Clinical trial NCT05109442
Conditions: Advanced Solid Tumor
Sponsor: Affimed GmbH
Start date: 2021-11-19; Completion date: 2025-06-11
Enrollment: 112 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
AFM24-102 is a Phase 1/2a open-label, non-randomized, multicenter, dose escalation, and expansion study evaluating AFM24 in combination with atezolizumab in patients with selected EGRF-expressing advanced solid malignancies whose disease has progressed after treatment with previous anticancer therapies.

Detailed description:
There will be 2 parts in this study: a dose escalation phase (phase 1) and an expansion phase (phase 2a). Patients will qualify to receive the investigational drugs (AFM24 + atezolizumab) in the dose escalation phase or the expansion phase only if they are deemed eligible following the safety lead-in phase. Seven days before the planned first combination treatment, patients will receive a single dose of AFM24 and will be observed for any adverse events for 1 week.

The aim of the dose escalation phase is to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of AFM24 in combination with atezolizumab.

The dose escalation phase will be followed by the expansion phase once the MTD/RP2D of AFM24 in combination with atezolizumab has been determined. The expansion phase of the study is intended to collect preliminary evidence of efficacy and to further confirm the safety of AFM24 in combination with atezolizumab.

The tumor types planned to be studied in the AFM24/atezolizumab combination study will be:

* Non-small cell lung cancer (EGFR-WT), with disease progression after chemotherapy and PD1/PD-L1 targeted therapy
* Gastric/GEJ cancer if intolerant to or with disease progression after standard platinum-based chemotherapy
* Pancreatic/hepatocellular/biliary tract cancer with disease progression after standard of care (SOC) therapy or if there is no appropriate SOC available for their condition
* Advanced or metastatic NSCLC harboring a targetable EGFR kinase domain mutation with disease progression on or after received ≥1 prior lines of treatment for advanced disease, including a Tyrosine-Kinase Inhibitor (TKI) for EGFR mutations

Arms: arm 1: The Escalation phase will determine the MTD/RP2D of AFM24 in combination with atezolizumab. A traditional 3+3 design will be used to determine the RP2D. arm 2: The expansion phase will collect preliminary evidence of efficacy and further confirm the safety of AFM24 in combination with atezolizumab.
Interventions: intervention 1: AFM24 intervention 2: Atezolizumab 840 MG in 14 ML Injection
Intervention descriptions: intervention 1: intravenous infusion intervention 2: intravenous infusion

Protocol documents:
Prot_000.pdf: 
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exp
 
 
 
PROTOCOL AFM24-102 
Study Title: 
A Phase 1/2a Open Label, Multicenter Study to Assess the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of 
AFM24 in Combination with Atezolizumab in Patients with 
Selected Advanced/Metastatic EGFR-expressing Cancers 
Protocol Number: 
AFM24-102 
Sponsor: 
Affimed 
 GmbH 
Im Neuenheimer Feld 582, 
69120 Heidelberg, Germany 
Products: 
AFM24 (innate immune cell engaging recombinant antibody 
against EGFR-expressing solid tumors)  
Atezolizumab (anti-PD-L1 antibody monoclonal IgG1) 
Indication Studied: 
Advanced/Metastatic EGFR-expressing cancers 
Study Phase: 
Phase 1/2a 
EudraCT Number: 
2021-000707-20 
IND Number: 
143500 
Medical Monitor: 
   
  
 
Final Version Date: 
Version 4.0, 10 May 2023 
CONFIDENTIAL 
The information contained in this document, especially unpublished data, is confidential communication from 
Affimed GmbH. Acceptance of this document constitutes the agreement of the recipient that this information will 
not be disclosed to others without written authorization from Affimed GmbH, except to the extent necessary for 
Ethics Committee/Institutional Review Board procedures and to obtain written informed consent from those persons 
to whom test drug may be administered. 






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Investigator’s Declaration and Approval: 
I have read this protocol and agree that it contains all the necessary details for carrying out this 
study. I will conduct the study as described in the current, approved protocol. I verify that I am 
suitably qualified by education, scientific and medical training and experience to conduct the 
study. Documentation of my qualifications and professional affiliations are contained in my 
up-to-date curriculum vitae provided to the Sponsor. 
I will provide the supplied copies of the protocol, including future protocol amendments, and all 
information relating to non-clinical and clinical experience when available (e.g., in updated 
editions of the Investigator’s Brochure), to all staff involved in the conduct of this study. I will 
discuss this material with them to ensure that they are fully conversant with the investigational 
medicinal product and study design, and that they will handle the data and information generated 
in the study confidentially. 
I will conduct the study in accordance with Good Clinical Practice, the Declaration of Helsinki, 
and the moral, ethical and scientific principles that justify medical research. I acknowledge that 
the study will be conducted in accordance with the relevant laws and regulations relating to clinical 
studies and the protection of patients, including data privacy laws. I confirm it is my duty and the 
duty of my study staff to ensure participating patients are informed comprehensively about the 
nature of the study and will give their written consent to participate before entry into the study. 
Patients will be informed that they may withdraw from their studies at any time without 
jeopardizing their future care. I will use only the patient informed consent form approved by the 
Sponsor and the Ethics Committee/Institutional Review Board for this study. I will supply the 
Sponsor with any written material prepared by myself or my study staff, e.g., summary of study, 
which is given to the Ethics Committee/Institutional Review Board in support of the application. 
Where applicable, the patient information contained in clinic records, reports and manuscripts will 
be transcribed to the study case report forms. I (or my delegates as described in my Study File) 
will attest to the authenticity of the data and accuracy and completeness of the transcription by 
signing the case report forms. I agree to the audit and monitoring procedures to verify study records 
against original records. Should it be requested by government regulatory agencies, I will make 
available additional background data from my records and from the hospital or institution where 
the study was conducted (as permitted by the hospital or institution). 
I understand that the case report forms and other data pertinent to this study are the property of 
Affimed GmbH and are confidential. I agree to only supply Affimed GmbH (or their delegates) 
with patient study data in such a way that the patient cannot be personally identified. 
 
Investigator:  
……………………………………  
……………………………… 
 
 
 
Signature 
 
 
 
 
Date 
Print Name: 
 
……………………………………………………………………………… 
Institution Name:  
……………………………………………………………………………… 
Institution Address: 
……………………………………………………………………………… 


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OTHER CONTACT INFORMATION 
Full contact details for each Investigational site, the Sponsor, the Medical Monitor(s), and key 
coordinating and operational personnel will be maintained in the Trial Master File and in each 
site’s Study File throughout the course of the study. 
 
 




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6.8.1. 
Acceptable Concomitant Medications ............................................................................60 
6.8.2. 
Prohibited Concomitant Medications .............................................................................61 
6.9. 
Blinding and Procedures for Unblinding the Study ........................................................62 
6.10. 
Management of AFM24-Related Toxicities ...................................................................62 
6.11. 
Management of Atezolizumab-Related Toxicities .........................................................63 
7. 
STUDY DRUG MATERIALS AND MANAGEMENT ............................................65 
7.1. 
Study Drug Materials AFM24 and Atezolizumab ..........................................................65 
7.1.1. 
Investigational Product ...................................................................................................65 
7.1.2. 
Provision and Replacement of AFM24 and Atezolizumab ............................................65 
7.1.3. 
Labeling of AFM24 and Atezolizumab ..........................................................................65 
7.1.4. 
Storage of AFM24 and Atezolizumab ............................................................................65 
7.1.5. 
Handling and Disposal ....................................................................................................65 
7.2. 
Accountability 
 ..............................................................................................65 
7.3. 
Treatment Compliance 
 ..............................................................................................66 
8. 
STUDY ASSESSMENTS AND PROCEDURES .......................................................67 
8.1. 
Informed Consent, Medical History, and Demographics ...............................................67 
8.2. 
Safety Assessments 
 ..............................................................................................67 
8.2.1. 
Adverse Events ...............................................................................................................67 
8.2.2. 
DLT Analysis ..................................................................................................................68 
8.2.3. 
Physical Examinations ....................................................................................................68 
8.2.4. 
Vital Signs .......................................................................................................................68 
8.2.5. 
Electrocardiogram ...........................................................................................................69 
8.2.6. 
Clinical Chemistry, Hematology, Urinalysis, Coagulation ............................................70 
8.2.7. 
ECOG Performance Status .............................................................................................70 
8.2.8. 
Pregnancy and FSH tests ................................................................................................70 
8.3. 
 
 
8.3.1. 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 .....................................71 
8.3.2. 
Efficacy Parameters ........................................................................................................71 
 
 
8.4.1. 
Volume of Blood Sampling ............................................................................................72 
 
 
8.6. 
Disease Response Assessment ........................................................................................72 
8.7. 
Tumor Genomics 
 ..............................................................................................73 
 
                          
 
8.9. 
Immunogenicity (Anti-Drug Antibodies) .......................................................................74 
9. 
STATISTICAL CONSIDERATIONS ........................................................................75 
9.1. 
Population for Analyses  ..............................................................................................75 
 
 
9.1.1. 
Dose escalation phase (Phase 1) .....................................................................................76 
9.1.2. 
Expansion phase (Phase 2a) ............................................................................................76 
9.2. 
Statistical Hypotheses 
 ..............................................................................................78 
9.3. 
Statistical Analyses 
 ..............................................................................................78 
9.3.1. 
Safety Analyses ...............................................................................................................78 
9.3.2. 
Efficacy Analyses ...........................................................................................................79 
9.3.3. 
Pharmacokinetic Analyses ..............................................................................................79 








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List of Abbreviations 
Abbreviation 
Definition/Explanation 
ADA 
anti-drug antibodies 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-168 
area under the concentration-time curve form time zero to 
168 hours  
AUCtau 
area under the concentration-time curve over the dose interval 
BOR 
best objective response 
C 
Cycle 
CBR 
clinical benefit rate 
CD16A 
Fcγ receptor IIIA 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
Cmin 
minimum plasma concentration 
CR 
complete response 
CRA 
clinical research associate 
CRO 
contract research organization 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CV 
coefficient of variation 
C1D1 
Cycle 1 Day 1 
D 
Day 
DDS 
dose-determining set 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
EC50 
half maximal effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EGFR 
epidermal growth factor receptor 
EOI 
end of infusion 
EOT 
End of Treatment 


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Abbreviation 
Definition/Explanation 
EU-CTR 
EU Clinical Trial Regulation 
EXP 
expansion cohort  
Fc 
fragment crystallizable 
FDA 
Food and Drug Administration 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GEJ 
gastro-esophageal junction 
GLP 
Good Laboratory Practice 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
interferon 
Ig 
immunoglobulin 
IgG 
immunoglobulin G 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
i.v. 
Intravenous(ly) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NK 
natural killer 
NSCLC 
non-small cell lung cancer 
OR 
objective response 
ORR 
objective response rate 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PS 
performance status 


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Abbreviation 
Definition/Explanation 
PT 
prothrombin time 
qw 
once weekly 
q1w 
every 1 week 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
RECIST 
Response Evaluate Criteria in Solid Tumors 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SCLC 
small cell lung cancer 
SD 
stable disease 
SOC 
standard of care 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to Cmax 
TNF-α 
tumor necrosis factor-alpha 
ULN 
upper limit of normal 
US 
United States 
WT 
wild type 
 
 






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Patient’s eligibility criteria must be re-confirmed on or within 7 days before Day -7, before administration of the first 
AFM24 infusion; refer to inclusion and exclusion criteria sections (Section 5.1 and Section 5.2, respectively) to see 
allowed time periods of screening assessments. 
Note: Patients are required to receive premedication approximately 1 hour before each dose of AFM24; the list of 
required pre-medications is provided below in the subsection “Study Treatment, Dose, and Mode of Administration.” 
Dose Escalation Phase (Phase 1) 
The aim of the dose escalation phase (Phase 1) is to determine the MTD/RP2D of AFM24 in combination with 
atezolizumab. 
Dose Escalation Phase (Phase 1) Study Design 
Patients will be enrolled sequentially in cohorts of 3 to 6 patients in this phase of the study. AFM24 will be 
administered at an escalating dose per each cohort as a weekly intravenous (i.v.) infusion (once weekly [qw]) in 
4-week cycles. Atezolizumab will be administered at a fixed dose of 840 mg as an i.v. infusion every 2 weeks (q2w) 
in 4-week cycles. Patients will receive study treatment (AFM24 + atezolizumab) until disease progression, intolerable 
toxicity, Investigator discretion, or patient withdrawal of consent. 
The 160 mg i.v. qw dose was selected as the starting dose for AFM24 in Cohort 1 based on the information from the 
ongoing AFM24-101 monotherapy study (A first-in-human [FIH] Phase 1/2a open-label, multicenter study to assess 
the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of AFM24 in patients with advanced solid 
cancers). Thereafter, the dose escalations for AFM24 will be based on the data from AFM24-101 in conjunction with 
the safety and available PK data emerging from this study (as determined by the Safety Review Committee [SRC]) 
(see Rationale for Dose Selection, Section 2.4). 
A 3+3 design will be used to determine the RP2D, with the schematic escalation rules: 
Number of patients with DLT at a given dose level will be evaluated as:  
• 
If 0 out of 3 
• 
Escalate to next higher dose level 
• 
If 1 out of 3  
• 
Enter 3 more patients at this dose level: 
o 
If 0 of these additional patients experience a DLT, proceed to the next higher dose level  
o 
If 1 or more of these additional patients experience a DLT, the dose escalation will be stopped. Up 
to 3 additional patients will be entered at the lower dose level if only 3 patients were treated 
previously at that dose level. Alternatively, up to 6 additional patients could be entered to receive 
intermediate dose levels, based on the emerging safety, pharmacokinetic, and pharmacodynamic 
data observed in the FIH AFM24-101 study. If this occurs in Cohort 1, there will be a de-escalation 
to Cohort -1. 
• 
≥ 2 out of 3  
• 
Dose escalation will be stopped. Up to 3 additional patients will be entered at the lower dose level if only 3 
patients were treated previously at that dose level. Alternatively, up to 6 additional patients could be entered 
to receive intermediate dose levels, based on the emerging safety, pharmacokinetic, and pharmacodynamic 
data observed in the FIH AFM24-101 study. If this occurs in Cohort 1, there will be a de-escalation to Cohort 
-1. 
MTD definition: The highest dose level below the maximum administered dose where the number of patients with 
DLT is <2 out of 6 is defined as the MTD. (At least 6 patients evaluable for the safety endpoint must be entered at 
this dose level and a toxicity rate of less than 0.33 must be observed in order to be confirmed as the MTD). 
RP2D definition: An RP2D can be declared at any dose level or schedule where the MTD criteria were not met, yet 
clinical, PK, pharmacodynamics and/or laboratory data indicate an optimal biologically active dose has been reached 
(with a toxicity rate of less than 0.33) and at least 6 patients have been treated at that given dose level. 
Expansion Phase (Phase 2a) 
The dose escalation phase (Phase 1) will be followed by the expansion phase (Phase 2a) once the MTD/RP2D of 
AFM24 in combination with atezolizumab has been determined. The expansion phase (Phase 2a) of the study is 
intended to collect preliminary evidence of efficacy and to further confirm the safety of AFM24 in combination with 
atezolizumab.  






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• 
“Delay of vaccination until immunosuppressive therapy is reduced and/or based on immunophenotyping 
of T cell and B cell immunity can be considered.”  
• 
“Systemic corticosteroids and targeted agents are expected to blunt immune responses to vaccination.” 
This study utilizes a mandatory premedication regimen that contains corticosteroids for at least the duration of the 
first cycle (i.e., Cycle 1). Therefore, every effort should be made to vaccinate patients prior to being considered for 
this study based on the Investigator’s risk/benefit analysis for each patient. If a patient receives the COVID-19 
vaccination prior to study participation, the vaccine should be administered at least 2 weeks prior to Day -7 or at least 
4 weeks prior to Day -7 for live attenuated vaccines. For patients whose opportunity for COVID-19 vaccination arrives 
during the conduct of the study (i.e., ongoing patients in the study), see instructions for COVID-19 vaccination 
provided in Section 6.8.1.1. 
Inclusion Criteria (Phase 1 and Phase 2a): 
Patients will be considered eligible to be enrolled in the study if ALL the following inclusion criteria are satisfied 
unless otherwise specified: 
1) 
Voluntary provision and understanding of signed and dated, written informed consent prior to any 
mandatory study-specific procedures, sampling, or analysis. 
2) 
Patients must be aged ≥18 years on the day of signing informed consent (or of an acceptable age 
according to local regulations, whichever is older). 
3) 
Patients must have documented radiological progression during or after their latest therapy for all 
phases. 
4) 
Patients have documented histologically or cytologically confirmed advanced or metastatic EGFR-
positive (positive staining for EGFR in ≥1% of tumor cells determined by a locally validated 
immunohistochemistry assay) select cancer types, except for NSCLC patients (cohorts EXP-1 and 
EXP-4); and meet the following criteria: 
Dose Escalation Phase (Phase 1):  
Dose Escalation Cohorts: Patients who meet the criteria specified for the expansion cohorts. 
Expansion phase (Phase 2a): 
• 
EXP-1: patients with advanced or metastatic, EGFR-WT expressing NSCLC whose disease has 
progressed after having received ≥1 prior lines of therapy for advanced disease. Patients must 
have received at least a platinum-based doublet in combination with an anti-programmed cell 
death protein 1 (PD1)/programmed death-ligand 1 (PD-L1) antibody or must have received an 
anti-PD1/PD-L1 antibody prior to or after a platinum-based doublet. Patients with a known 
actionable driver mutation (other than EGFR mutation) must have received an approved targeted 
treatment for the respective mutation. The patients should also have received a second line of 
treatment if approved and available, or they may be enrolled in the study if in the opinion of the 
Investigator it is in the patient’s best interest, or the standard of care (SOC) is not appropriate. 
• 
EXP-2: patients with locally advanced, unresectable, or metastatic gastric or GEJ adenocarcinoma 
refractory to or, intolerant of, standard therapy. Patients must have received ≥1 prior 
chemotherapy regimen including a platinum and fluoropyrimidine doublet. The patients should 
also have received a second line of treatment if approved and available, or they may be enrolled 
in the study if in the opinion of the Investigator it is in the patient’s best interest, or the SOC is 
not appropriate, 
• 
EXP-3: patients with advanced or metastatic hepatocellular carcinoma (other than fibrolamellar 
and sarcomatoid subtype; Barcelona Clinic Liver Cancer Stage C disease or Stage B disease not 
amenable to locoregional therapy or refractory to locoregional therapy), hepatobiliary-, or 
pancreatic adenocarcinoma. Patients must have been treated with at least 1 previous line of an 
approved, SOC therapy for the respective disease type or, in the opinion of the Investigator, 
available SOC is not appropriate. The patients should also have received a second line of treatment 
if approved and available, or they may be enrolled in the study if in the opinion of the Investigator 
it is in the patient’s best interest, or the SOC is not appropriate. 
• 
EXP-4: patients with advanced or metastatic NSCLC harboring a targetable EGFR kinase domain 
mutation and whose disease has progressed on or after having received ≥1 prior lines of therapy 














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2. 
INTRODUCTION 
AFM24 is a first-in-class, tetravalent, bispecific, fragment crystallizable (Fc)-silenced antibody 
designed to target epidermal growth factor receptor-expressing (EGFR+) solid tumors. Of its 
4 binding sites, 2 binding sites are specific for EGFR; the other 2 binding sites are specific for 
CD16A, which is the Fcγ receptor expressed by natural killer (NK) cells and macrophages. 
AFM24 is designed to utilize the cytotoxic potential of NK cells and macrophages for the 
elimination of EGFR+ cancer cells, offering a novel therapeutic approach to target EGFR+ tumors 
with active immunotherapy. This bispecific innate immune cell recruiting antibody binds to both 
EGFR+ cancer cells and CD16A+ NK cells and macrophages with strong avidity, thus creating an 
immunological synapse. This results in antibody-dependent cellular cytotoxicity (ADCC; induced 
by NK cells) and antibody-dependent cellular phagocytosis (ADCP; induced by macrophages) of 
EGFR+ tumor cells, thereby activating a potent anti-tumor immune response. At high 
concentrations, AFM24 can also down-modulate ligand-induced EGFR signaling. 
Due to its ADCC- and ADCP-related mode of actions, it is anticipated that AFM24 would be active 
in patients who harbor EGFR+ cancers, potentially also including cancers that have intrinsic or 
acquired resistance to EGFR targeting monoclonal antibodies and tyrosine kinase inhibitors 
(TKIs). Therefore, AFM24 has the potential to overcome the limitations of EGFR-targeting 
standard of care (SOC) monoclonal antibodies and TKIs. In addition, it is anticipated that AFM24 
would have an improved safety profile compared with these SOC agents. 
Patients with previously treated advanced or metastatic solid tumor malignancies that express 
EGFR represent a high unmet medical need due to the associated poor prognosis and limited 
number of effective treatment options available. NK cells and macrophages have an intrinsic 
ability to eliminate tumor cells; however, innate immunity is often suppressed in cancer patients. 
By utilizing AFM24 to redirect and activate such immune cells it may be possible to release the 
anti-tumor potential of patients’ own innate immunity to effectively control their cancers.  
Intact and effective immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades and requires a coordinated effort between the innate and adaptive 
component (Diss 2010). Limited response rates of T cell-based checkpoint immunotherapies 
against cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 
(PD-1)/programmed death-ligand 1 (PD-L1) indicate that additional checkpoint pathways exist to 
suppress efficient adaptive tumor immunity (Sharma 2015; Zou 2018). Tumors usually escape 
T cell immune surveillance by downregulating the expression of primary histocompatibility 
complex class I. Therefore, this compromises the tumor antigen presentation pathway 
(Keenan 2019; Bi 2017), making these tumors challenging to be recognized by T cells. 
Nevertheless, these tumors are highly susceptible to NK cell elimination via the “missing-self” 
recognition (Lanier 2005; Ljunggren 1990). 
The helper effects of NK cells are essential in the context of T cell-based checkpoint 
immunotherapy. Although anti-PD-1 immunotherapy mainly targets T cells, intratumoral NK 
cells’ frequency correlates with patient responsiveness to PD-1 blockade immunotherapy and 
increased overall survival (Barry 2018). These intratumoral NK cells form clusters with 
intratumoral stimulatory dendritic cells and play a role in stimulating anti-tumor T cell activity 
(Barry 2018). In line with this, data from mouse models showed that the depletion of NK cells 


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abrogated the efficacy of PD-L1 blockade immunotherapy (Zhang 2018). The presence of NK 
cells prevented the formation of an exhausted status of tumor-infiltrating CD8+ T cells even under 
conditions of PD-L1 blockade, as evidenced by decreased expression of degranulation marker 
CD107a, and effector cytokines, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and 
increased expression of exhaustion marker PD-1 by CD8+ T cells, after NK cell depletion (Zhang 
2018). Therefore, by facilitating an efficient anti-tumor T cell response, NK cells contribute to the 
PD-1/PD-L1 checkpoint immunotherapy. Also, higher levels of intra-tumoral NK cells might serve 
as a biomarker to predict better clinical response to PD-1/PD-L1 checkpoint immunotherapy. 
Immune checkpoint inhibition targeting PD-L1 or PD-1 has become an important approach in 
treating multiple human cancers, as PD-L1 expression on tumor cells and tumor-infiltrating 
immune cells can inhibit anticancer immune responses (Chen 2013). Atezolizumab, a humanized, 
engineered monoclonal immunoglobulin (Ig) G1 antibody, selectively targets PD-L1 to block 
interactions with its receptors to promote T-cell activation and reinvigorate and enhance the 
anticancer activity while leaving the interaction between PD-L2 and PD-1 intact (Chen 2012; 
Herbst 2014). Atezolizumab is approved to treat certain types of locally advanced or metastatic 
non-small cell lung cancer (NSCLC) and urothelial carcinoma in the United States (US), Europe, 
and elsewhere, extensive stage small cell lung cancer (SCLC), alveolar soft part sarcoma and 
melanoma in the United States (TECENTRIQ PI, 2022). 
Based on the above-described high unmet need in patients with relapsed/refractory EGFR 
expressing cancers and the potential for AFM24 and atezolizumab to synergistically target 
EGFR -expressing tumor cells, the current study (AFM24-102) is planned. 
2.1. 
EGFR and Description of Disease 
EGFR is a member of the human epidermal growth factor receptor family of receptor tyrosine 
kinases and is typically activated through ligand binding and homo- or heterodimerization 
resulting in intracellular tyrosine phosphorylation and signal transduction. It is expressed in a 
variety of different cell types (Huang & Harari, 1999) and is involved in the regulation of cellular 
differentiation and proliferation (Salomon et al., 1995). EGFR is known to be overexpressed in 
multiple tumor types (e.g., colorectal cancer, NSCLC, head and neck squamous cell carcinoma, 
glioblastoma multiforme, and prostate, kidney, cervical, bladder, ovarian, and triple-negative 
breast cancers) (Bast et al., 1993; Ishikawa et al., 1990; Itakura et al., 1994; Kim et al., 1996; 
Rikimaru et al., 1992; Robertson 1996; Sargent et al., 1989). In many cases, aberrant EGFR 
activation, mediated primarily through changes in gene amplification, gene mutations, and 
autocrine ligand stimulation, is an important factor in tumorigenesis. 
2.2. 
AFM24 
2.2.1. 
Mechanism of Action 
AFM24 is a first-in-class tetravalent bispecific IgG1-scFv fusion antibody with a silenced IgG1 
Fc functionality, which binds specifically to the EGFR and CD16A. The product is being 
investigated for the treatment of patients with advanced or metastatic cancers that express EGFR. 
Through binding to EGFR on target cells and to CD16A on NK cells and macrophages, AFM24 
mediates specific, potent, and efficient lysis of EGFR-positive human tumor cell lines via NK 
cell-mediated ADCC and macrophage-mediated ADCP. In contrast to other EGFR-targeting 
antibodies, like cetuximab, AFM24 shows a substantially reduced inhibition of EGFR signaling, 


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which potentially could be associated with an improved safety profile, particularly regarding skin 
toxicity. Nevertheless, residual inhibition of EGFR signaling and complement activation may 
both augment the ADCC and ADCP mechanisms of action and contribute to the anti-tumor 
activity of AFM24.  
2.2.2. 
Nonclinical Studies 
AFM24 has been characterized extensively in non-clinical studies and an overview of these results 
are provided below. Further details are provided in the AFM24 Investigator’s Brochure. 
AFM24 is highly specific for EGFR and does not cross-react with other members of the EGFR 
family. In addition, AFM24 binds exclusively to CD16A and does not cross-react with other 
human Fcγ receptors, except for the neonatal Fc receptor, via its silenced Fc moiety.  
In co-cultures of human peripheral blood mononuclear cells or purified human NK cells with a 
variety of different EGFR-positive tumor cells, AFM24 induced substantial ADCC. For all tested 
EGFR-positive target cells, mean half maximal effective concentration (EC50) values for inducing 
ADCC by AFM24 were in the lower picomolar range. Importantly, RAS-mutated human tumor 
cell lines were also efficiently killed by effector cells activated by AFM24 due to its mode of action 
(ADCC and/or ADCP). AFM24 did not induce ADCC by NK cells against EGFR-negative cells.  
AFM24 also induced ADCP of human EGFR-positive tumor target cells by macrophages, while 
leaving EGFR-negative cells unaffected.  
In vivo efficacy was assessed using a humanized mouse model bearing xeno-transplanted human 
EGFR-positive tumors. In the prophylactic treatment setting a trend of reduced tumor growth by 
AFM24 treatment was observed at 5 mg/kg and significant inhibition of tumor growth was 
observed at 10 mg/kg and higher. In the therapeutic setting significant inhibition of tumor growth 
by AFM24 treatment was also seen at a dose level of 10 mg/kg and higher.  
AFM24 induced cytokine release from human peripheral blood mononuclear cells in a 
concentration-dependent manner, but only when cultured in the presence of EGFR-positive target 
cells. The most dominant cytokine was interleukin-6, which was measured in co-cultures in 
substantial amounts after 24 h of stimulation.  
Safety pharmacology, and toxicology was assessed in cynomolgus monkeys which was validated 
as the only relevant and fully cross-reactive species. Animals showed no signs of behavioral 
alteration or neurotoxicity, no alteration of cardiovascular and respiratory parameters. No effect of 
AFM24 on coagulation and on ophthalmic examinations up to the highest dose level of 75 mg/kg 
was observed. 
Vomiting was observed in 2 of the 5 males on Day 1 of the dosing phase. This finding was only 
noted for the high dose; as such, it was considered AFM24-related. No other signs of 
gastrointestinal or renal effects were observed.  
The first dose of AFM24 caused a transient elevation of circulating interleukin -6 levels and 
transient, non-dose-dependent reductions in absolute peripheral NK cells. All observed 
immunological changes appear to be in line with the anticipated mode of action of AFM24 and are 
therefore not considered to be manifestations of immunotoxicity.  
Half-life of AFM24 ranged from 30 hours to more than 140 hours in cynomolgus monkeys. 
AFM24 exposures increased with the increase in dose level (mean maximum plasma concentration 


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[Cmax] and area under the concentration-time curve form time zero to 168 hours [AUC0-168] values). 
There was no sex-related difference in exposure. Increases in mean Cmax and AUC0-168 values were 
dose proportional from 8 to 75 mg/kg. The calculated apparent volume of distribution of AFM24 
was similar to or up to 3-fold greater than total plasma volume in the cynomolgus monkey, 
indicating only limited distribution of AFM24 into tissues. No accumulation of AFM24 was 
observed after 5 once-weekly doses in monkeys.  
Treatment-induced anti-drug antibodies (ADAs) were detected in 10/26 monkeys included in the 
Good Laboratory Practice study. In the majority of cases, the positive ADA analysis results were 
sporadic and/or associated with low electrochemiluminescence values, and AFM24 exposure was 
similar to that of ADA-negative animals. However, 2 animals in the intermediate dose group 
(24 mg/kg) gave consistent ADA-positive results, with notably higher and increasing 
electrochemiluminescence values, during the recovery phase. The exposure of AFM24 in these 
animals was notably lower than that of the other 2 animals in the dose group. These observations 
are consistent with ADA-mediated clearance of AFM24. 
2.2.3. 
AFM24 Clinical Experience 
A first-in-human (FIH) Phase 1/2a open-label, multicenter study to assess the safety, tolerability, 
pharmacokinetic (PK) and preliminary efficacy of AFM24 in patients with advanced solid cancers 
(AFM24-101) is currently ongoing. The recommended phase 2 dose (RP2D) of AFM24 as a 
monotherapy is 480 mg.  
Preliminary data from the ongoing study AFM24-101 indicate that AFM24 has an apparent half-
life estimated to be 11.2 days at doses ≥320 mg. Please refer to the latest version of the 
Investigator’s Brochure for further information.  
The most common treatment-emergent adverse events (TEAEs) for the study that were reported 
as related to AFM24 are infusion-related reactions (IRR).  
Data from the NSCLC EGFRmut cohort showed initial signs of activity, some cases of partial 
response and stable disease were observed.  
For details on the currently ongoing studies with AFM24, please refer to the most recent AFM24 
Investigator’s Brochure. 
2.3. 
Background Information Atezolizumab 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits the 
interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which 
function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD-L1 binding by 
atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T cell 
responses, resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 
2016). Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc-effector 
function and associated antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being 
studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and CIT. 








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Available data from clinical trials of atezolizumab have demonstrated favorable efficacy in 
patients with advanced solid tumors (liver cancer, NSCLC, Melanoma, Bladder cancer) previously 
treated with 2 or more prior chemotherapy regimens (Inman 2017, Socinski 2018, Tie 2019). 
Available data has also indicated that combined treatment of chemotherapy and anti-PD1/PDL1 
antibodies has a manageable safety profile (Horn 2018, West 2019). 
Considering the high unmet needs, and the currently known safety profiles of AFM24 and 
atezolizumab, the potential benefit outweighs the risks identified in association with the 
investigational treatment for this study (AFM24 + atezolizumab). 
2.7. 
Trial Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional Review 
Board (IRB), and according to Good Clinical Practice (GCP) guidelines. No deviation from the 
protocol will be implemented without the prior review and approval of the Sponsor and IRB except 
where it may be necessary to eliminate an immediate hazard to a research patient. In such case, the 
deviation will be reported to the Sponsor and IRB as soon as possible. 






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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
AFM24-102 is a Phase 1/2a open-label, non-randomized, multicenter, dose escalation and 
expansion study evaluating AFM24 in combination with atezolizumab (investigational treatment: 
AFM24 + atezolizumab) in patients with select EGFR-expressing advanced solid malignancies 
whose disease has progressed after treatment with previous anticancer therapies. 
There will be 2 parts in this study: a dose escalation phase (Phase 1) and an expansion phase 
(Phase 2a). Patients will qualify to receive the investigational treatment (AFM24 + atezolizumab) 
in the dose escalation phase (Phase 1) or in the expansion phase (Phase 2a) only if they are deemed 
eligible post the safety lead-in phase where they will receive a single i.v. AFM24 infusion (see 
Section 4.2.2). Patients who qualify the safety-lead in phase will receive AFM24 i.v. infusion, qw, 
in 4-week cycles and atezolizumab i.v. infusion, q2w, in 4-week cycles.   
Overall, the study will consist of following periods: 
• Pre-Screening period  
• Screening period (≤ 21 days prior to Day -7) 
• Safety lead-in phase (Day -7 through Day -1) to evaluate patient’s hypersensitivity to 
AFM24 only infusion 
Note: Some of the screening assessments will be allowed during the safety lead-in phase as well. 
Please review the Inclusion Criteria (Section 5.1) and Exclusion Criteria (Section 5.2) to see 
allowed time periods of screening assessments. 
• Treatment Period (AFM24 + atezolizumab) 
o Dose Escalation Phase (Phase 1) 
o Expansion Phase (Phase 2a) 
Note: Patients will receive the investigational treatment (AFM24 + atezolizumab) until disease 
progression, intolerable toxicity, Investigator discretion, or patient withdrawal of consent. 
• Follow-Up 
o End of Treatment (EOT) Visit (14 days [±2 days] after the last administration of 
AFM24 or before start of any new anti-cancer treatment whichever is sooner) 
o Safety Follow-Up Visit (30 days [±5 days] after the last administration of study 
treatment or before start of any new anti-cancer treatment whichever is sooner) 
o Long-term follow-up (patients will be contacted every 3 months [±2 weeks] to 
collect data on their subsequent therapies and disease status. 
Note: Patients who are permanently discontinued from the study during the safety lead-in 
phase should complete the EOT visit and the Safety follow-up visit but will not be required 
to complete the long-term follow up. 


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4.2. 
Overall Study Periods 
4.2.1. 
Pre-Screening and Screening 
Pre-Screening: 
Pre-Screening is required for all patients planned to be enrolled in this trial. EGFR expression is 
to be assessed for EXP-2 and EXP-3 cohorts as per Inclusion Criterion #4 before the patient enters 
the screening phase. Archived paraffin embedded tumor tissue is acceptable for EGFR 
determination otherwise, a fresh tumor biopsy must be performed. EGFR assessment by a locally 
validated immunohistochemistry assay test is acceptable. 
Patients will sign a Pre-screening informed consent form (ICF) allowing the testing of EGFR 
expression to determine whether eligibility criteria for EGFR expression have been met prior to 
entering Screening (Note: if a positive EGFR test has been performed from a patient’s tumor tissue, 
and the EGFR laboratory report is available, the patient does not have to sign the pre-screening 
ICF and perform the pre-screening assessment and can directly proceed to signing the Main ICF 
and the screening activities). 
The Screening phase starts only after the patient has met the eligibility criterion for EGFR 
expression for EXP-2 and EXP-3 cohorts, and has signed the main ICF for all cohorts. 
Screening: 
The screening period lasts up to 21 days prior to the safety lead-in phase (from Day -7 through 
Day -1). The screening period begins when the main ICF is signed and ends on the day before the 
first dose of AFM24 infusion on Day -7. Before entering the study, all study procedures and 
possible risks will be explained to each patient who is asked to participate in the study. After 
provision of main written informed consent for the study, screening assessments will include a 
careful review of the patient’s medical history, assessment of Eastern Cooperative Oncology 
Group (ECOG) performance status (PS), physical examination, electrocardiogram (ECG), 
laboratory assessments, and tumor assessments by computed tomography (CT) or magnetic 
resonance imaging (MRI), and tumor histopathology. Screening assessments are to be performed 
within 21 days of the first dose of AFM24 infusion (i.e., on Day -7); however, radiographic tumor 
assessment is allowed up to 28 days prior to first dose of AFM24 infusion (i.e., on Day -7). Patients 
who do not meet 1 or more eligibility criteria may be re-screened. Patient’s eligibility criteria must 
be re-confirmed on or within 7 days before Day -7, before administration of the first AFM24 
infusion. The assessments for hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) 
do not need to be repeated for re-screened patients if performed within 3 months before the first 
AFM24 infusion (i.e., on Day -7). Please review the inclusion (Section 5.1) and exclusion criteria 
(Section 5.2) to see allowed time periods of screening assessments. 
4.2.2. 
Safety Lead-In Phase (for Both the Dose Escalation Phase [Phase 1] and the 
Expansion Phase [Phase 2a]) 
Seven days prior to Cycle 1 Day 1 (C1D1) (i.e., at Day -7), patients will receive a single dose of 
AFM24 (dose assigned to a given cohort) and will be observed for any AE for 1 week (from Day -7 
through Day -1, the safety lead-in phase). Patients who have any Grade ≥3 cytokine release 
syndrome (CRS) or IRR symptoms lasting >6 hrs  or any other possibly treatment-related Grade 
≥3 non-hematological TEAEs or clinically significant hematological Grade ≥3 TEAEs during their 


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safety lead-in phase will be permanently discontinued from the study (please refer to Section 6.7 
. Patient’s eligibility criteria must be re-confirmed on or 
within 7 days before Day -7, before the administration of the first AFM24 infusion; please refer to 
inclusion and exclusion criteria sections (Sections 5.1 and 5.2, respectively) to see allowed time 
periods of screening assessments. 
Patients not proceeding to combination therapy (AFM24 + atezolizumab) will be replaced. 
Note: Patients are required to receive premedication approximately 1 hour before each dose of 
AFM24; a list of premedications is provided in Section 6.3. 
4.2.3. 
Dose Escalation Phase (Phase 1) Study Design  
The aim of the dose escalation phase (Phase 1) is to determine the MTD/RP2D of AFM24 in 
combination with atezolizumab.  
The 160 mg i.v. qw dose was selected as the starting dose for the AFM24-102 study, based on the 
data obtained from the FIH study (AFM24-101) (
). There are additional dose 
escalations planned for AFM24, where the dose increase will be based on data from AFM24-101 
in conjunction with the safety and PK data emerging from this study (
). Dose increases 
will not exceed 200% of the current dose. All dose escalation (and de-escalation) decisions will be 
determined by the SRC.  
It is estimated that approximately 18 patients will be treated in Phase 1 of the study. The number 
of patients is dependent on the tested dose cohorts and safety profile of AFM24 in combination 
with atezolizumab. 
Dose cohorts 
Patients will be enrolled sequentially in cohorts of 3 to 6 patients into dose escalation phase 
(Phase 1). The dose escalation will follow 3+3 dose escalation design. In each cohort there will be 
at least 3 patients enrolled. The first 2 patients of each dose cohort will begin treatment in a 
staggered approach with at least 7 days between first dosing of these 2 patients. Subsequent 
patients may be enrolled concurrently. All patients who start treatment need to complete the 28-
day DLT observation period or experience a DLT within the first cycle of treatment to be DLT 
evaluable. A minimum of 3 patients needs to be DLT evaluable per dose cohort. If no DLT is 
observed, the dose is escalated for the next cohort of 3 patients. If 1 DLT is observed, 3 additional 
patients will be treated at this dose level with dose escalation only if no additional DLTs occur. If 
less than 3 patients are evaluable for DLT assessment, replacement patient(s) will be enrolled. 
DLTs will be assessed in the first treatment cycle (i.e., the first 4 weeks of treatment for each 
patient, starting C1D1), referred to as the DLT observation period (28-days). Dose limiting toxicity 
will be defined by the criteria listed in Section 4.2.3.1. The number of patients included in each 
dose cohort may be increased from 3 up to 6 patients based on SRC decision to allow for further 
collection of safety, pharmacodynamic and PK data.  
A 3+3 design will be used to determine the RP2D, with the schematic escalation rules given 
below. The number of patients with DLT at a given dose level will be evaluated as: 
1. If 0 out of 3 
• Escalate to next higher dose level 


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2. If 1 out of 3  
• Enter 3 more patients at this dose level: 
o If 0 of these additional patients experience a DLT, proceed to the next higher 
dose level  
o If 1 or more of these additional patients experience a DLT, the dose escalation 
will be stopped. Up to 3 additional patients will be entered at the lower dose 
level if only 3 patients were treated previously at that dose level. Alternatively, 
up to 6 additional patients could be entered to receive intermediate dose levels, 
based on the emerging safety, PK, and pharmacodynamic data observed in the 
FIH AFM24-101 study If this occurs in Cohort 1, there will be a de-escalation 
to Cohort -1. 
3. ≥ 2 out of 3  
• Dose escalation will be stopped. Up to 3 additional patients will be entered at the lower 
dose level if only 3 patients were treated previously at that dose level. Alternatively, up 
to 6 additional patients could be entered to receive intermediate dose levels, based on 
the emerging safety, PK, and pharmacodynamic data observed in the FIH AFM24-101 
study. If this occurs in Cohort 1, there will be a de-escalation to Cohort -1. 
4.2.3.1. 
Definition of Dose-Limiting Toxicity (DLT) 
DLT is defined as an AE or abnormal laboratory value assessed as unrelated to underlying disease, 
disease progression, inter-current illness, or concomitant medications, that occurs ≤28 days 
following the first dose of AFM24 in combination with atezolizumab (Cycle 1) and that meets any 
of the following criteria shown in Table 1. Clinically relevant toxicities will be evaluated according 
to the National Cancer Institute (NCI)/National Institutes of Health (NIH) Common Terminology 
Criteria for Adverse Events (CTCAE) v5.0. Patients who experience a DLT during Cycle 1 must 
permanently discontinue AFM24 and atezolizumab. 
DLT observation period: 
In order to be considered evaluable for DLT, patients must meet the following criteria: 
• receive ≥ 75% of their assigned AFM24 dose in Cycle 1 and 
• receive ≥ 50% of their assigned atezolizumab dose in Cycle 1 and  
• either complete the 28-day DLT observation period or have had a DLT within the first 
cycle of treatment. 
Patients discontinuing the study after the safety lead-in phase will not be included in the DLT 
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Table 1: 
Definition of Dose-Limiting Toxicity 
Toxicity 
Any of the following criteria 
Hematologicala 
≥CTCAE Grade 4 neutropenia (ANC<0.5×109/L) lasting for longer than 4 consecutive days 
Febrile neutropenia (ANC<1.0×109/L of any duration accompanied by fever ≥38.5°C or 
systemic infection) that does not resolve within 48 hours after start of antibiotics 
CTCAE Grade 3 thrombocytopenia (platelets 25 to <50×109/L) associated with bleeding 
CTCAE Grade 4 thrombocytopenia (platelets <25×109/L) 
≥CTCAE Grade 4 anemia that is considered to be treatment related 
Non-
hematological 
 
Any ≥CTCAE Grade 3 AE including, but not limited to: 
• 
CTCAE Grade 3 infusion-related reaction/cytokine release syndrome not responsive to 
symptomatic treatment within 6 hours (i.e., no improvement to Grade 2 or better within 
6 hours with optimal medical management) 
• 
CTCAE Grade 4 infusion-related reaction/cytokine release syndrome  
• 
QTcF prolongation (>500 msec) confirmed by 2 separate ECGs at least 6 hours apart or 
if associated with arrhythmias; 
• 
CTCAE Grade 3 hypertension for >14 consecutive days despite optimal anti-
hypertension therapy; 
• 
CTCAE Grade 4 hypertension (any duration) 
• 
≥CTCAE Grade 3 total bilirubin (>3×ULN); 
• 
≥CTCAE Grade 3 ALT, AST, or alkaline phosphatase (>5×ULN) if not resolving to 
Grade 1 or baseline within 10 days; 
• 
≥CTCAE Grade 3 diarrhea for ≥72 hours despite optimal anti-diarrhea treatment 
Any death at least possibly related to any study treatment 
Any other ≥CTCAE Grade 3 AE not listed above, except for the exceptions noted below 
Exceptions to 
DLT criteriab 
Isolated laboratory changes of any grade without clinical sequelae or clinical significance 
except for those laboratory changes outlined above 
CTCAE Grade 3 fever (in the absence of neutropenia) or fatigue that resolves to <Grade 3 
within 72 hours 
CTCAE Grade 3 hypertension for ≤14 consecutive days  
CTCAE Grade 3 nausea, vomiting, diarrhea, or dehydration that resolves to <Grade 3 within 
72 hours of initiating optimal supportive care treatment 
CTCAE Grade 3 infusion-related reaction/cytokine release syndrome responsive to 
symptomatic treatment within 6 hours (i.e., improvement to Grade 2 or better within 6 hours 
with optimal medical management) 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ALP = alkaline phosphatase; ANC = absolute neutrophil 
count; AST = aspartate aminotransferase; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for 
Adverse Events; DLT = dose-limiting toxicity; ECG = electrocardiogram; IRR = infusion-related reaction; NCI = National 
Cancer Institute; QTcF = corrected QT interval by Fridericia; SRC = Safety Review Committee; ULN = upper limit of normal 
a. 
Patients may receive supportive care (e.g., use of granulocyte-colony stimulating factor, packed red blood cells, and 
platelets) as per local institutional guidelines. However, during the DLT observation period, it is not allowed to 
administer these supportive measures without clinical indication. 
b. 
The SRC (in Phase 1) and IDMC (in Phase 2) will closely monitor and review all AEs including the incidences of the 
AEs listed under the “Exceptions to DLT criteria” during the scheduled and any ad-hoc SRC/IDMC meetings. 
Note: NCI CTCAE v5.0 will be used for all grading. 


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4.2.3.2. 
Determination of Maximum Tolerated Dose  
The MTD will be defined as the highest dose level below the maximum administered dose where 
the number of patients with DLT is <2 out of 6. At least 6 patients evaluable for the safety endpoint 
must be entered at this dose level and a toxicity rate of less than 0.33 must be observed to be 
confirmed as the MTD. 
4.2.3.3. 
Recommended Phase 2 Dose (RP2D) Definition 
An RP2D can be declared at any dose level or schedule where the MTD criteria were not met, yet 
clinical, PK, pharmacodynamics and/ or laboratory data indicate an optimal biologically active 
dose has been reached (with a toxicity rate of less than 0.33) and at least 6 patients have been 
treated at that given dose level. 
4.2.4. 
Expansion Phase (Phase 2a) Study Design 
Once all patients have completed Cycle 1 of the dose escalation phase (Phase 1), the SRC has 
reviewed all available safety, clinical, laboratory, and PK data and recommends continuing, and 
the MTD/RP2D of AFM24 in combination with atezolizumab has been determined, enrollment 
into the expansion cohorts for the selected cancer indications in the expansion phase (Phase 2a) 
will begin (Section 9.5.1).  
A Simon two-stage optimal design will be utilized for EXP-1 and EXP-2. EXP-3 and EXP-4 are 
exploratory with no hypothesis testing. The expansion phase (Phase 2a) of the study is intended to 
collect preliminary evidence of efficacy and to further confirm the safety of AFM24 in 
combination with atezolizumab. 
During the expansion phase (Phase 2a), up to 130 patients will receive weekly infusions of AFM24 
at the RP2D in combination with every 2-weekly infusion of atezolizumab in 4-week cycles in the 
following 3 expansion phase cohorts based on tumor types:  
• EXP-1 will enroll patients with advanced or metastatic EGFR-wild type (EGFR-WT) 
expressing NSCLC; 
• EXP-2 will enroll patients with locally advanced, unresectable, or metastatic gastric or 
gastro-esophageal junction (GEJ) adenocarcinoma; 
• EXP-3 will enroll patients with advanced or metastatic hepatocellular carcinoma (other 
than fibrolamellar and sarcomatoid subtype, Barcelona Clinic Liver Cancer Stage C disease 
or Stage B disease not amenable to locoregional therapy or refractory to locoregional 
therapy), hepatobiliary-, or pancreatic adenocarcinoma; 
• EXP-4 will enroll patients with advanced or metastatic EGFR-mutated NSCLC 
Patients will receive the investigational treatment (AFM24 + atezolizumab) until disease 
progression, intolerable toxicity, Investigator discretion, or patient withdrawal of consent. 
Additional treatment schedules of AFM24 administration (e.g., q2w) may be explored as part of 
the expansion phase (Phase 2a) within or across cohorts. 
An Independent Data Monitoring Committee (IDMC), consisting of clinical experts who are not 
directly involved in this clinical study, will be established for Phase 2a of the study. The IDMC 
will review all safety data generated throughout the dose expansion phase (Phase 2a) of the study 






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• Has been treated until at least 4 weeks after the 1st post-baseline tumor assessment  
• Disease progression 
• Withdrawal from treatment due to a drug related AE 
• Fatal event 
• Lost to long-term follow-up 
• Withdrawal of consent 
• Start of other anti-cancer treatment 
In case patients are still being treated with study medication at the final data cut-off date for this 
study, such patients will be kept on treatment in the study and data collected will then be reported 
in an addendum to the final clinical study report (CSR). It will be noted in the final CSR that such 
a revised report may be provided. 
4.6. 
Scientific Rationale for Study Design 
Dose escalation phase (Phase 1) dose escalation consists of AFM24 administered qw at an 
escalating dose per each cohort with atezolizumab 840 mg q2w according to a 3+3 dose escalation 
design. The 3+3 design is a well-accepted design in oncology studies (Jaki, 2013), to expose the 
lowest possible number of patients to the investigational drug, while still being able to assess 
safety. Dose escalation will be performed until the MTD/R2PD is determined/confirmed with a 
28-day DLT assessment period.   
Once the MTD/R2PD is determined following completion of dose escalation phase (Phase 1), 
enrollment will initiate in Phase 2a with AFM24 given in combination with atezolizumab at the 
RP2D. Phase 2a is an open-label, multicenter basket study utilizing Simon’s two-stage optimal 
design (Simon 1989). This design allows determination of AFM24 given in combination with 
atezolizumab anti-tumor activity while minimizing the expected sample size. The measurement of 
most toxicities using the CTCAE v5.0 and assessment of tumor size using the RECIST v1.1 criteria 
(Eisenhauer et al., 2009; Schwartz et al., 2016) represent objective endpoints. 


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5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Patients will be considered eligible to be enrolled in the study if ALL of the inclusion and NONE 
of the exclusion criteria are met as defined below. Prospective approval of protocol deviations to 
recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not 
permitted. Please note that based on various guidelines (e.g., NCCN Guidelines: Cancer and 
COVID-19 Vaccination [NCCN 2023] and MHRA Guidance on Coronavirus [COVID-19]) 
[MHRA 2022], COVID-19 vaccination should be prioritized for patients with cancer with the 
understanding that there are limited safety and efficacy data in this patient group. These guidelines 
also state: 
• “Delay of vaccination until immunosuppressive therapy is reduced and/or based on 
immunophenotyping of T cell and B cell immunity can be considered.”  
• “Systemic corticosteroids and targeted agents are expected to blunt immune responses 
to vaccination.”   
This study utilizes a mandatory premedication regimen that contains corticosteroids for at least the 
duration of the first cycle (i.e., Cycle 1). Therefore, every effort should be made to vaccinate 
patients prior to being considered for this study based on the Investigator’s risk/benefit analysis 
for each patient. If a patient receives the COVID-19 vaccination prior to study participation, the 
vaccine should be administered at least 2 weeks prior to Day -7 or at least 4 weeks prior to Day -
7 for live attenuated vaccines. For patients whose opportunity for COVID-19 vaccination arrives 
during the conduct of the study (i.e., ongoing patients in the study), see instructions for 
COVID-19 vaccination provided in Section 6.8.1.1. 
5.1. 
Inclusion Criteria 
Patients will be considered eligible to be enrolled in the study if ALL the following inclusion 
criteria are satisfied unless otherwise specified: 
1) Voluntary provision and understanding of signed and dated, written informed consent prior 
to any mandatory study-specific procedures, sampling, or analysis. 
2) Patients must be aged ≥18 years on the day of signing informed consent (or of an acceptable 
age according to local regulations, whichever is older). 
3) Patients must have documented radiological progression during or after their latest therapy 
for all phases. 
4) Patients have documented histologically or cytologically confirmed advanced or metastatic 
EGFR-positive (positive staining for EGFR in ≥1% of tumor cells determined by a locally 
validated immunohistochemistry assay) select cancer types, except for NSCLC patients 
(cohorts EXP-1 and EXP-4); and meet the following criteria: 
Dose Escalation Phase (Phase 1):  
Dose Escalation Cohorts: Patients who meet the criteria specified for the expansion 
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measurable disease by RECIST v1.1. Measurable disease per RECIST v1.1 is defined as 
at least 1 measurable lesion ≥10 mm by CT scan or MRI or ≥20 mm by chest X-ray; 
malignant lymph nodes are considered measurable if short axis is ≥15 mm as assessed by 
CT scan. The last imaging must have been performed within 28 days prior to the first dose 
of AFM24 (i.e., Day -7). 
10) Female patients of childbearing potential must have a negative urine or serum pregnancy 
test at Screening and prior to first AFM24 infusion (i.e., Day -7) to be eligible in this study. 
If the urine pregnancy test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. The serum pregnancy test must be negative for the patient 
to be eligible. Non-childbearing potential is defined as: 
a. Postmenopausal, defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
b. Surgically sterile. Surgical sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
11) Females of childbearing potential must agree to sexual abstinence (defined below) or be 
willing to use a highly effective method of contraception for the course of the study from 
14 days prior to the first dose of study drug through 5 months after the last dose of study 
drug. Acceptable highly effective birth control methods include: 
a. Oral, intravaginal, or transdermal combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation; 
b. Oral, injectable, or implantable progestogen-only hormonal contraception 
associated with inhibition of ovulation; 
c. Intrauterine device; 
d. Intrauterine hormone-releasing system; 
e. Bilateral tubal occlusion; 
f. Vasectomized partner (provided that partner is the sole sexual partner of the female 
of reproductive potential and that the vasectomized partner has received medical 
assessment of the surgical success); and 
g. Sexual abstinence. In the context of this study sexual abstinence is considered a 
highly effective method only if defined as refraining from heterosexual intercourse 
from 14 days prior to the first dose of study drug up to 5 months after the last dose 
of study drug. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical study and the preferred and usual lifestyle of the 
patient. 
12) Males who have female partners of childbearing potential must agree to use a highly 
effective method of contraception as described in Inclusion Criterion 11) starting with the 
first dose of study therapy through 5 months after the last dose of study drug. 








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• Confirmed progressive disease (PD), as assessed by the treating Investigator in accordance 
with RECIST v1.1 (On a case-by case basis, patients may continue treatment after disease 
progression at their assigned dose if there is continuing clinical benefit per Investigator’s 
judgment and in consultation with the Sponsor’s Medical Monitor). 
• Symptomatic deterioration (clinical deterioration suggesting that no further benefit from 
treatment is likely). This category is applicable to patients with a global deterioration of 
health status requiring discontinuation of treatment. However, per RECIST v1.1, 
symptomatic deterioration is not a descriptor of an objective response (OR); it is a reason 
for stopping study therapy. Thus, every effort should be made to continue disease 
assessments per protocol until documented objective progression or initiation of alternate 
therapy. 
• The development of a DLT (as defined in Section 4.2.3.1) during the dose escalation part 
(Phase 1) of the study. 
• Pregnancy while receiving study drug. 
• At the request of the Sponsor, regulatory agency, or IRB/IEC. 
• Physician decision. 
• Loss to follow-up. 
• Death, otherwise not explainable by the above options. 
• Patient may be withdrawn from study treatment due to unacceptable or intolerable AEs. 
Patients who discontinue study treatment should be seen for the EOT visit when feasible, at which 
time all the assessments listed for the EOT visit will be completed. Patients who discontinue study 
treatment, after having received at least one dose of both AFM24 and atezolizumab, without 
confirmed progression of disease as per RECIST v1.1 should continue tumor assessment scans 
until criteria for disease progression are met, or until initiation of alternate anticancer therapies. 
5.5. 
Lost to Follow-up 
Study patients will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site. The following actions must be taken if a 
study patient fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in 
the study; 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a registered letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record; and 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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Situations of non-compliance will be reviewed on a case-by-case basis with the Sponsor and the 
site will be provided guidance on patient withdrawal from treatment and/or the study, where 
appropriate. 
5.6. 
Replacement of Patients 
In Phase 1 (dose escalation), a patient who does not fulfill the DLT requirements (Section 4.2.3.1) 
and who discontinues study participation prior to completing the DLT observation period due to 
any reason other than a DLT, will be replaced for DLT evaluation but will remain in the “safety 
analysis set”. 
For the dose escalation (Phase 1) and expansion phase (Phase 2a), all patients who begin AFM24 
treatment but discontinue prior to receiving any amount of atezolizumab will be replaced but will 
remain in the overall “safety analysis set”. A replacement patient will be enrolled and assigned the 
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6. 
STUDY TREATMENT 
6.1. 
Assignment of a Patient Number and Dose Level 
6.1.1. 
Assignment of a Patient Number 
Either at the Pre-Screening visit or at the Screening Visit, each patient will have a unique patient 
ID number assigned for patient identification.  
6.1.2. 
Assignment of Dose Level 
Prior to the first AFM24 infusion (i.e., on Day -7), sites must submit a patient eligibility packet to 
the Medical Monitor for review and confirmation of eligibility. After Medical Monitor 
confirmation of eligibility, patients can be enrolled in the appropriate dose level of the applicable 
cohort. 
6.2. 
Overview of Study Treatment and Administration 
The investigational treatment (AFM24 and atezolizumab) will be administered according to the 
procedure defined in the pharmacy manual at the clinical study site by appropriately trained staff. 
The infusion should be given in a monitored setting that has ready access to an intensive care unit 
in case of a severe infusion reaction. 
Patients are required to receive premedication approximately 1 hour before each dose of AFM24, 
a list of pre-medications is provided in Section 6.3. 
AFM24 will be administered as an i.v. infusion, qw, in 4-week cycles. Atezolizumab will be 
administered as an i.v. infusion, q2w, in 4-week cycles. The order in which the study treatment 
should be administered is depicted in Figure 1. 
On days when investigational treatment (AFM24 + atezolizumab) is to be administered, 
atezolizumab will be administered first over approximately 60 minutes, followed by an observation 
period of 1 hour. If the first infusion is well tolerated, the infusion time can be reduced to 30 
minutes for all subsequent infusions. After the end of the atezolizumab infusion, the premedication 
regimen required prior to AFM24 infusion will be administered.  
The first 2 subsequent AFM24 administrations (i.e., D-7 – Safety Lead-in – and C1D1 in qw dosing 
regimen and D-7 and C1D1 in q2w dosing regimen) should not take less than approximately 4 
hours (-10 minutes) with the ability to pause in case of IRRs > Grade 1 CTCAE v5.0. In general, 
as the dose escalation continues into higher dosing cohorts, the baseline infusion time may increase 
to > 4 hours and may take as long as over 2 days (i.e., split day dosing) as detailed in the Pharmacy 
Manual for each cohort based on a given patient’s tolerability. If the first 2 AFM24 infusions are 
well tolerated (defined as no IRR/CRS > Grade 2), then starting from the third infusion (C1D8 in 
qw and C1D15 q2w), the infusion time may be decreased to at least 1 hour at the discretion of the 
Investigator.  
For the first 2 AFM24 infusions (Safety Lead-in D-7 and C1D1), patients must be observed for at 
least 4 hours after the end of AFM24 infusion, with regular checks of vital signs. In case of a split 
day dosing (over 2 days) patients must be observed for at least 4 hours after the end of AFM24 
infusion on each day. Starting from the third AFM24 infusion (i.e., at any time point in the study 
starting from C1D8 in qw schedule and C1D15 in q2w dosing schedule), the below listed changes 


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may also be made for those patients who do not experience IRR/CRS symptoms > Grade 2 during 
the previous infusion, keeping in mind that only 1 modification should be made at a time per 
infusion day: 
• Decrease the infusion time to at least 1 hour, 
• Reduce observation period from 4 hours to ≥2 hours, or  
• Taper the steroid or any other premedication.  
Additionally, 
 provides guidance for the management of symptoms associated with 
IRR/CRS due to study treatment. For infusion times that span over 2 days (i.e., split day dosing), 
PK sampling times may be affected, and the Schedule of Assessment and the Pharmacokinetic 
Assessments should be referenced for details. 
Patients may receive AFM24 and atezolizumab until disease progression, intolerable toxicity, 
Investigator discretion, or patient withdrawal of consent. 
Please refer to the Pharmacy Manual for full details regarding study drug administration. 






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6.6. 
Expansion Phase (Phase 2a) Treatment Schedule 
Patients who are determined eligible post evaluation for AFM24-hypersensitivity during the 
safety-lead in phase (Day -7 through Day -1) will receive the investigational treatment 
(AFM24 + atezolizumab) as per the following regimens, with the RP2D defined as 480 mg as 
described in Section 2.5: 
• EXP-1 (EGFR-WT NSCLC): AFM24 i.v. qw or q2w at RP2D dose + Atezolizumab 840 
mg i.v. q2w 
• EXP-2 (gastric or GEJ adenocarcinoma): AFM24 i.v. qw or q2w at RP2D dose + 
Atezolizumab 840 mg i.v. q2w 
• EXP-3 (Hepatocellular Carcinoma, Hepatobiliary-, or Pancreatic Adenocarcinoma): RP2D 
AFM24 i.v. qw or q2w at RP2D dose + Atezolizumab 840 mg i.v. q2w 
• EXP-4 (advanced or metastatic NSCLC harboring a targetable EGFR kinase domain 
mutation): RP2D AFM24 i.v. qw or q2w at RP2D dose + Atezolizumab 840 mg i.v. q2w 
If AFM24 is given on a q2w schedule the daily dose of AFM24 will not be higher than the highest 
daily dose that was tested in the phase 1 part of the study and was considered safe. 
Additional treatment schedules of AFM24 administration (e.g., q2w) may be explored as part of 
the Phase 2a within or across cohorts. 
6.7. 
Dose Interruptions, Delays, Modifications and Discontinuations 
AFM24 
Treatment may be delayed for up to 3 weeks to allow sufficient time for recovery from 
treatment-related toxicities to baseline or Grade ≤1 (except for alopecia), except during the DLT 
observation period during the dose escalation phase (Phase 1). See Section 5.4.2 for criteria 
requiring permanent discontinuation of study treatment. 
Dosing delays longer than > 3 weeks may be permitted in a case-by-case basis per the 
Investigator’s judgement after consultation with the Medical Monitor. No dosing delays (including 
planned dosing delays such as elective surgery) will be allowed during the DLT observation 
period. Tumor assessments should continue as per protocol even if dosing is delayed. 
If an AE occurs during the AFM24 infusion Safety Lead-in (D-7), and the dose is interrupted, the 
patient can restart upon recovery to baseline or Grade ≤1 within the same day. If the patient already 
received 80 mg of the prescribed dose of AFM24 on the day of dose interruption or cannot recover 
within the same day of the event, the rest of the dose should be omitted. 
Weekly dosing schedule: 
If the patient recovers from an AE and can continue study treatment within 72 hours of the planned 
dose, the patient should receive the delayed dose and continue treatment as per the original 
schedule, by not shifting any later doses. There should be at least 3 days between infusions before 
the patient receives the next dose. An example: if the patient has an AE on Cycle 1 Day 15 and 
recovers in time and can receive the missed dose by Cycle 1 Day 18, then the next dose for the 
patient would be on Cycle 1 Day 22. 


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If the patient does not recover from an AE within 72 hours the missed dose(s) should be skipped 
and the patient should receive the next dose as per original schedule. An example: a missed dose 
on Cycle 2 Day 1 and the patient recovered on Cycle 2 Day 9, the next dose for this patient is on 
Cycle 2 Day 15. 
Every-2-weeks dosing schedule:  
If the patient recovers from an AE and is able to continue study drug within 1 week from the 
original scheduled dosing day then the patient should receive the delayed dose and continue 
treatment as per the original schedule, by not shifting any later doses. There should be at least 7 
days without treatment before the patient receives the next dose. An example: if the patient has an 
AE on C1D1 and recovers in time and can receive the missed dose latest on C1D8, then the next 
dose for the patient is on C1D15. 
If an AE happens during the AFM24 infusion, and the dose is interrupted, the patient can restart 
upon recovery to baseline or Grade ≤1 within the same day. If the patient already received ≥75% 
of the prescribed dose of AFM24 and 50% of atezolizumab that day at the time of the interruption 
or cannot recover within the same day of the event, the rest of the dose could be omitted. 
Patients who experience a DLT during the DLT observation period must permanently discontinue 
the study drugs. 
In addition, AFM24 re-challenge following a CTCAE Grade ≥3 IRR or CRS should be handled as 
the following and the Investigator should refer 
 for details: 
• Grade 3 IRR or CRS that are NOT responsive to symptomatic treatment (i.e., no 
improvement of IRR-related symptoms to Grade 2 or better within 6 hours with optimal 
medical management): AFM24 should be discontinued permanently. 
• Grade 4 IRR or CRS in all phases: AFM24 should be discontinued permanently. 
IRRs other than anaphylaxis responsive to symptomatic treatment (i.e., improvement to Grade 2 
or better within 6 hours with optimal medical management): 
• Restart if symptoms resolve to CTCAE Grade ≤1 or baseline only at the discretion of the 
investigator based on the clinical status of the patient.  
• If re-challenge is considered, infuse the next AFM24 infusion with a >4-hour infusion time. 
Dose Modification: 
During the dose escalation phase (Phase 1), if a patient is tolerating AFM24 in combination with 
atezolizumab well (i.e., no drug-related Grade ≥2 toxicity) without evidence of disease progression 
following 2 cycles, the patient may, beginning with Cycle 3 or a subsequent cycle, have the dose 
increased to a dose that has already been established as tolerable by the SRC, and with the 
agreement of the SRC.  
Atezolizumab 
Atezolizumab dosage modifications in case of related adverse reactions should be managed 
according to the recommended dosage modifications provided in the label (TECENTRIQ PI, 2022) 
and as summarized in
 For IRRs considered related to atezolizumab, interrupt, slow 
the rate of infusion, or permanently discontinue based on severity of the infusion reaction (
 
). 


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Continuation of therapy on-study in the setting of discontinuation of one component (AFM24 or 
Atezolizumab) of the study therapy 
If one component of the study therapy is permanently discontinued secondary to toxicity, then 
therapy with the other component may continue at the discretion of the investigator and the patient 
should remain on-study with full adherence to all protocol-related requirements, provided the 
patient continues to meet entry criteria and does not have evidence of disease progression. 
6.8. 
Permitted and Restricted Concomitant Medications 
6.8.1. 
Acceptable Concomitant Medications 
All treatments and supportive care that the Investigator considers necessary for a patient’s welfare 
may be administered at the discretion of the Investigator in keeping with the standards of medical 
care of the study site except for the prohibited concomitant medications listed in Section 6.8.2. All 
concomitant medication will be recorded in the patient’s medical records and in the eCRF 
including all prescription, over-the-counter, herbal supplements, and i.v. medications and fluids. 
If changes occur during the study period, documentation of drug dosage, frequency, route, and 
date needs to also be included in the eCRF. 
All concomitant medications received from Screening to the Safety Follow-up visit should be 
recorded (see Schedule of Assessments [
]). Concomitant medications administered after 
the Safety Follow-up visit should be recorded for SAEs which are considered related to study drug 
(Section 10). 
6.8.1.1. 
COVID-19 Vaccination 
Various guidelines (e.g., NCCN Guidelines: Cancer and COVID-19 Vaccination [NCCN 2023] 
and MHRA Guidance on Coronavirus [COVID-19]) [MHRA 2022] have noted that COVID-19 
vaccination should be prioritized for patients with cancer with the understanding that there are 
limited safety and efficacy data in this patient group. These guidelines also state: 
• “Delay of vaccination until immunosuppressive therapy is reduced and/or based on 
immunophenotyping of T cell and B cell immunity can be considered.”  
• “Systemic corticosteroids and targeted agents are expected to blunt immune responses to 
vaccination.”   
This study utilizes a mandatory premedication regimen that contains corticosteroids (i.e., 20 mg 
of i.v. dexamethasone [or equivalent of long-lasting steroid dose]) for at least the duration of the 
first cycle (i.e., Cycle 1). Therefore, every effort should be made to vaccinate patients prior to 
being considered for this study based on the Investigator’s risk/benefit analysis for each patient. If 
a patient receives the COVID-19 vaccination prior to study participation, the vaccine should be 
administered at least 2 weeks prior to Day -7 or at least 4 weeks prior to Day -7 for live attenuated 
vaccines. 
For patients whose opportunity for COVID-19 vaccination arrives during the conduct of the study 
(i.e., ongoing patients in the study), the following should be noted: 
• COVID-19 vaccination should be avoided during the DLT period or Cycle 1 of the study 
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Gastrointestinal Perforation: Permanently discontinue AFM24 in patients who develop 
gastrointestinal perforation. 
Other: For all CTCAE Grade 3 toxicities other than those that meet the definition of a DLT during 
Cycle 1 of the dose escalation (i.e., Phase 1) phase, and other than those described above, interrupt 
treatment with AFM24 until resolved to Grade ≤1 or baseline. If CTCAE Grade 3 toxicity recurs 
upon rechallenge or in case of CTCAE Grade 4 toxicity, permanently discontinue treatment. 
6.11. 
Management of Atezolizumab-Related Toxicities 
Atezolizumab-related toxicities should be managed according to recommendations provided in its 
label (TECENTRIQ PI, 2022) and IB v19. Recommended dose modifications for adverse reactions 
that are anticipated with the atezolizumab infusion are summarized in Table 2 and additional 
details are provided in 
 
Table 2: 
Recommended Dosage Modifications for Adverse Reactions 
Adverse Reaction 
Severity a 
Dosage Modification 
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) Section of TECENTRIQ PI] 
Pneumonitis 
Grade 1 
Consider withholding  
 
Grade 2 
Withhold b 
 
Grade 3 or 4 
Permanently discontinue 
Cardiac Events (Immune-mediated 
Myocarditis, Immune-mediated pericardial 
disorders) 
Grade 2 to 4 
Permanently discontinue 
Colitis 
Grade 2 or 3 
Withhold 
Grade 4 
Permanently discontinue 
Dermatologic Events 
Grade 3 
Withhold 
Grade 4 
Permanently discontinue 
Endocrinopathies 
Grade 2 
Consider withholding  
Grades 3 or 4 
Withhold until clinically 
stable or permanently 
discontinue depending on 
severity 
Exfoliative Dermatologic Conditions 
Suspected SJS, TEN, or DRESS 
Withhold 
Confirmed SJS, TEN, or DRESS 
Permanently discontinue 
Hepatitis with no tumor involvement of the 
liver 
AST or ALT increases to more 
than 3 and up to 5 times ULN or 
Total bilirubin increases to more 
than 1.5 and up to 3 times ULN  
Withhold b 
AST or ALT increases to more 
than 5 times ULN or Total bilirubin 
increases to more than 3 times 
ULN 
Permanently discontinue 
Hepatitis with tumor involvement of the 
liverc 
Baseline AST or ALT is more than 
1 and up to 3 times ULN and 
Withholdb 


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Adverse Reaction 
Severity a 
Dosage Modification 
increases to more than 5 and up to 
10 times ULN or Baseline AST or 
ALT is more than 3 and up to 5 
times ULN and increases to more 
than 8 and up to 10 times ULN 
If ALT/AST increases to >10x 
ULN or total bilirubin increases to 
>3x ULN 
Permanently discontinue 
Hypophysitis 
Grade 2 or 3 
Withhold 
Grade 4  
Permanently discontinue 
Nephritis with Renal Dysfunction 
Grade 2: (creatinine level > 1.5 to 
3.0 x baseline or >1.5 to 3.0 x 
ULN)   
Withholdb 
Grade 3 or 4: (creatinine level > 3.0 
x baseline or >3.0 x ULN)   
Permanently discontinue 
Meningoencephalitis 
All grades 
Permanently discontinue 
Myasthenic Syndrome/myasthenia gravis, 
Guillain-Barré syndrome and 
Meningoencephalitis 
All Grades 
Permanently discontinue 
Myositis 
Grade 2 
Withhold 
 
Grade 3 
Withhold 
 
Grade 4 
Permanently discontinue 
Neurological Toxicities 
Grade 2 
Withholdb 
Grades 3 or 4 
Permanently discontinue 
Ocular events 
Grade 2 
Withhold  
 
Grade 3 or 4 
Permanently discontinue 
Pancreatitis 
Grade 2 or 3 
Withhold  
Grade 4 
Permanently discontinue 
Other Adverse Reactions 
Infusion-Related Reactions [see Warnings 
and Precautions (5.2)] 
Grades 1 or 2 
Interrupt or slow the rate of 
infusion 
Grades 3 or 4 
Permanently discontinue 
Suspected HLH or MAS 
Any grade 
Permanently discontinue 
Abbreviations: ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit normal, 
DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson syndrome, TEN = toxic 
epidermal necrolysis, HLH = Hemophagocytic lymphohistiocytosis, MAS = Macrophage activation syndrome 
a. Based on Common Terminology Criteria for Adverse Events (CTCAE), version 4. 
b. Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently 
discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone 
to 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids.  
c. If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue TECENTRIQ based 
on recommendations for hepatitis with no liver involvement. 
Source: (TECENTRIQ PI, 2022). 


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7. 
STUDY DRUG MATERIALS AND MANAGEMENT 
7.1. 
Study Drug Materials AFM24 and Atezolizumab 
7.1.1. 
Investigational Product  
AFM24 is a tetravalent, bispecific, chimeric (anti-human EGFR × CD16A) recombinant antibody 
construct and is supplied for intravenous infusion. Please see the Pharmacy Manual for further 
details. 
Atezolizumab will be commercially procured and supplied by the Sponsor. Atezolizumab injection 
is a sterile, preservative-free, and colorless to slightly yellow solution for intravenous infusion in 
840 mg/14 mL single-dose vial. Further details for atezolizumab will be found in the package 
insert (TECENTRIQ PI, 2022). 
7.1.2. 
Provision and Replacement of AFM24 and Atezolizumab 
Sufficient doses of investigational treatment (AFM24 and atezolizumab) will be supplied. Where 
investigational drug supplies (or packaging) are apparently damaged on receipt or considered unfit 
for use by the study site, the Sponsor (or their delegate) must be notified immediately. Where 
required, clinical study supplies will be replaced. Further details on the handling of AFM24 and 
atezolizumab at site will be described in the Pharmacy Manual. Further details for atezolizumab 
will be found in the package insert (TECENTRIQ PI, 2022). 
7.1.3. 
Labeling of AFM24 and Atezolizumab 
AFM24 drug product is manufactured by
 AFM24 and 
atezolizumab clinical study supplies will be labeled in compliance with Good Manufacturing 
Practice Annex 13 requirements, (US Food and Drug Administration (FDA) requirements, and 
any other applicable local regulatory guidelines. 
7.1.4. 
Storage of AFM24 and Atezolizumab 
AFM24 lyophilized powder and atezolizumab must be stored at 2°C to 8°C (36-46°F). The 
investigational treatment for this study (AFM24 and atezolizumab) will be shipped to the site and 
must be stored at the site in a secure location under controlled conditions and in the required 
temperature range. Please see the Pharmacy Manual for further details. 
7.1.5. 
Handling and Disposal 
The infusions for investigational treatment (AFM24 and atezolizumab) should be made on the day 
of dosing and used immediately after preparation. If not administered immediately, the infusion 
solutions should preferably be stored at 2°C -8°C (36-46°F). A warm-up time of at least 30 minutes 
should be allowed before the start of infusion. Please see the Pharmacy Manual for further details. 
7.2. 
Accountability 
The Investigator is obliged to keep sufficient documentation of the delivery, use, and destruction 
or return of unused, used, or partially used investigational treatment (AFM24 and atezolizumab 
study drug). The documentation must include dates, quantities, patient numbers, batch numbers, 


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or other identification number. The Investigator may assign some or all the Investigator’s duties 
for drug accountability to an appropriate pharmacist. Roles and responsibilities of site staff will be 
recorded in the Investigator Site File. 
The Investigator should maintain records that document adequately that the patients were 
administered the doses specified in the protocol and reconcile all AFM24 and atezolizumab 
investigational treatment received for the study. The local clinical research associate (CRA) will 
be responsible for checking the drug accountability records maintained by the site during study 
monitoring visits. 
The investigational treatment (AFM24 and atezolizumab) provided for this study is for use only 
as directed in the protocol. It is the Investigator and their institution’s responsibility to establish a 
system for handling study drug to ensure that: 
• Deliveries of investigational treatment (AFM24 and atezolizumab) are correctly 
received by a responsible person; 
• Such deliveries are recorded; 
• Investigational treatment (AFM24 and atezolizumab) is handled and stored safely and 
properly as stated on the label; 
• Investigational treatment (AFM24 and atezolizumab) is only dispensed to study 
patients in accordance with the protocol; and 
• Any unused investigational treatment (AFM24 and atezolizumab) is destroyed locally 
or returned for destruction in liaison with the CRA after written approval by the 
Sponsor. 
Certificates of delivery and return must be signed by the responsible pharmacist and copies 
retained in the Pharmacy File. Throughout the study, it must be possible to reconcile delivery 
records with records of usage and any destroyed/returned stock of AFM24 and atezolizumab. To 
help with compliance checks, records of usage should include an appropriate form of identification 
of the patient to whom the study treatment was dispensed (using an indirect form to allow cross 
reference to the patients’ identity), plus the quantity and date of dispensing. 
The return or destruction of unused drug will be conducted after written approval by the Sponsor, 
with appropriate documentation and drug accountability procedures completed following 
destruction. 
7.3. 
Treatment Compliance 
Administration of investigational treatment (AFM24 and atezolizumab) will be supervised by the 
Investigator or sub-Investigator. Any delegation of this responsibility must follow the standard 
procedures. 
All patients will be dosed at the site; thus, they will receive study drug(s) directly from the 
Investigator or designee, under medical supervision. The date, time, and total amount delivered of 
each dose administered in the clinic will be recorded in the source documents and recorded in the 
eCRF. Should the total amount of study drug not be delivered or there is an interruption to dosing, 
the reason(s) and any associated AEs will be recorded in the source documents and recorded in the 
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8.2.2. 
DLT Analysis 
The MTD and/or RP2D dose of AFM24 in combination with atezolizumab as determined during 
the DLT evaluation period in the dose escalation phase (Phase 1), will be used in the expansion 
phase (Phase 2a). DLT is defined as an AE or abnormal laboratory value assessed as unrelated to 
underlying disease, disease progression, inter-current illness, or concomitant medications, that 
occurs ≤28 days following the first dose of AFM24 in combination with atezolizumab (Cycle 1) 
and that meets any of the following criteria shown in Table 1. Please see Section 4.2.3.1 for details 
on DLT analysis. 
8.2.3. 
Physical Examinations 
Physical examinations and weight will be performed at timepoints depicted in 
 
. A full physical examination will include assessment of the following categories: head, 
eyes, ears, nose, throat, heart, lungs, abdomen, skin, musculoskeletal, extremities, neurological, 
lymph nodes, and ‘other’. After the Screening assessment, the physical examination may be 
reduced to a symptom-directed assessment. 
Height and weight will be measured at Screening. Weight will be measured within 24 hours of 
administration of AFM24 plus atezolizumab on Day 1 of each cycle. Height and body weight will 
be obtained while the patient is wearing light clothing (without shoes). 
If any clinically significant findings are identified during the study, the Investigator will record 
these as an AE, where the finding represents a change from baseline.   
8.2.4. 
Vital Signs 
Vital sign parameters will be taken at timepoints depicted in 
. The date and 
time of collection will be recorded in the source data and in the eCRF. 
On all days when AFM24 is administered, vital sign parameters to be measured include 
temperature, resting heart rate, seated blood pressure (systolic/diastolic) after 5 minutes resting, 
oxygen saturation and respiratory rate. On all days when AFM24 is administered, vital signs are 
to be recorded following the schedule of vital signs parameters described in Table 3. Note: For the 
first two administrations of AFM24, patients must be observed for at least 4 hours after the end of 
infusion, with regular checks of vital signs. 
If the first two infusions of AFM24 are tolerated well (i.e., no IRR/CRS Grade >2), then starting 
from the third infusion (e.g., C1D8 in the escalation phase) the observation period after the end of 
infusion may be reduced from 4 hours to ≥ 2 hours (at least 2 hours), with vital signs recorded 
following the schedule of vital signs parameters described in Table 3 until the completion of 
infusion. Note: Please refer to Section 6.2 to note that only 1 modification should be made at a 
time per infusion day. 
On all days when atezolizumab is administered, vital signs are to be measured following the 
schedule of vital sign parameters described in Table 3. 


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Table 3: 
Recording Schedule of Vital Sign Parameters for Atezolizumab and AFM24 
Infusions 
 
Vital sign timepoints on dosing days 
(First 2 AFM24 infusions) 
Vital sign timepoints for subsequent 
dosing days if no CRS or IRR (no 
Grade >2) observed (Third 
consecutive AFM24 infusion) a 
Before 
atezolizumab 
infusion 
Baseline (within 15 minutes before start of 
the infusion) 
Baseline (within 15 minutes before start 
of the infusion) 
During 
atezolizumab 
infusion 
30 (±5) minutes after start of infusion 
60 (±5) minutes after start of infusion 
At the end of infusion (EOI ±10 minutes) b 
30 (±5) minutes after start of infusion  
60 (±5) minutes after start of infusion 
At the end of infusion (EOI ±10 
minutes) b 
After 
atezolizumab 
infusion 
+30 (±10) minutes post EOI 
+30 (±10) minutes post EOI 
Before AFM24 
infusionc 
Baseline (within 1 hour before start of the 
infusion) 
Baseline (within 1 hour before start of 
the infusion)  
During AFM24 
infusion c 
30 (±10) minutes after start of infusion 
Every 30 (±10) minutes thereafter until EOI 
At the EOI (±10 minutes) 
30 (±10) minutes after start of infusion d 
As clinically indicated d 
 
After AFM24 
infusion c 
+60 (±10) minutes post EOI 
Every 60 (±10) minutes thereafter until the 
end of the observation period 
As clinically indicated, with a minimum 
observation period of two hours d 
Note: In addition to the above listed time points, patients should be additionally monitored in accordance with the institutional 
guidelines/clinical practice and as clinically indicated. 
a If no CRS or IRR (no Grade >2) events are observed during or after the first two consecutive AFM24 dosing days, then a reduced 
schedule of vital signs assessments may be followed as indicated for Cycle 1 Day 8 and beyond.  
b Not required if timepoint aligns with a previous timepoint (e.g., infusion ends at 60 minutes after the start of infusion) 
c The recording schedule should be followed on both dosing days if a subject is assigned to a dose cohort that requires split dosing 
(Section 6.2 and Section 6.3) 
d In case of the occurrence of Grade >2 events of CRS or IRR at a later infusion (i.e., on Cycle 1 Day 8 or beyond), then the same 
schedule for increased vital signs assessments should be performed as done for Day -7 and Cycle 1 Day 1. If, after two consecutive 
infusions, the subject does not have an CRS or IRR event Grade > 2, then a reduced schedule of vital signs assessments may be 
followed. 
8.2.5. 
Electrocardiogram 
A resting 12-lead ECG will be performed at timepoints (with respect to AFM24 infusion) 
 
 
 
 
 
 For Phase 1 only, triplicate ECGs 
should be taken at least 5 minutes apart before infusion and within approximately 15-20 minutes 
after the end of infusion (note plus only). For Phase 2a, ECGs will be performed in triplicate 
approximately 5 minutes apart at the Screening visit only, all subsequent required ECGs will be 
performed as single ECGs and should be performed prior to treatment infusion. 
For those occasions when both an ECG and peripheral blood sample (PK and pharmacodynamic 
[cytokines]) collection are required at the end of infusion (EOI) of AFM24, the blood draw must 


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be completed first, as close to the AFM24 EOI as possible, followed by the ECG. Both procedures 
should be completed approximately within 15-20 minutes after the AFM24 EOI (note plus only).  
In case of split day dosing of AFM24, ECG assessments should be performed on the first day of 
the split day dosing before treatment start (Phase 1 and Phase 2a) and on the second day of the 
split day dosing after the end of infusion in Phase 1 only. 
All 12-lead ECGs should be recorded while the patient is in supine position. ECGs will be recorded 
at 25 mm/sec. All efforts should be made to ensure that an identical ECG machine is used to collect 
traces for individual patients. The Investigator or designated physician will review the ECG results. 
If any clinically significant findings are identified during the study, the Investigator will record 
these as an AE where the finding represents a change from baseline. 
An unscheduled ECG might be performed at any time if clinically indicated. 
8.2.6. 
Clinical Chemistry, Hematology, Urinalysis, Coagulation 
Blood and urine samples for determination of clinical chemistry, hematology and urinalysis 
parameters will be taken as described in Schedule of Assessments 
 Patients 
must demonstrate adequate organ function when assessed within 7 days before the first AFM24 
infusion on Day -7 to remain eligible as outlined in Section 5.1 (Inclusion Criteria 6). Clinical 
Chemistry, hematology, urinalysis, and coagulation samples must be taken on or the day before 
infusion (i.e., up to one day prior to atezolizumab infusion on dosing days when both atezolizumab 
and AFM24 are administered, and up to one day prior to AFM24 infusion on days when only 
AFM24 is administered). 
Hepatitis B, hepatitis C, and HIV serology testing will be performed at Screening.  
The laboratory variables to be measured are described in
  
Copies of laboratory accreditation certificates and reference ranges will be obtained from each 
study site prior to analysis of their first patient sample and maintained over the course of the study. 
If a clinically significant clinical chemistry, hematology, urinalysis, or coagulation finding is 
identified during the study, the Investigator will assess whether this finding is also considered an 
AE. 
8.2.7. 
ECOG Performance Status 
ECOG PS will be assessed at Screening and at time points specified in 
 
Details of the ECOG PS categories are presented in 
 Patients must be confirmed as 
ECOG PS 0 or 1 to be eligible for study participation. 
8.2.8. 
Pregnancy and FSH tests 
Female patients of reproductive potential will have a pregnancy test carried out at Screening and 
at timepoints specified in 
. A urine test is acceptable; however, where a urine 
test is equivocal, a blood test must be performed to confirm the result. Patients confirmed as 
pregnant will be excluded from participation in the clinical study. 
Female patients who require documented confirmation of post-menopausal status will have their 
FSH levels assessed at Screening. Where post-menopausal status is not confirmed, patients will be 
required to undergo pregnancy testing per protocol to confirm suitability to proceed.   








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8.9. 
Immunogenicity (Anti-Drug Antibodies) 
All patients will have blood samples drawn to assess for ADA as described in Schedule of 
Pharmacokinetic, 
Pharmacodynamic, 
Immunogenicity, 
and 
Translational 
Assessments 
 
 
Full details of sample collection and handling of ADA samples will be described in the Lab 
Manual. 










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All AEs meeting the DLT criteria will be summarized and listed for all patients throughout the 
study (in addition to the separate analysis of dose-determination using the DDS). 
COVID-19 impacts: 
Patients may be diagnosed with COVID-19 and experience SAEs associated with the disease that 
are not causally related to the investigational drug. However, it also is possible that an 
investigational drug might be causally related to a SAE associated with COVID-19 by making 
study patients more susceptible to complications from COVID-19. However, it is not possible to 
establish this potential causal relationship with a small number of SAEs reported in a clinical study. 
Descriptive statistics will be conducted to present SAEs by known and suspected COVID-19 
infection and no infection. If possible, with the existing literature, the rates in the clinical study 
will be compared to reports in patients with similar comorbidities and levels of care. If the 
difference in SAEs compared to an external population suggests a causal relationship between the 
investigational product and the SAEs in study patients diagnosed with COVID-19, this finding 
will be submitted to FDA as an Investigational New Drug (IND) safety report in accordance with 
United States Title 21 Code of Federal Regulations (CFR) Part 312.32.  
9.3.2. 
Efficacy Analyses 
Objective Response: The number and percentage of patients achieving each category of response 
for OR (including CR and PR) will be provided. Results will be presented by percentages and 95% 
CI. 
Clinical benefit rate (defined as CR or PR [any duration] OR SD ≥24 weeks): Results will be 
presented by percentages and 95% CI. 
Disease control rate (DCR) at months 3, 6, 9, 12 and 15, as defined by achieving CR and/or PR 
and/or SD assessed by RECIST v1.1 will be presented by percentage rates and where appropriate 
the 95% CIs. 
Progression-free survival will be measured from the date of the first dose of AFM24 and 
atezolizumab study drug to the date of disease progression or death from any cause, whichever 
occurs first. 
Overall survival will be measured from the date of the first dose of AFM24 study drug to the date 
of death for any cause. 
Duration of response will be measured from the date at which response criteria are met for CR or 
PR until the date of recurrence, PD, or death. Progression-free survival, overall survival, and DOR 
will be summarized using the Kaplan-Meier method. Censoring rules will be provided in the 
statistical analysis plan. 
9.3.3. 
Pharmacokinetic Analyses 
The PK analysis plan for the assessment of AFM24 will be described in a separate Data Analysis 
Plan. Where feasible, non-compartmental analysis will be conducted using concentration time data 
of AFM24. Summary statistics of PK parameters such as Cmax, time to Cmax (Tmax), Cmin, and area 
under the concentration-time curve over the dose interval (AUCtau) will be reported by dose group. 
Additional parameters or model-based analysis may be calculated depending on the available data. 








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10. 
SAFETY MANAGEMENT 
Timely and complete reporting of safety information is very important to assist in the identification 
of any untoward medical occurrence, thereby ensuring: 
• The safety of study patients; 
• A greater understanding of the overall safety profile of the investigational drug; 
• Recognition of any dose-related investigational drug toxicity; 
• Appropriate modification of study protocols; 
• Improvements in study design or procedures as required; and 
• Adherence to required ethical and regulatory requirements for clinical study conduct. 
10.1. 
Safety Definitions 
10.1.1. 
Adverse Events 
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical 
condition in a patient or clinical investigation patient administered a medicinal product and which 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product or study procedures, whether assessed as related or unrelated to AFM24. 
During clinical trials, AEs can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a patient. To prevent reporting bias, patients should not 
be questioned regarding the specific occurrence of one or more AEs. Adverse events include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the start 
of the study; 
• Intercurrent illness; 
• Drug interactions; 
• Experiences related or possibly related to concomitant medications; 
• Clinically significant abnormal laboratory values or shifts from baseline;  
• Clinically significant abnormalities in physical examination, vital signs, weight, or 
ECG; and 
• An accident or injury; 
• Adverse events which are related to study procedures (for example: a biopsy). 
Special Considerations related to AE Reporting 
The term “disease progression” alone should not be used when reporting AEs or SAEs, due to its 
lack of specificity. Rather, symptoms of disease progression should be reported. If death occurs as 
consequence of disease progression, this would be considered an outcome, and NOT an AE.  


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Example, a patient died due to a pulmonary hemorrhage secondary to tumor progression; 
an SAE report should be submitted with the event pulmonary hemorrhage notified as a 
Grade 5 (fatal).  
Surgical procedures or other therapeutic interventions themselves are not AEs, but the condition 
for which the surgery/intervention is required is an AE and should be documented accordingly. 
Planned surgical measures and the condition(s) leading to these measures are not AEs if the 
condition(s) was (were) known before the period of observation and did not worsen during study. 
In the latter case, the condition should be reported as medical history. 
Pregnancy is not an AE, although a patient will be withdrawn from the study if a pregnancy occurs. 
Refer to Section 10.3.4.1 for more information on reporting pregnancy events. 
10.1.2. 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose or due to study procedure 
causes or qualifies as the following: 
• Results in death; 
• Is life-threatening; 
o “Life-threatening” means that the patient was at immediate risk of death at the time 
of the SAE; it does not refer to an SAE that hypothetically might have caused death 
if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization; 
o This means that hospital inpatient admission or prolongation of hospital stay were 
required for the treatment of the SAE or that they occurred as a consequence of the 
event. 
o Visits to a hospital by ambulance or to the emergency room without admission will 
not be regarded as hospitalization unless the event fulfills any other of the serious 
criteria. 
• Results in persistent or significant disability or incapacity; 
o “Persistent or significant disability or incapacity” means a permanent or significant 
and substantial disruption of a person’s ability to carry out normal life functions. 
• Is a congenital anomaly or birth defect; and/or 
• Is an important medical event. 
o Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above 
occurred. Important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above 
should also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias, convulsions that do not result in inpatient hospitalization, or 
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o A diagnosis of new cancer/ malignant tumor during a treatment should always be 
considered as medically important. 
o For this study, any DLTs (as per Section 4.2.3.1) are considered as important 
medical events and should be reported as SAE. 
All SAEs will be followed until resolution, the condition stabilizes or is considered chronic, the 
event is otherwise explained, or the patient is lost to follow-up or withdraws consent. 
10.2. 
Evaluation and Classification 
10.2.1. 
Evaluation of Severity 
All AEs (including SAEs) are to be accurately recorded on the AE page of the patient’s eCRF. 
Each event will be graded for severity using the classifications of NCI CTCAE v5.0 (NCI 2017).  
For events not addressed in the NCI CTCAE v5.0 classifications, the following grading will apply: 
• Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
• Moderate (Grade 2) - Moderate; minimal, local, or noninvasive intervention 
indicated; limiting age-appropriate instrumental activity of daily living. 
• Severe (Grade 3) - Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activity of daily living. 
• Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention 
indicated. 
• Fatal (Grade 5) - Related to AE. 
During initial dosing and its respective post-observation period, any clinical finding despite its 
severity that represents a change from baseline (e.g., mild skin reaction, fatigue, myalgia, etc.) 
shall be recorded and followed until resolution.  
Likewise, any clinically significant finding identified during the remaining course of the study, 
which represents a change from baseline would be required to be recorded by the Investigator. 
10.2.2. 
Expectedness Assessment 
The Sponsor will assess all SAEs whether they are expected or unexpected. An unexpected AE is 
any adverse drug event, the outcome, specificity, or severity of which is not consistent with those 
noted in the Reference Safety Information section of the current Investigator’s Brochure (IB). 
10.2.3. 
Causality Assessments  
All AEs (including SAEs) will be assessed by the Investigator and Sponsor for the causal 
relationship of the AE to the study drug (AFM24, atezolizumab, or the combination of AFM24 
and atezolizumab) using the following definitions described in Table 6. 
For reporting and data analysis purposes, AEs reported with a causality assessment of “Definitely”, 
“Probably”, and “Possibly” are to be considered as “having a reasonable causal relationship” to 


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study drug. In case of disagreement between the Investigator and the Sponsor, the more 
conservative assessment will determine the reportability of the case. 
Table 6: 
Relationship to Study Drug 
 
Relationship 
Description 
1 
Not related 
This category applies to those AEs which, after careful consideration, are clearly and 
incontrovertibly due to extraneous causes (disease, environment, etc.). 
2 
Unlikely 
(must have 2) 
In general, this category can be considered applicable to those AEs which, after careful 
medical consideration at the time when they are evaluated, are judged to be unrelated 
to the study drug. An AE may be considered unlikely if or when: 
1. It does not follow a reasonable temporal sequence from administration of the test 
drug. 
2. It could readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient. 
3. It does not follow a known pattern of response to the test drug. 
4. It does not reappear or worsen when the drug is re-administered. 
3 
Possibly 
(must have 2) 
This category applies to those AEs for which, after careful medical consideration at 
the time they are evaluated, a connection with the test drug administration appears 
unlikely but cannot be ruled out with certainty. An AE may be considered possibly 
related if or when: 
1. It follows a reasonable temporal sequence from administration of the test drug. 
2. It could not readily have been produced by the patient’s clinical state, environmental 
or toxic factors, or other modes of therapy administered to the patient. 
3. It follows a known pattern of response to the test drug. 
4 
Probably 
(must have 3) 
This category applies to those AEs for which, after careful medical consideration at 
the time they are evaluated, are felt with a high degree of certainty to be related to the 
test drug. An AE may be considered probably related if or when: 
1. It follows a reasonable temporal sequence from administration of the test drug. 
2. It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the patient. 
3. It disappears or decreases on cessation or reduction in dose. There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-
relatedness clearly exists (e.g., bone marrow depression, fixed drug eruptions, tardive 
dyskinesia). 
4. It follows a known pattern of response to the test drug. 
5 
Definitely 
(must have 
all) 
This category applies to those AEs which the Investigator feels are incontrovertibly 
related to test drug. An AE may be assigned an attribution of definitely related if or 
when: 
1. It follows a reasonable temporal sequence from administration of the test drug. 
2. It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the patient. 
3. It disappears or decreases on cessation or reduction in dose with re-exposure to 
drug. (Note: this is not to be construed as requiring re-exposure of the patient, 
however, a category of definitely related can only be used when a recurrence is 
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to ensure consistency between the clinical and the safety database. The original signed paper-based 
query forms must be kept on file at the study site.  
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should 
be instituted. Appropriate consultation and follow-up evaluations should be carried out by the 
Investigator (or designee). An SAE is followed until it is considered resolved, returns to baseline, 
is chronically ongoing, stabilized or is otherwise explained by the Investigator. 
10.3.3.1.2. Reporting of Serious Adverse Events to Regulatory Authorities 
In accordance with the 21 CFR 312.32, the EU Clinical Trial Regulation 536/2014 (EU-CTR), and 
the ICH Guidelines for Clinical Safety Data Management Definitions and Standards for Expedited 
Reporting, the Sponsor must submit written documentation in the form of an Investigational New 
Drug Application (IND) safety report or suspected unexpected serious adverse reaction (SUSAR) 
reports, respectively. The Sponsor should submit to the regulatory authority all safety updates and 
periodic reports, as required by applicable regulatory requirements. IND safety reports/SUSARs 
are required to be reported within 7 calendar days for life-threatening events and those resulting in 
death or 15 calendar days for all others. These timeframes begin with the first notification of the 
IND safety reports/SUSARs to the Sponsor or their delegate from the Investigator. 
The Sponsor (or their delegate) will determine whether expedited reporting is necessary for SAEs 
depending on the assessment of seriousness, expectedness, and causal relationship. In case of 
disagreement between the Investigator and the Sponsor regarding causal relationship, the more 
conservative assessment will determine the reportability of the case. 
The Investigator must ensure they are aware and comply with any additional local reporting 
requirements. For all SAEs regardless of expectedness and relationship, the Sponsor (or their 
delegate) will assign a case number to be used in all future correspondence regarding the event 
and can provide a MedWatch or Council for International Organizations of Medical Sciences form 
describing the event, for the Investigators to report to their IRB/IEC, or other committee. Other 
SAEs (e.g., expected or unrelated SAEs) should be reported per the relevant institution’s 
procedures. 
Where required, submission of safety updates by the Investigator to Competent Authorities must 
be handled according to local regulations. Otherwise, periodic safety reports to the regulatory 
agencies will be handled by the Sponsor (or their delegate). These safety updates will also include 
SAEs that do not require expedited reporting to the authorities. 
Periodically (at least annually), the IB will be updated to include new and relevant safety 
information. Until such time that an AE becomes identified in the IB (see Summary of Data and 
Guidance for the Investigator), it should be considered unexpected. 
10.3.3.2. Adverse Events of Special Interest  
Infusion Related Reaction 
Occurrence of IRRs is within the anticipated safety profile of AFM24, considering experiences 
with other EGFR and CD16 targeting agents. Thus IRRs are realized by the sponsor as AESIs, for 
which ongoing monitoring and rapid communication is appropriate. 


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Infusion related- reactions can manifest with allergic or anaphylactic symptoms, including but not 
limited to chills, flushing, hypotension, fever, hypoxia, loss of consciousness, bronchospasm, and 
even cardiac arrest. Although the majority of such IRRs are mild to moderate, in some rare cases 
these can be life-threatening or even fatal. Most of the IRRs are associated with the first infusion 
(during or shortly after the infusion); however, IRRs can happen during or after any infusion, 
despite the lack of previous signs or symptoms. In the nonclinical studies of AFM24, there were 
no signs of IRRs or anaphylactic symptoms. For more information, refer to the latest IB edition. 
IRR events require further investigation in order to characterize and understand them. Of particular 
interest, is information related to the timely development of symptoms relative to dose per time, 
actions taken as well as outcome of events. IRR events must be reported within 24 hours of 
awareness as per Section 10.3.3. All symptoms suggesting an IRR should be mentioned in the 
report. 
The data will not be subject to reporting to Independent Ethics Committee (IEC)/Independent 
Review Board (IRB)/Regulatory Authorities unless such an event qualifies as an SAE.  
10.3.4. 
Other Reporting Obligations: 
Study drug misuse, medication error, or overdose, although not categorized as “serious”, shall be 
reported in the eCRF, even if they may not result in an adverse outcome.  
• Overdose is defined as: >10% above the intended AFM24 planned dose is given or a 
dose interval <4 days between two consecutive doses. If the pharmacy discovers that 
an overdose has or may have been administered, they should contact the Investigator 
and Sponsor (or their delegate) immediately. In the event of overdose, the patient 
should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
In clinical trials with atezolizumab, doses of up to 20 mg/kg have been administered. 
The standard fixed dose of 1200 mg is equivalent to 15 mg/kg in a typical patient. No 
DLTs were observed at the 20 mg/kg dose level and the incidence and intensity of AEs 
reported have not been shown to be dependent on dose. An MTD has not been 
established. For this study, atezolizumab is supplied in vials containing the fixed 840 
mg dose of drug substance, which minimizes the chance of overdose. Because the dose 
per patient is not based on weight or body surface area, and no dose calculation is 
required, the risk of overdose due to medication errors is minimal. The data available 
to date suggest that the potential for harm from overdose is very low. 
• Medication error is defined as: An unintended failure in the drug treatment process 
that leads to, or has the potential to lead to, harm to the patient. 
• Misuse is defined: Situations where an investigational medicinal product is 
intentionally and inappropriately used not in accordance with the terms of the current 
protocol. 
If any of the above events is associated with an SAE, it must be reported within 24 hours as per 
Section 10.3.3. 


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10.3.4.1. Exposure During Pregnancy or Lactation 
Pregnancy and breastfeeding are considered exclusion criteria for this study (Section 5.2). 
Although pregnancy and lactation are not considered AEs, it is the responsibility of Investigators 
or their designees to report any pregnancy or lactation in a patient (spontaneously reported to them) 
or pregnancy in a patient’s partner that occurs during the study. Immediately discontinue AFM24 
treatment permanently in case of pregnancy. 
Pregnancies and lactations that occur in patients after the ICF is signed but before starting study 
drug must be reported by the Investigator if they cause the patient to be excluded from the study.  
Pregnancies and lactations that occur in a study patient or a pregnancy in a patient’s partner from 
the time of first study treatment through up to 60 days following cessation of AFM24 study 
treatment, must be reported by the Investigator.  
All reported pregnancies must be followed to the completion or termination of the pregnancy. If 
the pregnancy continues to term, the outcome, i.e., the health of the infant, will be requested by 
the Sponsor. Parental and neonatal outcomes must be recorded even if they are completely normal 
and without AEs. Offspring should be followed up for at least 8 weeks after delivery. Longer 
observation periods may be determined by the Sponsor if an adverse outcome of the pregnancy 
was observed. 
Such events must be reported within 24 hours to the Sponsor or delegate as per Section 10.3.4.1. 
The reporting procedures can be found in the SAE completion guidelines located in the Study 
Operations Manual (or equivalent). 
10.3.4.2. Investigational Product Complaints 
Pharmaceutical technical complaints associated with the investigational product must be reported 
to the Sponsor immediately, following the guidance specified in the Pharmacy Manual. The same 
reporting timelines as for SAEs will apply. 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be conducted under GCP and all applicable regulatory requirements. To ensure 
data accuracy, completeness and compliance, the study center should have processes in place for 
data review and quality control. Sponsor (or delegate) may also conduct a quality assurance audit.   
11.1. 
Data Recording, Monitoring of the Study, and Regulatory 
Compliance 
The project manager, or their designee, will make an initiation site visit to each institution to review 
the protocol and its requirements with the Investigator(s), inspect the drug storage area, fully 
inform the Investigator of his/her responsibilities and the procedures for assuring adequate and 
correct documentation. During the initiation site visit, the eCRF and other pertinent study materials 
will be reviewed with the Investigator’s research staff. During the study, the CRA will make 
regular site visits to review protocol compliance, examine CRFs and individual patient’s medical 
records, and assure that the study is being conducted according to pertinent regulatory 
requirements including ICH-GCP. Sites should ensure that source documentation is available to 
enable verification of all eCRF data entries. The review of medical records will be done in a 
manner to ensure that patient confidentiality is maintained. 
All eCRF data will be collected using an eCRF within a fully validated and CFR 21 
Part 11-compliant electronic data capture system. All data will be entered into the eCRF by the 
site staff. These data will then be source-data verified and reviewed by the CRAs before data 
cleaning by Data Management is performed. All queries will be raised and resolved within the 
electronic data capture system. During entry, programmatic checking of the data will be performed 
and once saved into the database, more complex programmatic checks will also be performed. 
During the conduct of the study, all system users will have real-time access to the data. The level 
of access to the data and study privileges will be determined by their user role. 
After all queries have been resolved, the Statistical Analysis Plan approved and signed, and any 
summary/analysis populations approved, the database will be locked, and the data released for 
summary and analysis. All summary and analysis of the data will be performed using appropriate 
versions of SAS® and WinNonLin Pro, or equivalent. 
11.2. 
Study Monitoring 
Clinical research associates will be responsible for the monitoring of the study. The CRA will 
review the progress of the study on a regular basis to ensure adequate and accurate data collections. 
Monitoring site visits to review the eCRF, patient case notes, administrative documentation 
including the Investigator Site File, and frequent telephone/e-mail communications with site will 
be performed throughout the study. 
At each study monitoring visit, the Investigator will make available all records pertaining to the 
study. To allow sufficient time to assemble documentation for the CRA, monitoring visits will be 
confirmed in advance of planned visits. 
The process for study monitoring and source data verification requirements for the study will be 
specified in the Monitoring Plan (or equivalent). 


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11.3. 
Clinical Study Audit 
The Sponsor, Sponsor representative or external regulatory agency may at any time during or after 
completion of the study conduct a GCP audit. Prior notice will be given to each site selected for 
audit in advance of a planned audit. 
11.4. 
Clinical Study Report 
The results of the study will be presented in an integrated CSR according to ICH guidelines. The 
CSR will be written once all expansion cohorts reached the primary endpoint assessment. 
In case patients are still being treated with study medication at the final data cut-off date for this 
study, such patients will be kept on treatment in the study and data collected will then be reported 
in an addendum to the final CSR. It will be noted in the final CSR that such a revised report may 
be provided. 
11.5. 
Data Availability 
The Investigator is required to maintain copies of all essential study documentation, including the 
Site Study File, all eCRF data (including the full audit trail and all data queries), signed ICFs, and 
records for the receipt and disposition of study drug. 
During the study, the Investigator must make study data accessible to the CRA, the Sponsor (or a 
third-party auditor assigned by the Sponsor), and relevant IRB/EC and regulatory agencies. A file 
(or appropriate records) for each patient must be maintained that includes the signed ICF and all 
source documentation related to that patient. The Investigator must ensure the availability of 
source documents from which the information in the eCRF was derived. 
Please refer to Section 13.2 for details of required record retention for the study. 
11.6. 
Curricula Vitae and Financial Disclosure of Investigators  
All Principal Investigators will be required to provide a current signed and dated curriculum vitae, 
a completed FDA Form 1572 (or accepted equivalent) and a financial disclosure statement. All 
Sub-Investigators will be required to provide a current curriculum vitae and a financial disclosure 
statement. 
11.7. 
Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval of the 
Sponsor. Any such changes which may affect a patient’s treatment or informed consent, especially 
those increasing potential risks, must receive prior approval by the IRB/EC. The exception to this 
is where modifications are necessary to eliminate an immediate hazard to study patients, or when 
the change involves only logistical or administrative aspects of the study (e.g., change in monitor, 
change in telephone number). Other administrative revisions which may impact the clinical portion 
of a study will be duly reported to the IRB/EC by the Principal Investigator. 


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11.8. 
Study or Site Termination 
If the Sponsor or their representatives, Investigator, or Competent Authority discover conditions 
during the study that indicate that the study or site involvement should be terminated, this action 
may be taken after appropriate consultation with the Sponsor and the Investigator. Conditions that 
may warrant termination of the study or a study site include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in 
the study; 
• The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, 
or development of the study drug; 
• Failure of an Investigator(s) to comply with pertinent clinical study regulations; 
• Submission of knowingly false information from the study site to the Sponsor, CRA, 
or Competent Authority; and 
• Insufficient adherence to protocol requirements. 
Study termination and/or site close out will be performed in accordance with applicable local 
regulations. 


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12. 
ETHICAL CONSIDERATIONS 
The Investigator will obtain written informed consent from each patient, or their authorized 
representative, participating in the study. The form must be signed, witnessed, and dated. The ICF 
will contain all the Essential Elements of Informed Consent set forth in 21 CFR 50, the ICH 
Guideline for GCP, and the terms of the Declaration of Helsinki. Copies of the signed document 
should be given to the patient and filed in the Investigator’s Study File, as well as the patient’s 
medical record if in conformance with the institution’s Standard Operating Procedures. 
The final study protocol and patient ICF will be approved by the appropriate IRB/EC for each 
investigational site. Approval will be received in writing before initiation of the study. 
Changes to the protocol during the study will be documented as amendments. Depending on the 
contents of the amendment and local legal requirements, the amendment will be submitted for 
approval to the relevant IRB/EC and to the relevant competent authorities prior to implementation. 
Exceptions are cases of changes made to protect patient safety, which will be implemented 
immediately. 
If an amendment substantially alters the study design, increases the potential risk to the patients, 
affects the treatment of the patient, or might otherwise influence the willingness of the patient to 
participate in the study, then the ICF must be revised and submitted to the relevant IRB/EC and, 
where necessary, to the relevant competent authorities, for review and approval. When a patient is 
currently undergoing study procedures and is affected by the amendment, then the patient must be 
asked to consent again using the new ICF. 
12.1. 
Ethical Conduct of the Study 
The study will be conducted in accordance with ICH GCP, the Declaration of Helsinki, the 
European Union (EU) Clinical Trials Directive 2001/20/EC, the GCP Directive 2005/28/EC, the 
requirements of local IRB/EC, and the US Code of Federal Regulations, Title 21 CFR 50. 
12.2. 
Informed Consent 
The principles of informed consent in the Declaration of Helsinki and GCP guidelines will be 
implemented before any protocol-specific procedures or interventions are carried out. 
All patients will be informed that participation is voluntary and that they can cease participation 
at any time without necessarily giving a reason and without any penalty or loss of benefits to which 
they are entitled. 
With the help of the ICF, the patient will be informed about the AFM24 and atezolizumab study 
drug and anticipated effects and the reason, design, and implication of the study. The patient must 
give consent to participate prior to enrollment in the study. This consent must be given in writing 
and sufficient time must be given between the explanation of the study and obtaining consent. The 
Investigator who conducts the informed consent discussion must also sign. The Investigator may 
delegate this responsibility to a suitably qualified member of the study team (e.g., Sub Investigator) 
if permitted by local regulations. This delegation of responsibility must be recorded in the Study 
File. By giving signed consent, the patient will confirm that his or her participation is voluntary 
and that he or she will follow the instructions of the Investigator and answer the questions asked. 
Signatures must be personally dated. 


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The signed and dated consent form will be kept by the Investigator. Prior to participation in the 
study, the patient should receive a copy of the signed and dated written ICF. 
The ICF must include all elements required by law, local regulations, GCP guidelines, and ICH 
guidelines, including consent to allow the Sponsor, Sponsor representative, or external regulatory 
auditor to review the patient’s medical records. This gives permission to examine, analyze, verify, 
and reproduce any records and reports that are important to the evaluation of the study.  
Any party with direct access must take all reasonable precautions within the constraints of the 
applicable regulatory requirement(s) to maintain the confidentiality of the patients’ identities and 
Sponsor’s proprietary information. It is the CRA’s responsibility to verify that each patient has 
consented, in writing, to direct access. 
12.3. 
Patient Participation Card 
A study participation card will be provided to patients where required by local regulations or 
IRB/EC. The card will indicate that he or she is participating in a clinical study and give the name 
and contact details of the Sponsor and the Investigator/study site. The patient will be asked to 
retain this card while participating in the study and show it to any other medical practitioners 
consulted during this time. Patients will be advised to contact the Investigator/study site if there 
are any questions.  
12.4. 
Insurance 
Appropriate insurance for this study will be arranged by the Sponsor (or their delegate), as Sponsor 
of the clinical study, in accordance with the regulatory requirements of the countries involved. A 
copy of the country-specific insurance certificate will be held in the Trial Master File and in the 
Investigator Site File. 
12.5. 
Institutional Review Board/Independent Ethics Committee 
The study will not be initiated without approval of the IRB/EC and compliance with all 
administrative requirements of the governing body of the institution. This protocol, consent 
procedures, and any amendments must be approved by the IRB/EC in compliance with current 
regulations of the FDA and the EU as applicable and in accordance with ICH GCPs. A letter of 
approval will be sent to the Sponsor prior to initiation of the study and when any subsequent 
modifications are made. The IRB/EC will be kept informed by the Investigator, contract research 
organization (CRO), or the Sponsor, as required by national regulations, as to the progress of the 
study as well as to any serious and unexpected AEs.  
12.6. 
Patient Privacy  
The Investigator must ensure that patient privacy is maintained. On the eCRF or other documents 
submitted to the Sponsor, patients will be identified by a patient number only. Clinical study 
documents that are not submitted to the Sponsor (e.g., signed ICF) should be kept in a confidential 
file by the Principal Investigator. 
In accordance with local, national, or federal regulations, the Investigator will allow the Sponsor 
or their designee personnel access to all pertinent medical records to verify the data gathered on 
the CRFs and to audit the data collection process. Regulatory agencies such as the FDA may also 


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request access to all study records, including source documentation for inspection. Clinical 
information will not be released without the written permission of the patient as outlined in the 
patient consent form. 


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13. 
DATA HANDLING AND RECORDKEEPING 
13.1. 
Recording of Data 
The Investigator will be responsible for the recording of all data on the CRFs provided, as certified 
by the Investigator’s signature and date. Should any value be significantly different from normal, 
the Investigator will comment in the appropriate sections provided in the CRFs. 
The Investigator will provide access to his/her original records to permit a representative from the 
Sponsor to verify the proper transcription of data.  
13.2. 
Study Record Retention 
All clinical study documents must be retained by the Investigator until at least 2 years or according 
to local laws, whichever is longer, after the last approval of a marketing application in an ICH 
region (i.e., US, Europe, or Japan) and until there are no pending or planned marketing applications 
in an ICH region. If no application is filed or if the application is not approved for such indication, 
the Investigator must retain all clinical study documents until 2 years after the investigation is 
discontinued and regulatory authorities have been notified. Investigators may be required to retain 
documents longer if specified by regulatory requirements, or by local regulations. 
Patients’ medical files should be retained in accordance with applicable legislation and with the 
maximum period permitted by the hospital, institution, or private practice. 
13.3. 
Data Confidentiality and Publication Policy 
The original CRFs and all data generated during the clinical study are the property of the Sponsor. 
In addition, all information regarding AFM24 and the Sponsor’s operations (e.g., patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation information) 
supplied by the Sponsor to the Investigator and not previously published is considered confidential. 
This confidential information remains the sole property of the Sponsor and shall not be disclosed 
to others without the written consent of the Sponsor. The Investigator agrees to use this information 
only to perform this study and will not use it for other purposes, including publications and 
presentations, without the Sponsor’s written consent. 
The first publication of the study results shall be made by the Sponsor. Any proposed publication 
or presentation (including a manuscript, abstract, or poster) for submission to a journal or scientific 
meeting should be sent to the Sponsor for review prior to submission. Publication of the results 
will not include confidential information, including inventions, non-public intellectual property 
rights, and know how, without the permission of the Sponsor. The full terms of confidentiality, 
intellectual property, and publication policy are described in the current Clinical Trial Agreement 
between the Sponsor and the site. 
The Sponsor may announce quality assured summary data to comply with Financial Regulatory 
Authorities, while ensuring, so far as possible, that such announcements will not compromise the 
Investigators ability to publish the data in appropriate scientific forums. 


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14. 
REFERENCES 
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Chen DS, Irving BA, and Hodi FS. Molecular pathways: next-generation immunotherapy–
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Chen DS and Mellman I. Oncology meets immunology: the cancer-immunity cycle. 
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Chen R, Zinzani P, Fanale M, et al. Phase II study of the efficacy and safety of pembrolizumab 
for relapsed/refractory classic Hodgkin lymphoma. J. Clin. Oncol. 2017; 35(19): 2125-32. 
Disis, M.L., Immune regulation of cancer. J Clin Oncol. 2010; 28(29): 4531-8. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
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Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with 
previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 
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Herbst RS, Soria JC, Kowanetz M et al. Predictive correlates of response to the anti-PD-L1 
antibody MPDL3280A in cancer patients. Nature. 2014 Nov 27;515(7528):563-7. 
Horn L, Mansfield AS, Szczesna A et al. First-Line Atezolizumab plus Chemotherapy in 
Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018 Dec 6;379(23):2220-29. 
Huang S, Harari P. Epidermal growth factor receptor inhibition in cancer therapy: biology, 
rationale and preliminary clinical results. Invest New Drugs. 1999;17(3):259-69 
Inman BA, Longo TA, Ramalingam S, and Harrison MR. Atezolizumab: A PD-L1-Blocking 
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Ishikawa J, Maeda S, Umezu K, Sugiyama T, Kamidono S. Amplification and overexpression of 
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Itakura Y, Sasano H, Shiga C, Furukawa Y, Shiga K, Mori S, Nagura H. Epidermal growth factor 
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Jaki T, Clive S, and Weir CJ. Principles of dose finding studies in cancer: a comparison of trial 
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Keenan TE, Burke KP, and Van Allen EM. Genomic correlates of response to immune checkpoint 
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Kim J, Kim Y, Kim D, Song C, Lee J. Expression of epidermal growth factor receptor in carcinoma 
of the cervix. Gynecol Oncol. 1996 Feb;60(2):283-7. 
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diagnosis and management of cytokine release syndrome. Blood 2014; 124(2):188-195. 
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recognition. Immunol Today. 1990 Jul;11(7):237-44. 
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(COVID-19). 
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19#management-of-covid-19-vaccine-deployment-for-ongoing-non-covid-19-clinical-trials. 
Published: 19 March 2020 (Accessed 23 April 2023). 
NCCN: Cancer and COVID-19 Vaccination. Preliminary Recommendations of the NCCN 
COVID-19 Vaccination Advisory Committee. Version 8.0; June 03, 2023. National 
Comprehensive Cancer Network. 2021 covid-19 vaccination guidance v8-0.pdf (nccn.org). 
(Accessed 23 April 2023). 
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overexpression of epidermal growth factor receptor in squamous cell carcinoma of the head and 
neck. Head Neck. 1992 Jan-Feb;14(1):8-13. 
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of epidermal growth factor receptor and c-erbB-2 in human breast cancer. Cancer Res. 1996 A ug 
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and metastatic urothelial carcinoma who have progressed following treatment with platinum-based 
chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.  
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their receptors in human malignancies. Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232. 
Sargent E, Gomella L, Belldegrun A, Linehan W, Kasid A. Epidermal growth factor receptor gene 
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Sharma P and Allison JP. The Future of Immune Checkpoint Therapy. Science. 2015 Apr 
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Nonsquamous NSCLC. N Engl J Med. 2018 Jun 14;378(24):2288-2301. 
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systematic review and pooled-analysis. Drug Des Devel Ther. 2019; 13: 523–38. 
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SAP_001.pdf: 


CONFIDENTAL 
Page 1 of 23 
Affimed GmbH 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL AFM24-102 
 
A Phase 1/2a Open Label, Multicenter Study to Assess the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of AFM24 in Combination with Atezolizumab in 
Patients with Selected Advanced/Metastatic EGFR-expressing Cancers 
 
Protocol code:  
AFM24-102 
SAP Version:  
Final 2.0 
SAP Date:  
22 July 2024 
Author:  
, 
 
 
 
 


CONFIDENTAL 
Page 2 of 23 
DOCUMENT HISTORY 
VERSION HISTORY 
Version # 
Version Date 
Final 1.0 
22 September 2021 
Final 2.0 
22 July 2024 
REVISION HISTORY 
Version # 
Chapter 
Revision Summary 
Reason(s) for Revision 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan: AFM24-102 
Review Status: Draft 
 
Version: 2.0 
 
Version Date: 22-JUL-2024 
 
 
CONFIDENTAL 
Page 3 of 23 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan: AFM24-102 
Review Status: Draft 
 
Version: 2.0 
 
Version Date: 22-JUL-2024 
 
 
CONFIDENTAL 
Page 4 of 23 
 
APPROVAL SIGNATURES 
STUDY TITLE: A Phase 1/2a Open Label, Multicenter Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Efficacy of AFM24 in Combination with 
Atezolizumab in Patients with Selected Advanced/Metastatic EGFR-expressing Cancers 
PROTOCOL NUMBER: AFM24-102 
SAP Final 2.0, 22 July 2024 
 
PSI 
 
 
Signature: 
................................................................ 
Date: ...................... 
 
 
Signature: 
............................................................... 
Date: ...................... 
 
 
Signature: 
................................................................ 
Date: ...................... 
 
 
Signature: 
............................................................... 
Date: ...................... 
 
Affimed GmbH 
   
Signature: 
................................................................ 
Date: ...................... 
 


Statistical Analysis Plan: AFM24-102 
Review Status: Draft 
 
Version: 2.0 
 
Version Date: 22-JUL-2024 
 
 
CONFIDENTAL 
Page 5 of 23 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ................................................................................................................................. 6 
2. 
INTRODUCTION ................................................................................................................................................ 8 
3. 
STUDY OBJECTIVES ......................................................................................................................................... 8 
3.1 
Phase 1 (Dose Escalation) ........................................................................................................................ 8 
3.1.1 
Primary Objective ....................................................................................................................................... 8 
3.1.2 
Secondary Objectives ................................................................................................................................ 8 
3.1.3 
Exploratory Objectives ............................................................................................................................... 8 
3.2 
Phase 2a (Expansion) .............................................................................................................................. 8 
3.2.1 
Primary Objective ....................................................................................................................................... 8 
3.2.2 
Secondary Objectives ................................................................................................................................ 8 
3.2.3 
Exploratory Objectives ............................................................................................................................... 9 
4. 
STUDY DESCRIPTION .............................................................................................................................................................. 9 
4.1 
Overall Study Design ................................................................................................................................ 9 
4.2 
Safety Lead-In Phase ............................................................................................................................... 9 
4.3 
Phase 1 .................................................................................................................................................. 9 
4.4 
Phase 2a ...............................................................................................................................................10 
4.5 
Replacement of Patients ..........................................................................................................................10 
4.6 
Study Treatment .....................................................................................................................................10 
4.6.1 
Phase 1 Treatment Assignment and Schedule ............................................................................................11 
4.6.2 
Phase 2a Treatment Schedule ..................................................................................................................11 
4.7 
Safety Review Committee (SRC) ..............................................................................................................11 
4.8 
Independent Data Monitoring Committee (IDMC) ........................................................................................11 
5. 
SAMPLE SIZE AND POWER CALCULATION....................................................................................................................... 12 
6. 
ANALYSIS ENDPOINTS .......................................................................................................................................................... 12 
7. 
ANALYSIS POPULATIONS..................................................................................................................................................... 12 
7.1 
Safety Analysis Set  ................................................................................................................................12 
7.2 
Full Analysis Set (FAS) ............................................................................................................................12 
7.3 
Dose-Determining Set (DDS) ....................................................................................................................12 
7.4 
PK Set ...................................................................................................................................................12 
8. 
ANALYTICAL PLAN AND STATISTICAL METHODS........................................................................................................... 12 
8.1 
General Conventions and Statistical Considerations ....................................................................................12 
8.2 
Definition of Baseline, Study Visits, and Visit Windows .................................................................................13 
8.3 
Patient Disposition ..................................................................................................................................13 
8.4 
Protocol Deviations .................................................................................................................................14 
8.5 
Patient Characteristics .............................................................................................................................14 
8.5.1 
Baseline and Demographic Characteristics ............................................................................................ 14 
8.5.2 
Medical History and Current Medical Conditions .................................................................................... 14 
8.5.3 
Prior and Concomitant Medications and Procedures ............................................................................. 15 
8.6 
Primary and Efficacy Endpoints and Analysis..............................................................................................15 
8.6.1 
Analysis of Primary Endpoint ................................................................................................................... 15 
8.6.2 
Analysis of Secondary Endpoints ............................................................................................................ 17 
8.6.3 
Analysis of Exploratory Efficacy Endpoints and Additional Assessments.............................................. 18 
8.7 
Safety Endpoints and Analysis ..................................................................................................................20 
8.7.1 
Exposure to Study Treatment .................................................................................................................. 20 
8.7.2 
Adverse Events ........................................................................................................................................ 20 
8.7.3 
Laboratory Data ........................................................................................................................................ 21 
8.7.4 
Vital Signs and Other Safety Parameters................................................................................................ 21 
8.8 
Exploratory Analysis ................................................................................................................................22 
8.8.1 
Biomarker and Genomic Data Analysis................................................................................................... 22 
9. 
INTERIM ANALYSES ............................................................................................................................................................... 22 
10. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE PROTOCOL............................................................................. 23 
11. 
PROGRAMMING SPECIFICATIONS ...................................................................................................................................... 23 
 


Statistical Analysis Plan: AFM24-102 
Review Status: Draft 
 
Version: 2.0 
 
Version Date: 22-JUL-2024 
 
 
CONFIDENTAL 
Page 6 of 23 
 
1. 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ADA 
Anti-drug Antibodies 
CBR 
Clinical Benefit Rate 
COVID-19 
Coronavirus Disease 2019 
CR 
Complete Response 
CRS 
Cytokine Release Syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DDS 
Dose-determining set 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal growth factor receptor 
FAS 
Full Analysis Set 
GEJ 
gastro-esophageal junction 
i.v. 
Intravenously 
IA 
Interim Analysis 
IDMC 
Independent Data Monitoring Commitee 
IFN-⍺ 
Interferon alpha 
IFN-β 
Interferon beta 
IRR 
Infusion-related Reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NK 
Natural Killer 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
 
 
Preferred Term 
qw 
once weekly 
q2w 
once every 2 weeks 
RP2D 
Recommended Phase 2 Dose 
RECIST 
Response Evaluate Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment-Emergent Adverse Event 
TNF-⍺ 
Tumor Necrosis Factor-alpha 


Statistical Analysis Plan: AFM24-102 
Review Status: Draft 
 
Version: 2.0 
 
Version Date: 22-JUL-2024 
 
 
CONFIDENTAL 
Page 7 of 23 
 
WHO 
World Health Organization 
WT 
wild type 
 


Statistical Analysis Plan: AFM24-102 
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2. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical analysis and reporting for the study 
protocol AFM24-102 (version 4.0) dated 10 May 2023. It is based on the final electronic case 
report forms (eCRFs) v5.0 dated 13JUL2023. 
3. 
STUDY OBJECTIVES 
3.1 
PHASE 1 (DOSE ESCALATION) 
3.1.1 PRIMARY OBJECTIVE 
To determine the maximum tolerated dose (MTD) and/or to select one or more recommended 
phase 2 doses (RP2Ds) of AFM24 in combination with atezolizumab. 
3.1.2 SECONDARY OBJECTIVES 
- 
To assess the safety and tolerability of AFM24 in combination with atezolizumab 
- 
To evaluate the preliminary antitumor activity of AFM24 in combination with atezolizumab in 
terms of objective response rate (ORR) 
- 
To characterize the pharmacokinetic (PK) profile of AFM24 when AFM24 is given in 
combination with atezolizumab 
- 
To assess the immunogenicity of AFM24 when AFM24 is given in combination with 
atezolizumab 
3.1.3 EXPLORATORY OBJECTIVES 
- 
 
 
 
 
 
 
 
 
 
 
3.2 
PHASE 2A (EXPANSION) 
3.2.1 PRIMARY OBJECTIVE 
To evaluate the antitumor activity of AFM24 in combination with atezolizumab in terms of ORR. 
3.2.2 SECONDARY OBJECTIVES 
- 
To assess preliminary efficacy of AFM24 in combination with atezolizumab using additional 
measures of clinical benefit 
- 
To assess the safety and tolerability of AFM24 in combination with atezolizumab 
- 
To characterize the PK profile of AFM24 when AFM24 is given in combination with 
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- 
To assess the immunogenicity of AFM24 when AFM24 is given in combination with 
atezolizumab 
3.2.3 EXPLORATORY OBJECTIVES 
- 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
STUDY DESCRIPTION 
4.1 
OVERALL STUDY DESIGN 
AFM24-102 is a Phase 1/2a open label, non-randomized, multicenter, dose escalation and 
expansion study evaluating AFM24 in combination with atezolizumab (investigational treatment: 
AFM24 + atezolizumab) in patients with select epidermal growth factor receptor (EGFR)-
expressing advanced solid malignancies whose disease has progressed after treatment with 
previous anti-cancer therapies. 
There will be 2 parts in this study: a dose escalation phase (Phase 1) and an expansion phase 
(Phase 2a). Patients will qualify to receive the investigational treatment (AFM24 + atezolizumab) 
in the dose escalation phase (Phase 1) or in the expansion phase (Phase 2a) only if they are 
deemed eligible post the safety lead-in phase where they will receive a single intravenous (i.v.) 
AFM24 infusion. Patients who qualify for the safety-lead in phase will receive AFM24 i.v. 
infusion, once weekly (qw), in 4-week cycles and atezolizumab i.v. infusion, once every 2 weeks 
(q2w), in 4-week cycles. 
The full study scheme can be seen in the Protocol section 4.1. 
4.2 
SAFETY LEAD-IN PHASE 
Seven days prior to Cycle 1 Day 1 (C1D1) (i.e., at Day -7 [minus 7]), patients will receive a 
single dose of AFM24 (dose assigned to a given cohort) and will be observed for any Adverse 
Event (AE) for 1 week (from Day -7 through Day -1 the safety lead-in phase). Patients who have 
any Grade ≥3 cytokine release syndrome (CRS) or infusion-related reaction (IRR) symptoms 
lasting >6 hours or any other possibly related Grade ≥3 non-hematological Treatment-Emergent 
Adverse Events (TEAE) or clinically significant hematological Grade ≥3 TEAEs during their 
safety lead-in phase will be permanently discontinued from the study. Patients not proceeding to 
combination therapy (AFM24 + atezolizumab) will be replaced. 
4.3 
PHASE 1 
The aim of the dose escalation phase (Phase 1) is to determine the MTD/RP2D of AFM24 in 


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combination with atezolizumab. 
The 160 mg i.v. qw dose was selected as the starting dose for the AFM24-102 study, based on 
the data obtained from the first in human study (AFM24-101). There were 2 additional dose 
escalations completed for AFM24, where the dose increase was based on data from the 
AFM24-101 study, in conjunction with the safety and PK data emerging from this study (see 
Protocol Section 2.4). Dose increases did not exceed 200% of the current dose. All dose 
escalation (and de-escalation) decisions were determined by the Safety Review Committee 
(SRC). 
4.4 
PHASE 2A 
Once all patients completed Cycle 1 of the dose escalation phase (Phase 1), the SRC reviewed 
all available safety, clinical, laboratory, and PK data and recommended continuing with the 
phase 2 portion of the study. The RP2d of AFM24 in combination with atezolizumab was 
determined. The MTD was not reached. Enrollment into the expansion cohorts for the selected 
cancer indications in the expansion phase (Phase 2a) began (see Protocol Section Error! 
Reference source not found.). 
A Simon two-stage optimal design will be utilized for Expansion Cohorts 1 and 2. Expansion 
Cohorts 3 and 4 are exploratory with no hypothesis testing. The expansion phase (Phase 2a) of 
the study is intended to collect preliminary evidence of efficacy and to further confirm the safety 
of AFM24 in combination with atezolizumab. 
During the expansion phase (Phase 2a), up to 130 patients will receive weekly infusions of 
AFM24 at the RP2D in combination with an every two-week infusion of atezolizumab in four-
week cycles in four expansion phase cohorts based on tumor types. 
Based on results from dose-escalation phase (Phase 1), additional treatment schedules of 
AFM24 administration (i.e., q2w) may be explored as part of the expansion phase (Phase 2a) 
within or across cohorts. 
Patients will receive the investigational treatment (AFM24 + atezolizumab) until disease 
progression, intolerable toxicity, at the investigator’s discretion, or patient withdrawal of consent. 
4.5 
REPLACEMENT OF PATIENTS 
In Phase 1 (dose escalation), a patient who did not fulfill the Dose Limiting Toxicity (DLT) 
requirements (refer to the protocol section Error! Reference source not found.) and who 
discontinued study participation prior to completing the DLT observation period due to any 
reason other than a DLT, would be replaced for DLT evaluation but will remain in the Safety 
Analysis Set (see Section 7.1 for definition).  
For the dose escalation (Phase 1) and expansion phase (Phase 2a), all patients who begin 
AFM24 treatment (e.g. Day -7) but discontinue prior to receiving any amount of atezolizumab 
will be replaced but will remain in the overall Safety Analysis Set. A replacement patient will be 
enrolled and assigned the same cohort or dose level. 
4.6 
STUDY TREATMENT 
AFM24 will be administered as an i.v. infusion, qw (or q2w as part of the Phase 2a in case 


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additional treatment schedules of AFM24 administration are explored), in 4-week cycles. 
Atezolizumab will be administered as i.v. infusion, q2w, in 4-week cycles.  
Refer to the Pharmacy Manual for full details regarding study drug administration. 
4.6.1 PHASE 1 TREATMENT ASSIGNMENT AND SCHEDULE 
For the dose escalation phase (Phase 1), patients received AFM24 and atezolizumab in an 
open label fashion according to the following treatment schedule for their assigned cohort: 
- 
Cohort 1 (N= 4)  
160 mg AFM24 i.v. qw + Atezolizumab 840 mg i.v. q2w 
- 
Cohort 2 (N= 6)  
480 mg AFM24 i.v. qw + Atezolizumab 840 mg i.v. q2w 
 
4.6.2 PHASE 2A TREATMENT SCHEDULE 
Patients who are remain eligible post-evaluation for AFM24-hypersensitivity during the safety-
lead in phase (Day -7 through Day -1) will receive the investigational treatment 
(AFM24 + atezolizumab) as per the following regimens, with the RP2D defined as 480 mg: 
- 
EXP-1 (EGFR-wild type (WT) Non-small cell lung cancer (NSCLC)): 
AFM24 i.v. qw or q2w at RP2D dose + Atezolizumab 840 mg i.v. q2w 
- 
EXP-2 (gastric or gastro-esophageal junction [GEJ] adenocarcinoma): 
AFM24 i.v. qw or q2w at RP2D dose + Atezolizumab 840 mg i.v. q2w 
- 
EXP-3 (Hepatocellular Carcinoma, Hepatobiliary-, or Pancreatic Adenocarcinoma): 
RP2D AFM24 i.v. qw or q2w at RP2D dose + Atezolizumab 840 mg i.v. q2w 
- 
EXP-4 (advanced or metastatic NSCLC harboring a targetable EGFR kinase domain 
mutation): RP2D AFM24 i.v. qw or q2w at RP2D dose + Atezolizumab 840 mg i.v. q2w  
Additional treatment schedules of AFM24 administration (e.g., every 2 weeks) may be explored 
as part of the Phase 2a within or across cohorts. 
4.7 
SAFETY REVIEW COMMITTEE (SRC) 
The SRC convened to make a decision on the dose escalation in the Phase 1. 
All details regarding the SRC composition, meetings, reviewed data and the decision-making 
process will be documented in the study-specific SRC Charter. 
4.8 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
The IDMC, consisting of clinical experts who are not directly involved in this clinical study, will 
be established for the Phase 2a of the study. The IDMC will review all safety data generated 
throughout the dose expansion phase (Phase 2a) of the study on a regular basis. Based on the 
outcome of their review, the IDMC will provide recommendations to the Sponsor with regard to 
study conduct or study procedures. The set-up and operational process for this IDMC will be 
described in a separate IDMC charter. 


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5. 
SAMPLE SIZE AND POWER CALCULATION 
Please refer to the protocol section 9.1 for sample size justifications. 
6. 
ANALYSIS ENDPOINTS 
Please refer to the protocol section 3 for Objectives and Endpoints. 
7. 
ANALYSIS POPULATIONS 
7.1 
SAFETY ANALYSIS SET  
The Safety Analysis Set will consist of all patients who received at least any amount of AFM24 
or atezolizumab. The Safety Analysis Set will be the primary population for all safety related 
endpoints except determination of the dose-DLT relationship. 
7.2 
FULL ANALYSIS SET (FAS) 
The FAS will consist of all patients who received at least any amount of both AFM24 and 
atezolizumab. The FAS will be the primary population for all efficacy related endpoints. 
7.3 
DOSE-DETERMINING SET (DDS) 
The DDS will consist of all patients in the Safety Analysis Set, who have either (a) experienced 
DLT at any time during Cycle 1, or (b) met the minimum safety evaluation requirements without 
experiencing DLT within Cycle 1. 
Patients must receive ≥ 75% of their assigned AFM24 dose in Cycle 1, receive ≥ 50% of their 
assigned atezolizumab dose in Cycle 1, complete the 28-day DLT observation period and have 
at least one post-baseline assessment of the following safety parameters: Physical 
Examination, Vital Signs, Laboratory, and Electrocardiogram (ECG), or have had a DLT within 
the first cycle of treatment to be considered evaluable for DLT. 
7.4 
PK SET 
The PK set consists of all patients who have received at least 1 adequately documented dose of 
AFM24 and have at least 1 adequately documented post dose PK measurement. 
8. 
ANALYTICAL PLAN AND STATISTICAL METHODS 
8.1 
GENERAL CONVENTIONS AND STATISTICAL CONSIDERATIONS 
All analyses will be performed using SAS® statistical analysis software (SAS, SAS/GRAPH and 
SAS/STAT; version 9.4 or higher of SAS for Windows [SAS Institute Inc.; Cary, NC, USA]). 
Descriptive statistics for continuous variables will include the number of patients, mean, 
standard deviation, median, minimum, and maximum values. All raw data will be presented to 
the original number of decimal places. Means, medians, and confidence intervals will be 
presented to 1 more decimal place than in the raw data. Standard deviations will be presented 
to 2 more decimal places than in the raw data. Summary statistics for categorical variables will 
contain count and percentage. Percentages will be presented to one decimal, except for one 
hundred percent, which will be presented as 100%. Unless otherwise specified, percentages for 
baseline summaries will be based on the total number of patients in the treatment arm or 


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overall, for the indicated population (dependent on table column heading), percentages for post-
baseline summaries will be based on the total number of patients with non-missing values in the 
treatment arm or overall. 
Change from Baseline at Visit X is defined as Test Value at Visit X – Baseline Value. 
Unless otherwise stated, all analyses will be descriptive in nature, no formal statistical 
comparisons of data from different arms or cancer type will be done. 
Data will be listed individually by patient. 
The tables and the listings will be done separately for two phases. Phase 1 summaries will be 
presented by the dose level, and Phase 2a summaries by Expansion Cohort. 
8.2 
DEFINITION OF BASELINE, STUDY VISITS, AND VISIT WINDOWS 
Baseline is defined as the last non-missing observation prior to the first dose of either AFM24 or 
atezolizumab (screening assessment for most of the parameters, or Day -7 pre-dose, where 
applicable). 
Data will be analyzed in accordance with the visits recorded in the eCRF. No visit reassignment 
will be done. 
Time points for analysis of vital signs will be assigned using protocol-defined windows (refer to 
Protocol section 8.2.4 table 3). 
Handling of Missing Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3 
PATIENT DISPOSITION 
Total number of patients screened, enrolled and failed screening will be summarized on all 
screened patients, together with reasons for the screen failure; country of enrolled patients will 
also be summarized. All patients who have signed the informed consent form are considered 


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screened; enrolled refers to the eCRF field called “Was Subject enrolled in the study?”. Number 
of patients included in each analysis set and reasons for study discontinuation will also be 
summarized. Summaries will be done for all enrolled patients, DDS for Phase 1, and for all 
enrolled patients and Safety Analysis Set for Phase 2a. 
Listings of all screened patients, reasons for screen failure, study populations, and 
inclusion/exclusion criteria not met will be created. Study discontinuation data will also be listed. 
8.4 
PROTOCOL DEVIATIONS 
Protocol Deviations will be summarized by counts and percentages. Major important, major and 
minor deviations will be summarized separately. Rules for identifying and treating protocol 
deviations are described in the Protocol Deviations Management Plan. Summaries will be done 
for all enrolled patients. A listing of all protocol deviations, along with their grade as major 
important, major or minor, will be provided for all screened patients. 
8.5 
PATIENT CHARACTERISTICS 
All summaries in this section will be done for both Safety Analysis Set and FAS for Phase 1 and 
Phase 2a. 
8.5.1 BASELINE AND DEMOGRAPHIC CHARACTERISTICS 
Following characteristics at Baseline will be summarized for the Safety Analysis Set and the 
FAS: 
- 
Age (years) 
- 
Sex 
- 
Female with childbearing potential (and a reason, if not) 
- 
Race and Ethnicity 
- 
Height 
- 
Weight 
- 
Pulmonary Function test 
Smoking history (smoking status, smoking duration in years, number of cigarettes per day and 
number of years since quitting) and alcohol consumption will be summarized and listed with the 
demographic characteristics as well. 
Listings of the baseline demography data will be prepared for the Safety Analysis Set. 
8.5.2 MEDICAL HISTORY AND CURRENT MEDICAL CONDITIONS 
Prior Cancer History (Cancer Type, Cancer Stage, Histopathological Type, Extent at Screening, 
Location of Metastases, Gene Alteration / Protein Overexpression) together with the screening 
Eastern Cooperative Oncology Group (ECOG) performance status value will be summarized. 
Listings of Cancer History data will be created. 
Prior and Concurrent medical conditions other than cancer will also be summarized. All 
conditions will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.1 or higher. Summaries will be split by System Organ Class (SOC) and Preferred 
Term (PT). A condition will be considered prior if its end date is prior to the first date of the study 


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drug administration. A condition will be considered concurrent if its end date is equal to or 
greater than the first date of the study drug administration. 
Separate listings for Prior and Concurrent conditions will be created. 
8.5.3 PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES 
Prior Cancer Related Surgeries (number of surgeries and residual disease), Cancer Related 
Radiotherapy (number of radiotherapies and total dose) and Prior Cancer Therapy (number of 
regimens, regimen type, number of cycles, best response, reason for treatment discontinuation 
and coded therapy term) for cancer will be summarized. Numbers of prior surgeries and prior 
lines of treatment are calculated as the number of unique lines recorded on the respective 
eCRF page. Prior Cancer Therapies will be coded using World Health Organization (WHO) 
Drug Dictionary from March 2019. 
Prior and Concomitant Medications will also be coded according to WHO Drug Dictionary from 
March 2019. They will be summarized by counts and percentages splitting by ATC2 and ATC4. 
Medications will be considered prior if the end date is prior to the first date of the study drug 
administration. A medication will be considered concomitant if its end date is equal to or greater 
than the first date of the study drug administration. 
Separate listings will be created for Prior Cancer Related Surgeries, Radiotherapy Treatments 
and Therapies, and also for prior and concomitant medications. In addition, listings of Surgeries 
and other Procedures and Post-Study Anti-Cancer Treatment will be created. 
8.6 
PRIMARY AND EFFICACY ENDPOINTS AND ANALYSIS 
All the efficacy tables will be run for Full Analysis Set for Phase 1 and for Phase 2a. Where 
specified additionally, sensitivity analyses on DDS will be run. 
8.6.1 ANALYSIS OF PRIMARY ENDPOINT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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8.6.2 
ANALYSIS OF SECONDARY ENDPOINTS 
Phase 1 (Dose Escalation) 
Non-compartmental analysis will be conducted using concentration time data of AFM24. In 
addition, a population PK analysis may be conducted. Separate PK analysis plan(s) will be 
created as applicable, and results will be presented in separate PK report(s). As a part of the 
analysis described in this SAP, by time point summaries of PK concentration data will be 
created, grouped by dose level. Plots for individual PK concentrations will be generated as well. 
PK concentrations will be listed. 
Anti-drug Antibodies (ADA) results (both screening and confirmatory results as well as titer) will 
be summarized by visit and change from baseline to worst-post-baseline. Listing of ADA data 


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will be created. The Immunogenicity data will be summarized for the Safety Analysis Set in 
Phase 1. 
The ORR (CR or PR), Disease Control Rate (DCR) [CR or PR or stable disease (SD)] and 
Clinical Benefit Rate (CBR) [CR or PR or SD ≥24 weeks], assessed by the investigators using 
RECIST 1.1 will be summarized. Best overall response will be used to define the ORR, DCR 
and CBR. Best response is defined as the best observed response (CR>PR>SD>PD) 
throughout the study. See SAP Table 1 for rules of response confirmation. Summaries will 
include the count and percentages of different best overall responses, ORR, DCR and CBR for 
each dose level. The percentages will be based on the total number of patients in the Full 
Analysis Set for a given dose level. 
In addition, waterfall plots for percentage change from baseline for sum of longest diameter and 
swimmer plots showing timing and results of RECIST 1.1 response assessments will be 
prepared. Waterfall plots will only include tumor assessments that were done at least 42 days 
after C1D1. 
Phase 2a (Expansion) 
 
 
 
 
 
 
The ORR (CR or PR), DCR (CR or PR or SD) and CBR (CR or PR or SD ≥24 weeks) assessed 
by the investigators using RECIST 1.1 will be summarized. The best overall response will be 
used to define the ORR, DCR and CBR. Best response is defined as the best observed 
response (CR>PR>SD>PD) throughout the study. See SAP table 1 for rules of response 
confirmation. Summaries will include the count and percentages and the 95% confidence 
intervals where appropriate of different best overall responses, ORR, DCR and CBR for each 
dose level. The percentages will be based on the total number of patients in the Full Analysis 
Set for a given Expansion Arm. 
Waterfall and swimmer plots will also be created, similar to what is described for Phase 1, but 
additionally color coding of the Best Overall Response. 
PK and ADA results matching Phase 1 secondary endpoints will be analyzed, but the 
presentation will be done by Expansion Cohort rather than by dose level. Analysis of Adverse 
Events is described in section 8.7.2. 
8.6.3 
ANALYSIS OF EXPLORATORY EFFICACY ENDPOINTS AND ADDITIONAL ASSESSMENTS 
Phase 1 (Dose Escalation) 
 
 
  


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Frequency of patients developing neutralizing ADAs against AFM24 will be summarized. 
Lymphocyte subset counts, including number of total and activated Natural Killer (NK) cells and 
macrophages, will be summarized by descriptive statistics at each visit for each dose level. 
Listing of Lymphocyte subset counts and NK cells will be created as a part of the laboratory 
listings. 
 
 
Phase 2a (Expansion) 
The exploratory endpoints and assessments for Phase 2a match the ones for the Phase 1, 
excluding PFS and DOR. Similar analyses will be performed, but the presentation will be done 
by Expansion Arm rather than by dose level. 
8.7 
SAFETY ENDPOINTS AND ANALYSIS 
Summaries for safety parameters will be done for the Safety Analysis Set for Phase 1 and 
Phase 2a. Tables will be presented by dose level for Phase 1 and by Expansion Arm for Phase 
2a. 
8.7.1 EXPOSURE TO STUDY TREATMENT 
Total exposure to the AFM24 and Atezolizumab in mg will be summarized by visit and overall. 
Total Duration of Exposure to AFM24 and Atezolizumab in weeks, Delays, Interruptions and 
Dose Adjustments and reasons for those, overall number of cycles, Dose Intensity and Relative 
Dose Intensity will be summarized as well. Listings of AFM24 and Atezolizumab exposure data 
(doses and all dose adjustments) will be created. 
 
  
 
  
Dose Intensity for AFM24 or Atezolizumab will be defined as the total amount of AFM24 or 
Atezolizumab respectively received by the subject in mg divided by the Duration of Exposure. 
Relative Dose Intensity will be calculated as the total dose of AFM24 or Atezolizumab received 
divided by the planned dose of AFM24 or Atezolizumab respectively per cycle times the number 
of initiated cycles. 
The Exposure data will be summarized both for DDS and the Safety Analysis Set in Phase 1, 
and for Safety Analysis Set in Phase 2a. 
8.7.2 
ADVERSE EVENTS  
Adverse Events will be summarized with patient counts, percentages and event counts by 
MedDRA SOCs and PTs. Following categories of AEs will be summarized: TEAEs, to study 
drugs related TEAEs, non-serious TEAEs, serious TEAEs and related serious TEAEs, TEAEs 
with NCI CTCAE Grades ≥3 and related TEAEs with NCI CTCAE Grades ≥3, TEAEs leading to 
premature discontinuation and interruptions, TEAEs and IRR at the day of the dosing or at the 


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next day, fatal TEAEs and related fatal TEAEs. An event will be considered study drug related if 
it has ‘possibly’, ‘probably’ or ‘definitely’ in relationship to study drug eCRF field.  
Treatment-Emergent AEs, related TEAEs, serious TEAEs, related serious TEAEs, Grade 3/4/5 
TEAEs, related Grade 3/4/5 TEAEs, TEAEs leading to study drug interruption or discontinuation 
presented by SOC and PT will also be summarized by maximum severity/CTC grade. For all 
TEAEs’ summaries a number of patients with the event will be presented together with the total 
number of TEAEs.  
 
 
 
A worst-case approach will be followed in the event of missing severity or causality data. If the 
severity is missing, severity grade “4” will be imputed. If causality data is missing, ‘Related to 
study medication’ will be imputed. 
Listings of AE data will be created. 
Summaries of all deaths reported and deaths within 28 days after the last dose of study drug 
along with causes of death will be created. Listing of the death data will be created. 
8.7.3 
LABORATORY DATA 
Safety laboratory results (Serum Chemistry, Hematology, Coagulation and Thyroid Function) 
will be graded by NCI CTCAE v5.0. If no grading exists, values will be classified into 
Low/Normal/High based on laboratory normal ranges. As only the local laboratory data are 
collected, no quantitative summaries of the laboratory data will be created. Urinalysis results will 
be summarized categorically. 
For laboratory results reported with a “<” sign, half of the value that follows will be used for the 
analysis. Results reported after ">" sign will be analyzed as is. 
Shift tables classified by reference range indicator (Low, Normal, and High) and also by CTCAE 
toxicity grades (worst toxicity grade in a period from the first dose until final visit, not including 
Follow-Up period) from baseline will be presented separately by laboratory test, where 
applicable. 
All laboratory values will be listed. A separate listing for abnormal lab values (Grade 3 and 
higher, and low/high values) will be presented. 
8.7.4 
VITAL SIGNS AND OTHER SAFETY PARAMETERS 
Vital signs will be summarized by descriptive statistics at each visit including change from 
baseline will be presented and a listing will be provided. 
Local-read ECG data will be listed overall and a separate listing for any clinically significant 
finding in ECG values will be provided. The frequency and percentage of patients with clinically 
significant ECGs will be tabulated as well. 
Physical Examination data will be summarized by visit. Listing of the PE data will be created. 


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8.8 
EXPLORATORY ANALYSIS 
 
 
 
 
 
 
 
 
 
 
 
 
. 
9. 
INTERIM ANALYSES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE 
PROTOCOL 
The analysis of DCR by months 2, 6, 9, 12 and 15 is not appropriate and will be removed in the 
upcoming protocol amendment. Instead, the overall DCR is calculated and analyzed. 
11. PROGRAMMING SPECIFICATIONS 
All outputs will be produced using SAS© version 9.4 or a later version. 
The margins should be at least 1.50 inches for the binding edge and 1.0 inches for all others. 
In the top left portion of each table/listing/figure, the company name and protocol number will be 
presented. On the next line, an output number followed by the title of the table/listing/figure and 
population information will be displayed. Horizontal lines will appear after the column heading of 
the table/listing. Footnotes will be put under the main body of text at the bottom of the page. The 
source listing number will be displayed for all tables. The SAS program name and its location, 
programmer ID, the name of the program output and its location and date of used data sets will 
appear bottom left and the page number will appear on the top right corner of each table/listing. 
The date and time of creation of table/listing will appear top right just above the page number. 
Courier New 8-point bold font will be used for all tables and listings. Usually, a landscape layout 
is suggested for both tables and listings, but it is not mandatory. Any date information in the 
listing will use the date9. format; for example, 07MAY2002. 
The list of tables, listings, and figures is given in section below. Shells for unique tables and 
listings are provided in a separate Mock-Up Tables, Figures and Listings document.