinical Interest 
4.1 
Front page 
Sponsor’s address 
5.0 
Multiple sections 
Adding efti INN name and harmonization of name use 
5.0 
Multiple sections 
Updating various contact details 
5.0 
Synopsis, Section 5.3 
Update on study timelines, extending study end by 12 month to 
collect additional PFS/OS FU data 
5.0 
 
 
 
5.0 
Section 6.4 
Clarification to instructions on diluted pembrolizumab solution 
storage  
5.0 
Section 8.1.5 
Clarification to guiding source for date of disease progression or 
censoring 
 
 
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Signature Page for Investigator: 
 
IMPs:   
eftilagimod alfa and pembrolizumab  
Protocol No.:  TACTI-002 (IMP321-P015) 
Title:  
TACTI-002 (Two ACTive Immunotherapeutics): A multicenter, open label, Phase II study 
in patients with previously untreated unresectable or metastatic non-small cell lung cancer 
(NSCLC), or recurrent PD-X refractory NSCLC or with recurrent or metastatic squamous 
head and neck cancer (HNSCC) receiving the soluble LAG-3 fusion protein eftilagimod 
alpha (IMP321) in combination with pembrolizumab (PD-1 antagonist) 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the protocol 
and in accordance with all relevant local regulations, the current International Conference on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use 
Guideline for Good Clinical Practice (GCP), and with the principles of the most recent version of the 
Declaration of Helsinki. 
 
 
 
 
Investigator Name 
 
Signature 
 
Date 
[PRINT IN BLOCK CAPITAL LETTERS] 
 
 
Institution Name  
 
 
 
Site # 
 
 
City and State/Province 
 
 
 
Country 
 
 
 
 
 
 
 


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1 
CONTACT DETAILS 
Sponsor 
Chief Medical Officer & 
Medical Expert 
 
Immutep  
Email:
 
 
CRO 
Project Management 
Fortrea SARL (formerly Chiltern, Covance and Labcorp) 
2 rue Jacques Daguerre 
Immeuble Ariane 
92565 Rueil-Malmaison 
France 
Phone (office):  
 
Pharmacovigilance 
Allucent (formerly CATO-SMS) 
Stationsplein Noord-Oost 438 
1117 CL Schiphol 
The Netherlands 
Phone: 
 
Safety Database 
Allucent (formerly CATO-SMS) 
Stationsplein Noord-Oost 438 
1117 CL Schiphol 
The Netherlands 
Phone: 
 
Medical Monitoring 
 Fortrea SARL (formerly Chiltern, Covance and Labcorp) 
2 rue Jacques Daguerre 
Immeuble Ariane 
92565 Rueil-Malmaison 
France 
Phone (office):   
 
Data Management, Statistics 
 Fortrea SARL (formerly Chiltern, Covance and Labcorp) 
2 rue Jacques Daguerre 
Immeuble Ariane 
92565 Rueil-Malmaison 
France 
Phone (office):   
 
 
Other vendors 
IMP Management Vendor  
Clinigen Clinical Supplies Management SA (formerly: CSM Europe 
sa)   
Watson & Crick Hill 
Rue Granbonpré 11 
B-1435 Mont-Saint-Guibert, Belgium 
Phone: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Central Lab for PD-L1 
analyses 
Covance Central Laboratory Services 
Attn: Special Handling 
7, Rue Moïse-Marcinhes 
1217 Meyrin, Switzerland 
Phone : 
 
Central lab for gene 
expression profiling 
 
Labcorp Central Laboratory Services Limited Partnership 
Covance Genomics Laboratory (CGL) – Indianapolis 
8211 SciCor Dr. Dock 17 
Indianapolis, IN 46214 
USA 
Phone  
 
Central Laboratory for 
Pharmacokinetics of efti and 
Anti-drug Antibodies (efti) 
and Th1 biomarkers 
 
Charles River Laboratories Evreux 
RN13 / Route de Pacy 
27930 Miserey 
France 
 
Shipment of Central 
Laboratory Kits and Samples 
MLM Medical Labs GmbH 
Dohrweg 63 
41066 Mönchengladbach, Germany 
Phone: 
 
Central Imaging Laboratory 
Median Technologies 
Les Deux Arcs, Bldg.B 
1800, Route des Crêtes 
06560 Valbonne, France 
Phone: 
 
Central Laboratory for PK 
analysis (calculations only) 
PhinC Development 
Immeuble Le Classéa 
36, rue Victor Basch 
91 300 Massy 
France 
Phone 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
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2 
SYNOPSIS 
STUDY TITLE 
TACTI-002 (Two ACTive Immunotherapeutics): A multicenter, open label, Phase II study in patients 
with previously untreated unresectable or metastatic non-small cell lung cancer (NSCLC), or recurrent 
PD-X refractory NSCLC or with recurrent or metastatic squamous head and neck cancer (HNSCC) 
receiving the soluble LAG-3 fusion protein eftilagimod alpha (IMP321) in combination with 
pembrolizumab (PD-1 antagonist) 
SPONSOR  
Immutep S.A.S.   
BACKGROUND: 
Lymphocyte activation gene 3 protein (LAG-3) is a transmembrane protein found on activated T and 
natural killer (NK) cells and a key mediator of immune responses. Eftilagimod alfa (efti, eftilagimod 
alpha, IMP321) is a recombinant soluble human LAG-3Ig fusion protein which is under development as 
a cancer immunotherapeutic agent. Like endogenous LAG-3, efti binds to major histocompatibility 
complex (MHC) class II antigen presenting cells (APCs) such as dendritic cells (DCs) and triggers a T 
helper (Th) 1 response and T cell proliferation. Efti has an excellent preclinical safety profile. Clinical 
studies have been/are conducted in the following settings: efti monotherapy or as part of chemo-
immunotherapy or as part of a combination with PD-1 antagonists in patients with advanced and/or 
metastatic malignancies or as a vaccine adjuvant in patients with advanced malignancies. 
Pembrolizumab (Brand name: Keytruda®, MK-3475) is a potent humanized immunoglobulin G4 (IgG4) 
monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) 
receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed 
cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and 
potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile 
and is in clinical development as an intravenous (i.v.) immunotherapy for advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of indications. 
For more details on specific indications refer to the Investigator’s Brochure. Refer to the Investigator’s 
Brochure (IB)/approved labeling for detailed background information on MK-3475. 
STUDY RATIONALE 
Treatment of advanced solid tumors remains challenging despite the progress which has been made over 
the last years especially with targeted therapies like tyrosine kinase inhibitors, monoclonal antibodies, 
and immunotherapies like PD-1/PD-L1 and CTLA-4 antagonists. Recently, immune therapies like anti 
CTLA-4 and anti PD-1 antagonist have been approved by the Food and Drug Administration (FDA) in 
many different solid tumors. In general immune therapies as single agents achieved response rates 
between 12 % (ovarian cancer) and 40 % (melanoma, MSI-high) in a high number of solid tumors (i.e. 
NSCLC; small cell lung cancer (SCLC), renal cell cancer (RCC), HNSCC, triple negative breast cancer 
(TNBC), hepatocellular cancer (HCC), gastroesophageal cancer (GEC) and others) (1-6). 
Understanding the reasons why a majority of patients do not respond to PD-1/PD-L1 blockade is key to 
developing new therapy combinations. On-treatment tumor biopsies have shown that non-responding 
patients have either little or no tumor-infiltrating lymphocytes (TILs) in the tumor bed or a non-
functional immune response (i.e. no intratumoral IFN) with PD-1/PD-L1 negative TILs (7). Thus, 
immunogenic signals that induce tumor antigen-loaded DCs to escape peripheral tolerance and better 


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prime and activate effector T cells are expected to reactivate the deficient early steps of the cancer-
immunity cycle (8). 
In a mouse model of 
 
 
. 
In clinical studies with efti it has been shown that efti as an APC activator at a dose of ≥ 1 mg/injection 
induced a sustained increase in monocyte and dendritic cells blood counts as well as a sustained 
activation of blood monocytes over 6 months. Moreover, this APC activation led to a sustained increase 
of activated CD8 T cells over 6 months and a sustained increase in serum IFNJ, a Th1 cytokine.   
In the cross-talk between immune system and cancer, PD-1 antagonists like pembrolizumab address the 
immune escape (T cell downregulation). On the other hand, the capacity of the immune cells to recognize 
the tumor cells and prime an efficient effector response can be increased by an APC activator like efti.  
In patients eligible to anti-PD-1 therapy, the addition of a well-tolerated APC activator like efti may help 
to activate the cellular immune response mechanisms to mediate tumor recognition and killing and thus 
may lead to higher frequency of durable responses compared to pembrolizumab monotherapy in different 
solid tumor without adding substantial toxicity. 
The study will investigate three different patient populations as described below. This study aims to 
determine the response rate, safety and further antitumor activity of efti in combination with the anti-
PD-1 antagonist pembrolizumab in a larger patient population. Based on the complementary mechanism 
of action, the presented preclinical and clinical data it is believed that the addition of efti to 
pembrolizumab therapy increases the response rates of pembrolizumab in these indications. Patients will 
be enrolled regardless of their PD-L1 status and tumor samples will be collected and the PD-L1 status 
will be assessed centrally.  
The proposed statistical design (Simon`s 2 stage) ensures that initially a small number of patients is 
exposed to the combination of efti and pembrolizumab.  
STUDY LOCATION 
The study is planned to be conducted in Europe (Spain, Ukraine, United Kingdom, Poland), United 
States of America and Australia in 20-25 experienced clinical sites. 
STUDY OBJECTIVES 
Primary Objectives: 
x 
To evaluate the response rate of eftilagimod alfa in combination with pembrolizumab in patients 
with advanced, metastatic, recurrent NSCLC and HNSCC 
Secondary Objectives: 
x 
To evaluate the safety and tolerability of eftilagimod alfa when combined with pembrolizumab  
x 
To further evaluate the antitumor activity of eftilagimod alfa when combined with pembrolizumab 
x 
To assess the pharmacokinetic and immunogenic properties of eftilagimod alfa 
Exploratory Objectives: 
x 
To identify and characterize relevant biomarkers 
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x 
To further characterize the antitumor activity of eftilagimod alfa in combination with 
pembrolizumab 
STUDY ENDPOINTS 
Primary Endpoints: 
x 
To determine best overall response rate (ORR) according to iRECIST 
Secondary Endpoints: 
x 
Safety profile in terms of frequency, severity and duration of Adverse events (AEs) and serious 
adverse events (SAEs) and events of clinical interest (ECI) and abnormalities in vital signs, physical 
examination, 12-lead ECG and safety laboratory assessments 
x 
To assess time to and duration of responses according to iRECIST and RECIST 1.1 
x 
To assess the response rate according to RECIST 1.1 
x 
To assess the disease control rate according to iRECIST and RECIST 1.1 
x 
To assess progression free survival (PFS) and overall survival (OS) 
x 
To assess occurrence of anti- eftilagimod alfa -specific antibodies 
x 
To assess the plasma concentration time profile and derived PK parameters of eftilagimod alfa 
Exploratory Endpoints: 
x 
To asses PD-L1 expression assessed by central laboratory 
x 
 
x 
To assess Gene signature acc. to PanCancer Immune code set assessed by a central laboratory 
x 
To assess circulating level of Th1 biomarkers (i.e. IFN- J, CXCL10) assessed by a central 
laboratory 
x 
 
STUDY DESIGN 
The study is designed according to Simon's optimal two-stage design (9). During the first stage of the 
study the number of N1 patients will be recruited for each indication into this multicenter, open label, 
phase II study. In case there are more responses than threshold r1 observed in patients recruited in the 
initial stage (N1), additional patients (N2) will be recruited. Following the completion of the initial stage, 
the decision to recruit the additional patients (N2) will be taken by the Data Monitoring Committee 
(DMC), as described later.  
 
Indication 
Threshold r1 
Initial No of pts 
(N1) 
Add. No. of pts 
(N2) 
N total 
NSCLC 1st line 
4 
17 
19 
36 
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NSCLC 2nd line 1 
23 
13 
36 
HNSCC 
2 
18 
19 
37 
In case ORR in any part meets a predefined threshold an extension of this cohort may be set up to 
combine the patients of stages 1, 2, and newly enrolled patients in that respective part to provide a 
reasonable basis in sample size considerations for further clinical studies. For sample size considerations 
in the extension phase please refer to the section "sample size calculations" in the synopsis and chapter 
10 of the protocol.  
To be eligible for participation, patients must have either:  
Part A: Histologically- or cytologically confirmed diagnosis of non-small cell lung cancer stage IIIB 
not amenable to curative treatment or stage IV not amenable to EGFR/ALK based therapy, treatment 
naïve for advanced/metastatic disease.  
 
Note: patients who received durvalumab or any other PD-1 or PD-L1 therapy as maintenance therapy 
to the adjuvant chemotherapy regimen and hence are not naïve to anti-PD-X agents, can be recruited 
provided that all other necessary requirements are met. 
Part B: Histologically- or cytologically-confirmed diagnosis of NSCLC after failure of first-line 
treatment (for metastatic/advanced disease) with at least 2 cycles of any PD-1/PD-L1 therapy (e.g. 
nivolumab, pembrolizumab, avelumab, etc.) alone, or in combination with any other immunotherapeutic 
or chemotherapy given as part of first-line treatment. 
Note: Failure on therapy is defined as progress acc. to RECIST 1.1 and would require confirmation by 
a second assessment no less than four weeks from the first documented PD in the absence of rapid 
clinical progression. If patients discontinue PD-1/PD-L1 after being treated for at least 2 cycles for 
reasons other than progression, they may enroll in the study if initial progression occurs within 12 weeks 
after end of PD-1/PD-L1 therapy and progression is confirmed. Only patients to be receiving treatment 
in true second-line setting can be enrolled to Part B. Patients who have received durvalumab or any 
other PD-1 or PD-L1 therapy as part of their adjuvant therapy and no other PD-1/PD-L1 therapy in the 
first line treatment are not eligible for Part B. 
Note: in Parts A and B patients with neuroendocrine or sarcomatoid NSCLC tumor types are not 
eligible. Patients with undifferentiated lung carcinoma with some neuroendocrine features can be 
recruited. 
Part C: Histologically- or cytologically-confirmed recurrent disease not amenable to curative treatment 
with local or systemic therapy, or metastatic (disseminated) head and neck squamous cell carcinoma 
(HNSCC) of the oral cavity, oropharynx, hypopharynx, or larynx that is considered incurable by local 
therapies after failure of prior platinum-based therapy.  
Note: in all three parts patients will be enrolled regardless of their PD-L1 expression.  
Part A+B+C:  
Patients will receive pembrolizumab and efti starting from cycle 1 day 1 as follows:  
• 
200 mg pembrolizumab every 3 weeks i.v. (30 min) for up to 35 cycles; 1 cycle = 3 weeks 
• 
30 mg of efti every 2 weeks s.c. for the first six months (until including cycle 8) and shifted to every 
three weeks s.c. thereafter (cycle 9 to 18); 1 cycle = 3 weeks 


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Screening of patients for eligibility to enter this study will be done in the three weeks prior to cycle 1 
day 1. Patients will be enrolled in parallel except for the first three patients in each part who are to be 
enrolled at least 1 week apart. A patient will stay on treatment until disease progression, unacceptable 
toxicity, completion of 35 cycles of pembrolizumab (~2 yrs.; completion of study treatment) or 
discontinuation for any other reason. Three (3) weeks after the end of the combination therapy (cycle 
18) end of combination (EOC) therapy assessments will be performed. Three (3) weeks after end of any 
study treatment (cycle 35) an end of treatment (EOT) visit will be performed. Upon start of study 
treatment, patients will be followed for PFS and OS. PFS will be radiologically assessed at the study 
sites until progressive disease (PD), death, withdrawal of consent, loss to follow-up, or until the end of 
the study, whichever occurs first. Radiological assessment will be performed at intervals of 9 weeks until 
week 36 (week 9, 18, 27, 36) and every 12 weeks thereafter (after week 36). OS will be monitored until 
death, withdrawal of consent, loss to follow-up or until the end of the study, whichever occurs first. 
Measurability will be assessed according to iRECIST. Response to treatment and treatment decisions 
will be assessed according to iRECIST. Objective response (iPR, iCR) should be confirmed by a repeat 
imaging assessment at least 4 weeks after the first response is observed. Per iRECIST, disease 
progression should be confirmed 4 to 8 weeks after site-assessed first radiologic evidence of iUPD. 
Patients, who have unconfirmed disease progression (iUPD) should stay on treatment (if clinically 
stable) until progression is confirmed (iCPD), provided they have met the conditions detailed in Section 
8.1.3.  
Radiological scans and related information will be evaluated at the study sites for treatment decision and 
for primary objective and will be collected for potential later central evaluation by blinded independent 
radiologists.  
Any adverse event (AE) or events of clinical interest (ECI) that occurs during the first 30 days following 
the last dose of any study drug will be considered treatment emergent and must be recorded. Same 
accounts for all serious adverse events (SAEs) occurring during the first 90 days after last study drug 
administration.  
Data Monitoring Committee (DMC): 
The DMC will review the available safety data of all patients (part A-C) after 18 patients have completed 
at least two cycles (6 weeks) of therapy. In addition, the DMC will review the efficacy and safety data 
after the last patient N1 has been enrolled or the minimum number of responses is reached for each part 
of the study, whatever is first. The DMC will give a recommendation for each part of the study if stage 
2 or an extension can be opened independently. Patients included in this decision must have had at least 
one tumor imaging after treatment was initiated. Further details are described in the DMC charter.  
Furthermore, the DMC will monitor safety and efficacy data at regular intervals and in accordance with 
the DMC charter. The DMC may recommend stopping/changing the study if at any time during the trial 
there are unacceptable adverse events or safety concerns. Unless immediate action is required to protect 


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the safety and well-being of study patients, the sponsor will consult with appropriate regulatory 
authorities prior to early termination of the study based on any DMC recommendation. 
Study Visits: 
An overview of study visits is shown in the schedule of assessments (see Table 1).  
STUDY POPULATION 
Inclusion Criteria: 
Patients may be enrolled if they meet all of the following criteria at screening: 
1. Willing to give written informed consent and to comply with the protocol. 
2.2 Part A (1st line, PD-X naïve in metastatic setting NSCLC): histologically- or cytologically-
confirmed diagnosis of non-small cell lung carcinoma stage IIIB not amenable to curative 
treatment or stage IV not amenable to EGFR/ALK based therapy, treatment naïve for systemic 
therapy given for advanced/metastatic disease (previous palliative radiotherapy for 
advanced/metastatic disease acceptable). 
Note: patients who received durvalumab or any other PD-1 or PD-L1 therapy as maintenance 
therapy to the adjuvant chemotherapy regimen and hence are not naïve to anti-PD-X agents, can 
be recruited provided that all other necessary requirements are met. 
Part B (2nd line, PD-X refractory NSCLC): histologically- or cytologically-confirmed diagnosis 
of NSCLC after failure of first-line treatment (for metastatic/advanced disease) with at least 2 
cycles of any PD-1/PD-L1 containing based therapy (e.g. nivolumab, pembrolizumab, avelumab, 
durvalumab, etc.) alone, or in combination with any other immunotherapeutic or chemotherapy 
given as part of first-line treatment.  
Note: failure = failure on therapy is defined as progress acc. to RECIST 1.1 and would require 
confirmation by a second assessment no less than four weeks from the first documented PD in 
the absence of rapid clinical progression. If patients discontinue PD-1/PD-L1 after being treated 
for at least 2 cycles for reasons other than progression, they may enroll in the study if initial 
progression occurs within 12 weeks after end of PD-1/PD-L1 therapy and progression is 
confirmed. Only patients to be receiving treatment in true second-line setting can be enrolled to 
Part B. Patients who have received durvalumab or any other PD-1 or PD-L1 therapy as part of 
their adjuvant therapy and no other PD-1/PD-L1 therapy in the first line treatment are not 
eligible for Part B. 
Note: in Parts A and B patients with neuroendocrine or sarcomatoid NSCLC tumor types are not 
eligible. Patients with undifferentiated lung carcinoma with some neuroendocrine features can 
be recruited. 
Part C (2nd line PD-X naive HNSCC): Histologically- or cytologically confirmed recurrent 
disease not amenable to curative treatment with local or systemic therapy, or metastatic 
(disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx that is considered 
incurable by local therapies after failure of prior platinum-based therapy. 
3.1   Availability of formalin-fixed diagnostic tumor tissue (in the case of participants having received 
adjuvant therapy, the tissue should be taken after completion of this therapy). 
4. Female or male ≥18 years of age on the day of signing the informed consent. 


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5. All female patients of childbearing potential must have a negative highly sensitive pregnancy 
test at screening (within 72 hours prior to cycle 1 day 1); all patients of reproductive potential 
must agree to use highly effective method for contraception from study entry until at least 4 
months after the last administration of any study treatment. 
A woman must either be, 
• 
not of childbearing potential: postmenopausal (≥ 60 years of age, or < 60 years of age 
and amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, 
toremifene, or ovarian suppression with follicle-stimulating hormone (FSH) above 40 
U/L and estradiol below 30 ng/L, or if taking tamoxifen or toremifene, and age < 60 
years, then FSH and estradiol in the postmenopausal range), permanently sterilized (e.g., 
tubal occlusion, hysterectomy, bilateral salpingectomy), or otherwise incapable of 
pregnancy 
• 
of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for subjects 
participating in clinical studies: e.g., established use of oral, injected or implanted 
hormonal methods of contraception; placement of an intrauterine device or intrauterine 
system; male partner sterilization (the vasectomized partner should be the sole partner 
for that subject). 
6. A man who is sexually active and has not had a vasectomy must agree to use a barrier method 
of birth control e.g., either condom or partner with occlusive cap (diaphragm or cervical/vault 
caps) from study entry until at least 4 months after the last administration of study treatment. All 
men must also not donate sperm from time of study entry until at least 4 months after the last 
administration of study treatment. 
7. ECOG performance status 0-1. 
8. Expected survival > 3 months. 
9. Evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors 
version 1.1 modified for immune-based therapeutics (iRECIST). Lesions situated in a previously 
irradiated area are considered measurable if progression has been demonstrated in such lesions.  
10. Laboratory criteria (collected ≤ 10 days prior to cycle 1 day 1):  
• 
Absolute neutrophil count > 1.5 x 109/L 
• 
Platelet count ≥ 100 x 109/L 
• 
Hemoglobin ≥ 9 g/dL or 5.58 mmol/L1 
• 
Serum creatinine ≤ 1.5 × ULN, or if > 1.5 ULN with a clearance of ≥ 50 mL/min acc to. 
Gault-Cockcroft formula  
• 
Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin > 1.5 
x ULN 
• 
AST (=SGOT) and ALT (=SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present. 
 
1 Must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 2 
weeks prior to screening.  


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• 
International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN unless patient is 
receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) 
is within therapeutic range of intended use of anticoagulants 
Exclusion Criteria: 
Patients are to be excluded from the study at the time of screening for any of the following reasons: 
1.2 For part A (1st line, PD-X naïve in metastatic setting NSCLC): 
• 
The NSCLC can be treated with curative intent with either surgical resection and/or 
chemoradiation and/or radiation. 
• 
Has received systemic therapy for the treatment of their stage IV NSCLC. Completion 
of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is allowed as long as therapy was completed at least 6 months prior to the 
diagnosis of metastatic disease. 
• 
Epidermal growth factor receptor (EGFR)-sensitizing mutation and/or is echinoderm 
microtubule-associated protein-like 4(EML4) gene/anaplastic lymphoma kinase (ALK) 
gene fusion positive (ALK translocation). 
• 
Has received lung radiation therapy that is >30Gy within 6 months of the first dose of 
trial treatment. 
For Part B (2nd line, PD-X refractory NSCLC):  
• 
Symptomatic ascites or pleural effusion.  
• 
> 1 line of any systemic anticancer therapy for advanced or metastatic disease.  
• 
Has received lung radiation therapy that is >30Gy within 6 months of the first dose of 
trial treatment. 
For Part C (2nd line PD-X naive HNSCC):  
• 
Disease is suitable for local therapy administered with curative intent.  
• 
Previously treated with > 1 systemic regimen for recurrent and/or metastatic disease. 
2. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) (Part A 
and C only). 
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) 
and was discontinued from that treatment due to a Grade 3 or higher irAE (Part B only). 
4. No tumor specimen evaluable for PD-L1 expression by the central study laboratory. 
5.1 Prior anti LAG-3 therapy (e.g. anti-LAG-3 antibodies).  
6. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue. 
7. Prior targeted small molecule therapy (i.e. kinase inhibitors), or radiation therapy within 2 weeks 
prior to cycle 1 day 1. 
Note: Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or 
baseline. Patients with ≤Grade 2 neuropathy, alopecia and elevated transaminases in case of 


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liver metastases may be eligible. Participants must have recovered from all radiation-related 
toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week 
washout is permitted for palliative radiation to non-CNs disease 
8.1 Has received prior chemotherapy, anti-cancer monoclonal antibody, major surgery, another 
systemic cancer therapy or has participated in a study of an investigational agent or has used an 
investigational device within 4 weeks prior to cycle 1 day 1. 
Note: Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or 
baseline. Patients with ≤Grade 2 neuropathy, alopecia and elevated transaminases in case of 
liver metastases may be eligible. If patient received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention prior to starting study 
treatment. Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent. 
Note: wash-out period for pembrolizumab is not applicable to patients having received 
pembrolizumab and are to be enrolled into Part B. These patients are allowed to enter as long 
as the last pembrolizumab dose is ≥ 2 weeks prior to cycle 1 day 1 and they fulfill all other 
requirements in terms of adverse events.  
9.1 
Known active central nervous system metastasis and/or carcinomatous meningitis. Patients 
with previously treated brain metastases may participate provided they are radiologically 
stable: i.e. without evidence of progression documented by repeat imaging performed after 
therapy completed for CNS metastasis and with at least 4 weeks difference, clinically stable 
and without requirement for steroid treatment for at least 14 days prior to cycle 1 day 1.  
10. Women who are pregnant or lactating. A woman of child-bearing potential who has a positive 
serum pregnancy test (within 72 hours) prior to cycle 1 day 1.  
11. Serious intercurrent infection within 4 weeks prior to cycle 1 day 1 or active acute or chronic 
infection. 
12.1 Evidence of severe or uncontrolled cardiac disease within 6 months prior to first dose of study 
treatment including: myocardial infarction, severe/unstable angina, ongoing cardiac 
dysrhythmias of NCI CTCAE version 5.0 Grade ≥ 2, atrial fibrillation > grade 2 not controlled 
by a pacemaker, coronary/peripheral artery bypass graft, symptomatic congestive heart failure 
(NYHA III-IV), cerebrovascular accident including transient ischemic attack, or symptomatic 
pulmonary embolism. 
13. Has interstitial lung disease or history of (non-infectious) pneumonitis that required steroids or 
has current pneumonitis. 
14. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with 
use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. 
15. Has a known history of human immunodeficiency virus (HIV) infection.  
Note: No HIV testing is required unless mandated by local health authority.  
16.1 Has a known history of Hepatitis B (defined as a known Hepatitis B surface antigen [HBsAg] 
positive result) or known active Hepatitis C virus (defined as a known positive anti-Hepatitis C 
antibody result and known detectable level of HCV RNA [qualitative] on PCR) infection.  


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Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health 
authority. No treatment with antiviral therapy allowed.  
17. Has a life-threatening illness unrelated to cancer. 
18.1 Has previous malignancies within the last three years other than described in inclusion criterion 
2, except successfully treated basal or squamous cell carcinoma of the skin, superficial bladder 
cancer, ductal carcinoma in situ of the breast, and in situ carcinoma of the cervix. 
19. Receives continuous systemic treatment with either corticosteroids (>10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 7 days prior to cycle 1 day 1. 
Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone 
equivalents are permitted in the absence of active auto-immune disease. 
20.1 Has a hypersensitivity to eftilagimod alfa and/or pembrolizumab and/or any of its excipients. 
21. Live vaccine within 30 days of planned cycle 1 day 1. Examples of live vaccines include, but 
are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow 
fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. 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. 
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the patient's participation for the full duration of 
the study, or is not in the best interest of the patient to participate, in the opinion of the treating 
investigator.  
23. Has known psychiatric or substance abuse disorders that would interfere with cooperating with 
the requirements of the study. 
INVESTIGATIONAL PRODUCTS, DOSE AND MODE OF ADMINISTRATION 
Eftilagimod alfa (efti, eftilagimod alpha, IMP321): 
The efti drug product is a single-use, preservative-free, sterile solution of efti 
 
 for subcutaneous injections (s.c.) at a concentration of 25
 mg/mL. The drug product is 
filled into  mL glass vials with an extractable volume of 
 mL to be stored at 
 
. 
Efti will be injected at a dose of 30 mg every 2 weeks for the first 8 cycles (1 cycle = 3 weeks) and every 
3 weeks thereafter (starting cycle 9) until cycle 18. The maximum number of 22 efti injections may be 
administered (18 cycles). Efti is to be given always ≥ 30 minutes after pembrolizumab infusion is 
finished.  
The route of administration for efti will be subcutaneous injection (s.c., single anatomical site) in the 
anterior face of the thigh. The location of the injection site should be rotated with each injection and 
alternating left and right thighs (if, for example, the first injection is on the left thigh, the subsequent one 
will be on the right and so on). The injection should be performed slowly to avoid discomfort at the site 
of injection. 
No dose reductions of efti are allowed. Dose delays are allowed and are described in section 6.7.  
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Efti will be provided by the sponsor.  
Pembrolizumab: 
Pembrolizumab Solution for Infusion 100 mg/vial is a liquid DP. The vials are stored at 2°C to 8°C (36°F 
to 46°F). The liquid DP is clear to opalescent solution, essentially free of visible particles.  
Pembrolizumab will be given at a dose of 200 mg (flat) as a 30-minute i.v. infusion every 3 weeks. The 
maximum number of 35 pembrolizumab infusions (35 cycles) may be administered. Dose modifications 
and dosing interruptions will be performed as described section 6.7. Pembrolizumab will be provided by 
the sponsor.   
DURATION OF THE STUDY  
Individual patients will undergo up to 3 weeks screening period, followed by a 54-weeks combination 
treatment phase (18 cycles). Patients who benefit from the treatment may continue with another 51-
weeks of pembrolizumab monotherapy (17 cycles). Three (3) weeks after the last study drug 
administration an end of treatment visit (EOT) is to be conducted. Patient will be followed-up for 
progression and/or survival (dependent on patient status at EOT) until PD, death, study end, withdrawal 
of consent or loss to follow-up, whatever occurs first. 
The timelines are as follows: first patient first visit occurred March 2019. The recruitment time for stage 
1 was completed with last patient recruited in Nov 2021. The recruitment time for stage 2 ended in 
August 2021. Recruitment to extension for part A was completed with last patient recruited in Nov 2021. 
The last patient last visit in part A is expected to occur in H2 2023.  
The end of study is defined as 36 months after last patient first visit.  
STATISTICAL ANALYSIS  
Sample Size Calculation: 
The null hypothesis that the true response rate is [ p0 ] will be tested against a one-sided alternative. In 
the first stage, [ n1 ] patients will be accrued. If there are [ r1 ] or fewer responses in these [ n1 ] patients, 
the study will be stopped. Otherwise, [ n - n1 ] additional patients will be accrued for a total of [ n ]. The 
null hypothesis will be rejected if [ r2 + 1 ] or more responses are observed in [ n ] patients. This design 
yields a one-sided type I error rate of 
 and power of 
 when the true response rate is [ p1 ]. 
Mini-max results of this calculation were used for this clinical trial.  
Indication 
response 
rate p0 
Alternative 
p1 
r1 
r2 
Initial 
No 
of pts (n1) 
Add. No. of 
pts (n2) 
N total 
NSCLC 1st line 
23% 
% 
4 
 
17 
19 
36 
NSCLC 2nd line 
7 % 
 % 
1 
 
23 
13 
36 
HNSCC 
15 % 
% 
2 
 
18 
19 
37 
C
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C
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The “true response rates” for 1st line NSCLC were extracted from Keynote-024 and Keynote-042 under 
consideration that for PD-L1 all comers response rate will be lower (10, 11). For 2nd line NSCLC there 
are no available publications for pembrolizumab alone in PD-1/PD-L1 refractory patients, but due to the 
confirmation of progression it (p0) is considered close to 0 % for pembrolizumab alone. The alternative 
(p1) of 
 % was considered clinically relevant especially in comparison to available standard 
chemotherapy. For HNSCC relevant publications from Keynote 012 and Keynote-040 were used (2, 12) 
for p0.  
For part A an extension (Part A extension) is anticipated based on the ORR of efti in combination with 
pembrolizumab as test group in a single arm design. The true ORR of monotherapy pembrolizumab in 
NSCLC 1st line is expected to be 23%, whereas a rate of 
% is expected for the test group (in case PD-
L1 distribution is as expected from historical studies with ~70% of patients with <50% TPS PD-
L1expression). Using these assumptions with a power of 
% and a one-sided level of significance of 
% in this phase II trial, a sample size of 105 patients would be required for analysis. With a drop-out 
rate of 5%, a total of 110 patients need to be enrolled. With the 36 patients of stages 1 and 2, another 74 
patients would be needed to be enrolled in total in this extension. This sample size is regarded sufficient 
to provide a reasonable precision for the estimate of ORR as basis for sample size considerations for 
further clinical studies.  
Possible extensions of part B and C will be introduced via substantial amendments.    
Analysis Populations: 
x 
The Full Analysis Set (FAS) follows the intent to treat principles and includes all assigned patients 
who received at least one dose of study drug (i.e. one dose of either pembrolizumab or efti). This 
population will be the primary population for the analyses of efficacy endpoints and baseline 
characteristics.  
x 
The safety set is defined analogously to the full analysis set and includes all assigned patients who 
received at least one dose of study drug (i.e. one dose of either pembrolizumab or efti). This 
population will be the primary population for the analyses of safety. 
x 
In addition, a per protocol population and a PK population are defined.    
Baseline and Demographic Characteristics: 
Baseline characteristics and demographic information at baseline will be summarized with descriptive 
statistics for each part of the study independently. Medications will be coded using the most current 
version of the World Health Organization (WHO) Drug dictionary and will be summarized as treated 
for all patients in the safety population. Prior medications, medications used at study and concomitant 
medications will be described separately.  
Safety Analysis: 
Safety data will be summarized for the safety population. The baseline value for safety analysis is defined 
as the value collected at the time closest to and prior to the start of any study drug administration. The 
number and percentage of patients with at least 1 AE will be summarized by preferred term and system 
organ class. AEs will also be summarized by severity and relationship to study drug (i.e., either efti or 
pembrolizumab). Vital signs, 12-lead ECG variables, body weight, and safety laboratory parameters will 
be presented (each time point and changes from baseline) using descriptive statistics (mean, standard 
deviation, median, minimum, and maximum). Other safety data will be summarized and/or listed. 
For indications with an extension, the patients of stages 1 and 2 will be combined with the newly enrolled 
patients of the extension as combined dataset for analysis. Certain endpoints will in addition be analyzed 
in the subgroups "patients of stage 1+2" and "newly enrolled patients" to assess any effect of later 
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enrollment on the outcome. All endpoints assessed in stages 1 and 2 will also be assessed for the 
extension as described above. Details will be given in the SAP. 
Immunogenicity analyses: 
The development of anti-efti antibodies will be evaluated. Autoantibodies will also be evaluated. 
Pharmacokinetic analyses: 
The plasma concentration time profile of efti will be summarized and PK parameters such as area under 
the curve (AUC), peak serum concentration (Cmax), time to reach Cmax (tmax), systemic clearance (CL), 
elimination half-life (t1/2) and volume of distribution (VD) will be calculated. 
Efficacy Analysis: 
All efficacy analyses will be based on Investigator's assessment according to iRECIST. Overall response 
rate (ORR) will be summarized for each part A to C separately by binomial response rate with two-sided 
95% exact confidence intervals. using the Clopper-Pearson method.  
The DOR (based on iRECIST) will be summarized using the Kaplan-Meier product-limit method. The 
median time to event will be calculated along with 95% CIs using the Kaplan-Meier method. In addition, 
the proportion of responders still in response at different timepoints will be assessed based on a Kaplan-
Meier Plot.  
All secondary analyses will be performed descriptively. The time-to-event endpoints (PFS (based on 
iRECIST),
, OS) will be summarized using the Kaplan-Meier product-limit method. The median 
time to event will be calculated along with 95% CIs using the Kaplan-Meier method. The PFS and OS 
rate at 3, 6, 12, 18 and 24 months and corresponding 95 % confidence intervals will be estimated using 
the Kaplan-Meier method.   
As a sensitivity analysis ORR, DOR, PFS will be assessed based on RECIST 1.1. All efficacy analyses 
are based on local investigator assessments. A central independent assessment will be conducted, 
respective analyses will be specified in the SAP.  
For indications with an extension, the patients of stages 1 and 2 will be combined with the newly enrolled 
patients of the extension as combined dataset for analysis. Certain endpoints will in addition be analyzed 
in the subgroups "patients of stage 1+2" and "newly enrolled patients" to assess any effect of later 
enrollment on the outcome. All endpoints assessed in stages 1 and 2 will also be assessed for the 
extension as described above. Details will be given in the SAP.   
 
Tumor Biomarker Analysis: 
Archival tumor material or newly obtained core or excisional biopsy of a tumor lesion not previously 
irradiated will be provided by patients on a mandatory basis. These samples will be assessed for PD-L1 
staining intensity using a standardized diagnostic test. TH1 biomarker and gene expression profile 
according to the PanCancer immune code will be measured in the blood. Exploratory analyses to assess 
correlations between biomarkers and response endpoints will be done, depending on the available data. 
 
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Table 1: Schedule of Assessments (Part A + B + C) 
Phase 
Screening22 
Combined Immunotherapy (pembrolizumab + efti) 
EOC17 
Pembrolizumab 
monotherapy 
EOT 18 
PFS-FU 
OS-FU 
Cycle (1 cycle = 3 weeks) 
Cycle 1 / 3 / 5 / 7 
Cycle 2 / 4 / 6 / 8 
Cycle 9 / 10 / 
11 / … / 18 
Cycle 19 
Cycle 20-35 
NA 
NA 
NA 
Visit 
Screening 
1 / 5 / 9 / 13  
2 / 6 / 10 / 
14  
3 / 7 / 11 
/ 15  
4 / 8 / 12 
/ 16 
17 / 18 / …/26 
27 
28- 43 
44 
every 
12 wks19 
every 
12 wks20 
Reference Day (per period) 
Day -21 to -1 
D1 
D15 
D1 
D8 
D1 
D1 
D1 
NA 
NA 
NA 
Visit Week 
 
1/ 7 / 13 / 19 
3 / 9 / 15 / 
21 
4 / 10 / 
16 / 22 
5 / 11 / 
17 / 23 
25 / 28 / 31 / … 
52 
55 
58-105 
108 
NA 
NA 
Visit Window 
 
± 2 days 
± 3 days 
± 4 days 
± 4 days 
± 7 days 
± 9 days 
± 4 wks. 
Written informed consent22 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
x 
Only C1 
 
 
 
 
 
 
 
 
 
Assignment to treatment 
 
Only C1 
 
 
 
 
 
 
 
 
 
Medical history / 
demographics1 
x 
 
 
 
 
 
 
 
 
 
 
CT/MRI scan2  
x 
9-weekly until week 36 thereafter every 12 weeks until PD (from date of assignment; independent from study treatment) 
 
Tumor tissue sample3 
x 
 
 
 
 
 
 
 
 
 
 
Gene expression profile4 
x 
only C5 
 
 
 
 
 
 
 
 
 
Physical examination5 
x 
x 
 
x 
 
x 
x 
x 
x 
 
 
Body weight / height5 
x 
x 
 
x 
 
x 
x 
x 
x 
x 
 
ECOG PS + survival 
x 
x 
 
x 
 
x 
x 
x 
x 
x 16 
Survival 
Vital signs6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
ECG7 
x 
x 
 
x 
 
x 
x 
x 
x 
 
 
Safety laboratory8 
x 
x 
 
x 
 
x 
x 
x 
x 
 
 
Thyroid function tests23 
x 
 
 
x 
 
Only C10, 12, 
14,16,18 
 
Only C20, 22, 24, 
26, 28, 30, 32, 34 
x 
 
 
Pregnancy test9 
x 
x 
 
x 
 
x 
x 
x 
x 
 
 
HIV, HCV and HBV10 
x 
 
 
 
 
 
 
 
 
 
 
Auto-antibodies (pre-dose)21 
 
only C1 
 
 
 
only C9 
x 
 
x 
 
 
PK efti11 
 
only C1, C5  
 
 
 
only C9 
 
 
 
 
 
Anti-drug (efti) antibodies 
(pre-dose)12 
 
only C1, C5 
only C3 
 
Only C2 
only C9, C13 
x 
 
x 
 
 
Th1 Biomarker13 
 
only C1, C5 
 
 
 
only C9, C13 
x 
 
x 
 
 
Pembrolizumab  
 
x 
 
x 
 
x 
x 
x 
 
 
 
Efti14 
 
x 
x 
 
x 
x 
 
 
 
 
 
Adverse events 15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x15 
x15 
Concomitant 
medications/procedures15 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 


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DEFINITIONS:  ECG=Electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End of Treatment; PFS=Progression-Free Survival; FU=Follow-Up; PD=Progressive Disease, PS- 
Performance Status; 
 
List of Footnotes 
1. 
Patient medical history should include the complete cancer medical history. Inclusion-/exclusion criteria requiring documented medical history must be verified at a minimum 
by subject interview or other protocol-required assessment (e.g., physical examination, laboratory assessment) and documented in the source documents. Details are described 
in section 7.  
2. 
Patients need to undergo CT (contrast enhanced preferred) or MRI scan for assessment of eligibility at screening (historical images ≤28 days prior cycle 1 day 1 allowed), and 
for radiological assessments every 9 weeks until week 36 (scans may be performed ± 6 days) and every 12 weeks thereafter (scans may be performed ±9 days). In case brain 
imaging is required MRI is preferred; however, CT imaging will be acceptable, if MRI is medically contraindicated. Patients with HNSCC will have a CT of the neck and head 
as needed.  
3. 
If tumor tissue from the archived formalin-fixed block is not available, a tumor tissue sample will be collected at screening to assess PD-L1 (all study parts) and HPV positivity 
(for HNSCC only, if applicable).  
4. 
Whole blood samples will be collected from each patient at screening and pre-dose day 1 cycle 5 for gene expression profiling.  
5. 
The physical examination includes the following: head, eyes, ears, nose and throat; respiratory system/chest; cardiovascular system/heart; abdomen; skin, lymph nodes; 
extremities and (at the investigator’s discretion) genitourinary system/pelvis. Height should only be obtained once at screening.  
6. 
During the treatment phase, vital signs (resting blood pressure, heart rate and body temperature) will be assessed prior to administration of study drugs on each treatment day.  
7. 
During the treatment phase, single 12-lead ECGs in rest will be assessed prior to administration of study drugs on Day 1 of each Cycle and on EOT.  
8. 
The safety laboratory tests include hematology, biochemistry, coagulation and urinalysis. They may be performed up to 2 days before the dosing day except for screening 
where 10 days are allowed. All tests to be performed at screening and pre-dose on day 1 of each cycle.  
9. 
Women of childbearing potential must have a negative pregnancy test at screening (serum) and on Day 1 of each Cycle (urine) prior to any treatment. The test may be performed 
up to 3 days before the dosing day.  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required 
10. 
HIV, HCV* and HBV** if necessary according to local laws. *anti-HCV antibody (and HCV RNA quantitative PC R if anti-HCV antibody positive), **HBsAg 
11. 
Blood samples for PK assessment of efti will be collected in a subset of 20 patients in Stage 1 (selected sites in UK, ES) and an additional subset of at least 10 patients in Stage 
2, at selected sites in cycle 1, cycle 5 and cycle 9. PK sampling will be performed pre-dose, after 1 hour, after 2 hours, after 4 hours, after 8 hours, after 24, 48, 72 and 96 hours 
after efti injection. The following windows are permitted on the assessment time points for PK: up to 1 hour for the PRE-dose assessment, ±5 minutes for the 1-hour assessment, 
±15 minutes for the 2 hour and 4-hour assessments, ±30 minutes for the 8-hour assessments, ±2 hours for the 24, 48-hour assessments and -4 hours or up to +48 hours window 
for the 72 and 96-hour timepoints. 
12. 
Blood samples for assessment of potential anti-efti ADAs will always be collected pre-dose of efti and pembrolizumab administration day 1 of cycle 1, day 8 of cycle 2, day 
15 of cycle 3, day 1 of cycle 5, day 1 of cycle 9, day 1 of cycle 13, EOC and EOT. 
13. 
Blood samples for Th1 biomarker assessment will be collected for all patients on day 1 of Cycle 1, Cycle 5, Cycle 9, Cycle 13, End of Combo (EOC) and EOT prior to dosing 
with Pembrolizumab and/or efti. In subsets of patients with PK assessment, Th1 biomarkers will be additionally assessed in selected samples collected as part of PK assessment 
after dosing at cycle 1, cycle 5 and cycle 9 (no additional blood sampling needed). 
14. 
Eftilagimod alfa (efti, eftilagimod alpha, IMP321) administration will be every 2 weeks until week 23. Thereafter efti will be administered every 3 weeks until week 52 (starting 
week 25). Patients must stay for 30 minutes at the site after each efti administration. The combined immunotherapy of pembrolizumab and efti requires on several occasions 
that both treatments will be given on the same day. In these cases, efti will be given ≥ 30 minutes after end of the pembrolizumab infusion. 
15. 
Adverse events, events of clinical interest and concomitant medications will be recorded from the time of informed consent until 30 days after the last study treatment. SAEs 
(pregnancy or breastfeeding) will be recorded from the time of informed consent until 90 (120) after last study drug treatment. In case patients receive subsequent antitumor 


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therapy, the period is reduced accordingly. SAEs potentially related to the any of the study drugs will be reported also beyond the 90 days. Safety follow-up will be performed 
for each AE, SAE or ECI. 
16. 
Additionally, any next line of anti-cancer therapy and the outcome will be recorded. 
17. 
At end of combination (EoC) therapy visit will be performed three (3) weeks ±4 days after the last combination treatment (cycle 18) in case the patient continues on 
pembrolizumab monotherapy. 
18. 
Patients who discontinue the treatment phase prior to regular EOT have an EOT visit within 3 weeks (±7 days) after discontinuation or their last study drug administration. 
19. 
Progression free survival follow-up will be performed every 12 weeks ±9 days. The first PFS-FU will take place 12 weeks after last radiological scan under treatment and then 
every 12 weeks thereafter. PFS-FU is to be conducted until confirmed PD (iCPD), study end or any other reason, whatever occurs first.  
20. 
Overall survival follow-up will be performed every 12 weeks ±4 weeks. The first overall survival will take place 12 weeks after the last visit of the treatment phase (if not EOT 
took place), EOT or PFS-FU whatever was last. OS-FU is to be conducted until study end, death, withdrawal of consent or lost to follow-up whatever occurs first. 
21. 
Autoantibodies (i.e. antimitochondrial antibodies, rheumatoid factor, antithyroid (antithyroglobulin) antibodies, and antinuclear antibodies) will be evaluated at the local 
laboratory 
22. 
Patient can be consented up to 35 days before cycle 1 day 1 to allow planning of fresh tumor biopsy and/or perform CT scan for assessment of eligibility at screening (the latter 
for Part B only). All screening assessments including the biopsy or confirmatory tumor assessment for part B (to confirm progression) itself are still to be performed between 
-21 days and -1. 
23. 
Thyroid function tests (Triiodothyronine (T3) or Free Triiodothyronine (FT3), Free thyroxine (FT4) and Thyroid stimulating hormone (TSH)) are to be performed up to 2 days 
before the dosing day except for screening where 10 days are allowed. All tests to be performed at screening and pre-dose every 2nd cycle starting with cycle 2. Thyroid function 
test will also be performed at EoT.  
 


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TABLE OF CONTENTS 
1 
CONTACT DETAILS ...................................................................................................................... 6 
2 
SYNOPSIS ......................................................................................................................................... 8 
3 
INTRODUCTION ........................................................................................................................... 32 
3.1. 
Standard Treatment Options ..................................................................................................... 32 
3.1.1. Advanced non-small cell lung cancer (NSCLC) ............................................................... 32 
3.1.2. 1st line NSCLC .................................................................................................................. 32 
3.1.3. 2nd line NSCLC ................................................................................................................. 33 
3.1.4. Recurrent or metastatic head and neck cancer .................................................................. 33 
3.2. 
Eftilagimod alfa ........................................................................................................................ 34 
3.2.1. Non-clinical Data .............................................................................................................. 35 
3.2.2. Clinical Data ...................................................................................................................... 35 
3.3. 
Pembrolizumab ......................................................................................................................... 39 
3.3.1. Pharmaceutical and Therapeutic Background ................................................................... 39 
3.3.2. Pre-clinical and Clinical Data ........................................................................................... 40 
3.4. 
Study Rationale ........................................................................................................................ 40 
3.5. 
Benefit and Risk Ratio.............................................................................................................. 41 
3.5.1. Management of Risks ........................................................................................................ 44 
4 
STUDY OBJECTIVES & ENDPOINTS ...................................................................................... 45 
4.1. 
Primary Objectives ................................................................................................................... 45 
4.2. 
Secondary Objectives ............................................................................................................... 45 
4.3. 
Exploratory Objectives ............................................................................................................. 45 
4.4. 
Endpoints .................................................................................................................................. 45 
4.4.1. Primary endpoint ............................................................................................................... 45 
4.4.2. Secondary endpoints ......................................................................................................... 45 
4.4.3. Exploratory endpoints ....................................................................................................... 45 
5 
STUDY DESIGN ............................................................................................................................. 47 
5.1. 
DMC Review ............................................................................................................................ 49 
5.2. 
Study Stopping Rules ............................................................................................................... 49 
5.3. 
End of Study ............................................................................................................................. 49 
5.4. 
Justification for Dose of eftilagimod alfa ................................................................................. 49 
5.5. 
Justification for Dose of pembrolizumab ................................................................................. 51 
5.6. 
Selection of Patients ................................................................................................................. 52 
5.6.1. Inclusion Criteria ............................................................................................................... 52 
5.6.2. Exclusion Criteria .............................................................................................................. 53 
6 
STUDY TREATMENTS ................................................................................................................ 57 
6.1. 
Identity of Investigational Medicinal Products ........................................................................ 57 
6.1.1. Eftilagimod alfa ................................................................................................................. 57 
6.1.2. Pembrolizumab.................................................................................................................. 57 
6.2. 
Packaging, Labelling, and Shipping ......................................................................................... 57 
6.3. 
Storage ...................................................................................................................................... 57 
6.4. 
Dose Regimen, preparation and administration of study treatments ........................................ 57 
6.5. 
Methods of Assigning Patients ................................................................................................. 59 
6.6. 
Blinding and Procedure for Unblinding ................................................................................... 59 
6.7. 
Dose Modifications and treatment delays ................................................................................ 59 
6.7.1. Eftilagimod alfa (efti) ........................................................................................................ 59 


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6.7.2. Pembrolizumab.................................................................................................................. 61 
Dose modification and toxicity management for immune-related AEs ...................................... 61 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab .. 62 
6.8. 
Other allowed dose interruption for study treatment ................................................................ 67 
6.9. 
Rescue Medications & Supportive Care ................................................................................... 67 
6.10. 
Prior and Concomitant Therapy ............................................................................................... 67 
6.11. 
Treatment Compliance ............................................................................................................. 69 
6.12. 
Drug accountability .................................................................................................................. 69 
6.13. 
Contraception Methods ............................................................................................................ 69 
6.14. 
Pregnancy ................................................................................................................................. 70 
7 
INVESTIGATIONAL PLAN ......................................................................................................... 71 
7.1. 
Study visits and procedures ...................................................................................................... 71 
7.2. 
Overview of Study Assessment Schedule ................................................................................ 73 
7.2.1. End of Treatment Visit ...................................................................................................... 77 
7.2.2. Progression Free Survival (PFS) - Follow-Up .................................................................. 77 
7.2.3. Overall Survival (OS) - Follow-Up ................................................................................... 78 
7.2.4. Unscheduled Visits ............................................................................................................ 78 
7.3. 
Withdrawal, Discontinuation and Replacement of Patients ..................................................... 78 
7.3.1. Patient Withdrawal ............................................................................................................ 78 
7.3.2. Early Treatment Discontinuation for individual patients .................................................. 78 
7.3.3. Replacement of Patients .................................................................................................... 79 
7.4. 
Protocol Compliance ................................................................................................................ 79 
8 
STUDY ASSESSMENTS ................................................................................................................ 80 
8.1. 
Efficacy Assessments ............................................................................................................... 80 
8.1.1. Radiological Scans and color digital photography ............................................................ 80 
8.1.2. Tumor Response acc. to iRECIST .................................................................................... 81 
8.1.3. Confirmation of Progressive Disease acc. to iRECIST ..................................................... 84 
8.1.4. Tumor Response acc. to RECIST 1.1................................................................................ 85 
8.1.5. Progression-Free Survival ................................................................................................. 86 
8.1.6. Overall Survival ................................................................................................................ 87 
8.2. 
Pharmacokinetics ...................................................................................................................... 87 
8.3. 
Biomarkers ............................................................................................................................... 88 
8.3.1. Th1 Biomarkers ................................................................................................................. 88 
8.3.2. Tumor tissue sample.......................................................................................................... 88 
8.3.3. Gene expression profile analyses ...................................................................................... 88 
8.4. 
Immunogenicity ........................................................................................................................ 88 
8.5. 
Safety Assessments .................................................................................................................. 89 
8.5.1. Laboratory Tests ................................................................................................................ 89 
8.5.2. 12-Lead ECGs ................................................................................................................... 89 
8.5.3. Vital Signs Assessments.................................................................................................... 89 
8.5.4. Adverse Events .................................................................................................................. 90 
8.6. 
Medical History ........................................................................................................................ 90 
8.7. 
Concomitant Therapy and Concomitant Procedures Assessment ............................................ 90 
9 
Adverse & Serious Adverse Events ............................................................................................... 91 
9.1. 
Adverse Events ......................................................................................................................... 91 
9.2. 
Serious Adverse Events ............................................................................................................ 92 
9.3. 
Events of clinical interest ......................................................................................................... 92 
9.4. 
Time period and frequency for collecting AEs, SAEs, pregnancy and ECIs ........................... 93 


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9.5. 
Expedited reporting of SAEs, ECIs or pregnancy .................................................................... 93 
10 
StatistIcal methods .......................................................................................................................... 95 
10.1. 
Sample Size Determination ...................................................................................................... 95 
10.2. 
Assignment to treatment ........................................................................................................... 96 
10.3. 
Analysis Populations ................................................................................................................ 96 
10.4. 
Handling of Missing Data ........................................................................................................ 97 
10.5. 
Subgroup Analyses ................................................................................................................... 97 
10.6. 
Interim Analyses ....................................................................................................................... 97 
10.7. 
Timing of analysis .................................................................................................................... 97 
10.8. 
Baseline and Demographic Characteristics .............................................................................. 97 
10.9. 
Efficacy Analyses ..................................................................................................................... 97 
10.9.1. Analysis of the primary endpoint.................................................................................... 97 
10.9.2. Analysis of the secondary and exploratory endpoints .................................................... 98 
10.10. Pharmacokinetic Analyses ........................................................................................................ 99 
10.11. Immunogenicity analyses ......................................................................................................... 99 
10.12. Biomarker Analyses ................................................................................................................. 99 
10.13. Safety Analyses ........................................................................................................................ 99 
11 
DATA HANDLING AND RECORD KEEPING ....................................................................... 101 
11.1. 
Case Report Forms ................................................................................................................. 101 
11.2. 
Source Documents .................................................................................................................. 101 
11.3. 
Record Retention .................................................................................................................... 101 
11.4. 
Drug Accountability ............................................................................................................... 101 
12 
MONITORING ............................................................................................................................. 102 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................................... 102 
14 
PROTOCOL AMENDMENT AND PROTOCOL DEVIATION ............................................ 102 
14.1. 
Protocol Amendment .............................................................................................................. 102 
14.2. 
Protocol Deviation .................................................................................................................. 102 
15 
ETHICAL CONSIDERATIONS ................................................................................................. 103 
15.1. 
Site Review ............................................................................................................................. 103 
15.2. 
Informed Consent ................................................................................................................... 103 
16 
FINANCING AND INSURANCE ............................................................................................... 104 
17 
PUBLICATION POLICY ............................................................................................................ 104 
18 
REFERENCES .............................................................................................................................. 105 
19 
APPENDICES ............................................................................................................................... 109 
19.1. 
ECOG Performance Status ..................................................................................................... 109 
19.2. 
iRECIST: Guidelines for response criteria for use in trials testing Immunotherapeutics ...... 109 
19.3. 
Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 ................................. 109 
19.4. 
Imaging Protocols ................................................................................................................... 109 
19.5. 
Definitions for Clinical and Laboratory AEs ......................................................................... 111 
 
 


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LIST OF TABLES 
Table 1: Schedule of Assessments (Part A + B + C) .................................................................................. 21
Table 2: Overall exposure to efti (cut-off Oct 2018)................................................................................... 36
Table 3: Overview TEAE related to the mechanism of action of efti and overall. n is the number of subjects. 
Total number of patients investigated N=84. ...................................................................................... 36
Table 4: Study P012 - adverse events by PT and worst severity. n= number of pts ................................... 37
Table 5: Study P012 – ORR acc to irRC. ................................................................................................... 38
Table 6: Exposure of efti over time at  and
 mg .................................................................................... 50
Table 7: Toxicity Management and Discontinuation Guidelines for local injection site reactions and 
systemic hypersensitivity reactions related to eftilagimod ................................................................. 60
Table 8: Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab ................................................................................................................................... 63
Table 9: Pembrolizumab Infusion Reaction Dose modifications and Treatment guidelines ...................... 66
Table 10: Overview of study assessment specifications. All assessments are done locally if not otherwise 
indicated .............................................................................................................................................. 71
Table 11: Overview of assessments at Screening ....................................................................................... 74
Table 12: Overview of Assessments during combination treatment Cycle 1 to 8 ...................................... 74
Table 13: Overview of Assessments on Day 8 of each even cycle and Day 15 each odd cycle ................. 75
Table 14: Overview of assessments during day 1 of cycles 9 to 18............................................................ 75
Table 15: Assessments for subset of patients who participate in the PK part ............................................. 76
Table 16: Overview of Assessments during Cycle 19 until 35 (Pembrolizumab monotherapy). Cycle 19 
may also be end of combination treatment ......................................................................................... 76
Table 17: Overview of Assessments at the End of Treatment .................................................................... 77
Table 18: Assessment of overall response at a specific timepoint (61). ..................................................... 83
Table 19: Censoring rules for PFS. ............................................................................................................ 87
Table 20: CT Imaging Protocol ................................................................................................................ 110
 
LIST OF FIGURES 
Figure 1: Treatment paradigm HNC. (25) .................................................................................................. 33
Figure 2: Diagrammatic structure of efti (IMP321), a first-in-class APC activator.................................... 34
Figure 3: Trial P012 – Spiderplot (irRC) by subject. Data cut-off 15-Oct-2018. ....................................... 39
Figure 4: Study flow chart for part A, B and C. .......................................................................................... 48
Figure 5 Management of hypersensitivity reactions, adapted from (59) .................................................... 61
Figure 6: Imaging and Treatment for Clinically Stable Patients Treated with Pembrolizumab after First 
Radiologic Evidence of PD Assessed by the Investigator .................................................................. 85
 
 
CCI
C
CI


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GLOSSARY OF TERMS AND ABBREVIATIONS 
Abbreviation 
Definition 
5-FU 
5-Fluorouracil 
AACR 
American Association for Cancer Research 
ADA 
Anti-Drug Antibodies (in this context against eftilagimod alpha) 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase  
ALK 
Anaplastic Lymphoma Kinase 
AMA 
Antimitochondrial Antibodies 
ANA 
Antinuclear Antibodies 
ANC 
Absolute Neutrophil Count 
APC 
Antigen-Presenting Cells 
APTT 
Activated Partial Thromboplastin Time 
ASAT 
Aspartate Aminotransferase 
ATA 
Antithyroid (Antithyroglobulin) Antibodies 
AUC 
Area Under the Curve 
BCG 
Bacillus Calmette–Guérin 
BOR 
Best Overall Response 
CCDS 
Company Core Data Sheet 
CD 
Cluster of Differentiation 
CI 
Confidence Interval 
CL 
Systemic Clearance 
Cmax 
Maximum (or Peak) Serum Concentration 
CMH 
Cochran-Mantel Haenszel 
COVID-19 
infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2) 
CR 
Complete Response 
CRF 
Case Record Form 
CRP 
C-reactive Protein 
CRS 
Cytokine Release Syndrome 
CT 
Computed Tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events  
CTL 
Cytotoxic T Lymphocyte(s) 
CXCL 
C-X-C motif chemokine 
DC 
Dendritic Cell 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DOR 
Duration of response 
DP 
Drug Product 
DSUR 
Developmental Safety Update Report 
ECG 
Electrocardiogram 
ECI 
Event of Clinical Interest  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture  
efti 
Eftilagimod alfa (eftilagimod alpha, IMP321) 
EGFR 
Epidermal Growth Factor Receptor 
EoC 
End of Combo (visit) 
EoT 
End of Treatment (visit) 
EORTC 
European Organization for Research and Treatment of Cancer 
EU 
European Union 


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Abbreviation 
Definition 
EudraCT  
European Clinical Study s Database 
FAS 
 Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
FU 
Follow Up 
GCP 
Good Clinical Practice 
GEC 
Gastroesophageal Cancer 
GGT 
Gamma-Glutamyl Transpeptidase 
GMP 
Good Manufacturing Practice 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Cancer 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HNSCC 
Head and Neck squamous cell carcinoma  
HR 
Hazard Ratio 
i.v. IV 
Intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
iCPD 
Confirmed progressive disease according to iRECIST 
iCR 
Complete Response acc to iRECIST 
IEC 
Independent Ethics Committee 
IgG4 
Immunoglobulin G4 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
IND 
Investigational New Drug 
INF-g 
Interferon Gamma 
IP 10 
Interferon gamma-induced protein 10  
iPR 
Partial Response acc to iRECIST 
irAE 
Immune-Related Adverse Event 
IRB 
Institutional Review Board 
iRECIST 
Guidelines for response criteria for use in trials testing Immunotherapeutics  
iSD 
Stable Disease acc to iRECIST 
iUPD 
Unconfirmed progressive disease 
LAG-3 
Lymphocyte Activation Gene 3 
LAG-3Ig 
Lymphocyte Activation Gene 3 Immunoglobulin (=Efti or IMP321) 
LDH 
Lactate Dehydrogenase 
LLOQ 
Lower Limit of Quantification 
MBC 
Metastatic Breast Cancer 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major Histocompatibility Complex 
MICD 
Minimal Important Clinical Difference 
mLAG-3Ig 
Murine homologue of IMP321 (hLAG-3Ig) 
MNC 
Mononuclear Cell 
MoA 
Mechanism/Mode of Action 
MRCC 
Metastatic Renal Cell Cancer 
MRI 
Magnetic Resonance Imaging 


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Abbreviation 
Definition 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NE 
Non-Evaluable 
NK cell 
Natural Killer Cell 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Objective Response Rate 
OS 
Overall Survival 
OTC 
Over the Counter 
PBMC 
Peripheral Blood Mononuclear Cell 
PBPK 
Physiologically-based PK 
PD 
Progressive Disease or Pharmacodynamic dependent on the context 
PD-1 
Programmed Cell Death Protein 1 
PD-L1 
Programmed Death Ligand 1 
PD-L2 
Programmed Death Ligand 2 
PD-X 
PD-1 or PD-L1 (targeted therapy) 
PFS 
Progression-Free Survival 
 
 
 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Partial Response 
PR interval 
ECG parameter (represents the time the impulse takes to reach the ventricles from the sinus 
node) 
Q3W 
Every 3 weeks 
QOL 
Quality of Life 
QRS complex 
ECG parameter (represents the time for ventricular depolarization) 
QT interval 
ECG parameter (represents the time from depolarization to repolarization of the ventricles) 
QTc 
Heart rate-corrected QT interval 
RBC 
Red Blood Cell 
RCC 
Renal Cell Cancer 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RHF 
Rheumatoid Factor 
ROC 
Recurrent Ovarian Cancer   
RPTD 
Recommended Phase Two Dose 
RR interval 
ECG parameter (represents the duration of one complete cardiac cycle, a measure of the 
heart rate) 
RSD 
Reference Safety Database 
SAD 
Short Axis Diameter
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC s.c. 
Subcutaneous 
SD 
Stable Disease 
SIM 
Site Imaging Manual 
sLAG-3 
Soluble LAG-3 (Lymphocyte Activation Gene-3) Protein 
SOP 
Standard Operating Procedure 
Study agent/drug 
Every IMP used in this study (i.e. efti or pembrolizumab). The Terminology Study agent is 
used as equal to Study drug  
Study treatment 
Any combination of pembrolizumab + efti  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Tesla 
t1/2 
Elimination Half-Life 
CCI
CCI


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Abbreviation 
Definition 
TdP 
Torsade de Pointes 
TEAE 
Treatment-emergent Adverse Events 
Th1 
Helper T Cells Type 1 
TIL 
Tumor Infiltrating Lymphocytes 
TLR 
Toll-like Receptor 
Tmax 
Time to Reach Cmax 
TMDD 
Target-mediated Drug Disposition 
TNBC 
Triple Negative Breast Cancer 
Treg 
Regulatory T Cell 
TTNT 
Time to Next Treatment 
ULN 
Upper Limit of Normal 
US, USA 
United States 
VD 
Volume of Distribution 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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3 
INTRODUCTION 
The information given in this section is an overview of the pre-clinical and clinical development program 
for eftilagimod alfa (efti, eftilagimod alpha, IMP321) and pembrolizumab to date that underpin the 
proposed Phase II clinical study. Further specific and more detailed information is provided in the 
Investigator’s Brochure (IB) for efti. The IB will be updated at regular intervals and whenever new safety 
relevant data become available. 
 
3.1. Standard Treatment Options 
3.1.1. Advanced non-small cell lung cancer (NSCLC) 
Almost 800.000 new cases of NSCLC are reported worldwide every year accounting for approximately 
85 % of all lung cancers (13). NSCLC can be divided into adeno-, large cell and squamous cell carcinoma 
representing approximately 50-60 %, 30-40 % and 2-10 % with differences between the regions.  
NSCLC is the indication leading to the most cancer related death worldwide as it is mostly diagnosed 
relatively late. In the US approximately 180.000 new cases were recorded in 2015 (13). The 5-year survival 
rate published by the American Cancer Society in 2017 for patients with stage IIIA NSCLC is about 36 %. 
For stage IIIB cancers the survival rate is about 26 %. For stage IIIC cancers the survival rate is about 13 %. 
(14). Approximately 41 % are diagnosed with stage IVA with a 5-year survival rate of ~ 10 % or stage IVB 
with a survival rate of <1 % (13).  
3.1.2. 1st line NSCLC  
Treatment of NSCLC is dependent on histological subtypes (squamous vs. non-squamous) and presence of 
EGFR, BRAF, ALK or ROS1 mutations. Patients with actionable mutations (10-20 % of all NSCLC 
patients (15)) will receive targeted therapies such as dabrafenib or ceretinib, depending on the mutation 
(16).  
Patients with >50 % programmed death ligand 1 (PD-L1) expression and non-squamous NSCLC can be 
treated with the programmed death 1 (PD-1) blocking antibody pembrolizumab as first line therapy (16). 
In the Keynote-024 study an objective response rate (ORR) of 45 %, median progression free survival (PFS) 
of 10.3 and median overall survival (OS) of 30 months were reported (10). These results were confirmed 
in the Keynote-042 study where single agent pembrolizumab led to a statistically significant overall survival 
benefit compared to doublet chemotherapy in first line NSCLC patients with either squamous or non-
squamous disease and PD-L1 expression of >1 % (17). The response rate for pembrolizumab in this patient 
population was reported with 27 % (11).  
For patients not amenable to treatment with therapies targeting the EGFR pathway or pembrolizumab 
monotherapy will receive (based on the performance status) platinum-based doublet chemotherapy in 
combination with pemetrexed. The ORR of platinum plus pemetrexed was reported with 28 %. The median 
PFS was 6 months (10).  
Just recently at American association for Cancer Research (AACR) congress April 2018, results from the 
Keynote-189 trial were reported for the combination of platinum-based chemotherapy plus pemetrexed ± 
pembrolizumab (18) in first line non-squamous NSCLC patients. An ORR of 47.6 % compared to 18.9 %, 
and overall survival hazard ratio (HR) of 0.49 was reported regardless of PD-L1 expression. The 
combination of ipilimumab and nivolumab (CTLA-4 and PD-1 antagonists) also reported superior efficacy 
(median PFS of 7.2 months) compared to chemotherapy (median PFS of 5.5 months) in a large Phase III 
trial, in NSCLC patients with high tumor mutational burden (19). Pembrolizumab has been submitted for 
registration for the patient population investigated in Keynote-189 and accepted for 1st line treatment of 


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NSCLC not harboring EGFR and ALK driver mutations in combination with pemetrexed and platinum 
chemotherapy. 
3.1.3. 2nd line NSCLC  
Although it is difficult to estimate the proportion of NSCLC patients receiving 2nd line therapy, it was about 
40-50 % in recent clinical trials (20). Single agent chemotherapy was the mainstay for long. Docetaxel, a 
widely used single agent chemotherapy, results in a ORR of 9-12 %, a median PFS of about 4 months, and 
a median OS of about 9 months (21, 22). Different PD-1/PD-L1 targeting therapies (pembrolizumab, 
nivolumab or atezolizumab) are approved and recommended for monotherapy for different 2nd line NSCLC 
subsets. In PD-X naïve (having not received any PD-1 or PD-L1 antagonist) 2nd line patients with non-
squamous NSCLC and PD-L1 expression >1 % pembrolizumab at doses of 2 or 10 mg/kg led an ORR of 
18 %, a median PFS of ~4 months and a median OS of 10.4-12.7 months (3). Nivolumab obtained 
comparable results with ORR of 19 %, median PFS of 2.3 and OS of 12.3 months regardless of PD-L1 
expression. Both drugs are approved in 2nd line NSCLC after failure of platinum-based 1st line 
chemotherapy.  
The majority of patients with metastatic NSCLC will progress and ultimately succumb to their disease. 
Based on the results published at AACR 2018 it is assumed that shortly the clear majority of patients not 
amenable to ALK/EGFR targeted therapy will receive a PD-X antibody in the first line setting. Therefore, 
new treatment regimens for 1st line in combination with an anti-PD-1 antibody and for PD-X refractory 2nd 
line NSCLC are needed to improve clinical benefit in this incurable setting.  
3.1.4. Recurrent or metastatic head and neck cancer  
Worldwide about half a million new cases of head and neck cancer (HNC) are reported every year. For the 
US 58.115 cases were reported for 2016 with an anticipated annual growth rate of approximately 1.5 % for 
the next decade. Initial treatment options for stage I-III are, if feasible, surgery and/or radiation therapy 
together with adjuvant regimes. If the cancer is non-resectable, chemoradiotherapy is offered as standard 
of care.  
HNC has a recurrence rate of 20-50 % depending on the stage of diagnosis and is responsible for about 
300.000 death per year worldwide (23, 24). The treatment paradigm for HNC is schematically depicted in 
Figure 1.  
 
Figure 1: Treatment paradigm HNC. (25) 


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First line systemic treatment for recurrent or stage IV non-nasopharyngeal HNC consist according to the 
National Comprehensive Cancer Network (NCCN) guideline mostly of platinum-based combination 
therapies, especially the combination of cisplatin, 5-FU and cetuximab followed by cetuximab maintenance 
therapy (23, 24).  
Standard 2nd line treatments include methotrexate or docetaxel with an ORR of around 6 % and an OS of 
about 6 months (24, 26). In the last years, several PD-1 targeted therapies (nivolumab, pembrolizumab) 
have been approved by the Food and Drug Administration (FDA) with reported ORR of 13.3-16.2 %, 
median PFS of around 2.1 month and a median OS of 7.1-8.4 month (24, 26). Despite some durable 
responses observed under pembrolizumab and nivolumab therapy improvement of the treatment options for 
recurrent head and neck squamous cell carcinoma (HNSCC) patients is warranted. Further improvement 
for 2nd line recurrent HNSCC patients is urgently needed, given the short OS time and the low response 
rate. 
 
3.2. 
Eftilagimod alfa 
Eftilagimod alfa (efti, eftilagimod alpha, IMP321) consists of the extracellular portion of the human LAG-
3 protein (27, 28) fused to the Fc fraction of a human IgG1 (Figure 2). This soluble LAG-3Ig fusion protein, 
like the membrane form of LAG-3 naturally expressed on human T cells, binds to Major Histocompatibility 
Complex (MHC) class II molecules on the surface of antigen presenting cells (APC) and promotes the 
activation, maturation and chemokine secretion of APC (29-35). Efti is a first-in-class APC activator. 
 
 
Figure 2: Diagrammatic structure of efti (IMP321), a first-in-class APC activator 
 
APC such as dendritic cells (DC) and monocytes/ macrophages form a network in tissues. Following a 
“danger signal” (e.g., local infection/ tumor) DC capture non-self-microbial/ oncogenic proteins, digest 
these proteins into immunogenic peptides, migrate to the draining lymph nodes a few centimeters away and 
present these peptides to CD4 and CD8 T-lymphocytes. The binding of efti to MHC class II leads to APC 
activation/ expansion with enhanced presentation of tumor antigens to T-cells. As a result, strong and 
sustained anti-tumor cytotoxic T-cell responses are obtained. This natural process is made even more 
effective when efti is given the day after chemotherapy at a time when APC are fully loaded by tumor cell 
antigenic debris from the dying tumor cells. 
CH3
CH3
CH2
CH2
Hinge
Hinge
CH1
CH1
VH
VH
VL
VL
CL
CL
Human 
Human Ig
Ig
sLAG
sLAG-3
D4        D3         D2        D1
D4        D3         D2        D1
CH3
CH3
CH2
CH2
Hinge
Hinge
IMP321
IMP321 : a 
: a dimeric
dimeric, very stable 
, very stable 
human protein with high affinity for DC 
human protein with high affinity for DC 
“LAG
LAG-3Ig
3Ig”
two cGMP batches used in
clinical trials in EU and US
CH3
CH3
CH2
CH2
Hinge
Hinge
CH1
CH1
VH
VH
VL
VL
CL
CL
CH3
CH3
CH2
CH2
Hinge
Hinge
CH1
CH1
VH
VH
VL
VL
CL
CL
Human 
Human Ig
Ig
sLAG
sLAG-3
D4        D3         D2        D1
D4        D3         D2        D1
CH3
CH3
CH2
CH2
Hinge
Hinge
CH3
CH3
CH2
CH2
Hinge
Hinge
IMP321
IMP321 : a 
: a dimeric
dimeric, very stable 
, very stable 
human protein with high affinity for DC 
human protein with high affinity for DC 
“LAG
LAG-3Ig
3Ig”
two cGMP batches used in
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3.2.1.  
Non-clinical Data 
As already mentioned above, LAG-3 is a membrane protein associated with the T-cell receptor on the 
surface of activated T cells, which binds to MHC class II molecules on the surface of APC (28, 34, 36-38) 
and promotes the activation, maturation and chemokine secretion of human DC (31-33). In addition, a 
natural soluble form of the LAG-3 molecule (sLAG-3), is found in normal sera and has been shown to be 
a good prognostic factor as a Th1 marker in tuberculosis and breast cancer.  
Immune checkpoint pathways strongly downregulate T-cell activation with the intent of keeping nascent 
T-cell responses in check and reducing the likelihood of an immune attack against normal tissues. During 
tumorigenesis, however, cancer cells may exploit these inhibitory pathways to resist detection or avoid 
elimination by the adaptive immune system. PD-1 is a critical checkpoint molecule that is expressed by T 
cells upon activation. The PD-1 pathway blockers display a remarkable success in anti-tumor response but 
with heterogeneous efficacy depending on patients and cancer types. 
Exploiting these two aspects of immune system regulation by combining efti as APC activator with 
checkpoint blockers is therefore an attractive way to increase the response level and number of responsive 
patients. The benefit of combining these two agents is supported by in vitro and in vivo experiments. In 
culture, primary human blood cells stimulated with sub-optimal dose of antigen, incubated with low dose 
of efti or low dose of anti-PD-1 or PD-L1 blocking antibody produced Type-1 cytokines and T cell 
expressed activation markers. When combining low dose of both reagents, a synergy is observed inducing 
more cytokines secretion and more T cells to express activation markers compared to the response observed 
even at concentration of PD-1 pathway blockers that was 30 or 100-fold higher. It was concluded from 
these results that the ex vivo type-1 response induced by PD-1 pathway antagonists is synergistically 
increased by efti.   
In a mouse model of 
 
. Further details can be found in the latest version 
of the Investigators Brochure.  
3.2.2.  
Clinical Data  
Based on the mechanism of action of efti as an APC activator, several options exist for the use of efti in the 
treatment of cancer: 
x 
In combination with chemotherapy (chemo-immunotherapy) - amplifying the immune system 
response using the antigens released by dying tumor cells;  
x 
In combination with other active immunotherapies, having a complementary mechanism of action as 
an immune checkpoint inhibitor (e.g. anti-PD-1/PD-L1, CTLA-4 mAb); and  
x 
As an adjuvant for cancer vaccines or after intra-tumoral injections (in situ immunization) – 
locally boosting the immune response to specific tumor antigens. 
Although efti was first tested as an adjuvant to cancer vaccines and later in combination with chemotherapy, 
this protocol is investigating the combination of efti with pembrolizumab, hence combining two active 
immunotherapies.  
In total 234 cancer patients have received at least one dose of efti2 (for details see Table 2). In all subjects, 
efti has been administered s.c. All patients had advanced/metastatic solid tumours, including 21 patients 
 
2 Thereof appr. 70 pts (50 % from 141) may have received placebo instead of IMP321.  
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with metastatic renal cell carcinoma, 189 with metastatic breast cancer and 24 with advanced metastatic 
melanoma. One-hundred-eighty-six (189) patients have received different dose levels of efti in combination 
with paclitaxel (80 mg/m2 i.v. day 1, 8 and 15, every 4 weeks) and 24 patients have received efti in 
combination with pembrolizumab (2 mg/kg i.v. every 3 weeks). Of the 234 subjects 55 were treated with 
efti produced under the Henogen process and 180 with efti produced by Wuxi process (for details see 
respective IB). 
Table 2: Overall exposure to efti (cut-off Oct 2018). 
Parameter 
Subjects with cancer 
(Henogen material) 
Subjects with Cancer 
(Wuxi material) 
Overall 
Overall 
54 
180 
234 
mRCC (as monotherapy) 
21 
- 
21  
MBC (combination with paclitaxel) 
33 
156* 
189  
Met. 
Melanoma 
(combination 
with 
pembrolizumab) 
0 
24 
24 

A total of 234 subjects with advanced cancer were evaluated. No efti related death was reported in any of 
the trials. One subject within P011 had a fatal serious adverse event of Massive Pulmonary Embolism, 
which was considered unrelated to efti. 52 out of 234 (22.2 %) subjects experienced at least one SAE (in 
total 67 SAEs).  
 
 
 
.  
 
 
 
 
 
 
 
 
 
 and for both patient’s treatment was permanently discontinued. Other SUSARs 
are most likely related to the underlying disease or the adjunctive chemotherapy and are described in detail 
in the IB.  
Detailed analysis on adverse event level were performed for run.in phase of P011, P012 (part A) and P003 
and P005 (n overall = 84). The majority of the adverse events reported were related to the underlying disease 
(late stage advanced, metastatic cancer), the adjunctive chemotherapy or to pembrolizumab.  
Transient dose dependent 
 
 
 reported as shown in Table 3. These are likely related to the s.c. administration of efti.  
 
 were the most common (≥10 %) adverse events related to the mechanism of action 
of efti.  
Table 3: Overview TEAE related to the mechanism of action of efti and overall. n is the number of subjects. Total 
number of patients investigated 
.   
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Preferred Term (> 10 % of pts) 
Overall N (%) 
 
   
) 
 
   
) 
 
   (
) 
 
 (
) 
 
  
) 
* - only includes FAS population for P005; # - incl. 
 
Repeated (every 2 weeks) subcutaneous injections of efti up to 30 mg alone or in combination with weekly 
paclitaxel or pembrolizumab as a treatment for advanced cancer are safe and well tolerated. At 30 mg one 
dose limiting toxicity (DLT) was observed (in combination with weekly paclitaxel), but the maximal 
tolerable dose was not reached in any of the clinical trials.  
In the P012 (TACTI-mel) study 18 patients (17 male, 1 female) with advanced/metastatic melanoma and a 
median age of 67 years (range 48-85) were enrolled. Patients have been treated with the combination of 
pembrolizumab and efti (1, 6, and 30 mg) starting from cycle 5 of pembrolizumab. 6 patients have been 
treated at 30 mg level.  
 
Table 4: Study P012 - adverse events by PT and worst severity. n= number of pts 
Reported Term by 
frequency 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Overall (N=18) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Fatigue 
 
 
 
 
Rash# 
 
 
Diarrhoea 
 
 
 
Nausea 
 
 
 
 
Arthralgia 
 
 
 
 
Hyperglycaemia 
 
 
 
 
 
 
Altered liver function 
 
 
 
 
 
 
Anaemia of chronic 
disease 
 
 
 
 
 
 
Bilateral axillary dissection 
 
 
 
 
 
 
Decreased renal function 
 
 
 
 
 
 
Intestinal perforation 
 
 
 
 
Colitis 
 
 
 
 
 
 
Influenza A 
 
 
 
 
 
 
Intracranial Haemorrhage 
 
 
 
 
Hyponatraemia 
 
 
 
 
 
 
Pulmonary embolism 
 
 
 
 
 
 
Right sided chest pain 
 
 
 
 
 
 
Sepsis of unknown origin 
 
 
 
 
 
 
Shortness of breath 
 
 
 
 
 
 
Listed if occurred in ≥15 % or ≥ grade 3.  # - including 
 
The data cut-off is Oct 2018. No treatment related death was reported. No treatment related death was 
reported. Seven SAEs in 6 subjects were reported. None of the SAEs were related to the study treatment. 
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One grade 4 intracranial haemorrhage was reported (not related) leading to death in one subject. Another 
subject permanently discontinued the treatment due to an anaemia of chronic disease grade 3 (not related 
to efti or pembrolizumab). No dose limiting toxicity at any dose was reported.  
In summary efti given subcutaneously biweekly at a dose of 1, 6 or 30 mg in combination with 2 mg/kg IV 
pembrolizumab every 3 weeks was well tolerated without any DLT.  
In total 133 AEs were reported in 18 subjects. The most frequently (>10 %) reported AEs were fatigue 
(44 %), rash (including maculo-papular rash) (39 %), diarrhea (28 %), nausea (28 %), arthralgia (17 %) and 
hyperglycemia (17 %). 
One subject experienced not related a grade 4 AE (intracranial haemorrhage, 6 mg efti). Eighteen (18) AEs 
grade 3 were reported in eight subjects as listed. No adverse event grade 3 occurred twice except 
hyperglycemia. 
Eighteen (18) AEs in 9 subjects were related to efti. One patient experienced grade 3 decreased renal 
function. All other AEs were grade 1 or 2.  
The majority (78 %) of subjects had M1c stage disease. The ECOG status at screening was 0 in 14 (78 %) 
and 1 in 4 (22 %) subjects, respectively. Five (27.8 %) patients have received prior systemic therapy for 
metastatic disease. None of the patients had prior PD-1 or PD-L1 antibodies except the four cycles of 
pembrolizumab prior to study start. The majority of subjects had either an irSD (39 %) or irPD (28 %) as 
best response after the first 3 cycles of pembrolizumab monotherapy. Overall an ORR of 33.3 % was 
achieved incl. 1 subject (5.6 %) with a complete response as shown in Table 5. Besides six subjects with a 
tumor size decrease > 50 % compared to baseline including 2 subjects with complete disappearance of all 
target lesions, four subjects showed a decrease in target lesions between 45 and 49 %. In total ten subjects 
(55.6 %) had a target lesion decrease and disease control rate was 66.6 %.  
 
Table 5: Study P012 – ORR acc to irRC.  
Parameter acc. to irRC 
Total  
N=18 
Complete Response 
1 (5.6 %) 
Partial response 
5 (16.7 %) 
Stable disease 
6 (33.3 %) 
Progressive disease 
6 (33.3 %) 
Not evaluable# 
0 (0.0 %) 
Disease control rate (DCR) 
11 (61.1 %) 
Objective Response Rate (ORR) 
6 (33.3 %) 
 
There is little experience in large clinical studies in patients not responding well to pembrolizumab 
monotherapy and continuing on pembrolizumab. In treatment naïve melanoma patients with metastatic 
disease, pembrolizumab resulted in an ORR of 33-34 % (incl. 6-10 % complete responses) (39). In patients 
pre-treated with either BRAF/MEK inhibitors or ipilimumab pembrolizumab resulted in an ORR of 21-
25 % with 2-3 % of complete responders (40, 41). Responses were assessed according to response 
evaluation criteria in solid tumors (RECIST) 1.1.  
 


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Figure 3: Trial P012 – Spiderplot (irRC) by subject. Data cut-off 15-Oct-2018.  
 
In the P012 study 28 % have been pre-treated with either ipilimumab or a BRAF/MEK inhibitor and 28 % 
progressed on pembrolizumab monotherapy prior to study start. Responses were assessed according to irRC 
and not RECIST 1.1. Five partial and one complete response were observed leading to an ORR of 33.3 %. 
Although some of the patients initially had a progression on pembrolizumab monotherapy and others have 
been pre-treated the disease control rate and response rates observed so far are encouraging.  
 
3.3. 
Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high 
specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with 
programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on preclinical 
in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous 
(i.v.) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment 
of patients across a number of indications. For more details on specific indications refer to the Investigator’s 
Brochure.  
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on MK-
3475. 
 
3.3.1. Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades . Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies. In particular, the 
presence of CD8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) 
correlates with improved prognosis and long-term survival in solid malignancies, such as ovarian, 
colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma (42). 
0
3
6
9
12
15
18
21
24
27
-100
-50
0
50
100
400
800
months
% change compared to start of combo
pre-
pembro start of
combo
n =18
irPD
irSD
irPR
irCR


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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. 
The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, 
is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 
(encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to cluster of 
differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown 
to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
(43). 
The structure of murine PD-1 has been resolved. PD-1 and its family members are type I transmembrane 
glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for ligand binding and a 
cytoplasmic tail responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 
2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif, and an 
immunoreceptor tyrosine-based switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling 
cascade (43, 44). The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins (45, 46). 
As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in NSCLC 
and HNSCC.  
3.3.2. Pre-clinical and Clinical Data 
Therapeutic studies in mouse models have shown that administration of antibodies blocking PD-1/PD-L1 
interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads to tumor rejection, 
either as a monotherapy or in combination with other treatment modalities (47-53). Anti-mouse PD-1 or 
anti-mouse PD-L1 antibodies have demonstrated antitumor responses in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia, and colorectal carcinoma (50, 52-
55). In such studies, tumor infiltration by CD8+ T cells and increased interferon (IFN)-γ, granzyme B and 
perforin expression were observed, indicating that the mechanism underlying the antitumor activity of PD-
1 checkpoint inhibition involved local infiltration and activation of effector T cell function in vivo (52). 
Experiments have confirmed the in vivo efficacy of anti-mouse PD-1 antibody as a monotherapy, as well 
as in combination with chemotherapy, in syngeneic mouse tumor models (see the IB). 
Efficacy data for the Merck-sponsored clinical trials used to support approvals in the US for the following 
indications: melanoma, NSCLC, HNSCC, cHL, UC, and MSI-H tumors.   
The Reference Safety Database (RSD) is used to present the characterization of pembrolizumab’s safety 
profile. 
 
 
. Pembrolizumab is well tolerated in the approved indications, 
as evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs 
%), discontinuations due to Aes 
(
%), and deaths due to drug-related Aes 
%). Furthermore, the frequency of immune-mediated 
AEOSIs is low, and these events are readily managed in the clinical setting.  
3.4. Study Rationale  
Treatment of advanced solid tumors remains challenging despite the progress which has been made over 
the last years especially with targeted therapies like tyrosine kinase inhibitors, monoclonal antibodies and 
immunotherapies like PD-1/PD-L1 and CTLA-4 antagonists. Recently, immune therapies like anti CTLA-
4 and anti PD-1 antagonist have been approved by the FDA in many different solid tumors. In general 
immune therapies as single agents achieved response rates between 12 % (ovarian cancer) and 40 % 
(melanoma, MSI-high) in a high number of solid tumors (i.e. NSCLC; small cell lung cancer , renal cell 
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cancer (RCC), HNSCC, triple negative breast cancer, hepatocellular cancer , gastroesophageal cancer and 
others) (1-6). 
Understanding the reasons why a majority of patients does not respond to PD-1/PD-L1 blockade is key to 
develop new therapy combinations. On-treatment tumor biopsies have shown that non-responding patients 
have either little or no tumor-infiltrating lymphocytes (TILs) in the tumor bed or a non-functional immune 
response (i.e. no intratumoral IFNJ) with PD-1/PD-L1 negative TILs (7). Thus, immunogenic signals that 
induce tumor antigen-loaded DCs to escape peripheral tolerance and better prime and activate effector 
T cells are expected to reactivate the deficient early steps of the cancer-immunity cycle (8, 56). 
In a mouse model of 
 
 
 
In clinical studies with efti it has been shown that efti as an APC activator at a dose of ≥ 1 mg/injection 
induced a sustained increase in monocyte and dendritic cells blood counts as well as a sustained activation 
of blood monocytes over 6 months. Moreover, this APC activation led to a sustained increase of activated 
CD8 T cells over 6 months and a sustained increase in serum IFNJ, a Th1 cytokine.   
In the crosstalk between immune system and cancer, PD-1 antagonists like pembrolizumab address the 
immune escape (T cell downregulation). On the other hand, the capacity of the immune cells to recognize 
the tumor cells and prime an efficient effector response can be increased by an APC activator like efti.  
In patients eligible to anti-PD-1 therapy, the addition of a well-tolerated APC activator like efti may help 
to activate the cellular immune response mechanisms to mediate tumor recognition and killing and thus 
may lead to higher frequency of durable responses compared to pembrolizumab monotherapy in different 
solid tumor without adding substantial toxicity.  
 
3.5. Benefit and Risk Ratio 
In toxicology studies in mice, efti was well tolerated with no sign of inflammation, either injected alone or 
as an adjuvant with strongly immunogenic antigens (57). 
 
 
. 
The nonclinical toxicity studies for pembrolizumab consisted of 
 
 
. These 
studies were supported by toxicokinetic evaluation of pembrolizumab. Additional evaluation included
 
 
 
 There were no findings of 
toxicological significance in any of the conducted studies. 
In previous clinical studies, repeated s.c. doses of up to 30 mg efti alone (in metastatic RCC patients), in 
combination with paclitaxel (metastatic breast cancer (MBC) patients) and in combination with 
pembrolizumab (melanoma patients) were generally well tolerated and had an acceptable safety profile.  
Efti is a soluble human recombinant protein with the potential risk of inducing an allergic reaction. Possible 
symptoms associated with an allergic reaction can include fever, chills, weakness, headache, nausea, 
vomiting, diarrhoea, swollen lips and neck, low blood pressure, respiratory symptoms and rashes.  
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, 
 and 
 immediate systemic hypersensitivity 
reactions were reported in 
 trial subjects receiving 30 mg efti(/placebo) in combination with either 
paclitaxel or pembrolizumab. All 
 reactions show consistent time to onset from start of administration 
(i.e. within 30 minutes) and similar pattern of symptoms. All 
 cases occurred after multiple efti 
injections without any preceding signs/events suggesting systemic involvement and in all four cases the 
hypersensitivity symptoms resolved within one day.  
As there is a risk of an 
 
 
. 
 
 
 
. 
In both dose finding trials (P011 – AIPAC, P012 – TACTI-mel) cytokine levels were closely monitored 
after the first and 12th injection of efti. No increase of 
 have been observed at any dose 
level up to 30 mg efti s.c.. Increase of 
, 
, 
 and 
) have been reported from both trials at different dose levels (1-30 mg) of efti but these 
serum concentrations levels were too low to induce systemic reactions such as fever. Vital signs and other 
parameters are closely and frequently monitored during clinical trials with efti.  
Transient injection site reactions (including skin changes e.g. erythema, pain and induration) of mild and 
moderate intensity have been reported from all trials.  
Details on management of efti related adverse reaction are discussed in Section 6.7.1. 
In studies P003 and P005, no ADAs were detected in the serum of patients even after 12 s.c. injections of 
efti over 6 months. However, confirmed ADAs against efti have been reported with low to intermediate 
titers in the studies P012 
 patients tested post-treatment start) and P011 (
 patients tested post-
treatment start) and are further investigated. To evaluate this risk, the relationship between the therapeutic 
protein and endogenous LAG-3 (a co-inhibitory receptor expressed on activated  T cells) should be 
considered. If ADAs are induced in metastatic breast cancer patients and if a significant fraction of these 
ADAs are neutralizing antibodies, the function of the endogenous LAG-3 receptor expressed on activated 
effector T cells and on Treg cells will be blocked. Consequently, the anti-tumor cellular responses of these 
patients would be increased due to immune checkpoint blockade. This could lead to additional clinical 
benefit for cancer patients which outweighs the risks of immune-related adverse events (irAEs).  
Generally speaking, irAEs have been reported after the blocking of inhibitory receptors (CTLA-4, PD-1) 
expressed on T cells but not after stimulation of APCs (TLR8 or TLR9 agonists, anti-CD40 agonist mAb). 
So far, no irAEs have been observed. However, occurrence of irAEs cannot be excluded, especially when 
more patients are treated, potentially including patients predisposed to autoimmune reactions.  
The rationale to combine pembrolizumab and efti comes from its complementary mechanism of action. Efti 
activates APCs and
 
 to pembrolizumab. 
In this study, efti will be combined with pembrolizumab. The 
 
 
 
. 
Based on the RSD, Pembrolizumab is well tolerated in the approved indications, as evidenced by a low rate 
of Grade 3 to 5 drug-related AEs (
 %), discontinuations due to AEs 
 %), and deaths due to drug-
related AEs 
 %). Furthermore, the frequency of immune-mediated adverse events of special interest is 
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low, and these events are readily managed in the clinical setting based on guidance provided to investigators 
on the management of immune and non-immune-mediated events of interest. 
Pembrolizumab provided substantial, clinically meaningful benefits in terms of prolonged OS and PFS, and 
increased ORR in patients with NSCLC who progressed after platinum-containing chemotherapy and 
whose tumor cells expressed PD-L1. In previously treated patients with PD-L1 expression ≥1 % and disease 
progression following platinum-containing chemotherapy, pembrolizumab provided a statistically 
significant and clinically meaningful OS benefit compared to standard docetaxel chemotherapy.  
For patients with previously untreated metastatic NSCLC whose tumors expressed high (≥ 50 %) levels of 
PD-L1, pembrolizumab demonstrated significant improvements in PFS and OS over standard of care 
chemotherapy. For patients with previously untreated squamous or non-squamous NSCLC with ≥1 % 
PD-L1 expression pembrolizumab increased the overall survival significantly. Pembrolizumab in 
combination with pemetrexed/carboplatin for the first-line treatment of metastatic non-squamous NSCLC 
demonstrated both a statistically significant and clinically meaningful difference in ORR and a statistically 
significant benefit in PFS compared with pemetrexed/carboplatin alone.  
In the treatment of advanced HNSCC after platinum based first line chemotherapy, pembrolizumab 
demonstrated a clinically meaningful ORR of ~15 % and a prolonged duration of response that was 
substantially distinct from what is expected with standard of care (i.e. methotrexate with ~ 8 % ORR) in 
previously treated patients with HNSCC. However, a treatment benefit of pembrolizumab over standard of 
care for overall survival has not been confirmed.  
Efti has shown antitumor activity in combination with paclitaxel (P005 and P011) and in combination with 
pembrolizumab (P012) in MBC and metastatic melanoma patients with suboptimal response to 
pembrolizumab alone, respectively. 
The principal aim of this study is to investigate the efficacy and safety of efti in combination with 
pembrolizumab in patients with: advanced/metastatic treatment naive NSCLC (1st line) (Part A), advanced 
recurrent PD-X refractory NSCLC after failure of 1st line PD-X containing therapy (Part B), and HNSCC 
after failure of prior platinum-containing 1st line therapy (Part C). The patients intended to be enrolled have 
no curative treatment options and especially for 2nd line NSCLC and 2nd line HNSCC there are only very 
limited treatment options (see section 3.1). Pembrolizumab monotherapy is approved for 1st line NSCLC 
patients with ≥50 % PD-L1 positivity and for ≥2nd line NSCLC patients progressing on (platinum 
containing) chemotherapy and with ≥1% PD-L1 positivity by EMA, FDA and TGA and for 2nd line HNSCC 
patients by the FDA and TGA. Efti injected s.c. every 2 weeks up to 30 mg has shown to be well tolerated 
in patients with advanced cancer in combination with chemotherapy or pembrolizumab. The dose finding 
was based on the preclinical and clinical data.  
Furthermore, this trial will help to identify patients who may especially benefit from the combination of 
efti and pembrolizumab as different biomarkers (PD-L1 expression, gene expression profile acc. to 
PanCancer Immune code, circulating level of Th1 biomarkers) will be assessed and analyzed under the 
current protocol.  
The anticipated risks are based on efti and pembrolizumab non-clinical and clinical experience. Patients 
will be treated at well trained sites and with an emergency unit under the supervision of investigators 
experienced with the use of checkpoint therapies and experts in the treatment of NSCLC and HNSCC.  
Despite the COVID-19 pandemic, due to the late-stage cancer disease of the subject populations under 
investigation, the risk benefit assessment does not change. 
In summary it is considered that the combination of pembrolizumab and efti has an acceptable risk/benefit 
profile. The expected benefit outweighs the expected risks for the patients. 
 


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3.5.1. Management of Risks 
To minimize the risk to patients and maximize safety, the following factors have been incorporated into the 
study design: 
• 
Detailed safety and laboratory assessments will be performed as outlined in section 8.5 of this 
protocol. 
• 
All clinical observations will be evaluated by the investigator on an ongoing basis.  
• 
The DMC will review the safety and efficacy data of all patients (part A-C) on a regular basis as 
specified in the DMC charter. 
• 
Each patient must stay on site for at least 30 minutes after the last study drug administration on 
each treatment day 
• 
The inclusion and exclusion criteria have been defined to exclude patients with unacceptable risks  
• 
Special events of clinical interest have been defined which needs expedited reporting see section 
9.3) 


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4 
STUDY OBJECTIVES & ENDPOINTS 
4.1. Primary Objectives 
• To evaluate the response rate of eftilagimod alfa in combination with pembrolizumab in patients with 
advanced, metastatic, recurrent NSCLC and HNSCC 
 
4.2. Secondary Objectives 
• To evaluate the safety and tolerability of eftilagimod alfa when combined with pembrolizumab  
• To further evaluate the antitumor activity of eftilagimod alfa when combined with pembrolizumab 
• To assess the pharmacokinetic and immunogenic properties of eftilagimod alfa 
 
4.3. Exploratory Objectives 
• 
To identify and characterize relevant biomarkers 
• 
To further characterize the antitumor activity of eftilagimod alfa in combination with 
pembrolizumab 
 
4.4. Endpoints 
4.4.1. Primary endpoint  
• 
To determine the best overall response rate (ORR) according to iRECIST. 
4.4.2. Secondary endpoints 
• 
Safety profile in terms of frequency, severity, and duration of Adverse events (AEs), serious 
adverse events (SAEs) according to the current National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) V5.0, events of clinical interest (ECI) and 
abnormalities in vital signs, physical examination, 12-lead electrocardiogram (ECG) and safety 
laboratory and urine assessments. 
• 
To assess time to and duration of responses according to iRECIST and RECIST 1.1 
• 
To assess the response rate according to RECIST 1.1 
• 
To assess the disease control rate according to iRECIST and RECIST 1.1 
• 
To assess progression free survival (PFS) and overall survival (OS) 
• 
To assess occurrence and nature of anti-eftilagimod alfa-specific antibodies. 
• 
To assess the plasma concentration time profile and derived PK parameters which may include but 
will be not limited to area under the curve (AUC), peak plasma concentration (Cmax), time to reach 
Cmax (tmax), systemic clearance (CL), elimination half-life (t1/2) and volume of distribution (VD) of 
eftilagimod alfa. 
4.4.3. Exploratory endpoints 


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x 
To assess PD-L1 expression assessed by central laboratory. 
x 
 
x 
To assess Gene signature acc. to PanCancer Immune code set assessed by a central laboratory. 
x 
To assess circulating level of Th1 biomarkers (i.e. IFN-J, CXCL10) assessed by a central 
laboratory. 
x 
 
 
 
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5 
STUDY DESIGN 
The study is designed according to Simon's optimal two-stage design (9). During the first stage of the study 
the number of N1 patients will be recruited for each indication into this multicenter, open label, phase II 
study. In case there are more responses than threshold r1 observed in patients recruited in the initial stage 
(N1), additional patients (N2) will be recruited. Following the completion of the initial stage, the decision 
to recruit the additional patients (N2) will be taken by the Data Monitoring Committee (DMC), as described 
later.  
 
Indication 
Threshold r1 
Initial No of 
pts (N1) 
Add. No. of pts 
(N2) 
N total 
NSCLC 1st line 
4 
17 
19 
36 
NSCLC 2nd line 
1 
23 
13 
36 
HNSCC 
2 
18 
19 
37 
In case ORR in any part meets a predefined threshold an extension of this cohort may be set up to combine 
the patients of stages 1, 2, and newly enrolled patients in that respective part, to provide a reasonable basis 
in sample size considerations for further clinical studies. For sample size considerations in the extension 
phase please refer to the section "sample size calculations" in the synopsis and chapter 10 of the protocol.  
To be eligible for participation, patients must have either:  
Part A: Histologically- or cytologically-confirmed diagnosis of non-small cell lung cancer stage IIIB not 
amenable to curative treatment (unresectable) or stage IV not amenable to EGFR/ALK based therapy, 
treatment naïve for advanced/metastatic disease.  
Note: Patients who received durvalumab or any other PD-1 or PD-L1 therapy as maintenance therapy to 
the adjuvant chemotherapy regimen and hence are not naïve to anti-PD-X agents, can be recruited provided 
that all other necessary requirements are met. 
Part B: Histologically- or cytologically-confirmed diagnosis of NSCLC after failure of first-line treatment 
(for metastatic/advanced disease) with at least 2 cycles of any PD-1/PD-L1 therapy (e.g. nivolumab, 
pembrolizumab, avelumab, durvalumab, etc.) alone, or in combination with any other immunotherapeutic 
or chemotherapy given as part of first-line treatment 
Note: Failure on therapy is defined as progress acc. to RECIST 1.1 and would require confirmation by a 
second assessment no less than four weeks from the first documented PD in the absence of rapid clinical 
progression. If patients discontinue PD-1/PD-L1 after being treated for at least 2 cycles for reasons other 
than progression, they may enroll in the study if initial progression occurs within 12 weeks after end of PD-
1/PD-L1 therapy and progression is confirmed. Only patients to be receiving treatment in true second-line 
setting can be enrolled to Part B. Patients who have received durvalumab or any other PD-1 or PD-L1 
therapy as part of their adjuvant therapy and no other PD-1/PD-L1 therapy in the first line treatment are 
not eligible for Part B. 
Note: In Parts A and B patients with neuroendocrine or sarcomatoid NSCLC tumor types are not eligible. 
Patients with undifferentiated lung carcinoma with some neuroendocrine features can be recruited. 
Part C: Histologically- or cytologically-confirmed recurrent disease not amenable to curative treatment 
with local or systemic therapy, or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, 


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hypopharynx, or larynx that is considered incurable by local therapies after failure of prior platinum-based 
therapy.  
Note: In all three parts patients will be enrolled regardless of their PD-L1 expression.  
 
Part A+B+C:  
Patients will receive pembrolizumab and efti starting from cycle 1 day 1 as follows:  
• 
200 mg pembrolizumab every 3 weeks IV (30 min) for up to 35 cycles; 1 cycle = 3 weeks 
• 
30 mg of efti every 2 weeks s.c. for the first six months (until including cycle 8) and shifted to every 
three weeks s.c. thereafter (cycle 9 to 18); 1 cycle = 3 weeks 
 
Figure 4: Study flow chart for part A, B and C.  
 
Screening of patients for eligibility to enter this study will be done in the three weeks prior to cycle 1 day 
1. Patients will be enrolled in parallel except for the first three patients in each part who are to be enrolled 
at least 1 week apart. A patient will stay on treatment until disease progression, unacceptable toxicity, 
completion of 35 cycles of pembrolizumab (~2 yrs.; completion of study treatment) or discontinuation for 
any other reason. Three (3) weeks after the end of the combination therapy (cycle 18) end of combination 
(EOC) therapy assessments will be performed. Three (3) weeks after end of any study treatment (cycle 35) 
an end of treatment (EOT) visit will be performed. Upon start of study treatment, patients will be followed 
for PFS and OS. PFS will be radiologically assessed at the study sites until progressive disease (PD), death, 
withdrawal of consent, loss to follow-up, or until the end of the study, whichever occurs first. Radiological 
assessment will be performed at intervals of 9 weeks until week 36 (week 9, 18, 27, 36) and every 12 weeks 
thereafter (after week 36). OS will be monitored until death, withdrawal of consent, loss to follow-up or 
until the end of the study, whichever occurs first. Measurability will be assessed according to iRECIST. 
Response to treatment and treatment decisions will be assessed according to iRECIST. Objective response 
(iPR, iCR) should be confirmed by a repeat imaging assessment at least 4 weeks after the first response is 
observed. Per iRECIST, disease progression should be confirmed 4 to 8 weeks after site-assessed first 
radiologic evidence of iUPD. Patients, who have unconfirmed disease progression (iUPD) should stay on 
treatment (if clinically stable) until progression is confirmed (iCPD), provided they have met the conditions 
detailed in Section 8.1.3.  
Radiological scans and related information will be evaluated at the study sites for treatment decision and 
for primary objective and will be collected for potential later central evaluation by blinded independent 
radiologists.  


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Safety procedures are described in section 9.  
The study agents must be administered in a clinical setting where emergency resuscitative equipment and 
personnel trained in the management of anaphylaxis are immediately available to treat systemic reactions 
under the direct supervision of the physician. 
5.1. DMC Review 
The DMC will review the available safety data of all patients (part A-C) after 18 patients have completed 
at least two cycles (6 weeks) of therapy. In addition, the DMC will review the efficacy and safety data after 
the last patient N1 has been enrolled or the minimum number of responses is reached for each part of the 
study, whatever is first. Patients included in this decision must have had at least one tumor imaging after 
treatment was initiated. The DMC will give a recommendation for each part of the study if stage 2 or an 
extension can be opened independently. Further details are described in the DMC charter.  
Furthermore, the DMC will monitor safety and efficacy data at regular intervals and in accordance with the 
DMC charter. The DMC may recommend stopping/changing the study if at any time during the trial there 
are unacceptable adverse events or safety concerns. Unless immediate action is required to protect the safety 
and well-being of study patients, the sponsor will consult with appropriate regulatory authorities prior to 
early termination of the study based on any DMC recommendation. 
 
5.2.  Study Stopping Rules 
The Sponsor may after careful evaluation decide to temporarily suspend or prematurely discontinue this 
study either at a single site, multiple sites or at all sites at any time for reasons including but not limited to, 
incidence or severity of AEs in this study that indicate a potential health hazard to study patients, 
unacceptable safety concerns, unfavorable risk/benefit ratio, ethical issues, inaccurate or incomplete data 
recording, noncompliance or unsatisfactory enrolment with respect to quality or quantity and decision by 
the Sponsor to suspend or discontinue testing, evaluation, or development of the product. 
Patient safety will be monitored at study level (within the DMC) and on substance level (Immutep safety 
monitoring board). The recommendation of the above committees will be taken into consideration in such 
decisions of the Sponsor. The Investigators will be notified by the sponsor if the study is terminated or 
placed on hold. The relevant Independent Ethics Committees (IEC) / Institutional Review Boards (IRB) 
and health authorities will also be informed according to applicable regulatory requirements. 
 
5.3. End of Study 
The end of study is defined 36 months after last patient first visit.  
 
5.4. Justification for Dose of eftilagimod alfa 
Efti dose selection is based upon previous experience in studies P003, P005, P011 and P012.  
As efti is an agonist binding to MHC class II receptors injected subcutaneously, Pharmacokinetics (PK) 
and Pharmacodynamic (PD) parameters were considered for guiding the correct dosing of efti. Deep s.c. 
injections in the thigh means that efti as a large molecule (MW of 160 kDa) is primarily (> 80 %) being 
absorbed by convection through the lymphatic vessels and not directly through the blood venules (58). It 
will have to pass through the inguinal nodes and then migrate to the lymph duct to reach the subclavicular 
vein and the blood stream. In between, the product migrates directly from the lymphatics vessels to the 


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tissues to reach their MHC class II expressing target cells (i.e. monocytes and dendritic cells). This explains, 
in part, why only 
 ng/ml (and not μg/ml) concentrations of efti are measured in the plasma as maximum 
(or peak) serum concentration (Cmax) and 
 after s.c. administration of 
 mg 
efti. The 
 and 
 can be 
 
. 
Therefore, dosing was primarily based on pharmacodynamic parameters
 
 measured directly 
ex vivo in fresh PBMCs of patients treated with efti.  
Dose levels of 0.25 to 30 mg efti injected s.c. biweekly either alone, in combination with weekly paclitaxel 
(80 mg/m2 IV D1, 8, 15 in a 4-week schedule) in MBC patients or in combination with pembrolizumab 
(2 mg/kg i.v. every 3 weeks) in melanoma patients were safe and well tolerated with one DLT (isolated 
gamma-GT increase grade 3 for > 7 days) and 
 
 mg. Various types of local injection site reactions up to grade 2 are the most common adverse 
event associated with efti. The number of patients affected and the frequency per patient, but not the severity 
increased with increasing dose levels of efti.  
 
Table 6: Exposure of efti over time at  and 
 mg 
Dose efti 
[mg/treatment] 
Cmax >  ng/ml 
ng/ml at
hours 
ng/ml at 
hours 
 
 (
 %) 
 (
 %) 
 (  %) 
 
 (
 %) 
 
 %) 
 (
 %) 
Efti showed
 
 from 1 to 30 mg. 
After 
mg s.c. injection Cmax is higher and concentrations above  ng/ml (a preclinically active 
concentration in vitro) were found in the majority of patients compared to  mg dose as shown in Table 6. 
At dose level below  mg PK parameters could not be established reliably in all patients due to the Lower 
Limit of Quantitation (LLOQ).   
Dose levels of
mg (
 mg and 
 mg) were found to be pharmacodynamically active with dose 
dependent effects on secondary target cells (increase in activated CD8 T cells) after 3 months. In the P005 
study number of monocytes, dendritic cells, natural killer (NK) cells and activated CD8 T cells were 
increased after injection of either 0.25, 1.25 or 6.25 mg efti s.c. biweekly in conjunction with weekly 
paclitaxel (80 mg/m2 D1,8 and 15 in a 4-week cycle). 
 
. The number 
 
. In the P011 study, number of primary (monocytes 
and dendritic cells) and secondary target cells (NK and CD8 T cells) as well as circulating cytotoxic T 
lymphocyte (CTL) immune response biomarkers like interferon gamma (IFN-γ) and C-X-C motif 
chemokine 10 (CXCL-10) were measured after injection of 6 and 30 mg efti s.c. biweekly in conjunction 
with weekly paclitaxel (80 mg/m2 D1,8 and 15 in a 4-week cycle). Immuno-monitoring of circulating blood 
cells after three and six months showed an increase in the number of all primary and secondary target cells. 
The 
 
 
, and therefore of a good systemic CTL immune 
response. It can be concluded that biweekly s.c. injections of ≥ 1 mg efti induced a sustained (i.e. observed 
13 days after efti injection) increase in primary target cell (monocyte and dendritic cells) numbers and 
activation markers throughout the treatment. Moreover, this APC activation led to a sustained increase of 
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activated CD8 T cells (secondary target cells) over 6 months and a sustained increase in serum IFN-J and 
CXCL-10, specially for the 30 mg dose.  
The 
 
 
. In all three studies, pharmacodynamic evaluations were made directly prior to 
the next dosing of efti, 13 or 14 days after the last administration. Hence, the pharmacodynamic effects 
described above correspond to the minimal residual effect of efti two weeks after administration. Since efti 
is then injected again, this observed minimal residual effect is said to be sustainable for months as long as 
efti continues to be injected every 2 weeks.  
Thus, efti should be injected s.c. at a dose level of 30 mg. 
 
5.5. Justification for Dose of pembrolizumab 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the totality 
of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose of 
pembrolizumab for adults across all indications and regardless of tumor type. As outlined below, this dose 
is justified by: 
x 
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
x 
Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 mg 
Q3W across multiple indications, and 
x 
Pharmacology data showing full target saturation in both systemic circulation (inferred from PK 
data) and tumor (inferred from physiologically-based PK (PBPK) analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 patients were enrolled with melanoma 
and NSCLC, covering different disease settings (treatment naïve, previously treated, PD-L1 enriched, and 
all-comers) and different treatment settings (monotherapy and in combination with chemotherapy). Five 
studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, 
KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5- to 7.5-fold difference in exposure. 
The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer, and classical Hodgkin Lymphoma, confirming 200 
mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and not via direct 
binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in KN001 
evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of PD-1 in 
systemic circulation at doses much lower than 200 mg Q3W. Second, a PBPK analysis was conducted to 
predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expression. This evaluation 
concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight and 
other patient covariates on exposure, has shown that the fixed-dosing provides similar control of PK 
variability as weight-based dosing, with considerable overlap in the distribution of exposures from the 
200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by these PK characteristics and given that 
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fixed-dose has advantages of reduced dosing complexity and reduced potential of dosing errors, the 200 mg 
Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols. 
5.6. Selection of Patients 
5.6.1.  
Inclusion Criteria 
Patients may be enrolled if they meet all of the following criteria at screening: 
1. Willing to give written informed consent and to comply with the protocol. 
2.2  Part A (1st line, PD-X naïve in metastatic setting NSCLC): histologically- or cytologically-
confirmed diagnosis of non-small cell lung carcinoma stage IIIB not amenable to curative treatment 
or stage IV not amenable to EGFR/ALK based therapy, treatment naïve for systemic therapy given 
for advanced/metastatic disease (previous palliative radiotherapy for advanced/metastatic disease 
acceptable). 
Note: Patients who received durvalumab or any other PD-1 or PD-L1 therapy as maintenance 
therapy to the adjuvant chemotherapy regimen and hence are not naïve to anti-PD-X agents, can 
be recruited provided that all other necessary requirements are met. 
Part B (2nd line, PD-X refractory NSCLC): Histologically- or cytologically-confirmed diagnosis of 
NSCLC after failure of first-line treatment (for metastatic/advanced disease) with at least 2 cycles 
of any PD-1/PD-L1 containing based therapy (e.g. nivolumab, pembrolizumab, avelumab, 
durvalumab, etc.) alone, or in combination with any other immunotherapeutic or chemotherapy 
given as part of first-line treatment. 
Note: Failure on therapy is defined as progress acc. to RECIST 1.1 and would require confirmation 
by a second assessment no less than four weeks from the first documented PD in the absence of 
rapid clinical progression. If patients discontinue PD-1/PD-L1 after being treated for at least 2 
cycles for reasons other than progression, they may enroll in the study if initial progression occurs 
within 12 weeks after end of PD-1/PD-L1 therapy and progression is confirmed. Only patients to 
be receiving treatment in true second-line setting can be enrolled to Part B. Patients who have 
received durvalumab or any other PD-1 or PD-L1 therapy as part of their adjuvant therapy and 
no other PD-1/PD-L1 therapy in the first line treatment are not eligible for Part B. 
Note: In Parts A and B patients with neuroendocrine or sarcomatoid NSCLC tumor types are not 
eligible. Patients with undifferentiated lung carcinoma with some neuroendocrine features can be 
recruited. 
Part C (2nd line PD-X naive HNSCC): Histologically- or cytologically-confirmed recurrent disease 
not amenable to curative treatment with local or systemic therapy, or metastatic (disseminated) 
head and HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx that is considered 
incurable by local therapies after failure of prior platinum-based therapy. 
3.1 Availability of formalin-fixed diagnostic tumor tissue (in the case of participants having received 
adjuvant therapy, the tissue should be taken after completion of this therapy). 
4. Female or male ≥18 years of age on the day of signing the informed consent. 
5. All female patients of childbearing potential must have a negative highly sensitive pregnancy test 
at screening (within 72 hours prior to cycle 1 day 1); all patients of reproductive potential must 
agree to use highly effective method for contraception from study entry until at least 4 months after 
the last administration of any study treatment. 


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A woman must either be, 
• 
not of childbearing potential: postmenopausal (≥ 60 years of age, or < 60 years of age and 
amenorrhoeic for 12 months in the absence of chemotherapy, tamoxifen, toremifene, or 
ovarian suppression with follicle-stimulating hormone (FSH) above 40 U/L and estradiol 
below 30 ng/L, or if taking tamoxifen or toremifene, and age < 60 years, then FSH and 
estradiol in the postmenopausal range), permanently sterilized (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy), or otherwise incapable of pregnancy 
• 
of childbearing potential and practicing a highly effective method of birth control 
consistent with local regulations regarding the use of birth control methods for subjects 
participating in clinical studies: e.g., established use of oral, injected or implanted 
hormonal methods of contraception; placement of an intrauterine device or intrauterine 
system; male partner sterilization (the vasectomized partner should be the sole partner for 
that subject). 
6. A man who is sexually active and has not had a vasectomy must agree to use a barrier method of 
birth control e.g., either condom or partner with occlusive cap (diaphragm or cervical/vault caps) 
from study entry until at least 4 months after the last administration of study treatment. All men 
must also not donate sperm from time of study entry until at least 4 months after the last 
administration of study treatment. 
7. ECOG performance status 0-1. 
8. Expected survival > 3 months. 
9. Evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors 
version 1.1 modified for immune-based therapeutics (iRECIST). Lesions situated in a previously 
irradiated area are considered measurable if progression has been demonstrated in such lesions.  
10. Laboratory criteria: (collected ≤ 10 days prior to cycle 1 day 1):  
• 
Absolute neutrophil count > 1.5 x 109/L 
• 
Platelet count ≥ 100 x 109/L 
• 
Hemoglobin ≥ 9 g/dL or 5.58 mmol/L3 
• 
Serum creatinine ≤ 1.5 × ULN, or if > 1.5 ULN with a clearance of ≥ 50 mL/min acc to. Gault- 
Cockcroft formula  
• 
Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin > 1.5 x 
ULN 
• 
AST (=SGOT) and ALT (=SGPT) ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present. 
• 
International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN unless patient is 
receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is 
within therapeutic range of intended use of anticoagulants. 
5.6.2. Exclusion Criteria 
Patients are to be excluded from the study at the time of screening for any of the following reasons: 
 
3 Must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 2 
weeks prior to screening.  


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1.2 
For part A (1st line, PD-X naïve in metastatic setting NSCLC): 
• 
The NSCLC can be treated with curative intent with either surgical resection and/or 
chemoradiation and/or radiation. 
• 
Has received systemic therapy for the treatment of their stage IV NSCLC. Completion of 
treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is 
allowed as long as therapy was completed at least 6 months prior to the diagnosis of 
metastatic disease. 
• 
Epidermal growth factor receptor (EGFR)-sensitizing mutation and/or is echinoderm 
microtubule-associated protein-like 4(EML4) gene/anaplastic lymphoma kinase (ALK) 
gene fusion positive (ALK translocation). 
• 
Has received radiation therapy to the lung that is >30Gy within 6 months of the first dose 
of trial treatment. 
For Part B (2nd line, PD-X refractory NSCLC):  
• 
Symptomatic ascites or pleural effusion.  
• 
>1 line of any systemic anticancer therapy for advanced or metastatic disease.  
• 
Has received radiation therapy to the lung that is >30Gy within 6 months of the first dose 
of trial treatment. 
For Part C (2nd line PD-X naive HNSCC):  
• 
Disease is suitable for local therapy administered with curative intent.  
• 
Previously treated with > 1 systemic regimen for recurrent and/or metastatic disease. 
2. 
Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-
lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint pathways) (Part A and C only). 
3. 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and 
was discontinued from that treatment due to a Grade 3 or higher irAE (Part B only). 
4. 
No tumor specimen evaluable for PD-L1 expression by the central study laboratory. 
5.1 
Prior anti LAG-3 therapy (e.g. anti-LAG-3 antibodies).  
6. 
Prior high-dose chemotherapy requiring hematopoietic stem cell rescue. 
7. 
Prior targeted small molecule therapy (i.e. kinase inhibitors), or radiation therapy within 2 weeks 
prior to cycle 1 day 1. 
Note: Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. 
Patients with ≤Grade 2 neuropathy, alopecia and elevated transaminases in case of liver 
metastases may be eligible. Participants must have recovered from all radiation-related toxicities, 
not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted 
for palliative radiation to non-CNs disease 
8.1 
Has received prior chemotherapy, anti-cancer monoclonal antibody, major surgery, another 
systemic cancer therapy or has participated in a study of an investigational agent or has used an 
investigational device within 4 weeks prior to cycle 1 day 1. 


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Note: Patients must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. 
Patients with ≤Grade 2 neuropathy, alopecia and elevated transaminases in case of liver 
metastases may be eligible. If patient received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting study treatment. 
Participants who have entered the follow-up phase of an investigational study may participate as 
long as it has been 4 weeks after the last dose of the previous investigational agent. 
Note: Wash-out period for pembrolizumab is not applicable to patients having received 
pembrolizumab and are to be enrolled into Part B. These patients are allowed to enter as long as 
the last pembrolizumab dose is ≥ 2 weeks prior to cycle 1 day 1 and they fulfill all other 
requirements in terms of adverse events.  
9.1 
Known active central nervous system metastasis and/or carcinomatous meningitis. Patients with 
previously treated brain metastases may participate provided they are radiologically stable: i.e. 
without evidence of progression for at least 4 weeks documented by repeat imaging performed after 
therapy completed for CNS metastasis and with at least 4 weeks difference, clinically stable and 
without requirement for steroid treatment for at least 14 days prior to cycle 1 day 1.  
10. 
Women who are pregnant or lactating. A woman of child-bearing potential who has a positive 
serum pregnancy test (within 72 hours) prior to cycle 1 day 1.  
11. 
Serious intercurrent infection within 4 weeks prior to cycle 1 day 1 or active acute or chronic 
infection. 
12.1 Evidence of severe or uncontrolled cardiac disease within 6 months prior to first dose of study 
treatment including: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias 
of NCI CTCAE version 5.0 Grade ≥ 2, atrial fibrillation > grade 2 not controlled by a pacemaker, 
coronary/peripheral artery bypass graft, symptomatic congestive heart failure  (NYHA III-IV), 
cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary 
embolism. 
13. 
Has interstitial lung disease or history of (non-infectious) pneumonitis that required steroids or has 
current pneumonitis. 
14. 
Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency) is not considered a form of systemic treatment and is allowed. 
15. 
Has a known history of human immunodeficiency virus (HIV) infection.  
Note: No HIV testing is required unless mandated by local health authority.  
16.1 Has a known history of Hepatitis B ((defined as a known Hepatitis B surface antigen [HBsAg] 
positive result) or known active Hepatitis C virus (defined as a known positive anti-Hepatitis C 
antibody result and known detectable level of HCV RNA [qualitative] on PCR)) infection.  
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health 
authority. No treatment with antiviral therapy allowed.  
17. 
Has a life-threatening illness unrelated to cancer. 
18.1 Has previous malignancies within the last three years other than described in inclusion criterion 2, 
except successfully treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, 
ductal carcinoma in situ of the breast, and in situ carcinoma of the cervix. 


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19. 
Receives continuous systemic treatment with either corticosteroids (>10 mg daily prednisone 
equivalents) or other immunosuppressive medications within 7 days prior to cycle 1 day 1. Inhaled 
or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalents 
are permitted in the absence of active auto-immune disease. 
20.1 Has a hypersensitivity to efti and/or pembrolizumab and/or any of its excipients. 
21. Live vaccine within 30 days of planned cycle 1 day 1. Examples of live vaccines include, but are 
not limited to, the following:  measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, 
rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. 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. 
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the patient's participation for the full duration of 
the study, or is not in the best interest of the patient to participate, in the opinion of the treating 
investigator.  
23. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the 
requirements of the study. 
 


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6 
STUDY TREATMENTS 
6.1. Identity of Investigational Medicinal Products 
6.1.1. 
Eftilagimod alfa 
The efti drug product is a single-use, preservative-free, sterile solution of efti for subcutaneous injections 
at a concentration of 25
 
 mg/mL in 
 
 
. The drug 
product is filled into  mL glass vials with an extractable fill volume of
 mL.  
6.1.2. 
Pembrolizumab 
Pembrolizumab Solution for Infusion is a sterile, non-pyrogenic aqueous solution supplied in single-use 
Type I glass vial containing 100 mg/4 mL of pembrolizumab. The product is preservative-free, latex free 
solution which is essentially free of extraneous particulates.  
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion and 
administration of infusion solution. 
6.2. Packaging, Labelling, and Shipping  
Efti will be provided free of charge by the Sponsor. Efti has been manufactured by WuXi Biologics 
(formerly WuXi AppTec) (Wuxi, China) according to EU and US GMP guidelines (EU GMP: Volume 4 
of "The rules governing medicinal products in the European Union"; US GMP: US Codes of Federal 
Regulations 21 CFR Part 210/211 and 21 CFR Part 11) and released by a European qualified person 
according to respective GMP guidelines.  
Pembrolizumab will be provided free of charge by the sponsor. Pembrolizumab has been manufactured 
using facilities and practices under Good Manufacturing Practice (GMP) requirements.  
Vials of the two study treatments will be packaged to maintain cooled 
) 
temperature and shipped by courier to the clinical site as per instructions in the IMP Handling Manual. Each 
vial will contain a label that conforms to Annex 13 EU-GMP guideline as well as to Code of Federal 
Regulations Title 21 and the appropriate local regulations. Full details of product packaging, labelling, 
storage and shipping are provided in the IMP Handling Manual. 
 
6.3. Storage 
Efti must be stored at 
 and 
 as described in the IMP Handling 
Manual. Pembrolizumab must be stored at 2°C to 8°C (36°F to 46°F) and protected from light as described 
in the IMP Handling Manual. Upon receipt of efti or pembrolizumab shipper container, the site pharmacists 
or designated personnel should record the receipt, date and time. The temperature loggers need to be read 
out. Any efti or pembrolizumab that arrives with a temperature recording out of the predefined temperature 
range needs to be handled as described in the IMP Handling Manual.  
 
6.4. Dose Regimen, preparation and administration of study treatments 
Pembrolizumab will be administered as intravenous infusion on Day 1 of each 3-week treatment cycle after 
all procedures and assessments have been completed. Pembrolizumab will be given on day 1 from cycle 1 
to cycle 35. Pembrolizumab will be administered at a dose of 200 mg using a 30-minute i.v. infusion.  
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Withdraw the required volume from the vial(s) of pembrolizumab from the 100 mg/4 mL vial solution for 
infusion and transfer into an i.v. bag containing 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. 
Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 
1 mg/mL to 10 mg/mL. Store the diluted solution: 
- 
At room temperature for no more than 6 hours from the time of dilution. This includes room 
temperature storage of the infusion solution in the i.v. bag, and the duration of infusion. 
- 
Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution 
(96 hours is acceptable dependent upon country approved commercial Keytruda label). If 
refrigerated, allow the diluted solution to come to room temperature prior to administration. 
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).  
Efti will be injected every 2 weeks until end of cycle 8 (12 doses). Thereafter efti will be administered every 
3 weeks starting cycle 9 until end of cycle 18 (10 doses). Efti will be administered as subcutaneous injection 
(single anatomical site) anterior face of the thigh (it is recommended to rotate the injections site every 
injection). The injection should be performed slowly to avoid discomfort at the site of injection.  
 
). 
Syringes should be 
 and until administration 
of the product. Efti should be administered immediately after preparation.  
Full details of efti and pembrolizumab preparation and handling are provided in the IMP Handling Manual 
for each study treatment. 
All doses of study treatment must be administered by the Investigator or designated study personnel. The 
exact times of dosing must be recorded in the source and entered into the electronic CRF. 
The combined immunotherapy of pembrolizumab and efti requires on several occasions that both treatments 
will be given on the same day. Efti is always administered at least 30 minutes after pembrolizumab infusions 
has been completed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
A patient will stay on treatment until disease progression, unacceptable toxicity, completion of 35 cycles 
of pembrolizumab (~2 yrs.; completion of study treatment) or discontinuation for any other reason whatever 
occurs first.  
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6.5. Methods of Assigning Patients  
In the initial stage, patients will be recruited to according to their temporal availability, which can be 
characterized as a 'first comes, first chosen' approach. Therefore, the recruitment of patients for part A, B, 
C will be influenced neither by the study personnel nor by any characteristics of the patients, but only by 
temporal availability. The same applies for the additional recruitment (N2 and any extensions), if 
applicable.  
Screening and enrolment number will be assigned to each patient prior to the first pembrolizumab or efti 
administration on cycle 1 day 1. Once an enrolment number has been assigned, it cannot be reassigned to 
any other patient. 
 
6.6. Blinding and Procedure for Unblinding 
This trial will be conducted in an open label fashion, hence no procedure for unblinding is in place.   
 
6.7. Dose Modifications and treatment delays 
6.7.1. Eftilagimod alfa (efti) 
No dose modifications for efti are allowed.  
On days pembrolizumab and efti are given the same day (e.g. cycle 1 day 1), in case there is an adverse 
event after pembrolizumab administration which necessitates delay of efti administration, efti 
administration can be delayed up to 72 hours after end of pembrolizumab infusion. If the recovery (as 
described below) occurs more than 72 hours after end of pembrolizumab administration, then the efti 
administration will be omitted. Next treatment of efti will then occur at the next planned injection of efti in 
case adverse events improved as described in the next paragraph.  
On days efti is given alone, in case during the study there is an adverse event which necessitates delay (but 
not discontinuation) of efti administration, then the medical monitor should be informed, and efti should be 
delayed until the patient has recovered to ≤ grade 1, except for isolated laboratory values abnormalities 
which should recover to ≤ grade 2 or baseline. Please contact your medical monitor in such cases. All grade 
3 adverse events related to efti need to be discussed individually with the medical monitor to assess potential 
treatment delay or discontinuation. Exceptions to this rule are any ≥3 grade systemic immediate or delayed 
hypersensitivity reactions ) related to efti, after which the patient must be permanently discontinued from 
any further study treatment. Grade 4 adverse events related to efti will result in discontinuation of efti 
treatment. Treatment decision for grade 4 laboratory abnormalities related to efti may be discussed with the 
medical monitor. In case efti needs to be discontinued due to safety reasons, patients who have completed 
at least 2 cycles are allowed to switch to pembrolizumab treatment only. Investigator must ask the medical 
monitor beforehand.  
 
 
 
 
 


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Table 7: Toxicity Management and Discontinuation Guidelines for local injection site reactions and systemic 
hypersensitivity reactions related to eftilagimod 
Type of AE 
Toxicity 
grade 
or 
conditions 
Action 
taken 
to 
eftilagimod 
AE management 
Monitor and follow-up  
Local injection 
site reactions 
Grade 1, 2 
Treatment may 
continue or delayed 
at the discretion of 
the investigator  
In case of local pain: 
NSAIDs (e.g. ibuprofen 3 x 
200 mg PO) 
o If treatment continues then 
for subsequent cycles: 
NSAID starting on day of 
administration few hours 
prior to injection 
o Continue for 2-3 days 
 
In case of local itching: 
topical steroid. Oral 
antihistamine may also be 
considered. 
Monitor patients for signs and 
symptoms until resolution. 
Grade 3 
To be discussed 
with study medical 
monitor if treatment 
needs to be delayed 
or discontinued 
permanently 
Grade 4 
Permanently 
discontinue 
Immediate 
(occurring 
within 30 
minutes of 
injection) or 
delayed 
(occurring after 
30 minutes of 
injection) 
hypersensitivity 
reactions  
Grade 1, 2 
Treatment may 
continue only after 
consultation with, 
and agreement by 
study medical 
monitor 
As clinically indicated. 
Additional blood samples may be 
required, based on discussion with 
study medical monitor. 
 
Monitor patients for signs and 
symptoms until resolution. 
Grade ≥3 
Permanently 
discontinue 
See summary and Figure 5 
below. 
 
Management of trial subjects developing severe, immediate hypersensitivity reaction, beyond standard 
measures of emergency medical care (i.e. provision if intravenous access, assessment of breathing, 
circulation and vital signs, oxygen support on demand) should include administration of epinephrine i.m., 
antihistamine i.v. and corticosteroid i.v., in line with the state-of-the-art good medical practice and 
applicable professional guidelines (59, 60). Figure 5 below outlines a study tailored management of 
hypersensitivity reactions. 6.7.1 


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Figure 5 Management of hypersensitivity reactions, adapted from (59) 
 
The number of doses of efti allowed to miss are described in section 6.11.  
 
6.7.2. Pembrolizumab 
Dose modification and toxicity management for immune-related AEs  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These immune-
related AEs (irAEs) may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than on body system simultaneously. Therefore, early 
recognition and initiation of treatment is critical to reduce complications. Based on existing clinical study 
data, most irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 8.  
In case pembrolizumab needs to be discontinued due to safety reasons, patients who have completed at least 
four infusions of pembrolizumab are allowed to switch to efti treatment only. Investigator must ask the 
medical monitor beforehand.  
 
 
 


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Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe hypersensitivity 
or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. Dose modification and toxicity management 
guidelines on pembrolizumab associated infusion reaction are provided in Table 8 and Table 9. 
 


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Table 8: Dose Modification and Toxicity Management Guidelines for irAEs associated with pembrolizumab 
General instructions: 
• 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
• 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
• 
For severe and life-threatening irAEs, i.v. corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related AEs 
Toxicity grade or 
conditions 
Action 
taken 
to 
pembrolizumab 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids 
(initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
 
Monitor 
patients 
for 
signs 
and 
symptoms of pneumonitis; Evaluate 
patients with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid 
treatment; 
Add 
prophylactic 
antibiotics 
for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
Administer 
corticosteroids 
(initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
 
Monitor 
patients 
for 
signs 
and 
symptoms 
of 
enterocolitis 
(i.e., 
diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) 
and of bowel perforation (ie. peritoneal 
signs and ileus). 
Patients with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy 
to rule out colitis.  
Patients with diarrhea/colitis should be 
advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be substituted via 
i.v. infusion. 
Grade 4, or recurrent 
Grade 3 
Permanently discontinue 
AST / ALT elevation 
or Increased bilirubin 
Grade 2a 
Withhold 
Administer 
corticosteroids 
(initial 
dose of 0.5 to 1 mg/kg prednisone or 
equivalent) followed by taper 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable 
Grade 3b or 4c  
Permanently discontinue 
Administer 
corticosteroids 
(initial 
dose of 1 to2 mg/kg prednisone or 
equivalent) followed by taper 


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Type 
1 
diabetes 
mellitus (T1DM) or 
Hyperglycemia 
 
Newly onset T1DM 
or Grade 3 or 4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure 
Withholdd 
Initiate insulin replacement therapy for 
patients with T1DM  
Administer 
antihyperglycemic 
in 
patients with hyperglycemia  
 
Monitor patients for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.   
 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 or 4  
Withhold or permanently 
discontinued 
Hyperthyroidism 
Grade 2 
Continue  
Treat with nonselective beta-blockers 
(e.g., propranolol) or thionamides as 
appropriate  
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinued 
Hypothyroidism 
Grade 2, 3 or 4 
Continue  
Initiate thyroid replacement hormones 
(e.g., levothyroxine or liothyroinine) 
per standard of care 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Nephritis:  grading 
according 
to 
increased creatinine 
or acute kidney injury 
Grade 2 
Withhold  
Administer 
corticosteroids 
(prednisone 
1 
to 
2 
mg/kg 
or 
equivalent) followed by taper. 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently discontinue 
Neurological 
toxicities 
Grade 2 
Withhold  
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
Grade 3 or 4 
Permanently discontinue 
Myocarditis 
Grade  2, 3 or 4 
 
Permanently discontinue 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, TEN 
or DRESS 
Withhold 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 


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Confirmed SJS, TEN 
or DRESS 
Permanently discontinue 
Other irAEs 
Intolerable/ 
persistent Grade 2 
Withhold 
Based on type and severity of AE 
administer corticosteroids  
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or discontinue 
based on the type of 
event.e   
Grade 4 or recurrent 
Grade 3  
Permanently discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a) AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 
x baseline if baseline abnormal 
b) AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 
10.0 x baseline if baseline abnormal 
c) AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
1- d) The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the Investigator or treating physician. If control 
achieved or ≤ Grade 2, pembrolizumab may be resumed. 
NOTE: For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
2- e)  Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and sclerosing 
cholangitis). 
 
 
 
 
 
 
 


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Table 9: Pembrolizumab Infusion Reaction Dose modifications and Treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication 
subsequent Dosing 
Grade 1 
Mild 
reaction; 
infusion 
interruption 
not 
indicated; intervention not indicated 
Increase monitoring of vital signs as medically indicated until the patient is 
deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, i.v. 
fluids); prophylactic medications indicated for 
≤24 hrs. 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
• 
i.v. fluids; Antihistamines; NSAIDs; Acetaminophen; Narcotics 
Increase monitoring of vital signs as medically indicated until the patient is 
deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr. to 50 
mL/hr.). Otherwise, dosing will be held until symptoms resolve and the patient 
should be premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further study drug treatment 
Patient 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 
500-
1000 mg 
po 
(or 
equivalent 
dose 
of 
analgesic). 
Grades 3 or 4 
Grade 3: Prolonged (i.e., not rapidly responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following 
initial 
improvement; 
hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: Life-threatening; pressor or ventilator 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine**; i.v. fluids; Antihistamines; NSAIDs; Acetaminophen; Narcotics; 
Oxygen; Pressors; Corticosteroids 
Increase monitoring of vital signs as medically indicated until the patient is 
deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Patient is permanently discontinued from further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.  
 


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6.8. Other allowed dose interruption for study treatment  
Pembrolizumab and/or efti may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons (e.g. COVID-19) not related to study therapy. Medical 
Monitor must be consulted prior to the event to discuss the best option for each patient. Patients should be 
placed back on study treatment within 3 weeks of the scheduled interruption, unless otherwise discussed 
with the Medical Monitor. The reason for interruption and missed doses should be documented in the 
patient's study record. The maximum number of interruptions and missed doses per patient before non-
compliance is reached is described in section 6.11.  
 
6.9. Rescue Medications & Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section above. Where appropriate, 
these guidelines include the use of oral or i.v. treatment with corticosteroids, as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids. Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial 
or viral infection, which might require additional supportive care. The treatment guidelines are intended to 
be applied when the investigator determines the events to be related to pembrolizumab and/or efti.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab and/or efti, 
the investigator does not need to follow the treatment guidance.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
 
6.10. Prior and Concomitant Therapy 
Medications or vaccinations specifically prohibited in the exclusion criteria (including the timeframe 
mentioned there) are not allowed during the ongoing trial. If there is a clinical indication for any medication 
or vaccination specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required. The investigator should discuss any questions regarding this with the Medical Monitor.  The 
final decision on any supportive therapy or vaccination rests with the investigator and/or the patient's 
primary physician. However, the decision to continue the patient on study treatment requires the mutual 
agreement of the investigator, the Sponsor and the patient. 
Listed below are specific restrictions for concomitant therapy or vaccination during the course of the study: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab and/or efti 
• 
Radiation therapy Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.  
• 
Live vaccines within 30 days prior to the first dose of study treatment, while participating in the 
study and four months after the last dose of IMP. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 


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typhoid vaccine. 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.  
• 
Systemic glucocorticoids for any purpose other than (1) to modulate symptoms from an AE that is 
suspected to have an immunologic etiology or (2) to treat an AE of not immunologic etiology, only 
for a short course (i.e. no longer than 10 days) and if that is in line with the site’s SOC. Inhaled or 
topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalents 
are permitted in the absence of active auto-immune disease. In case of doubt, the study Medical 
Monitor should be contacted. 
Patients who, in the assessment of the investigator, require the use of any of the aforementioned treatments 
for clinical management should be removed from the study treatment.  
All treatments that the investigator considers necessary for a patient’s welfare may be administered at the 
discretion of the investigator in keeping with the community standards of medical care.  
Acceptable concomitant therapy is defined as follows: 
• 
Patients may receive supportive care including but not limited to antibiotics, analgesics, transfusion 
of blood products, anti-diarrheal medication or laxatives according to local clinical practice and the 
approved pembrolizumab label. 
• 
Growth factors (such as filgrastim) are allowed a minimum of 2 days after efti or pembrolizumab 
administration 
• 
Vaccination (e.g. influenza, COVID-19) with any non-live vaccine (e.g. Vector based, mRNA 
based) is allowed if it takes place more than 3 days prior to or after any efti or pembrolizumab 
administration. Live attenuated vaccines cannot be used. 
• 
Bisphosphonates and RANK-targeted therapy as clinically indicated. 
• 
Patients receiving opiates will be given preventive treatment for constipation and followed 
carefully. 
• 
Inhaled or topical steroids. 
• 
Acute surgery or elective (pre-planned) surgical procedures with non-oncological intent.  
All concomitant medication will be recorded on the eCRF including all prescription, over-the-counter 
(OTC) products, herbal supplements, and i.v. medications and fluids. If changes occur during the study 
period, documentation of drug dosage, frequency, route, and date should also be included on the eCRF. 
Prior chemotherapy (neoadjuvant or adjuvant, first line), targeted small molecule, anti-cancer monoclonal 
antibody or other systemic investigational drug therapy to treat the cancer disease including but not limited 
to are allowed in respective time windows defined in the inclusion and exclusion criteria and is to be 
recorded in the eCRF.  
Prior high-dose chemotherapy requiring hematopoietic stem cell rescue or chemotherapy for metastatic 
disease is not permitted. 
All concomitant medications received within 28 days prior to the first dose of study treatment and up to 30 
days after the last dose of study treatment should be recorded. Concomitant medications administered 30 
days after the last dose of study treatment should be recorded for SAEs and events of clinical interest (ECIs) 
as defined in section 9.3.  
The medical monitor should always be contacted to clarify and discuss the use of any concomitant 
therapies/procedures beforehand if not in line with the protocol. 


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6.11. Treatment Compliance 
Patients are expected to receive both intravenous pembrolizumab infusion and subcutaneous injections of 
efti as per protocol schedule within the allowable time window (see section 6.7). 
In the event a patient misses a dose, the Investigator must contact the Medical Monitor to determine whether 
to dose the patient out of window or to miss the dose. Any subsequent dose should then be given according 
to the previous schedule as outlined in section 6.7.  
Patients who miss more than a total of 3 (2) injections of efti (pembrolizumab) within the first 8 cycles or 
a total of more than 5 (5) doses of efti (pembrolizumab) in total until cycle end of combo treatment (end of 
cycle 18) will be regarded as treatment non-compliant. Patients will need to end the treatment. An end of 
treatment (EOT) visit will be performed. The patients should then continue with PFS (if not progressed) or 
OS follow-up (if progressed or receiving another therapy). 
 
6.12. Drug accountability 
Investigators must maintain accurate records regarding the receipt, dispensing, and return or destruction of 
pembrolizumab and efti for each patient in the study. Any used vials, as well as any unused vials or unused 
portions of vials, must be maintained until accounted by the monitor. After accountability by the monitor 
and written approval from the Sponsor, all unused vials or medication not dispensed should be sent back to 
the Sponsor or a representative or is destroyed locally after prior approval by the sponsor (details are 
provided in the IMP Handling Manual). All used vials may be destroyed locally, if the destruction is fully 
documented, and following the site’s SOP for destruction of biological waste. 
 
6.13. Contraception Methods 
Efti and Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab and/or efti have transient adverse effects on the
.   
Patient should be informed that taking the study medication may involve unknown risks to the fetus (unborn 
baby) if pregnancy were to occur during the study. In order to participate in the study, patients of 
childbearing potential must adhere to the contraception requirement (from the day of study medication 
initiation (or 14 days prior to the initiation of study medication for oral contraception) throughout the study 
period up to 4 months after the last dose of the last study treatment. If there is any question that a patient of 
childbearing potential will not reliably comply with the requirements for contraception, that patient should 
not be entered into the study. 
The following 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. Highly effective birth control 
methods include: 
x 
intrauterine device  
x 
bilateral tubal occlusion  
x 
vasectomized partner  
x 
sexual abstinence 
x 
hormonal contraceptives as clinically allowed  
Notes: abstinence is only acceptable as true abstinence when it is in line with the preferred and usual lifestyle 
of the patient, periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and 
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withdrawal are not acceptable methods.  
6.14. Pregnancy  
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab or efti, the patient will 
be immediately discontinued from study treatment. The site will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated. The outcome of 
patient`s pregnancy will be reported to the Sponsor without delay and within 24 hours if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study investigator will make every effort to obtain permission 
to follow the outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. 
Details are described in section 9.2. 


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7 
 INVESTIGATIONAL PLAN 
7.1. Study visits and procedures 
Patients will be screened for suitability for participation in the study within -21 to -1 days prior to the first 
administration of pembrolizumab and efti (VISIT 1: Day 1 of Cycle 1).  
Screening assessments will include: 
• 
Obtaining of written informed consent prior to any study specific procedure (including screening 
procedures) being performed. Note: Patient can be consented up to 35 days before cycle 1 day 1 to 
allow planning of fresh tumor biopsy and/or perform CT scan for assessment of eligibility at 
screening (the latter for Part B only). All screening assessments including the biopsy or 
confirmatory tumor assessment for part B (to confirm progression) itself are still to be performed 
between -21 days and -1. 
• 
Check for every inclusion and exclusion criteria 
Re-testing in the case of isolated out-of-range lab results during the screening period may be allowed on a 
case-by-case basis. The investigator must receive the approval from the Medical Monitor for each case 
beforehand A patient who failed screening due to an isolated out-of-range lab value may be allowed to be 
re-screened once, only on a case-by-case basis and only after approval by the MM. 
Additional procedures (assessments) will be performed at screening and throughout the study. The 
following table provides a brief overview of the assessments and indicate references to specific chapters.  
 
Table 10: Overview of study assessment specifications. All assessments are done locally if not otherwise indicated 
Assessment 
Specification 
Physical examination 
(incl. Height & 
Weight) 
Includes the following: head, eyes, ears, nose and throat; respiratory system/ 
chest; cardiovascular system/ heart; abdomen; skin, lymph nodes; extremities 
and (at the investigator’s discretion) genitourinary system/ pelvis.  
For height and body weight measurements preferably, the same equipment 
should be used throughout the study. To obtain the actual body weight, 
patients must be weighed lightly clothed.   
Medical History & 
Demographics 
Each patient’s medical history will be taken during screening. This includes 
patient demographics (date of birth or age whatever is allowed by local law, 
race and ethnicity if allowed by local law, sex) details of cancer onset, prior 
surgery, and past treatment including chemotherapy and/ or radiation 
therapy. Medical history should also include history of HIV, HCV and HBV 
exposure.  
ECOG Status 
The ECOG of each patient will be assessed regularly according to the ECOG 
scale. See appendix – section 19.1 
Electrocardiogram 
(ECG)  
Single 12-lead ECGs will be recorded according to local practice after the 
patients have rested for at least 10 min in a supine position.  
ECGs should preferably be performed prior to meals, vital sign measurements 
and any scheduled blood draws.  
Vital Signs 
Vital signs will be assessed and recorded (i.e. after a 10 min resting period 
and without any change of posture). Blood pressure and pulse rate should 
always be measured on the same arm. Parameters to be assessed are: 


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Assessment 
Specification 
• 
Pulse rate  
• 
Systolic and diastolic blood pressure 
• 
Body temperature 
Hematology 
 
Parameters to be assessed: 
White Blood Cell (WBC) count with differential (absolute neutrophil count 
(ANC); absolute lymphocyte count, absolute monocyte count, absolute 
basophil count, absolute eosinophil count; neutrophil %, lymphocyte %, 
monocyte%, basophil %, eosinophil %); Red Blood Cells (RBCs); Platelet 
count; Hemoglobin; Hematocrit 
Biochemistry 
 
Parameters to be assessed: 
Creatinine, creatinine clearance according to Cockroft-Gault formula, 
random glucose, urea, alkaline phosphatase, alanine aminotransferase (ALT 
= GPT), aspartate aminotransferase (AST = GOT), gamma glutamyl 
transpeptidase (GGT), lactate dehydrogenase (LDH), total bilirubin (direct 
bilirubin in case total bilirubin >1.5 ULN), total protein, albumin/globulin 
ratio, sodium, potassium, chloride, calcium, phosphate, bicarbonates, uric 
acid, cholesterol, triglycerides, plasma amylase, CRP 
Thyroid function 
testing 
Parameters to be assessed:  
Triiodothyronine (T3) or Free Triiodothyronine (FT3); Thyroxine (T4) or 
Free thyroxine (FT4);  
Thyroid stimulating hormone (TSH) 
Coagulation 
Parameters to be assessed: 
Prothrombin time (PT), INR, activated partial thromboplastin time (APTT), 
APTT Ratio. 
Pregnancy test 
A serum pregnancy test will be performed at screening (<72 hours prior to 
cycle 1 day 1). On  all other occasions, a negative urine test before any study 
treatment is administered is sufficient. If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required. For the 
assessment of childbearing potential, FSH and estradiol tests may be required 
at screening. 
HIV, HBV*, HCV** 
tests 
A serum test is to be performed at screening if applicable by local laws. 
* HBsAg; **anti-HCV antibodies and HCV RNA quantitative PCR (in case 
of positive anti-HCV antibodies) 
Autoantibodies 
Autoantibodies (i.e. anti-mitochondrial antibodies, rheumatoid factor, 
antithyroid [antithyroglobulin] antibodies and antinuclear antibodies) are to 
be assessed 
Anti-drug (efti) 
antibodies (central lab) 
Anti-drug (efti) antibodies (ADA) are to be assessed 
Urinalysis 
Parameters to be assessed: 
dipstick, or standard urinalysis (UA) with reflex microscopy and culture if 
clinically indicated. Gross urine examination (dipstick) and other tests, 


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Assessment 
Specification 
should include visual inspection, pH, protein, ketones, glucose, bilirubin, 
nitrite, urobilinogen, occult blood, WBCs 
ECIs 
Events of clinical interest as described in section 9.3 are to be assessed as 
described in section 9 
(S)AEs 
To be assessed according to the current National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE v5.0) – see 
section 9 
Concomitant 
medications/procedures  
Each concomitant medication or procedure is to be recorded 
Radiological Scans  
Radiological scans will be performed throughout the study to assess the 
tumor response to study treatment. Modalities and frequencies are described 
in section 8.1 
Tumor response will be evaluated according to RECIST and iRECIST. For 
details please see section 8.1 and section 19.2.  
Color digital 
photography 
In case of superficial clinical lesion (e.g., skin nodule) they must be measured 
in at least one dimension (longest diameter in the plane of measurement will 
be recorded) with a minimum size of the longest axis being ≥ 10 mm as imaged 
with scale in color photography. Details are described in section 8.1. 
Gene expression 
profile (central lab) 
Gene expression profile analyses will be performed (i.e. acc. to PanCancer 
Immune Code) 
Pharmacokinetics 
(central lab) 
The plasma concentration time profile of efti and derived PK parameters will 
be assessed (selected sites in UK/ES) for patients in subset of 20 patients in 
Stage 1  and an additional subset of at least 10 patients in Stage 2. 
Tumor tissue (Central 
lab) 
Tumor tissue samples will be obtained from every patient to assess certain 
biomarker (e.g. PD-L1 expression, HPV status (for HNSSC only, if 
applicable). (Note: regardless of the above, if the patient has known results of 
HPV (for HNSCC) or PD-L1 expression status from previous records that 
should be documented in the designated form in the eCRF.) 
Th1 biomarker 
(central laboratory)   
The plasma concentration of Th1 biomarkers (e.g. IFN- , CXCL-10) will be 
assessed.  
 
7.2. Overview of Study Assessment Schedule 
Each treatment cycle consists of 3 weeks. After enrolment, each patient will need to visit the hospital 
according to the schedule of assessments (see Table 1).  
The assessment procedures will be performed as already indicated in Table 10 and further details are 
provided in section 8 regarding imaging. The tables below provide detailed breakdown of assessment per 
visit and cycle/ day during screening (Table 11), combination treatment phase (Table 12, Table 13 and 
Table 14), monotherapy (Table 16) and EOT (Table 17). Details for patients participating in the PK part 
are described in Table 15.  
The order in which assessments should be performed is also indicated. 


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Information on concurrent illness/ therapy is to be collected during each patient visit. 
Important Note: Radiological assessment will be determined based on the treatment assignment date. 
All details are described in section 8.1.  
Table 11: Overview of assessments at Screening 
All assessments to be performed on the day of the screening visit (Day: -21 to -1) 
1) Confirmation of written inform consent form4 of patient and Investigator (including PK consent for 
20 patients in Stage 1 and at least additional 10 patients in Stage 2) 
2) Inclusion & Exclusion criteria  
3) Medical history & demographics 
4) Physical examination including height and weight 
5) ECOG performance status 
6) Adverse events  
7) Prior Concomitant medications/procedures  
8) 12- lead ECG (single) 
9) Vital signs 
10) Laboratory testing  
a. hematology, biochemistry, coagulation and urinalysis 
b. thyroid function test 
c. Pregnancy  
d. HIV, HBV and HCV in case applicable  
e. Gene expression profiling 
11) Radiological assessment (as described in section 8.1.1) 
12) Tumor tissue sample 
 
Table 12: Overview of Assessments during combination treatment Cycle 1 to 8 
Day 1 of Cycles 1 to 8  
Prior to pembrolizumab and efti administration  
1) Confirmation of eligibility and assignment to treatment – ONLY cycle 1 
2) Physical examination including weight 
3) ECOG performance status 
4) Adverse events 
5) Concomitant medication/procedures  
6) 12-lead ECG 
7) Vital signs 
8) Laboratory testing:  
a. hematology, biochemistry, coagulation and urinalysis 
b. Thyroid function tests – ONLY Cycle 2, 4, 6 and 8  
c. Autoantibodies – ONLY pre-dose cycle 1  
d. Pregnancy testing (urine) 
e. Anti-drug (efti) antibodies – ONLY pre-dose cycle 1 and 5  
 
4 Note: Patients in Part B can be consented up to 35 days before cycle 1 day 1 to allow planning of fresh tumor biopsy 
and/or perform CT scan for assessment of eligibility at screening (the latter for Part B only). All screening assessments 
including the biopsy or confirmatory tumor assessment for part B (to confirm progression) itself are still to be 
performed between -21 days and -1. 


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f. Th1 biomarker – ONLY pre-dose Cycle 1 and 5  
g. Gene expression profile – ONLY pre-dose Cycle 5  
9) Pembrolizumab infusion 
10) For patients who participate in the PK sampling please refer to Table 15 
11) Efti injection ≥ 30 minutes after pembrolizumab infusion was completed ONLY cycle 1, 3, 5 
and 7 
Patients should remain in the ward for a minimum of 30 min after last study drug administration 
 
Table 13: Overview of Assessments on Day 8 of each even cycle and Day 15 each odd cycle 
Day 15 of Cycles 1, 3, 5, 7   
Prior to efti administration  
1) Adverse Event 
2) Concomitant Medication/procedures  
3) Vital signs  
4) Laboratory testing: 
a. Anti-drug (efti) antibodies – ONLY pre-dose Cycle 3 
5) Efti administration 
Patients should remain in the ward for a minimum of 30 min after injection 
Day 8 of Cycles 2, 4, 6, 8 
Prior to efti administration  
1) Adverse Events 
2) Concomitant medication/procedures   
3) Vital signs 
4) Laboratory testing: 
a. Anti-drug (efti) antibodies – ONLY pre-dose Cycle 2  
5) Efti administration 
Patients should remain in the ward for a minimum of 30 min after injection 
 
Table 14: Overview of assessments during day 1 of cycles 9 to 18 
Day 1 of Cycles 9 to 18 
Prior to Pembrolizumab and efti administration  
1) Physical examination including weight  
2) ECOG performance status 
3) Adverse Events  
4) Concomitant medication/procedures   
5) 12-lead ECG  
6) Vital signs  
7) Laboratory tests:  
a. hematology, biochemistry, coagulation and urinalysis 


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b. Thyroid function test – ONLY cycle 10, 12, 14, 16 and 18 
c. Pregnancy testing(urine) 
d. Autoantibodies – ONLY Cycle 9  
e. Anti-drug (efti) antibodies (ADA) – ONLY pre-dose Cycle 9 and 13   
f.  Th1 biomarkers – ONLY Cycle 9 and 13 
8) Pembrolizumab infusion 
9) For patients who participate in the PK sampling please refer to Table 15 
10) Efti injection ≥ 30 minutes after pembrolizumab infusion was completed  
Patients should remain in the ward for a minimum of 30 min after last study drug administration 
 
Table 15: Assessments for subset of patients who participate in the PK part 
Day 1 of Cycles 1, 5 and 9 (in subset of 20 patients in Stage 1 and additional 10 patients in Stage 2, at 
selected sites) 
Prior to efti administration: blood sampling pre-dose 
After administration: blood sampling at 1, 2, 4 and 8h post-injection 
Days 2, 3, 4 & 5 of Cycle 1, 5 and 9 (in subset of 20 patients at selected sites) 
After administration: blood sampling at 24, 48, 72, 96 hours post-injection 
Adverse events and concomitant medications are to be recorded as well.  
 
Table 16: Overview of Assessments during Cycle 19 until 35 (Pembrolizumab monotherapy). Cycle 19 may also be 
end of combination treatment 
Cycle 19 until Cycle 35 Day 1 (every 3 weeks) 
Prior to Pembrolizumab administration  
1) Physical examination including weight 
2) ECOG performance status  
3) Adverse Events  
4) Concomitant medication/procedures  
5) 12-lead ECG   
6) Vital signs  
7) Laboratory testing: 
a. hematology, biochemistry, coagulation and urinalysis 
b. Pregnancy testing (urine) 
c. Thyroid function test ONLY at Cycle 20, 22, 24, 26, 28, 30, 32, 34  
d. Autoantibodies – ONLY Cycle 19  
e. Anti-drug (efti) antibodies (ADA) – ONLY Cycle 19  
f. Th1 biomarkers – ONLY Cycle 19 
➢ Administration Pembrolizumab  
 
 
 


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7.2.1. End of Treatment Visit 
All patients are scheduled to receive 8 cycles of combined pembrolizumab every 3 weeks and efti every 2 
weeks followed by further 10 cycles of pembrolizumab and efti every 3 weeks. Thereafter pembrolizumab 
will be given every 3 weeks (cycle 19 till cycle 35) unless any of the reasons as specified in section 7.3 
occur. An End of Treatment (EOT) visit will be performed 3 weeks (± 7 days) after the last dose of any 
study treatment. The patients should then continue with PFS follow-up or OS follow-up dependent on the 
status of their disease. 
 
Table 17: Overview of Assessments at the End of Treatment  
All assessments to be performed at EOT visit 
1) Adverse Events 
2) Concomitant medication/procedures   
3) Physical examination including weight 
4) ECOG performance status  
5) 12-lead ECG  
6) Vital signs 
7) Laboratory testing: 
a. hematology, biochemistry, coagulation and urinalysis 
b. Pregnancy testing (urine) 
c. Thyroid function test  
d. Autoantibodies  
e. Anti-drug (efti) antibodies (ADA) 
f. Th1 biomarkers 
 
7.2.2. Progression Free Survival (PFS) - Follow-Up 
Patients who complete all study Treatment Visits without documented PD will attend PFS Follow-Up Visits 
every 12 weeks (± 9 days) until PD, start of next anticancer therapy, pregnancy, withdrawal of consent, loss 
to follow-up, death from any cause, or the end of the study (whichever occurs first).  
For patients who prematurely discontinue treatment for any reason except PD and do not receive any other 
anti-cancer therapy or any other investigational therapy, PFS Follow-Up Visits will occur every 9 weeks 
until week 36 after treatment assignment and every 12 weeks after week 36 dependent on the most recent 
radiological assessment prior to discontinuation.  
At each PFS Follow-Up Visit, the following will be performed:  
• 
Radiological assessment as described in section 8.1 
• 
Eastern Cooperative Oncology Group (ECOG) performance status and body weight 
• 
Adverse event follow-up  
Note: Once a patient starts new line of anti-cancer therapy, the patient will be followed up for OS. Details 
on the next anti-cancer therapies will be recorded. 
 
 


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7.2.3. Overall Survival (OS) - Follow-Up 
After documented PD, or after start of any next line of anti-cancer therapy, the patient will be followed up 
for survival every 12 weeks (± 4 weeks) until end of study, lost to follow-up, withdrawal of consent or 
death whatever occurs first. The first overall survival visit will take place 12 weeks after the last visit of the 
treatment phase (EOC, EOT) or PFS follow up whatever was last. The visit can be performed via a 
telephone call. If necessary, patients may be contacted occasionally outside of this follow up (FU) window. 
Patients who progress while on study treatment may receive any other next line of therapy, as clinically 
indicated, after performing the EOT visit. Patient who do not progress and complete the study treatment 
period (i.e. reach the end of cycle 35 without progression) may receive any other next line of therapy, as 
clinically indicated, after performing the EOT visit. In both cases this is to be recorded during overall 
survival follow-up. Additionally, any details on the next anti-cancer therapies and its duration/outcome will 
be recorded. 
7.2.4. Unscheduled Visits 
Additional unscheduled visits may be conducted to assess adverse events or to evaluate disease status or 
for any other reason according to the Investigator’s clinical judgment. These visits will be documented in 
the eCRF.  
 
7.3. Withdrawal, Discontinuation and Replacement of Patients 
7.3.1. Patient Withdrawal 
Patients should be withdrawn from the study, if patient:  
• 
withdraws consent 
• 
is non-compliant with the study visits and procedures (refer to section 7.4) 
• 
becomes pregnant 
It is recommended that the Investigator attempts to perform an EOT visit evaluations if a patient withdraws 
consent during the treatment period. 
The reason for patient withdrawal will be noted on the eCRF. The Investigator should attempt to follow 
withdrawn patients until resolution of any adverse events, or at least 30 days after the last dose of study 
agent, or until completion of pregnancy whichever takes longer. 
Upon withdrawal, no further dosing, or follow-up visits should be performed for these patients. 
Investigators shall make reasonable attempts to contact lost-to-follow-up patients for evaluation of OS. 
7.3.2. Early Treatment Discontinuation for individual patients 
Patients may discontinue treatment other than for death, end of study, withdrawal of consent, lost to follow-
up or (confirmed) progression, but remain on the study (e.g. PFS follow-up in case the patient has not 
progressed, otherwise OS follow-up) if: 
• 
is non-compliant with the study treatments (refer to section 7.4) 
• 
the patient has clinically significant lab abnormalities or AEs (i.e. recurrent pneumonitis grade 2) 
that, in the Investigator’s judgment, would preclude continued treatment 
• 
any other reason except withdrawal of consent 


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• 
patient has attained a confirmed complete response and have been treated for at least 8 cycles 
receiving at least 2 cycles of pembrolizumab after the iCR was first declared.  
The reason for treatment discontinuation will be noted and an end of treatment visit will be performed.  The 
patients should then continue with PFS and/or OS follow-up as applicable. 
7.3.3. Replacement of Patients 
The number of patients to be included in the study may be increased in order to achieve the expected number 
of patients with evaluable data for the primary objective analysis. Therefore, patients discontinued from 
study treatment due to SARS-CoV-2 infection before their on treatment radiological assessments incl. 
iRECIST assessment, are to be replaced. Details on the analysis will be described in the SAP. 
 
7.4. Protocol Compliance 
Patients are expected to have all visits and procedures done within the allowable time window as indicated 
in Table 1. Discontinuation due to safety reasons is described in the respective section.  
In the event a patient misses a scheduled radiology scan, this should be rescheduled for the earliest possible 
date. Subsequent scans will then be performed every 6 weeks from the original scheduled scan date until 
week 12, every 9 weeks until week 30 and every 12 weeks thereafter. Patients who are persistently 
noncompliant may be withdrawn from the study at the Investigator’s or the Sponsor’s discretion.  
 
 


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8 
STUDY ASSESSMENTS 
8.1. Efficacy Assessments 
8.1.1.  
Radiological Scans and color digital photography 
A computed tomography (CT) scan with contrast of the chest, abdomen and pelvis is required for each 
patient at each timepoint. For patients in part C (HNSCC) a head and neck CT scan is required at each 
timepoint in addition. Tumor imaging is strongly preferred to be acquired by CT with contrast enhancement. 
For the abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when CT 
with iodinated contrast is contraindicated, or when mandated by local practice. For the chest, a non-contrast 
CT of the chest is recommended to evaluate the lung parenchyma. If brain imaging is performed to 
document the stability of existing metastases, MRI is the strongly preferred modality (not mandatory for 
patients without evidence of brain disease). The same imaging technique regarding modality, ideally the 
same scanner, and the use of contrast should be used in a patient throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the accuracy of the 
assessment of response or progression based on imaging.  
The machines (CT or MRI) to be used are described in the imaging manual. The process for image 
collection and transmission to the central imaging vendor can be found in the Site Imaging Manual (SIM).  
All scheduled images for all study patients from the sites will be submitted to the central imaging vendor. 
In addition, images (including via other modalities) that are obtained at an unscheduled time point to 
determine disease progression, as well as imaging obtained for other reasons, but captures radiologic 
progression based on investigator assessment, should also be submitted to the central imaging vendor.  
The Imaging Central Laboratory will receive all information that is relevant (e.g., previous radiation, 
bisphosphonate therapy, etc.). Specific methodological details for all radiological assessments will be 
provided in the Imaging Review Charter. 
All treatment decisions will be based on the investigator`s read.  
A lesion identified at follow-up in an anatomical location that was not scanned at screening is considered a 
new lesion and will be handled accordingly. An example of this is when a patient has visceral disease at 
screening and while on study requires a CT or MRI scan of the brain which reveals metastases. The patient’s 
brain metastases are considered new lesions even if there was no brain imaging conducted at screening.  
Imaging will be performed independently to the treatment schedule according to the following schedule: 
• 
Screening: ≤ 21 days prior to initiation of therapy, historical images (obtained within a window of 
≤ 28 days prior to the start of study treatment) can be used for assessment of patient eligibility for 
part A and C, if they are in line with the imaging protocol. For part B a confirmatory scan needs to 
be performed to confirm initial progression if patient was on PD-1 therapy at the time of consenting 
as detailed in the respective inclusion criterion.  
• 
9-weekly (± 6 days) intervals starting from date of assignment to treatment until week 36, meaning 
week 9, 18, 27 and 36 
• 
12 weekly (± 9 days) intervals thereafter, meaning week 48, 60, 72, etc. 
 
Please Note: Actions taken with the study treatment /study agent (e.g. drug withdrawn or delayed) do not 
affect the imaging schedule. The imaging schedule shall remain as determined from date of assignment.  
 
Skin (Clinical) lesions if present at screening will be assessed in the same intervals as described above.  
Clinical Lesions: Clinical lesions detected by physical examination will only be considered measurable if 
they are superficial and ≥ 10 mm in diameter as measured with calipers (for example skin nodules). If skin 


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lesions are present at screening the documentation of these visible lesions (e.g. index tumor lesion and/or 
new skin lesions) by color photography including a centimeter ruler to estimate the size of the lesion is 
recommended. All photographs will maintain the anonymity of the patient and will be labelled using the 
patient’s study identifier and photograph date. Detailed photography instructions will be provided in the 
Imaging Manual. 
If skin lesions can be evaluated by both, clinical examination and imaging, imaging evaluation should be 
undertaken since it provides a more objective evaluation.     
Superficial clinical lesion (e.g., skin nodule) must be measured in at least one dimension (longest diameter 
in the plane of measurement will be recorded) with a minimum size of the longest axis being ≥ 10 mm as 
imaged with scale in color photography per RECIST 1.1. 
If a patient has clinically-indicated skin lesion(s), the investigator site will perform color digital 
photography of all skin lesions using a ruler held flush to the skin next to the longest diameter of the lesion 
to indicate the size of the lesion at every time point scheduled for radiological scans that a lesion is present. 
Once a lesion(s) is documented, the target area should be documented at every subsequent time point for 
the duration of the study.  
 
8.1.2. Tumor Response acc. to iRECIST 
Only patients with measurable disease at screening will be included in this study. When more than one 
measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum 
of two lesions per organ) representative of all involved organs should be identified as target lesions and 
will be assessed at baseline and specified time points throughout the study. Initial tumor response and 
treatment decisions will be done according to iRECIST. iRECIST is based on RECIST 1.1, but adapted to 
account for the unique tumor response seen with immunotherapeutic drugs. iRECIST will be used by the 
Investigator to assess tumor response and progression and make treatment decisions. When clinically stable 
(see section 8.1.3), patients should not be discontinued until progression is confirmed by the Investigator, 
working with local radiology, according to the rules outlined in section 8.1.3. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some patients can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. This data will be captured in the clinical database. 
Tumor response for target lesions will be evaluated at each timepoint according to the iRECIST.  
• 
Complete Response (iCR): disappearance of all target and non-target lesions 
• 
Partial Response (iPR): at least 30 % decrease from baseline in the sum of the longest diameters 
(longest axis for non-nodal lesions, short axis for nodal regions) of target lesions 
• 
Unconfirmed progressive Disease (iUPD): at least 20 % increase (≥ 5 mm) in the sum of the longest 
diameters (longest axis for non-nodal lesions, short axis for nodal regions) of target lesions, taking 
as a reference the smallest sum on study 
• 
Confirmed progressive Disease (iCPD): a further increase of at least ≥ 5 mm in the sum of the 
longest diameters (longest axis for non-nodal lesions, short axis for nodal regions) of target lesions, 
taking as a reference the last iUPD assessment on study 
• 
Stable Disease (iSD): small changes that do not qualify for the above criteria 
For target lesions iCR, iPR and iSD can all be assigned after iUPD (unconfirmed progress).  


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All other lesions (or sites of disease) should be identified as non-target lesions and will also be assessed at 
baseline and specified time points throughout the study. Tumor response for the group of non-target lesions 
will be evaluated according to the iRECIST: 
• 
iCR: Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
• 
iNon-CR/ iNon-PD: Persistence of one or more non-target lesion(s). 
• 
iUPD: Unequivocal progression of existing non-target lesions.  
• 
iCPD: Further increase of non-target lesions taking as a reference the last iUPD assessment on 
study. 
New lesions are assessed and classified as non-measurable or measurable (if ≥ 10 mm; ≥ 15 mm for nodal 
lesions as per RECIST 1.1). From measurable new lesions, up to 5 lesions total (up to 2 per organ), may be 
selected as New Lesions – Target.  The sum of diameters of these lesions will be calculated and kept distinct 
from the sum of diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target. First occurrence of new lesions leads to iUPD.  
The Medical Monitor is to be contacted within due time after a patient is assessed as having iUPD. 
Confirmation in clinically stable patients as described in section 8.1.3 is necessary. Progression is 
considered confirmed, and the overall response will be iCPD, if ANY of the following occurs: 
• 
Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, compared 
to the latest prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared to the 
latest prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 
1.1 
o For new lesions, worsening is any of these: 
▪ 
an increase in the new lesion sum of diameters by ≥5 mm from the latest prior iUPD time 
point  
▪ 
visible growth of new non-target lesions  
▪ 
the appearance of additional new lesions 
• 
Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• 
None of the progression-confirming factors identified above occurs AND 
• 
The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on which iUPD is 
seen. This may correspond to the next visit in the original visit schedule. The assessment of the subsequent 
confirmation imaging proceeds in an identical manner, with possible outcomes of iCPD, iUPD, and 
iSD/iPR/iCR. 
The reason why iUPD cannot be confirmed (e.g. patient clinically not stable, treatment stopped but patient 
not reassessed/imaging not performed due to patient refusal, protocol noncompliance or patient death) 
should be recorded. 


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Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• 
None of the progression-confirming factors identified above occurs, AND 
• 
The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”. This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response 
of iCPD can be assigned. 
At each specified time point, the overall response will be determined as described below. For each patient 
the best overall response rate will be evaluated according to 19.2. 
 
Table 18: Assessment of overall response at a specific timepoint (61). 
 
 


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8.1.3. Confirmation of Progressive Disease acc. to iRECIST 
Efti and pembrolizumab are expected to produce their anti-tumor effects by inducing a cancer-specific 
immune response. This may result in a clinical response pattern different to cytotoxic agents characterized 
by an initial increase in tumor burden including the appearance of new lesions due to either continued tumor 
growth until a sufficient immune response develops or transient immune-cell infiltrates.  
In order to account for the expected delayed onset of action a confirmation of progression is required. Per 
iRECIST (section 19.2), disease progression should be confirmed by the site 4 to 8 weeks after site-assessed 
first radiologic evidence of PD in clinically stable patients. Patients, who have unconfirmed disease 
progression may continue on treatment at the discretion of the investigator until progression is confirmed 
by the site, provided the patient is clinically stable. Clinical stability is defined as the following:  
• 
Absence of symptoms and signs indicating clinically significant progression of disease 
• 
No decline in ECOG performance status  
• 
No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
Any patient deemed clinically unstable should be discontinued from study treatment at site-assessed first 
radiologic evidence of PD and is not required to have repeat tumor imaging for confirmation of PD by 
iRECIST. 
If the Investigator decides to continue treatment, the patient may continue to receive study treatment and 
the tumor assessment should be repeated 4 to 8 weeks later (i.e. earlier than originally scheduled according 
to the protocol but not earlier than 4 weeks after the previous one) to confirm PD by iRECIST, per 
Investigator assessment.   
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the patient 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule 
(e.g., in the combo-treatment phase scans were to be done at week 9, 18, 27, 36, and a scan was done at 
week 13 to confirm progression, then the next scans should be done at week 18, 27 and 36, as planned). 
Patients who receive confirmatory imaging do not need to undergo the next scheduled tumor imaging if it 
is less than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point, if 
clinically stable. 
If however PD is confirmed (iCPD) as defined in Appendix 1, patients should be discontinued from study 
treatment. Nevertheless, if a patient with confirmed radiographic progression (iCPD) is achieving a 
clinically meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging should continue 
to be performed following the intervals as outlined in Section 13 and submitted to the central imaging 
vendor. 
A description of the adaptations and iRECIST process is provided in section 19.2, with additional details 
in the iRECIST publication (61). A summary of imaging and treatment requirements after first radiologic 
evidence of progression is provided and illustrated as a flowchart in the figure below: 


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Figure 6: Imaging and Treatment for Clinically Stable Patients Treated with Pembrolizumab after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
Confirmation of objective response by repeat imaging assessment is required as well. As opposed to the 
rules in place for confirmation of iUPD, confirmation of iPR and iCR can be done within 4 to 9 weeks until 
week 36 and within 4 to 12 weeks thereafter, respectively. In other words, the radiological confirmation of 
the response can be done earlier but also as per the original radiological assessment schedule, at the 
discretion of the Investigator.  
Patients who receive confirmatory imaging do not need to undergo the next scheduled tumor imaging if it 
is less than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point, if 
clinically stable. 
 
8.1.4. Tumor Response acc. to RECIST 1.1 
Only patients with measurable disease at screening will be included in this study. When more than one 
measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum 
of two lesions per organ) representative of all involved organs should be identified as target lesions and 
will be assessed at baseline and specified time points throughout the study. Tumor response for target 
lesions will be evaluated according to the RECIST version 1.1: 
• 
Complete Response (CR): disappearance of all target lesions 


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• 
Partial Response (PR): at least 30 % decrease from baseline in the sum of the longest diameters 
(longest axis for non-nodal lesions, short axis for nodal regions) of target lesions 
• 
Progressive Disease (PD): at least 20 % increase in the sum of the longest diameters (longest axis 
for non-nodal lesions, short axis for nodal regions) of target lesions, taking as a reference the 
smallest sum on study 
• 
Stable Disease (SD): small changes that do not qualify for the above criteria 
All other lesions (or sites of disease) should be identified as non-target lesions and will also be assessed at 
baseline and specified time points throughout the study. Tumor response for the group of non-target lesions 
will be evaluated according to the RECIST version 1.1: 
• 
CR: Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size 
(<10mm short axis). 
• 
Non-CR/ Non-PD: Persistence of one or more non-target lesion(s). 
• 
PD: Unequivocal progression of existing non-target lesions. 
At each protocol-specified time point, the overall response will be determined as shown below:  
Target lesions 
Non-target lesions 
New lesions Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated No 
PR 
SD 
Non-PD or not all evaluated No 
SD 
Not all evaluated Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
8.1.5. Progression-Free Survival 
PFS is defined as the number of days between the date of treatment assignment and the earliest date of 
documented disease progression or death without prior progression. The date of disease progression or 
censoring for PFS will be determined according to the conventions listed below. These conventions are 
based on the May 2018 FDA Guidance for Industry, ‘Clinical Study Endpoints for the Approval of Cancer 
Drugs and Biologics’ (https://www.fda.gov/media/71195/download) and on the Apr 2015 FDA Guidance 
for the Industry, ‘Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
Biologics’ (https://www.fda.gov/media/116860/download).  
 
 
 
 
 


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Table 19: Censoring rules for PFS.  
 
8.1.6. Overall Survival 
Overall survival (OS) is defined as the time between the date of treatment assignment and the date of death. 
For patients without documentation of death, OS will be censored on the last date the patient was known to 
be alive. OS will be followed continuously while patients are on the study treatment and during OS follow-
up via in-person or phone contact after patients discontinue the study treatment. If necessary, patients may 
be contacted occasionally outside of this FU window. 
 
8.2. Pharmacokinetics  
At each time point a single blood sample collected will be sufficient for all test to be performed for PK 
analysis purposes.  
In the subpopulations of 20 patients in Stage 1 and at least additional 10 patients in Stage 2, samples will 
be collected in EDTA tubes on day 1 of cycle 1, 5 and 9 before and after the efti injections (pre-dose and 
then at 1, 2, 4, 8, 24, 48, 72 and 96 hours after dosing). PK sampling will be done at selected sites in ES 
and UK.  
Plasma, prepared from the blood samples, will be stored at -80°C (-112 F). Details on handling of blood 
samples will be described in detail in the Laboratory Manual.  
Note: The following windows are permitted on the assessment time points for PK sampling:  
• 
up to 1 hour for the pre-dose assessment 
Situation 
Date of Progression or Censoring 
Outcome 
Death or disease progression between 
planned radiological assessments 
Date of death or first radiological 
assessment showing disease progression, 
whichever occurs first 
Progressed 
Death before first radiological 
assessment 
Date of death 
Progressed 
No baseline or post-baseline 
radiological assessments 
Start date of treatment with the study drug 
Censored 
New anticancer treatment started 
before documentation of disease 
progression or death 
Date of last radiological assessment prior 
to the start of non-protocol anticancer 
treatment 
Censored 
Death or progression after one missed 
radiological assessment 
Date of missed radiological assessment 
visit  
Progressed 
Death or progression after more than 
one missed radiological assessment 
Date of last radiological assessment visit 
without documentation of disease 
progression that is before the missed visit 
Censored 
Alive and without documentation of 
disease progression 
Date of last radiological assessment 
Censored 


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• 
±5 minutes for the 1-hour assessment 
• 
±15 minutes for the 2 hour and 4-hour assessments 
• 
±30 minutes for the 8-hour assessment 
• 
±2 hours for the 24 and 48-hour assessment,  
• 
- 4 hours and up to +48 hours for the 72 and 96-hour assessments 
 
8.3. 
Biomarkers 
Details on biomarker collection and shipment will be described in the Laboratory Manual.  
8.3.1. Th1 Biomarkers  
All patients are expected to have Th1 biomarkers assessments.  
Plasma samples will be collected in EDTA tubes to assess for Th1 biomarkers (e.g. IFN-, CXCL10) pre-
dose on Day 1 Cycle 1, 5, 9, 13, EOC and EOT. Plasma, prepared from the blood samples, will be stored 
at -80°C (-112 F) and shipped in batches to the central laboratory. 
In the subsets of patients with PK assessment, Th1 biomarkers will be additionally assessed in samples 
collected at selected timepoints after dosing with efti at cycle 1, cycle 5 and cycle 9. No additional blood 
samples will be taken. The PK samples available at these timepoints will be sufficient.  
8.3.2. Tumor tissue sample 
Archival tumor material or newly obtained core or excisional biopsy of a tumor lesion not previously 
irradiated will be provided by patients on a mandatory basis. Samples will be shipped in batches to the 
central laboratory.  
It will be analyzed in order to identify potential biomarkers of response (i.e. PD-L1 expression). These 
analyses will involve histopathological (e.g., immunohistochemistry) and/or molecular (e.g., protein 
sequencing, MS-based proteomics5) and/or genetic (e.g. gene expression profile analysis) assay 
technologies. Other potential biomarkers may also be assessed depending on emerging scientific data. 
Specific methodological details for all tumor tissue assessments will be provided in the Tumor Tissue 
Manual. 
8.3.3. Gene expression profile analyses 
Whole blood will be collected at screening and pre-dose cycle 5 from each patient for gene expression 
profile analyses (acc to PanCancer Immune Code). Blood samples will be shipped to the central laboratory 
according to the instructions on the Laboratory Manual.  
 
8.4. 
Immunogenicity 
Autoantibodies (i.e. antimitochondrial antibodies, rheumatoid factor, antithyroid (antithyroglobulin) 
antibodies, and antinuclear antibodies) will be evaluated at the local laboratory at cycle 1 day 1, cycle 9 day 
1, EOC and EOT. 
 
5 No DNA analysis or genotyping will be performed. 


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The formation of anti-drug antibodies (ADA) against efti will be assessed at the central laboratory in blood 
samples collected at cycle 1 day 1, cycle 2 day 8, cycle 3 day 15, cycle 5 day 1, cycle 9 day 1, cycle 13 day 
1, EOC prior to dosing and at the EOT visit. 
Blood samples for ADA will be collected in a tube without any anticoagulant to prepare serum. These 
samples will be stored at -80°C (-112 F). ADA samples will be shipped in batches to the central laboratory. 
Details on handling of all blood samples will be described in detail in the Laboratory Manual. 
 
8.5. 
Safety Assessments 
Details for all safety assessments will be recorded in both the eCRF and the patient’s source documents. 
8.5.1.  
Laboratory Tests  
All laboratory test results fulfilling one or more criteria defined in section 9.1 are to be recorded as AE. 
Pregnancy is an exclusion criterion. Any positive pregnancy test must be reported immediately using a 
pregnancy form (see section 9.5) and further study treatment must be discontinued. Patients must be 
followed throughout the duration of the pregnancy. Abnormal pregnancy outcomes are considered SAEs 
and must be reported using the SAE form. 
Routine safety laboratory assessment, including hematology, biochemistry, coagulation, thyroid function 
test and urinalysis values will be performed as specified in Table 9 in Section 7.1.  
8.5.2. 
12-Lead ECGs 
ECGs will be evaluated by the Investigator or a designee according to the usual site procedures. All patients 
will have single ECG recordings at screening on day 1 of each cycle, EOC and at EOT. Patients must be 
supine for approximately 10 minutes before ECG collection and remain supine but awake during ECG 
collection. For all patient ECG should be performed prior to meals.   
For the purpose of immediate patient safety at the site, a qualified physician (the Investigator or qualified 
designee) will be responsible for interpreting the ECGs. If a clinically significant quantitative or qualitative 
change from baseline is identified after enrolment, the Investigator will assess the patient for symptoms to 
determine whether the patient can continue in the study. The Investigator or qualified designee is 
responsible for determining if any change in patient management is needed and must document his/her 
review of the ECG printed at the time of evaluation. The following variables will be measured or calculated 
for each ECG: QRS duration and axis; PR interval; Heart rate and RR interval and QT interval.  
8.5.3. Vital Signs Assessments 
Vital signs will be assessed at regular intervals as indicated in the schedule of assessments. Vital signs will 
be recorded after a 10 minute resting (supine position) period. The following variables will be measured: 
• 
Systolic and diastolic blood pressure (mm/Hg)  
• 
Pulse rate (beats per minute) 
• 
Body temperature (Celsius or Fahrenheit ) 
• 
Body weight  
• 
Height (at screening only) 
All blood pressure measurements should be made using the same type of device on the same arm, using a 
completely automated device. Manual techniques will be used only if an automated device is not available. 
Body temperature will be measured in a consistent manner throughout the study. 


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8.5.4. Adverse Events 
AEs will be collected, categorized and reported as described in section 9. 
 
8.6. 
Medical History  
Each patient’s medical history will be taken during screening. This includes in particular patient 
demographics, smoking history, details of cancer onset, cancer history including prior PD-L1 status, prior 
surgery, and past treatment including chemotherapy and/ or radiation therapy and for HNSCC prior HPV 
status. Medical history should also include history of HIV, HCV and HBV exposure. 
 
8.7. 
Concomitant Therapy and Concomitant Procedures Assessment 
Prior medications comprise all therapies that were stopped prior to cycle 1 day 1. Concomitant medications 
are defined as medications that were started on or after cycle 1 day 1 until 28 days after end of treatment 
(last dose of any study drug). Acceptable concomitant therapy is described in section 6.10. Concomitant 
procedures will be assessed, starting from cycle 1 day 1 until 28 days after end of treatment (last dose of 
any study drug). Concomitant therapy and concomitant procedures need to be assessed at every visit.  


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9 
ADVERSE & SERIOUS ADVERSE EVENTS 
9.1. 
Adverse Events 
An AE is any untoward medical occurrence (which does not necessarily have to have a causal relationship 
with this treatment). An AE can be any unfavorable and unintended sign (including abnormal laboratory 
findings as described below), symptom, or disease, whether or not related to any study drug. This includes 
any occurrence that was new in onset or aggravated in severity or frequency from the baseline condition.  
All AEs, regardless of severity or causality, will be documented for type of adverse event, date and time of 
onset, date of resolution, duration, severity grade according to the current CTCAE version 5.0 where 
applicable, relationship (unrelated, possibly related, or related) to each of the study drugs separately (efti 
or pembrolizumab), remedial actions taken, and outcome (see section 19.5).  
If no common toxicity criteria (CTC) grading is available, the severity of an AE is graded as mild, moderate, 
severe, life-threatening or fatal. The respective translation in the gradings 1 to 5 is described in section 19.5. 
It is the Investigator’s responsibility to review all laboratory findings and vital sign measurements. 
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are considered AEs if 
they result in any of the following:  
• Discontinuation of study treatment  
• Requirement for treatment or any other therapeutic intervention  
• Necessity for further diagnostic evaluation (excluding a repetition of the same procedure to confirm 
the abnormality)  
• Association with clinical signs or symptoms that may have a significant clinical impact, as 
determined by the Investigator. 
• Clinically significant (as assessed by the investigator) changes of any laboratory parameter 
throughout the study (i.e. compared to the last assessment prior to any study treatment) 
• Any abnormal laboratory parameter qualifying for any ≥ grade 3 NCI-CTC criteria 
Note: If the abnormal result was already present at baseline with the same severity, it will be recorded as 
medical history. Only abnormal results of ≥ grade 3 that have changed in severity compared to baseline 
will be reported as AE, irrespective of clinical significance. 
Patients should be encouraged to report AEs spontaneously or in response to general, non-directed 
questioning. The Investigator should question patients about AEs and changes in pre-existing illnesses since 
their last visit and must record the information in the patient’s medical records. All AEs are to be recorded 
on the appropriate eCRFs and in detail on the source documents. 
If it concerns a SAE, it must be reported to the Sponsor or its delegate within 24 hours of becoming aware 
of the event (for details see sections 9.2 and 9.5). Safety follow-up is to be performed.  
Patients who experience AEs will be monitored with relevant clinical assessments and laboratory tests, as 
determined by the Investigator. All AEs and laboratory abnormalities encountered during the study should 
be followed until resolution or stabilization of the event(s). Any action taken and follow-up results must be 
recorded in the patient’s medical record. Follow-up laboratory results should be filed with the patient’s 
source documentation and eCRF. Adverse events that are ongoing after the end of safety follow-up should 
be marked as ongoing.  
 
For all AEs related to study treatment that require the patient to discontinue treatment, relevant clinical 
assessments and laboratory tests should be repeated on at least a monthly basis until final resolution or 


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stabilization of the event(s). These assessments should be captured in the source data, SAE forms and be 
entered in the eCRFs. 
Observations of the same laboratory abnormality or vital sign abnormality from visit to visit should not be 
repeatedly recorded on the CRF, unless the etiology changes. The initial severity of the event should be 
recorded. If the severity or seriousness of the event changes, a new AE should be reported. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and symptoms 
should be identified by the Investigator and recorded. However, if the Investigator does not consider an 
observed or reported sign or symptom a component of a specific disease or syndrome, it should be recorded 
as a separate AE. 
 
9.2. 
Serious Adverse Events 
A SAE is generally any AE that results in one or more of the following:  
• 
Death (not resulting due to disease progression). 
• 
Is immediately life threatening (i.e. presents an immediate risk of death at the time of the AE, not an 
AE that hypothetically might have caused death if it were more severe). 
• 
Requires or prolongs inpatient hospitalization. 
• 
Causes persistent or significant disability/ incapacity. 
• 
Is a congenital anomaly/ birth defect. 
• 
Qualifies for ECIs as described in section 9.3. 
• 
Other important medical events that may not be immediately life threatening or result in death or 
hospitalization, but based upon appropriate medical judgment, are thought to jeopardize the patient 
and/or require medical or surgical intervention to prevent one of the outcomes defining a SAE 
Elective pre-planned hospitalizations for treatment of an existing condition prior to entering the study or 
hospitalization due to social reasons or administration of study drug are not considered SAEs. Tumor 
progression and associated signs or symptoms are not considered SAEs, based upon investigators 
discretion.  
The Investigator should consult with the Medical Monitor if there is any doubt regarding classification of 
a SAE. 
Definition of Life-Threatening Adverse Events: An adverse event is life threatening if the patient was at 
immediate risk of death from the event as it occurred (i.e. it does not include a reaction that, had it occurred 
in a more serious form, might have caused death). For example, drug-induced hepatitis that resolved without 
evidence of hepatic failure would not be considered life threatening, even though drug-induced hepatitis 
can be fatal.   
Definition of Disabling/ Incapacitating Experience: An adverse experience is incapacitating or disabling 
if the experience results in a substantial and/ or permanent disruption of the patient’s ability to carry out 
normal life functions. 
9.3. 
Events of clinical interest  
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and 
must be reported to the Sponsor within 24 hours of awareness. 
Events of clinical interest* for this trial include:  


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• an overdose of pembrolizumab or efti (For this study, an overdose of pembrolizumab will be defined 
as any dose of 1000 mg or ≥5 times the indicated dose and an overdose for efti will be defined as any 
dose of 150 mg or ≥5 times the indicated dose) – Treatment of Overdose, that is not associated with 
clinical symptoms or abnormal laboratory results. 
• an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an 
elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose of the criteria 
is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an 
underlying etiology. The trial site guidance for assessment and follow up of these criteria can be made 
available. It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline phosphatase that 
do not meet the criteria noted above. In these cases, the decision to proceed with additional evaluation will 
be made through consultation between the study investigators and the Medical monitor. However, 
abnormalities of liver blood tests that do not meet the criteria noted above are not ECIs for this trial. 
 
9.4. 
Time period and frequency for collecting AEs, SAEs, pregnancy and ECIs 
All AEs, SAEs and other reportable safety events (i.e. Pregnancy, ECIs) that occur after the consent form 
is signed but before treatment /allocation must be reported by the investigator. If an AE occurred after 
signing informed consent, the AE is to be recorded in the AE section of the eCRF. 
. 
All AEs or ECIs (Events of Clinical Interest) from the time of treatment/ allocation through 30 days 
following cessation of study treatment must be reported by the investigator.  
All AEs meeting serious criteria, from the time of treatment/ allocation through 90 days following cessation 
of study treatment, or 30 days following cessation of study treatment if the participant initiates new 
anticancer therapy, whichever is earlier must be reported by the investigator.  
All pregnancies and exposure during breastfeeding, from the time of treatment/ allocation through 120 days 
following cessation of study treatment, or 30 days following cessation of study treatment if the participant 
initiates new anticancer therapy must be reported by the investigator.  
Additionally, any SAE brought to the attention of an investigator at any time outside of the time period 
specified above must be reported immediately to the Sponsor if the event is considered to be drug-related. 
Safety follow-up is to be performed until resolution of AEs/ECIs/SAEs or for a minimum of 2 months after 
last study drug administration or until patients is receiving any other anti-cancer therapy or any other 
investigational therapy. 
9.5. 
Expedited reporting of SAEs, ECIs or pregnancy  
All AEs that meet the criteria for SAE require the completion of a study specific SAE Form (or Additional 
Safety Information (ASI) Form). This applies to all SAEs, whether or not they were considered to be related 
to the study treatment.  
The Investigator must report all SAEs to the sponsor or its designee immediately, i.e. within 24 hours (by 
fax or e-mail) of learning of its occurrence. For this reporting, a SAE Form (provided in the Investigator 


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File) needs to be completed in English. Follow-up information about a previously reported SAE must also 
be reported within 24 hours of receiving the information. This follow-up data should ideally be provided 
on an updated SAE form.  
If a SAE occurred after signing informed consent, but before study treatment and the patient continues on 
study, a SAE must also be entered on the relevant Medical History page of the CRF. 
The SAE report should provide a detailed description of the AE and may include anonymized copies of 
hospital records and other relevant documents. Autopsy results, if applicable, should also be sent to the 
sponsor or its designee as soon as they become available. Copies of each report will be kept in the 
Investigator File.  
All SAEs will need to be followed actively until resolution or stabilization (but for at least 2 months after 
last study drug administration). The above is also applicable to follow-up SAE information. 
If a female patient becomes pregnant during the study, she will be removed from the study without receiving 
further study medication. Follow-up regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant is required. Pregnancies are considered immediately reportable AEs (within 1 working day) and 
are to be documented in the eCRF. Furthermore, a Pregnancy Reporting Form (provided in the Investigator 
File) needs to be completed in English. 
Suspected Unexpected Serious Adverse Reactions (SUSARs): SUSARs are SAEs that are at a minimum 
possibly related to any of the study agents or study treatment (efti or pembrolizumab) and are unexpected 
(i.e. not listed in the investigator brochure and/or SmPC). SUSARs will be collected and reported 
expeditiously to competent authorities and IECs)/IRBs according to regulations. 
 The reporting timelines are as follows:  
• 
All fatal/ life-threatening SUSARs need to be reported within 7 calendar days of initial notification. 
• 
All other SUSARs within 15 calendar days of initial notification.  
Expectedness is determined by the sponsor according to the designated reference safety information. 
Medical and scientific judgment is to be exercised in deciding whether expedited reporting is appropriate 
in other situations, such as for important medical events that are not immediately life threatening or do not 
result in death or hospitalization but jeopardize the patient or the patient population. 
In addition to the expedited reporting of SUSARs, the Sponsor will submit, once a year throughout the 
clinical study, an aggregated safety report (Developmental Safety Update Report, DSUR) to the Regulatory 
Authorities and Ethics Committees of the participating sites in the concerned countries. This DSUR 
includes cumulative listings of all SAEs and SUSARs from the Sponsor’s clinical studies with efti during 
the reporting period. 
 


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10 STATISTICAL METHODS 
A statistical analysis plan (SAP) will provide details on the methods of analysis to address all study 
objectives. The SAP may be amended during the study, but will be finalized before the cut-off date for any 
statistical analysis.  
For continuous variables, data will be summarized with the number of patients, mean, standard deviation, 
median, and minimum and maximum values. For categorical variables, data will be tabulated in frequency 
tables to display the number and proportion of patients for each category. Baseline assessments for each 
outcome variable will be defined as the last measurement obtained before the first dose of study drug. 
 
10.1. Sample Size Determination 
The null hypothesis that the true response rate is [ p0 ] will be tested against a one-sided alternative. In the 
first stage, [ n1 ] patients will be accrued. If there are [ r1 ] or fewer responses in these [ n1 ] patients, the 
study will be stopped. Otherwise, [ n - n1 ] additional patients will be accrued for a total of [ n ]. The null 
hypothesis will be rejected if [ r2 + 1 ] or more responses are observed in [ n ] patients. This design yields 
a one-sided type I error rate of 
 and power of 
 % when the true response rate is [ p1 ]. Calculations 
reveal that 17 patients in the initial step and an additional 19 subjects, in total 36 patients to be recruited 
into the study for the NSCLC first line and the other numbers as presented in the table below. Outcome of 
the calculation do not necessarily have to agree with the assumed proportions for the calculations (r1/N1 
and r2/Ntotal and p1), especially for such small sample numbers. 
Mini-max results of this calculation were used for this clinical trial.  
Indication 
response 
rate p0 
Alternative 
p1 
r1 
r2 
Initial 
No 
of pts (n1) 
Add. No. of 
pts (n2) 
N total 
NSCLC 1st 
line 
23% 
 % 
4 
17 
19 
36 
NSCLC 2nd 
line 
7 % 
 % 
1 
23 
13 
36 
HNSCC 
15 % 
 % 
2 
18 
19 
37 
The “true response rates” for 1st line NSCLC were extracted from Keynote-024 and Keynote-042 under 
consideration that for PD-1 all comers response rate will be lower (10, 11). For 2nd line NSCLC there are 
no available publications for pembrolizumab alone in PD-1/PD-L1 refractory patients, but due to the 
confirmation of progression it (p0) is considered close to 0 % for pembrolizumab alone. The alternative (p1) 
of 
 % was considered clinically relevant especially in comparison to available standard chemotherapy6. 
For HNSCC relevant publications from Keynote 012 and Keynote-040 were used (2, 12) for p0. 
Sample size calculations were performed using the validated software R R version 3.3.3 (2017-03-06), 
Package:   
Kieser M, Wirths M, Englert S, Kunz CU and Rauch G (2017). “One Arm Phase Two Study: An R Package 
 
6 Given the available treatment option in this patients population (mostly single agent chemo therapy) and its efficacy 
(about 20 % SD at 6 months; median OS 6-12 months), long-term stabilization of the disease (6+ months) are 
considered as a meaningful clinical benefit and will be counted equal to a response for the decision if stage 2 can be 
opened. Final decision is to be made by the DMC based on an updated risk benefit assessment.   
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for Planning, Conducting, and Analyzing Single-Arm Phase II Studies.” _Journal of Statistical 
Software_, *81*(8), pp. 1-28. doi: 10.18637/jss.v081.i08 (URL: http://doi.org/10.18637/jss.v081.i08). 
 
For part A an extension (Part A extension) is anticipated based on the ORR of efti in combination with 
pembrolizumab as test group in a single arm design. The true ORR of monotherapy pembrolizumab in 
NSCLC 1st line is expected to be 23%, whereas a rate of 
% is expected for the test group (in case PD-
L1 distribution is as expected from historical studies with ~70% <50% PD-L1expression). Using these 
assumptions with a power of 
% and a one-sided level of significance of 
% in this phase II trial, a 
sample size of 105 patients would be required for analysis. With a drop-out rate of 5%, a total of 110 
patients need to be enrolled. With the 36 patients of stages 1 and 2, another 74 patients would be needed to 
be enrolled in total in this extension. This sample size is regarded sufficient to provide a reasonable 
precision for the estimate of ORR as basis for sample size considerations for further clinical studies.  
Possible extensions of part B and C will be introduced via substantial amendments.    
 
Calculations were performed using PASS 2019 Power Analysis and Sample Size Software (2019). NCSS, 
LLC. Kaysville, Utah, USA, ncss.com/software/pass. 
10.2. Assignment to treatment  
Patients will be assigned to the single treatment arm according to the indication as assessed during 
screening.  
 
10.3. Analysis Populations 
Full Analysis Set 
The Full Analysis Set (FAS) includes all assigned patients who received at least one dose of study drug (i.e. 
one dose of either pembrolizumab or efti). This population will be the primary population for the analyses 
of efficacy endpoints and baseline characteristics. 
Per-protocol Population 
In addition, a per protocol population analysis will be performed. Details are described in the SAP. 
Safety Population 
The safety set is defined analogously to the full analysis set and includes all assigned patients who received 
at least one dose of study drug (i.e. one dose of either pembrolizumab or efti). This population will be the 
primary population for the analyses of safety. 
Pharmacokinetic population (PK population) 
All patients of the subpopulations (20 in Stage 1 and additional 10 in Stage 2) will be taken into account 
who: 
x 
received at least one dose of efti and  
x 
have sufficient plasma concentration data to calculate reliable estimates of at least one PK 
parameter, and 
x 
are without any protocol deviation that would interfere with the interpretation of PK results. 
 
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10.4. Handling of Missing Data 
When tumor response (as defined by local image interpretation) based on target lesions is missing, it will 
be set to PD if the last non-missing observation is PD. No imputation will be used to handle any other 
patterns of missing data for tumor response (i.e., it will be censored in the efficacy analysis). Rules for 
handling of missing data for secondary endpoints including missing/ partial dates will be defined in the 
SAP.  
 
10.5. Subgroup Analyses 
Subgroup analyses (e.g. PD-L1 positivity) will be described in the SAP.   
 
10.6. Interim Analyses 
Descriptive interim analyses (incl. abbreviated report, if needed) may be performed e.g. for the DMC 
meetings or when one stage of one part of the study is completed, which do not affect the analysis of the 
primary endpoint. No adjustments for multiplicity are needed as no statistical test will be performed. Details 
will be described in the SAP.  
 
10.7. Timing of analysis 
The analyses (also interim analyses) may be performed separately for each indication (dependent on 
availability of the results) as described in the SAP. Separate clinical study reports (also interim analyses) 
may be written for each indication (dependent on availability of the results) as described in the SAP. 
 
10.8. Baseline and Demographic Characteristics 
Baseline characteristics and demographic information at baseline will be summarized with descriptive 
statistics for the FAS of each part A-C of the study. Medications will be coded using the most current 
version of the World Health Organization (WHO) Drug dictionary and will be summarized as treated for 
all patients in the safety population. Prior medications are defined as medications that were stopped prior 
to the treatment period/cycle 1 day 1. Medications used at study entry are defined as medication that started 
on or prior to the treatment period/cycle 1 day 1. Concomitant medications are defined as medications that 
were taken from cycle 1 day 1 until 28 days after end of treatment (last dose of any study drug).  
 
10.9. Efficacy Analyses 
Efficacy analyses will be performed for each part of the study independently.  
For indications with an extension, the patients of stages 1 and 2 will be combined with the newly enrolled 
patients of the extension as combined dataset for analysis. Certain endpoints will in addition be analyzed 
in the subgroups "patients of stage 1+2" and "newly enrolled patients" to assess any effect of later 
enrollment on the outcome. All endpoints assessed in stages 1 and 2 will also be assessed for the extension 
as described above. Details will be given in the SAP. 
10.9.1. Analysis of the primary endpoint 


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Primary endpoint is the objective response rate (ORR). The ORR is defined as the number of subjects with 
a best overall response (BOR) according to iRECIST as complete response (CR) or partial response (PR) 
divided by the number of subjects. The BOR is the best response as determined by the investigator between 
the date of assignment and date of objective measurement of progression by iRECIST or the date of 
subsequent therapy, whichever comes first. For patients with no documented progression or subsequent 
therapy, all available response assessments will be used to define BOR. In addition, analysis of confirmed 
responses will be described in the SAP.  
The response will be further evaluated by the duration of response (DOR) based on iRECIST, calculated 
for all patients with CR or PR up to an objective documentation of progression or death, whichever occurs 
first. For patients with no documented progression or death, DOR will be censored at the date of last 
documentation of response.  
DOR = Date of disease progression / death – Date of first partial or complete response + 1. 
ORR will be summarized by binomial response rate with two-sided 95% exact confidence intervals using 
the Clopper-Pearson method.  
The DOR will be summarized using the Kaplan-Meier product-limit method. The median time to event will 
be calculated along with 95% CIs using the Kaplan-Meier method. In addition, the proportion of responders 
still in response at different timepoints (3 and 6 months) will be assessed based on a Kaplan-Meier Plot.  
As a sensitivity analysis ORR and DOR will be assessed based on RECIST 1.1 based on the investigator 
assessment. All efficacy analyses are based local investigator assessments. A central independent 
assessment may be conducted as specified in the SAP. 
10.9.2. Analysis of the secondary and exploratory endpoints 
All secondary analyses will be performed descriptively.  
The time-to-event endpoints (PFS, 
 OS) will be summarized using the Kaplan-Meier product-limit 
method. The median time to event will be calculated along with 95% CIs using the Kaplan-Meier method. 
In addition, the proportion of responders still in response at different timepoints (3, 6 and 9 months) will be 
assessed based on a Kaplan-Meier Plot. The assessment of progression will be based on iRECIST (this does 
not apply to 
). 
PFS will be calculated as the time from the date of assignment into the study to the date of first 
documentation of disease progression or date of death due to any cause, whichever occurs first: 
PFS = Date of disease progression/ death – Date of assignment into the study + 1. 
The PFS rate at 6, 12, 18 and 24 months and corresponding 95% confidence intervals will be estimated 
using the Kaplan-Meier method.  
The OS rate at 6, 12, 18, and 24 months and corresponding 95% confidence intervals will be estimated 
using the Kaplan-Meier method.  
The overall survival (OS) will be calculated as the time from the date of assignment into the study treatment 
to the date of death from any cause:  
OS = Date of death – Date of assignment into the study + 1. 
 
, will be estimated using the Kaplan-Meier method. 
As a sensitivity analysis PFS will be assessed based on RECIST 1.1. All efficacy analyses are based on 
local investigator assessments. A central independent assessment will be conducted as specified in the SAP.  
 
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10.10. Pharmacokinetic Analyses 
The plasma concentration time profile of efti will be summarized and PK parameters such as area under the 
curve (AUC), peak serum concentration (Cmax), time to reach Cmax (tmax), systemic clearance (CL), 
elimination half-life (t1/2) and volume of distribution (VD) will be calculated. 
 
10.11. Immunogenicity analyses 
The development of anti-efti antibodies will be evaluated and characterized. Autoantibodies will also be 
evaluated. 
 
10.12. Biomarker Analyses 
Tumor material or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated will 
be provided by patients on a mandatory basis. Blood sampling for potential biomarker will be conducted 
throughout the study. Exploratory analyses to assess correlations between biomarkers (PD-L1 expression, 
PancGen Score, TH-1 levels) and response endpoints will be done, depending on the available data. 
10.13. Safety Analyses 
Safety data will be summarized for the safety population. The baseline value for safety analysis is defined 
as the value collected at the time closest to and prior to the start of any study drug (pembrolizumab or efti 
whichever was first) administration (i.e. Day 1 of week 1 of cycle 1). 
An adverse event (AE) summary table will include treatment-emergent adverse events (TEAE; i.e., AEs 
with onset dates on or after the first dose of study drug regardless of causality), serious TEAEs, TEAEs 
related to pembrolizumab and efti, fatal TEAEs, TEAEs leading to temporary and permanent stop, TEAEs 
according to worst severity and combinations of previously mentioned type of AEs. 
The number and percentage of patients with at least 1 TEAE will be tabulated by preferred term and system 
organ class (i.e. from MedDRA). For these tabulations, the number of patients (i.e., patients with multiple 
events will be counted only once per preferred term) and the number of events (i.e. except for by severity 
tabulations) with that particular TEAE are presented. The AE tabulations including all TEAEs (by severity), 
serious TEAEs, fatal TEAEs, permanent stop of study agent TEAEs will be presented. The previously 
mentioned type of TEAEs might also be presented in combination with treatment-relatedness. AEs will also 
be tabulated by severity and/or relationship to study drug. At each level of tabulation, the event with the 
highest level of severity or strongest drug relationship will be presented. The tables will be described in 
detail in the SAP prior to any analysis.  
All AEs will be listed. In addition, detailed listings will be provided for patients who die, experience a SAE, 
or discontinue the study because of an AE. These listings will include age, duration of follow up, number 
of doses received, and time since last dose. 
Vital signs (blood pressure, temperature and pulse rate), body weight and derived body mass index, and 
laboratory parameters (e.g., hematology, biochemistry, coagulation, thyroid function testing, urinalysis, and 
ADA results) will be presented at each time point using descriptive statistics (number, arithmetic mean, 
standard error, standard deviation, 95% confidence interval of the mean, median, 1st and 3rd quartile, 
minimum, and maximum).  
Cross-tabulations of hematology, biochemistry results, and other parameters as described in the SAP will 
be prepared to examine the worst CTCAE toxicity grade / abnormality versus the grade / abnormality at 
baseline. Cross-tabulations of vital sign results and categorical laboratory results will be prepared to 


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examine the result / abnormality per time point versus the result / abnormality at baseline. A tabulation of 
elevated liver function test will be presented and explained more in depth in the Statistical Analysis Plan. 
All data from the 12-lead ECG will be analyzed descriptively.  
For indications with an extension, the patients of stages 1 and 2 will be combined with the newly enrolled 
patients of the extension as combined dataset for analysis. Certain endpoints will in addition be analyzed 
in the subgroups "patients of stage 1+2" and "newly enrolled patients" to assess any effect of later 
enrollment on the outcome. All endpoints assessed in stages 1 and 2 will also be assessed for the extension 
as described above. Details will be given in the SAP.  
 


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11 DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms 
All patient data generated in the study, and documented on the source documents on site, will be recorded 
in each patient’s eCRFs. Data reported on the eCRFs that are derived from source documents should be 
consistent with the source documents or the discrepancies should be explained. eCRFs will be considered 
complete when all missing and/ or incorrect data have been resolved and all safety data have been recorded. 
 
11.2. Source Documents 
Source documents are considered to be all information in original records and certified copies of original 
records of clinical findings, observations, data, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. 
The Investigator and designees agree to maintain accurate eCRFs and source documentation as part of the 
case histories. Source documents are the originals of any documents used by the Investigator, sub-
investigator, or hospital/ institution that will allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the study. 
eCRFs must be completed only by  people designated by the Investigator. All data entered into the eCRF 
also must be available in the source documents. The Investigator will allow designated representatives of 
the Sponsor and regulatory bodies to have direct access to the source documents to verify the data reported 
in the eCRFs. 
Each completed eCRF must be reviewed and digitally signed by the Investigator or designee in a timely 
manner. The completed eCRF will be reviewed by the Sponsor or its agents on a routine basis.  
 
11.3. Record Retention 
Study records and source documents need to be preserved for at least 15 years after the completion or 
discontinuation of/ withdrawal from the study, or 2 years after the last approval of a marketing application 
in an International Conference on Harmonization (ICH) region, whichever is the longest time period. 
 
11.4. Drug Accountability 
Each time study drug is dispensed to a patient this must be recorded on a drug dispensing/accountability 
log. Copies of this form will be supplied in the Investigator File. 
At regular intervals the CRA(s) will perform a ‘drug reconciliation visit’, verifying if all study medication 
that has been shipped to the institute can be accounted for by records of receipt, dispensing and destruction. 
At the end of the study, it must be possible to reconcile delivery records with records of usage and destroyed 
or returned stock. It is essential that all study treatment be accounted for by the Investigator or institute, and 
that any discrepancies are explained and documented. 
After accountability by the monitor and written approval from the sponsor, all unused vials or medication 
not dispensed should be sent back to the sponsor or representative of the sponsor (details provided in the 
IMP Handling Manual). All used vials may be destroyed locally, if the destruction is fully documented, and 
following the site’s SOP for destruction of biological waste. Unused vials might be destroyed locally only 
upon approval by the Sponsor. 
 


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12 MONITORING 
In accordance with current applicable regulations, Good Clinical Practice (GCP), and applicable standard 
operating procedures, monitors will contact the site before the start of the study to review with the site staff 
the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and Sponsor 
requirements.  
When reviewing procedures for data collection, the discussion will include identification, agreement, and 
documentation of data items which will be recorded in each patient’s eCRF. 
The study will be monitored to ensure the following: 
• 
Data are authentic, accurate, and complete. 
• 
The safety and rights of patients are being protected. 
• 
The study is being conducted in accordance with the currently approved protocol, any other study 
agreements, GCP, and all applicable regulatory requirements. 
The exact extent of the monitoring procedures is described in a separate monitoring plan. All Investigators 
agree that the monitor regularly visits the clinical site and ensure that the monitor will receive appropriate 
support in their activities at the clinical site, as agreed in separate contracts with each clinical site. Under 
special circumstances, such as for example limitations caused by the COVID-19 (SARS-CoV-2 infection) 
pandemic and limitations for on-site visits, remote monitoring and remote source data verification (SDV) 
will be considered as per approval/guidelines from relevant regulatory authorities, ethics committees and 
sites and as per the clinical monitoring plan.   
 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor or its designee will perform the quality assurance and quality control activities of this study. 
However, responsibility for the accuracy, completeness and reliability of the study data presented to the 
sponsor lies with the Principal or qualified Investigator generating the data. 
Quality control check (e.g. by monitoring, data management and medical review) of all key safety and 
efficacy data in the database will be made on an ongoing manner until the final database lock. By the 
conclusion of the study the occurrence of any Protocol violations will be determined. 
 
14 PROTOCOL AMENDMENT AND PROTOCOL DEVIATION 
14.1. Protocol Amendment 
Administrative amendments to the protocol will be classified as amendments of typographical errors, 
clarifications of confusing wording, name changes, and minor modifications that have no impact on the 
safety of the patients or the science of the study. Administrative amendments will be submitted to the IRB/ 
IEC for information only. The Sponsor will ensure that acknowledgement of receipt is received and filed. 
Any other amendment will be classified as a substantial amendment and will be submitted to the appropriate 
regulatory authorities and the IRBs/IECs for approval. 
 
14.2. Protocol Deviation 
Important protocol deviations are any deviations that might significantly affect the completeness, accuracy, 
and/or reliability of the study data or that might significantly affect a patient's rights, safety, or well-being. 


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This includes deviations related to patient eligibility, informed consent, IMP dosing errors or failing to 
perform assessments required to interpret the primary endpoint. Additional categories may be identified as 
deemed necessary by the Medical Monitor.     
 
If a protocol deviation occurred due to COVID-19 crisis, this information should be captured clearly. All 
protocol deviations should be recorded by the monitor. The clinical team reviews all deviations recorded 
and determines whether a deviation is major or not. Deviations are reported to the Sponsor and Investigator 
as part of the regular reporting. Important protocol deviations will be summarized in the clinical study 
report. In accordance with applicable regulatory authority mandates, the investigator is responsible for 
reporting major protocol deviations to the IRB/ IEC as requested or deemed necessary. 
 
15 ETHICAL CONSIDERATIONS 
The study will be conducted according to current GCP, including any future revisions, all relevant local 
laws and regulations, as well as the principles of the Declaration of Helsinki and its amendments. IRB/ IEC 
committees will review and approve this protocol and informed consent. All patients must provide written 
informed consent before participation in the study. This study will be performed by qualified clinical 
investigators and in accordance with GCP. The study specifically incorporates all of the following features: 
• 
Multicenter study design  
• 
Prospectively stated objectives and analytical plan 
• 
Accepted, pre-specified outcome measures for safety and efficacy 
• 
Investigator meeting prior to study start and a detailed protocol to promote consistency across sites 
• 
Compliance with current GCP, with assessment via regular monitoring 
• 
Quality assurance procedures performed at study sites and during data management to ensure that 
safety and efficacy data are adequate and well documented.  
 
15.1. Site Review 
The Investigator will submit this Protocol, the site-specific informed consent form, and any required 
documents for review and approval as applicable by local law or regulation. All necessary approvals have 
to be in place prior to study start on site.   
Prior to study start, the Investigator is required to sign a Protocol signature page confirming his/ her 
agreement to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this Protocol and to give access to all relevant data and records to CRAs, auditors, and 
regulatory authorities as required. Investigators ascertain they will apply due diligence to avoid Protocol 
deviations. 
The Investigator will make appropriate reports on the progress of this study to CRO in accordance with 
applicable government regulations and their agreement with the CRO. 
 
15.2. Informed Consent  
Prior to obtaining informed consent, the purpose and nature of the study as well as possible adverse effects 
resulting from study drug administration must be explained to each patient. Written informed consent must 
be obtained in accordance with ICH-GCP guidelines using the approved informed consent form, before any 


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study specific procedures (including screening procedures) are performed. The process of obtaining 
informed consent should be documented in the patient source documents.  
The Investigator shall provide a copy of the signed informed consent form to the patient and the signed 
original shall be maintained in the Investigator File. A copy of the signed informed consent form must be 
filed in the patient file. At any stage, the patient may withdraw their consent and such a decision will not 
affect any further treatment options. 
 
16 FINANCING AND INSURANCE 
Financial aspects of the study are addressed in a separate clinical study agreement. 
The Investigator/ institution is required to have adequate current insurance to cover claims for negligence 
and/ or malpractice according to applicable national regulations. The sponsor will provide insurance 
coverage for the clinical study as required by applicable national regulations. 
Study patients will not be paid for their participation. Any study-related travel expenses made by the patient 
or the accompanying person will be reimbursed on the basis of actual cost as proven by original or copies 
of receipts, or an allowance per kilometer travelled. 
 
17 PUBLICATION POLICY 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
The Investigator should be aware that intellectual property rights (and related matters) generated by the 
investigator and others performing the clinical study will be patient to the terms of a clinical study 
agreement that will be agreed upon between the institution and the Sponsor or designee. With respect to 
such rights, the Sponsor or designee will solely own all rights and interest in any materials, data, and 
intellectual property rights developed by any party performing the clinical study described in this protocol, 
patient to the terms of any such agreement. In order to facilitate such ownership, the relevant party will be 
required to assign all such inventions either to the relevant institution or directly to the sponsor or their 
designee, as will be set forth in the clinical study agreement. 


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L. M. Lewis, P. L. Lieberman, D. D. Metcalfe, R. O'Connor, A. Muraro, A. Rudman, C. Schmitt, D. Scherrer, 
F. E. Simons, S. Thomas, J. P. Wood, and W. W. Decker. 2006. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 117: 391-397. 
61. 
Seymour, L., J. Bogaerts, A. Perrone, R. Ford, L. H. Schwartz, S. Mandrekar, N. U. Lin, S. Litiere, J. Dancey, 
A. Chen, F. S. Hodi, P. Therasse, O. S. Hoekstra, L. K. Shankar, J. D. Wolchok, M. Ballinger, C. Caramella, 
and E. G. de Vries. 2017. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol 18: e143-e152. 
 


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19 APPENDICES 
19.1. ECOG Performance Status 
The ECOG performance status is in the public domain and therefore available for public use (Oken M, 
Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and Response Criteria 
of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55).  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g. light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
 
19.2. iRECIST: Guidelines for response criteria for use in trials testing Immunotherapeutics 
The iRECIST guideline can be assessed using the following link:  
http://recist.eortc.org/irecist/  
 
19.3. Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 
The RECIST guideline, version 1.1, can be accessed using the following link: 
https://recist.eortc.org/recist-1-1-2/ 
 
19.4. Imaging Protocols 
CT Imaging Protocol: The specific parameters of the CT imaging protocol are shown in Table 20, below.  
CT scan with contrast of the thorax, abdomen and pelvis is the recommended modality. If there are brain 
metastases/tumors, an MRI scan of the head must also be performed. Patients with HNSCC will perform a 
head and neck CT.  
Intravenous contrast on CT and MRI exams is recommended when not medically contraindicated.   
Patients who have a contraindication to i.v. contrast may have MRI exams performed instead, except for 
exams of the chest.  In these cases, a non-contrast CT of the chest is recommended to evaluate the lung 
parenchyma.  


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Note: The anatomical coverage must be complete at baseline and all follow-up visits.  Scans lacking 
complete anatomical coverage will be considered non-readable data and will exclude patients at screening. 
• 
MRI without and with i.v. contrast is the preferred modality for brain imaging. If there is a 
contraindication to MRI, then CT of the brain without and with i.v. contrast is a second choice. 
• 
It is recommended that CT scans be performed with i.v. contrast. However, scans should be 
performed according to local site imaging protocols based on the clinical status of the patient. 
MRI Imaging Protocol: MRI examinations should be performed with the recommended 1.5T or 3T MRI 
system. It is preferable that repeat MRI examinations are performed on the same type of T system. The 
specific parameters of the MRI imaging protocol will be provided in an imaging manual. 
Bone Scan Imaging Protocol: Radionuclide bone scans should only be performed when clinically 
indicated.  If bone scans were clinically indicated and positive at baseline, they should be repeated at the 
time of confirmation of response either if these lesions are not assessable on CT, or to confirm CR. The 
choice of radionuclide scanning, bone scan (i.e. Technetium-99m bone scintigraphy (Tc-99m bone scans)) 
should be based on site standard of care. The specific parameters will be provided in an imaging manual.  
Color Digital Photography: Superficial clinical lesion (e.g., skin nodule) must be measured in at least one 
dimension (longest diameter in the plane of measurement will be recorded) with a minimum size of the 
longest axis being ≥ 10 mm as imaged with scale in color photography per RECIST 1.1. 
If a patient has clinically-indicated skin lesion(s), the investigator site will perform color digital 
photography of all skin lesions using a ruler held flush to the skin next to the longest diameter of the lesion 
to indicate the size of the lesion at every time point scheduled for radiological scans that a lesion is present. 
Once a lesion(s) is documented, the target area should be documented at every subsequent time point for 
the duration of the study. The imaging manual will include more detailed instructions for the site to follow 
during image capture. 
 
Table 20: CT Imaging Protocol 
Type of scan 
Spiral CT 
Patient 
orientation 
Supine, head first, arms above the head 
Anatomy 
Chest-abdomen-pelvis (from lung apices to the pubic symphysis)   
Breathing 
instructions 
Suspended inspiration 
kV/mAs 
Use the normal dose, but not low dose settings 
 
Detector 
collimation 
Use vendor specification 
Filter 
Standard and High-resolution reconstruction algorithm (lung window) for lungs 
Soft tissue filter for abdomen and pelvis 
Slice 
thickness 
3 mm recommended (acceptable range is 2.5-5 mm), continuous slices 


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Gap (slice 
spacing) 
None 
i.v. contrast 
100 ml Omnipaque 350 or equivalent non-ionic contrast medium at a concentration of 
350mgl/ml  
Injection rate 
3ml/sec + 50ml saline flush 
Scan delay 
 Given 3ml/sec, start delay optimized for venous portal phase during abdominal 
scanning (routinely 70 seconds).  
If done locally, biphasic neck injection can be used. 
Contrast 
enhancement 
The portal phase implies that the contrast reached the liver and portal venous system. 
The liver parenchyma enhances through blood supply by the portal vein and hepatic 
veins should already enhance. 
 
19.5. Definitions for Clinical and Laboratory AEs 
All AEs (clinical and laboratory) will be rated AEs and SAEs, according to the current National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE v5.0)  
The applicable National Cancer Institute CTCAE, can be accessed using the following link: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
AEs will also be categorized in terms of a) severity, b) causal relationship, c) action taken regarding to 
study treatment and d) outcome to date, as follows: 
 
a) Severity (Clinical Events Only) if not listed in the CTCAE v5.0  
Severities of clinical events are to be graded as follows: 
Code 
Descriptor 
Definition 
1  
Mild 
An event that may be associated with the awareness of a sign or 
symptom and is easily tolerated or discomfort noted, but no disruption 
of normal daily activity 
2  
Moderate 
An event that causes discomfort enough to cause interference with 
usual activity or discomfort sufficient to reduce or affect normal daily 
activity 
3  
Severe 
An event that is incapacitating with inability to work or do usual 
activity or inability to work or perform normal daily activity 
4  
Life threatening or 
disabling 
An event that is life threatening or disabling 
5  
Fatal 
An event that is fatal 
 
b) Causal Relationship 


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The Investigator should use medical judgment to determine whether there is a reasonable causal 
relationship, including all relevant factors such as temporal course and latency, results from de-challenge 
or re-challenge, pattern of the reaction, known pharmacological properties of the product, and alternative 
explanations (e.g., other drugs, medical history, concomitant diseases). The expression “reasonable causal 
relationship” means to convey in general that there is evidence or argument to suggest a causal 
relationship. Causality assessment will be documented on the AE and SAE form.  
No reasonable possibility of causal relationship: 
• 
Unrelated: 
o There is no reasonable causal relationship between the investigational medicinal product 
and the event. 
Reasonable possibility of causal relationship: 
• 
Possibly related: 
o Event or laboratory test abnormality, with reasonable time relationship to drug intake.  
o Could also be explained by disease or other drugs.  
o Information on drug withdrawal may be lacking or unclear.  
• 
Related: 
There is a reasonable causal relationship between the investigational medicinal product and the event.  
For CIOMS forms a binary form of causality assessment will be used as outlined in the safety handling 
manual: 
• 
Yes: There is a reasonable causal relationship between the investigational medicinal product and 
the AE  
• 
No: There is no reasonable causal relationship between the investigational medicinal product and 
the AE 
 
c) Action Taken Regarding any study treatment 
The investigators are to record the action taken regarding treatment agent using the following 4 categories: 
Code 
Descriptor 
Definition 
1  
None 
No change in study treatment was made 
2  
Discontinued 
The study treatment was permanently stopped 
3  
Delayed/ 
Interrupted 
Study treatment/study agent was delayed or was temporarily stopped 
4  
Partial/ Incomplete 
Dose 
The complete Study treatment dosage was not given 
 
d) Outcome to Date 
The investigators are to record the outcome to date using the following 5 categories: 


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Code 
Descriptor 
Definition 
1 
Recovered 
The patient fully recovered from the AE with no residual effect 
observable 
2 
Recovered with 
sequelae 
AE resolved, but residual effect(s) are present. Residual effects of the 
AE are still present and observable 
3 
Ongoing 
The AE itself is still present and observable 
4 
Death 
Death 
5 
Unknown 
 
 

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