Clinical trial NCT04259450
Conditions: Advanced Solid Tumor
Sponsor: Affimed GmbH
Start date: 2020-04-07; Completion date: 2024-06-24
Enrollment: 85 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
AFM24-101 is a first in human Phase 1/2a open-label, non-randomized, multi-center, multiple ascending dose escalation/expansion study evaluating AFM24 as monotherapy in patients with advanced solid malignancies whose disease has progressed after treatment with previous anticancer therapies.

AFM24 is a tetravalent bispecific (anti-human EGFR x anti-human CD16A) innate immune cell engaging recombinant antibody being developed to target EGFR-expressing solid tumors and has been designed to specifically utilize the cytotoxic potential of the innate immune system, in particular natural killer cells and macrophages for the specific and efficient elimination of EGFR expressing cancer cells.

Detailed description:
There will be two parts to this study: a dose escalation phase (1) and a dose expansion phase (2a).

The aim of the dose escalation phase is to determine the maximum tolerated dose (MTD) and establish the recommended Phase 2a dose (RP2D).

The dose escalation phase will be followed by the dose expansion phase once the MTD/RP2D of AFM24 monotherapy has been determined. The dose expansion phase of the study using the MTD/P2D is intended to collect preliminary evidence of efficacy and to further confirm the safety of AFM24 as a monotherapy. The expansion phase will have 3 arms based on tumor type.

* Renal cell carcinoma(clear cell), failing standard of care (SoC) that includes TKIs and PD1 targeted therapy
* Non-small cell lung cancer (EGFR-mut), failing SoC TKIs
* Colorectal cancer, failing SOC chemotherapy, VEGF(R) and EGFR targeted antibodies

Arms: arm 1: Subjects, with tumors known to express EGFR, who received 14 milligram (mg) AFM24 on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. arm 2: Subjects, with tumors known to express EGFR, who received 40 milligram (mg) AFM24 on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. arm 3: Subjects, with tumors known to express EGFR, who received 80 milligram (mg) AFM24 on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. arm 4: Subjects, with tumors known to express EGFR, who received 160 milligram (mg) AFM24 on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. arm 5: Subjects, with tumors known to express EGFR, who received 320 milligram (mg) AFM24 on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. arm 6: Subjects, with tumors known to express EGFR, who received 480 milligram (mg) AFM24 on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. arm 7: Subjects, with tumors known to express EGFR, who received 720 milligram (mg) AFM24 on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. A dose could be given over two days (split day dosing). arm 8: Subjects with microsatellite stable (MSS) colorectal cancer (CRC) with rat sarcoma gene (RAS) wild-type tumor expressing EGFR who received 480 milligram (mg) AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. A dose could be given over two days (split day dosing). arm 9: Subjects with clear cell renal cell carcinoma (ccRCC) expressing EGFR who received 480 milligram (mg) AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. A dose could be given over two days (split day dosing). arm 10: Subjects with advanced or metastatic (non-small cell lung cancer) NSCLC with an epidermal growth factor receptor (EGFR) mutation who received 480 milligram (mg) AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. A dose could be given over two days (split day dosing).
Interventions: intervention 1: 14 mg AFM24 intervention 2: 40 mg AFM24 intervention 3: 80 mg AFM24 intervention 4: 160 mg AFM24 intervention 5: 320 mg AFM24 intervention 6: 480 mg AFM24 intervention 7: 720 mg AFM24
Intervention descriptions: intervention 1: 14 milligram AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. intervention 2: 40 milligram AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. intervention 3: 80 milligram AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. intervention 4: 160 milligram AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. intervention 5: 320 milligram AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. intervention 6: 480 milligram AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle. intervention 7: 720 milligram AFM24 weekly on Day 1, Day 8, Day 15, and Day 22 of a 28-day cycle.

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
A Phase 1/2a Open Label, Multicenter Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Preliminary Efficacy of AFM24 in Patients with Advanced Solid 
Cancers 
 
Protocol No.: AFM24-101 
Version No: V10.0 
Version Date: 26 July 2023 
EudraCT No: 2019-003296-19 
IND No.: 143500 
 
Affimed GmbH 
Gottlieb-Daimler Straße 2,  
68165 Mannheim,  
Germany 
The information contained in this document, especially unpublished data, is confidential communication 
from Affimed. Acceptance of this document constitutes the agreement of the recipient that this information 
will not be disclosed to others without written authorization from Affimed, 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 [IB]), 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 subjects, including data privacy laws. I confirm it is my 
duty and the duty of my study staff to ensure participating subjects are informed 
comprehensively about the nature of the study and will give their written consent to participate 
before entry into the study. Subjects will be informed that they may withdraw from the study 
at any time without jeopardizing their future care. I will use only the subject 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 subject 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 subject study data in such a way that the subject 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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PROTOCOL SYNOPSIS 
Study Title 
A Phase 1/2a Open-Label, Multicenter Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Preliminary Efficacy of AFM24 in Patients with Advanced 
Solid Cancers 
Investigational 
Product 
AFM24 
Protocol Number 
AFM24-101 
EudraCT 
Number 
2019-003296-19 
IND Number 
143500 
Sponsor and 
Contract 
Research 
Organization 
Sponsor: Affimed GmbH 
Contract Research Organization: PSI CRO AG 
Study Phase 
1/2a 
Study Regions 
Multicenter; United States, Europe, and Asia Pacific  
Rationale 
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 was 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 antitumor 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 (mAbs) and tyrosine kinase inhibitors (TKIs). Therefore, AFM24 has the 
potential to overcome the limitations of EGFR-targeting standard of care (SOC) 
mAbs 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 patient populations with 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 
antitumor potential of patients’ own innate immunity to effectively control their 
cancers. 


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Study Objectives 
PHASE 1 
Primary Objective: 
• 
Determine the maximum tolerated dose (MTD), select one or more 
recommended phase 2 doses (RP2Ds), and investigate the safety and 
tolerability of AFM24 in subjects with advanced or metastatic solid 
malignancies. 
Secondary Objectives: 
• 
Characterize the safety and tolerability of AFM24, including both acute 
and chronic toxicities; 
• 
Characterize the pharmacokinetics (PK) of AFM24 administered 
intravenously (i.v.); 
• 
Characterize the immunogenicity of AFM24; and 
• 
Assess the preliminary antitumor efficacy of AFM24. 
Exploratory: 
• 
Assess the preliminary antitumor efficacy of AFM24, using Response 
Evaluation Criteria in Solid Tumors for immunotherapy (iRECIST) tumor 
response criteria; 
• 
Assess AFM24 pharmacodynamics 
PHASE 2a 
Primary Objective: 
• 
Assess the preliminary antitumor efficacy of AFM24, by local Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
Secondary Objectives: 
• 
Characterize the safety and tolerability of AFM24, including both acute 
and chronic toxicities; 
• 
Characterize the PK of AFM24 administered i.v.; 
• 
Characterize the immunogenicity of AFM24; and 
• 
Assess the preliminary antitumor efficacy of AFM24. 
Exploratory: 
• 
Assess the preliminary antitumor efficacy of AFM24, using iRECIST 
tumor response criteria; 
• 
Assess AFM24 pharmacodynamics 
• 
Explore the predictive potential of biomarkers measured in blood and/or 
tumor tissue in response to AFM24 
Methodology 
AFM24-101 is a first in human (FIH), Phase 1/2a, open-label, non-randomized, 
multicenter, multiple ascending dose escalation/expansion study evaluating AFM24 
as monotherapy in subjects with advanced or metastatic solid malignancies whose 
disease has progressed after treatment with previous anticancer therapies. 
There will be 2 parts to this study: a dose escalation phase (Phase 1) and a dose 
expansion phase (Phase 2a). The aim of the dose escalation phase is to determine the 
MTD and/or establish one or more RP2Ds. An adaptive 2-parameter Bayesian logistic 
regression model (BLRM) guided by the dose escalation with overdose control 
(EWOC) will be used in the escalation phase to guide determination of the MTD 
and/or RP2D in subjects with advanced or metastatic solid malignancies. 
The dose escalation phase (Phase 1) will be followed by the dose expansion phase 
(Phase 2a) once the MTD and/or at least one RP2D of AFM24 monotherapy has been 
determined. The dose expansion phase (Phase 2a) of the study is intended to collect 
preliminary evidence of antitumor efficacy and to further confirm the safety of 
AFM24 as monotherapy in distinct patient populations. The expansion phase will have 
3 cohorts based on tumor type. An overview of study design is provided in Figure 1. 


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The expansion cohorts may be opened in parallel or subsequently. Based on the 
findings in the Phase 1 part of the study, additional treatment schedules (i.e., every 2 
weeks [q2w] dosing) may be explored in the Phase 2a expansion cohorts. 
An overview of the study scheme for each subject in weekly and q2w is described in 
Figure 5 and Figure 6 respectively. 
For each subject, the study starts with provision of written informed consent, followed 
by a screening phase lasting up to 21 days. For Phase 2a only, pre-screening will be 
required for subjects to determine whether eligibility criteria for EGFR expression (for 
subjects without a positive EGFR test) have been met prior to entering the screening 
phase (Note: if a positive EGFR test has been performed from a subject’s tumor tissue, 
and the EGFR laboratory report is available, the subject can proceed directly to the 
screening activities). Following the up to 21-day screening phase, eligible subjects 
will be treated with AFM24 administered as an i.v. infusion for as long as they 
continue to show clinical benefit, as judged by the Investigator, or until disease 
progression, intolerable toxicity, Investigator discretion, subject withdrawal of 
consent, or other discontinuation criteria are met.  
After the end of treatment, subjects will be followed for duration of response (DOR), 
progression-free-survival (PFS) and overall survival (OS) until the end of the study, 
which is defined as the date the last subject ending treatment has completed the first 
Long-term Follow-Up interval.  
To minimize the number of subjects treated at potentially subtherapeutic dose levels 
in the dose escalation phase (Phase 1), cohorts 1 and 2 will enroll minimum 2 subjects, 
whereas cohorts 3 and above will enroll 3 to 4 subjects. In cohorts 3 and above, a 
fourth subject may be enrolled if treatment of the fourth subject is anticipated to begin 
within 14 days of treatment initiation of the third subject in the cohort. Treatment in 
each cohort will begin in a staggered approach with at least 7 days between the first 
dose of the first subject and the first dose of subsequent subjects. After the first subject 
in each cohort has begun treatment and been observed for at least 7 days, additional 
subjects within the cohort may begin treatment concurrently.  
In cohorts 1 and 2, a minimum of 2 subjects in each cohort need to be treated and 
complete the 28-day dose-limiting toxicity (DLT) observation period before the 
Safety Review Committee (SRC) may convene and decide on the dose level for the 
next cohort of subjects. In Cohorts 3 and above, a minimum of 3 subjects in each 
cohort need to be treated and be evaluable for DLT assessment to allow for a dose 
escalation decision by the SRC. All subjects who start treatment need to complete the 
28-day DLT observation period or experience a DLT before the SRC meeting and 
dose escalation decision (minimum of 2 patients in cohorts 1/2 and 3 patients in 
cohorts 3/4). The dose cohorts might be escalated, de-escalated or expanded to up to 
6 subjects based on the SRC decision. 
Dose escalation decisions will be made by the SRC, consisting of the Principal 
Investigators at each study center and the Sponsor’s Medical representative(s), and 
additional clinical experts, as needed. The BLRM will be assessed for all subjects in 
the dose-determining set (DDS) consisting of all subjects who received at least 1 dose 
of AFM24, and either experienced a DLT at any time during Cycle 1 or met the 
minimum treatment and safety evaluation requirements without experiencing a DLT 
within Cycle 1. After completion of a given dose cohort, or at any time the BLRM is 
updated, the decision to dose escalate and the actual dose chosen will be based on the 
recommendation of the BLRM regarding the highest admissible dose according to the 
EWOC principle and the medical review of all available clinical, laboratory, and PK 
data. The outcome of these analyses and the respective datasets will be reviewed by 
the SRC. The SRC will then decide the dose level selection of the next dose cohort 
prior to enrollment. In the event of a Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 5 adverse event (AE) or a second CTCAE Grade 4 AE at least 
possibly related to AFM24 at any time during Phase 1, the Sponsor will suspend 
further accrual and the Sponsor will perform a safety analysis that will be reviewed 
by an ad-hoc SRC meeting to decide on further progression of the study. 


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Prior to initiation of dose expansion phase (Phase 2a), an Independent Data 
Monitoring Committee (IDMC) will be established consisting of clinical experts who 
are not directly involved in this clinical study. The IDMC will review all safety data 
generated throughout the dose expansion phase (Phase 2a) part 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. 
Once at least one RP2D dose has been determined, enrollment into 1 or more 
expansion cohorts for selected cancer indication in Phase 2a will begin (Figure 1). 
Other expansion cohorts may follow with the same or a different RP2D dose level. 
An optimum Simon’s two-stage design will be applied for the preliminary efficacy 
analyses for the following expansion cohorts. 
• 
Expansion Cohort A will enroll up to a total of 39 subjects with 
microsatellite stable colorectal cancer (CRC) with rat sarcoma gene (RAS) 
wild-type tumor, the interim analysis (IA) will be conducted after 11 
subjects; 
• 
Expansion Cohort B will enroll up to a total of 41 subjects with clear cell 
“renal cell carcinoma (ccRCC), the IA was planned after 15 subjects. 
However, Cohort A and C did not meet the criteria for continuation based 
on objective response (OR) and were stopped for futility. It is considered 
unlikely that the continuation criteria can be met in Cohort B. Hence it 
was decided to prematurely stop enrolment after 8 patients in Cohort B. 
• 
Expansion Cohort C will enroll up to a total of 41 subjects with advanced 
or metastatic non-small cell lung cancer (NSCLC) with an EGFR 
mutation, the IA will be conducted after 15 subjects 
Figure 1: 
Overall Study Design 
 
approx. = approximately; ccRCC = clear cell renal cell carcinoma; CRC = colorectal cancer; 
EGFR = epidermal 
growth 
factor 
receptor; 
MTD = maximum 
tolerated 
dose; 
NSCLC = non-small cell lung cancer; RAS = rat sarcoma gene; RP2D = recommended 
phase 2 dose; wt = wild type. 
Number of 
Subjects 
(planned) 
Approximately 25 to 41 subjects will be enrolled in the dose escalation phase 
(Phase 1), dependent on the tested dose cohorts and the safety profile of AFM24. 
Additionally, 3 expansion cohorts, with up to a total of 39, 41, and 41 subjects in 
Cohorts A, B, and C, respectively, will be enrolled in the dose expansion phase 
(Phase 2a), for a maximum of 121 subjects. Depending on the preliminary efficacy 
observed in the dose escalation phase (Phase 1) of the study, additional expansion 
cohorts may be added by a protocol amendment. 
 
 


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Diagnosis and 
Main Criteria 
Subjects will be considered eligible to be enrolled in the study if ALL of the inclusion 
criteria 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 Advisory Committee. Version 8.0;Jun 03, 2023 MHRA 
Guidance on Coronavirus [COVID-19] [MHRA 2021]), COVID-19 vaccination 
should be prioritized for subjects with cancer with the understanding that there are 
limited safety and efficacy data in this subject 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) for at least the duration of the first cycle (i.e., Cycle 
1). Therefore, for any new subjects to be enrolled in the study, every effort should 
be made to vaccinate subjects prior to being considered for this study based on the 
Investigator’s risk/benefit analysis for each subject. Any COVID-19 vaccination 
should be at least 2 weeks prior to C1D1; live attenuated vaccines at least 4 weeks 
prior to C1D1. For subjects whose opportunity for COVID-19 vaccination arrives 
during the conduct of the study (i.e., ongoing subjects in the study), see 
instructions for COVID-19 vaccination provided in Section 5.6.1.1. 
INCLUSION CRITERIA 
The study will enroll subjects with advanced or metastatic solid malignancies whose 
disease has progressed after treatment with previous anticancer therapies. 
Subjects are eligible only if all the following criteria are met: 
1) For the dose escalation phase (Phase 1): histologically or 
cytologically confirmed advanced or metastatic solid malignancies 
that are known to express EGFR. 
For the dose expansion phase (Phase 2a): histologically or 
cytologically confirmed advanced or metastatic EGFR+ 
malignancies. EGFR expression is defined as positive staining for 
EGFR in ≥1% of tumor cells determined by a validated 
immunohistochemistry assay. Archived paraffin embedded tumor 
tissue is acceptable for EGFR determination– otherwise a fresh 
tumor biopsy must be performed. Local laboratory EGFR 
assessment is acceptable. 
2) For dose escalation phase (Phase 1): Subjects must have been 
previously treated with 1 or more lines of anticancer therapy and 
have documented disease progression during or after their most 
recent line of anticancer therapy. In addition, either there is no 
further SOC therapy for the subject or the remaining SOC 
therapies are deemed not appropriate for the subject by the 
Investigator. 
3) Subjects must have documented radiological progression during or 
after their latest therapy for all phases. 
4) Voluntary provision and understanding of signed and dated, 
written informed consent prior to any mandatory study-specific 
procedures, sampling, or analysis. 


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5) Male or female aged ≥18 years on the day of signing informed 
consent (or of an acceptable age according to local regulations, 
whichever is older). 
6) Eastern Cooperative Oncology Group (ECOG) Performance Score 
(PS) 0 or 1  
7) Adequate organ function, assessed within 14 and within 7 days 
before first AFM24 infusion, defined as follows: 
Note: transfusions and hematopoietic growth factors to help meet 
eligibility are not allowed.  
• 
Bone marrow: Absolute neutrophil count ≥1.5×109/L, platelet count 
≥100×109/L, and hemoglobin ≥8 g/dL;  
 
Hepatic: total bilirubin ≤1.5× upper limit of normal (ULN) (or 
≤3×ULN in participants with Gilbert’s syndrome), alanine 
aminotransferase and aspartate aminotransferase ≤2.5×ULN for 
subjects without liver metastasis, and alanine aminotransferase and 
aspartate aminotransferase ≤5×ULN for subjects with liver metastasis; 
 
Renal: If serum creatinine concentration ≥1.5×ULN, then estimated 
creatinine clearance must be ≥50 mL/min (Cockcroft-Gault formula). 
8) Serum potassium, calcium, magnesium, and phosphate within normal limits 
or not worse than CTCAE v5.0 Grade 1 and asymptomatic. If values are 
low on the initial screening assessment, supplements may be given, if 
clinically appropriate, and values repeated to confirm within CTCAE v5.0 
Grade 1 limits.  
9) For dose escalation phase (Phase 1): Subjects must have (mandatory) at 
least 1 tumor site that is accessible to biopsy and that is considered by the 
Investigator to be low risk and of sufficient size to undergo a core biopsy 
procedure on at least 2 separate occasions. 
10) For the dose expansion phase (Phase 2a) only: Subjects must have 
measurable disease per RECIST v1.1 (i.e., at least 1 measurable lesion 
≥10 mm by computed tomography [CT] scan or magnetic resonance 
imaging (MRI) or ≥20 mm by chest X-ray, malignant lymph nodes are 
considered measurable if short axis is ≥15 mm assessed by CT scan), with 
the last imaging performed within 28 days before Cycle 1 Day 1 (C1D1).  
11) Subjects in dose expansion phase (Phase 2a) must have histologically 
confirmed advanced or metastatic EGFR-positive malignancy for each 
expansion cohort as listed below:  
• 
Cohort A: Subjects with RAS wild type, microsatellite stable CRC 
whose disease has progressed after having received ≥2 prior lines of 
therapy, which must have included oxaliplatin, irinotecan, and 
fluoropyrimidine. If available, prior therapy must also have included an 
anti-vascular endothelial growth factor (anti-VEGF) or anti-vascular 
endothelial growth factor and its receptor (anti-VEGFR) therapy (e.g., 
bevacizumab, aflibercept, or ramucirumab), and an anti-EGFR therapy 
(e.g., cetuximab or panitumumab).  
• 
Cohort B: Subjects with ccRCC whose disease has progressed after 
having received ≥1 prior line(s) of therapy, which must have included a 
TKI (e.g., sunitinib, pazopanib) and a checkpoint inhibitor (e.g., 
pembrolizumab, avelumab, nivolumab). 
• 
Cohort C: Subjects 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 for 
advanced disease including ≥1 prior TKI approved for EGFR mutated 
NSCLC, such as gefitinib, erlotinib, afatinib, dacomitinib or 
osimertinib. Subjects who were treated with a 1st or 2nd generation TKI 
in 1st line and developed a documented T790M mutation must have 


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received a TKI targeting this mutation such as osimertinib or lazertinib 
to be eligible. Subjects must have documentation of EGFR mutated 
NSCLC as assessed by an approved test using genomic sequencing of 
tumor or circulating free tumor DNA.  
12) Female subjects must have a negative urine or serum pregnancy 
test within 7 days prior to first dose of AFM24 if of childbearing 
potential or be of non-childbearing potential. 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 subject to be eligible. Non-childbearing 
potential is defined as: 
• 
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. 
• 
Surgically sterile. Surgical sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
13) 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 120 days after the last dose of study 
drug. Acceptable highly effective birth control methods include: 
• 
Oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of 
ovulation; 
• 
Oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation; 
• 
Intrauterine device; 
• 
Intrauterine hormone-releasing system; 
• 
Bilateral tubal occlusion; 
• 
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 
• 
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 120 days 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 subject. 
14) Males who have female partners of childbearing potential must 
agree to use a highly effective method of contraception as described 
in inclusion criterion 13, starting with the first dose of study drug 
through 120 days after the last dose of study drug. 
EXCLUSION CRITERIA 
Subjects are eligible only if none of the following criteria are met: 
1) Currently participating in a study and receiving study therapy or 
participated in a study of an investigational agent and received 
study therapy or used an investigational device within 4 weeks of 
the first dose of study drug. 


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2) Treatment with systemic anticancer therapy within 4 weeks 
(6 weeks if therapy was mitomycin C and/or nitrosoureas), or within 
5 half-lives of the agent if half-life is known and it is shorter, before 
first dose of study drug. Anticancer therapies include cytotoxic 
chemotherapy, targeted inhibitors, and immunotherapies, but do not 
include hormonal therapy or radiotherapy.  
3) Radiation therapy within 2 weeks before first dose of study drug or 
unresolved (National Cancer Institute [NCI] CTCAE v5.0 
>Grade 1) toxicity from previous radiotherapy (eg, radiation 
dermatitis). 
Note: Palliative (limited field) radiotherapy for managing pain 
associated with bone metastases present at baseline is permitted 
during the study. 
4) Major surgical procedure, open biopsy, or significant traumatic 
injury within 4 weeks before first dose of study drug or anticipation 
of need of a major surgical procedure during the course of study.  
Note: Procedures that are considered to be minimally invasive (eg, 
peripherally inserted central catheters lines and/or port placements) 
will be exceptions. 
5) Subjects with toxicities (as a result of prior anticancer therapy) 
which have not recovered to baseline or CTCAE v5.0 ≤Grade 2, 
except for AEs not considered a likely safety risk (eg, alopecia, 
specific laboratory abnormalities). 
6) History of any other invasive malignancy, unless previously treated 
with curative intent and the subject has been disease free for 3 years 
or longer. Examples for acceptable previous malignancies include: 
completely removed in situ cervical intra-epithelial neoplasia, non-
melanoma skin cancer, ductal carcinoma in situ, and early-stage 
prostate cancer that has been adequately treated 
7) One or more of the following cardiac criteria: 
• 
Unstable angina; 
• 
Myocardial infarction within 6 months prior to screening; 
• 
New York Heart Association Class III to IV heart failure; 
• 
Corrected QT interval >470 msec obtained as the mean from 
3 consecutive resting electrocardiograms (ECGs) using the Fridericia’s 
formula; 
• 
Clinically important abnormalities in rhythm, conduction, or 
morphology of resting ECG (eg, complete left bundle branch block or 
third-degree heart block); 
• 
Congenital long QT syndrome; 
• 
Uncontrolled hypertension (≥150/100 mmHg based on accurate 
measurement and average of ≥2 readings which are ≥5 minutes apart on 
≥2 occasions) despite maximum antihypertensive therapy.  
Note: Patients who initially fail screening due to uncontrolled 
hypertension as defined above, but who then attain controlled 
hypertension with intensified antihypertensive therapy are allowed to 
undergo rescreening.  
8) Stroke or transient ischemic attack within 6 months prior to 
screening. 
9) History of leptomeningeal disease or spinal cord compression. 


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10) Known brain metastases unless asymptomatic and not requiring 
steroids for at least 4 weeks prior to start of study drug. 
11) Subjects with primary brain tumor who require high dose steroids 
(defined as ≥30 mg prednisolone or equivalent per day) or who 
received high dose steroids within 4 weeks prior to first dose of 
study drug. 
12) Diagnosis of immunodeficiency or active infection including 
known hepatitis B, hepatitis C, or human immunodeficiency virus 
(HIV). A negative confirmatory test within 3 months of treatment 
start does not have to be repeated during the screening period 
13) Active autoimmune disease that requires systemic treatment with 
steroids or other immunosuppressive agents, or subjects who have 
received such agents within 4 weeks prior to first dose of study drug:  
Exceptions: 
• 
Topical (≤20% of the skin surface area), ocular, intra-articular, 
intranasal, or inhalation corticosteroids with minimal systemic 
absorption 
• 
A short course (≤7 days) of corticosteroids prescribed prophylactically 
(eg, for contrast dye allergy or antiemetic therapy) or for treatment of 
non-autoimmune causes (eg, delayed hypersensitivity reaction caused 
by contact allergen)  
• 
Physiological replacement doses of corticosteroids for adrenal or 
pituitary insufficiency 
14) Has received a live vaccine administered within 28 days of planned 
treatment start (C1D1) or while participating in the study. Seasonal 
vaccines for influenza are generally inactivated vaccines and are 
allowed. Intranasal vaccines are live vaccines and are not allowed. 
15) Subjects who require systemic steroid treatment or any other 
immunosuppressive therapy, or subjects who received such therapy 
within 4 weeks prior to the first dose of study drug, with the 
exceptions as outlined under exclusion criterion #13. 
16) Pregnant, breastfeeding, or expecting to conceive or father children 
within the projected duration of the study, starting with the 
Screening visit (females) or first dose of study drug (males) through 
120 days after the last dose of study drug. 
17) Subject’s unwillingness to comply with the protocol or inability to 
appreciate the nature, meaning, and consequences of the study and 
to formulate his/her own wishes correspondingly. 
18) Any medical, psychological, or social condition that would interfere 
with the subject’s participation in the study. 
Investigational 
product, dosage 
and mode of 
administration  
During the dose escalation phase (Phase 1) AFM24 will be administered as weekly 
infusion. Based on results from the dose escalation phase (Phase 1), additional dosing 
regimen (ie, every 2 weeks) may be explored in the dose expansion phase (Phase 2a) 
only.  
For dose escalation phase (Phase 1) and dose expansion phase (Phase 2a) 
• 
Weekly dosing regimen (every 1 week [q1w]): ie, on Day 1, Day 8, Day 15, 
and Day 22 of a 28-day cycle (see APPENDIX A [Section 14.1]).  
For dose expansion phase (Phase 2a) only 
In addition to the weekly dosing regimen mentioned above, the following dosing 
regimen may be used: 


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• 
Every 2 weeks dosing regimen: i.e., on Day 1 and Day 15 of a 28-day cycle 
(see APPENDIX B [Section 14.2]). If the drug is given on a q2w schedule, 
the daily dose will not be higher than the highest daily dose that was tested 
in Phase 1 part of the study and was considered safe. 
The baseline infusion time should not take less than approximately 4 hours (Note: 
infusion time is approximately 4 hours, any infusion time ≥3 hour 50 minutes will not 
be a deviation) for at least the first 2 AFM24 infusions. It should also be noted that as 
the dose escalation continues into the higher dosing cohorts, the baseline infusion time 
may increase to >4 hours and as long as over 2 days (i.e., split day dosing) based on a 
given subject’s tolerability as detailed in the Pharmacy Manual for each cohort. For 
infusion times that span over 2 days (i.e., split day dosing), timepoints for different 
assessments may be affected and the Schedule of Assessment (SoA) tables should be 
referenced for details (See APPENDIX A [Section 14.1] and APPENDIX B [Section 
14.2] for SoA tables for weekly and q2w dosing schedules, respectively). If the first 2 
consecutive AFM24 infusions are well tolerated (defined as no infusion-related 
reaction (IRR)/cytokine release syndrome (CRS) >Grade 1), then the infusion time 
may be decreased to <4 hours to a minimum of 1 hour starting with the third 
subsequent infusion (i.e., C1D15 for weekly dosing regimen and C2D1 for q2w dosing 
regimen) at the discretion of the Investigator along with a potential reduction of post 
infusion- observation period from 4 hours to a minimum of 2 hours and a taper of 
corticosteroid premedication. Investigators should only make 1 modification per 
infusion at 1 time (See APPENDIX F [Section 14.6] for details regarding treatment 
management for symptoms of IRR/CRS due to study drug). Refer to the Pharmacy 
Manual for full details regarding study drug administration. 
Subjects may receive AFM24 as long as they continue to show clinical benefit, as 
judged by the Investigator, or until disease progression, other treatment 
discontinuation criteria are met, or withdrawal of consent. 
For the dose escalation phase (Phase 1), the starting first in human dose for AFM24 
will be 14 mg. Five provisional dose levels are defined for the dose escalation 
(increasing incrementally at 200% per dose to 40 mg, 120 mg, 360 mg, and 1000 mg). 
If the first dose level of 14 mg is not well tolerated, a 50% lower dose (7 mg) may be 
evaluated. It is possible for additional, intermediate dose levels to be tested during the 
study.  
Criteria for 
evaluation 
Safety will be assessed by periodic vital signs, physical examinations, ECOG PS, 
12--lead ECGs, clinical laboratory assessments, and monitoring of AEs. Adverse 
events will be graded using the NCI CTCAE, v5.0. 
Disease response will be assessed by the Investigator, using local RECIST v1.1 and 
iRECIST (Eisenhauer et al., 2009; Schwartz et al., 2016). In Phase 1 and 2a, imaging 
results will also be sent for independent central review. Tumor assessment with CT 
and/or MRI will occur at Screening as well as at timepoints specified in the respective 
SoA tables for weekly and every-2-week dose regimens (see APPENDIX A 
[Section 14.1] and APPENDIX B [Section 14.2], respectively). Partial or complete 
response needs to be confirmed with repeated assessment at least 4 weeks after the 
initial assessment. 
The PK profile will be assessed by determining serum levels of AFM24 at intervals 
throughout the study. 
The pharmacodynamics (PD) will be assessed by measuring cytokine levels and 
various lymphocyte subsets including NK cells, activated NK cells, and macrophages 
in peripheral blood.  
Statistical 
methods 
The safety set will consist of all subjects who received at least 1 dose of AFM24. The 
safety set will be the primary population for all safety related endpoints except 
determination of the dose-DLT relationship, and for all efficacy related endpoints.  


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The DDS will consist of all subjects in the safety set who have either (a) experienced 
DLT at any time during Cycle 1, or (b) met the minimum treatment and safety 
evaluation requirements without experiencing DLT within Cycle 1. 
During the study, for the first 2 dose levels of AFM24 treatment, at least 2 subjects 
need to be evaluable for dose escalation to occur. For the remaining cohorts, a 
minimum of 3 subjects evaluable for the DDS will be treated per dose cohort until 
determination of the MTD and/or one or more RP2Ds. Subjects must receive ≥80% 
of their assigned AFM24 dose in Cycle 1 and complete the 28-day DLT observation 
period or have had a DLT within the first cycle of treatment to be considered evaluable 
for DLT.  
The DDS will be used in the BLRM to estimate the dose-DLT relationship. 
The PK set consists of all subjects who have received at least 1 adequately documented 
dose of study drug and have at least 1 adequately documented post dose PK 
measurement. 
Data will be summarized with respect to demographic and baseline characteristics, 
medical history, prior cancer history and anticancer therapies, prior medication, safety 
measurements, efficacy measurements and all relevant PK and PD measurements 
using descriptive statistics (quantitative data) and contingency (frequency and 
percentages) tables (qualitative data) by dose cohort. 
Primary Analysis 
Phase 1 (Dose Escalation) 
The safety analysis will consist of listings and summaries of AEs (frequency tables 
based on CTCAE grades), summaries of laboratory abnormalities (CTCAE grade shift 
tables, low/normal/high shift tables based on laboratory normal ranges, and summary 
statistics tables) and flagging of notable values in listings, with results of other tests 
(eg, ECG, vital signs) being listed and summarized. 
A 2-parameter BLRM guided by the EWOC principle will be used for dose escalation 
of the AFM24 therapy. Standardized doses will be used such that 1 of the doses (d*) 
equals 1, eg, doses are rescaled as d/d*. Consequently, α is equal to the odds of the 
probability of toxicity at d*. All information currently available about the dose-DLT 
relationship of AFM24 is summarized in a prior distribution. For this study, this 
includes preclinical data about the starting dose and predicted MTD of AFM24 within 
different animal species. This prior distribution is then updated after each cohort of 
subjects with all the DLT data available in the DDS from the current study. Once 
updated, the distribution summarizes the probability that the true rate of DLT for each 
dose lies in the following categories: 
• 
0% to <16%: under-dosing; 
• 
≥16% to <33%: targeted toxicity; and 
• 
≥33% to 100%: excessive toxicity. 
The frequency of DLTs will be tabulated by dose for subjects in the dose escalation 
phase (Phase 1) (especially for Cycle 1 and subjects in the DDS as the primary 
endpoint tabulation) and information about all DLTs will be listed by dose. 
Phase 2a (Dose Expansion) 
Once the MTD and/or at least one RP2D is determined, enrollment of subjects into 1 
of several expansion cohorts for selected tumor indications can begin. 
The primary objective of the expansion phase is to determine preliminary efficacy as 
objective response (OR) using a Simon's two-stage design. The primary endpoint is 
based on the objective response assessed by local Investigator according to RECIST 
v1.1. The primary analysis will take place once all subjects per cohort had at least 1 
confirmed response assessment (ie, ≥12 weeks post-baseline) or have been withdrawn 
from the study. 


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Secondary Analyses 
Phase 1 (Dose Escalation) & Phase 2a (Dose Expansion) 
Overall response as defined by achieving confirmed complete response (CR) and/or 
partial response (PR) will be assessed by RECIST v1.1. DOR, PFS, and OS will be 
summarized using descriptive statistics and Kaplan-Meier estimates. 
The PK analysis plan 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 area under the concentration-
time curve over the dose interval, maximum plasma concentration, time to maximum 
plasma concentration, and minimum plasma concentration, will be reported by dose 
group. Additional parameters or model-based analysis may be calculated depending 
on the available data. 
In the expansion cohorts, owing to sparse data sampling an exploratory population PK 
analysis may be conducted to provide more comprehensive PK parameters for these 
subjects. If a population PK analysis is conducted, all available clinical PK data from 
AFM24 will be used. 
Immunogenicity parameters will be summarized by descriptive statistics. Exploratory 
analyses will be summarized by descriptive or summary statistics. Potential 
relationships between dose, safety, PK, and exploratory PD endpoints will be 
examined. NK cells, macrophages, and molecular tumor markers will be examined for 
possible correlations with Investigator assessed RECIST efficacy endpoints where 
appropriate.  
Interim Analyses 
Phase 1 (Dose Escalation) 
An interim analysis (IA) will be conducted at each dose escalation step. The BLRM 
will be updated with the respective number of subjects treated and the number of DLTs 
observed in the last cohort. The updated model will then give a statistical 
recommendation for the next escalation step. In addition, a risk-benefit assessment 
that includes a comprehensive analysis of safety and available clinical information 
will be done to decide on the next escalation steps. 
In the event of a CTCAE Grade 5 AE or a second CTCAE Grade 4 AE at least possibly 
related to AFM24 at any time during Phase 1, the Sponsor will suspend further 
enrollment and an interim safety analysis will be done. The interim safety analysis 
will be reviewed by an ad-hoc SRC meeting to decide on further progression of the 
study. 
At least 1 IA (end of Phase 1) will be performed after all subjects treated in Phase 1 
have completed their first post-baseline disease assessment and its confirmation (2nd 
post-baseline assessment, i.e., ≥12 weeks post-baseline) or have withdrawn from the 
study. In case several RP2Ds will be determined, additional IAs might be performed 
after the respective dose level. No formal interim report will be written. All subjects 
still ongoing at this timepoint will continue until disease progression, intolerable 
toxicity, Investigator discretion, or subject’s withdrawal of consent and all 
assessments will be included in final analysis at the end of study. 
Phase 2a (Dose Expansion) 
An IA, without a formal IA report, will be performed for each cohort independently, 
once the defined number of subjects (11, 15, and 15 subjects for Cohorts A, B, and C, 
respectively) in the respective cohort have completed a confirmed disease assessment 
or have withdrawn from the study. In case of a negative result, the respective cohort 
may be stopped for futility. The results of the IA will be non-binding. Safety criteria 
will also be evaluated to guide the decision to continue the study cohorts. During the 
conduct of the study, after the interim analysis of Cohort A and C and stopping these 
cohorts for futility, it was considered unlikely that the continuation criteria can be met 


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in Cohort B.  Hence it was decided to prematurely stop enrolment after 8 patients in 
Cohort B. 


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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES  
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ........................................................................................................ 5 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...................... 18 
LIST OF ABBREVIATIONS................................................................................................ 24 
1.0 
INTRODUCTION ...................................................................................................... 26 
1.1 
EGFR and Description of Disease ............................................................................... 26 
1.2 
Mode of Action of AFM24 .......................................................................................... 27 
1.3 
Nonclinical Studies ...................................................................................................... 27 
1.3.1 Pharmacology ............................................................................................................... 27 
1.3.1.1 Primary Pharmacodynamics......................................................................................... 27 
1.3.1.2 Secondary Pharmacodynamics..................................................................................... 28 
1.3.2 Pharmacokinetics ......................................................................................................... 28 
1.3.3 Non-Clinical Toxicity .................................................................................................. 29 
1.3.4 AFM24 Clinical Experience ........................................................................................ 30 
1.4 
Study Rationale ............................................................................................................ 30 
1.5 
Rationale for Starting Dose Selection in Phase 1......................................................... 31 
1.6 
Rationale for the Recommended Phase 2 Dose Selection............................................ 33 
1.7 
Safety Guidance Information for Investigators ............................................................ 34 
1.8 
Benefit-Risk Assessment ............................................................................................. 34 
2.0 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 37 
3.0 
INVESTIGATIONAL PLAN.................................................................................... 39 
3.1 
Overall Study Design ................................................................................................... 39 
3.2 
Pre-screening and Screening ........................................................................................ 40 
3.3 
Treatment Assignment ................................................................................................. 40 
3.4 
Dose Escalation Phase (Phase 1).................................................................................. 40 
3.4.1 Definition of Maximum Tolerated Dose ...................................................................... 42 
3.4.2 Definition of Dose-Limiting Toxicity (DLT)............................................................... 42 
3.4.3 Estimation of MTD/RP2D ........................................................................................... 44 
3.4.4 Replacement of Subjects .............................................................................................. 45 
3.5 
Dose and Schedule Modifications ................................................................................ 45 
3.6 
Safety Review Committee............................................................................................ 45 
3.7 
Independent Data Monitoring Committee.................................................................... 46 
3.8 
Dose Expansion Phase (Phase 2a)................................................................................ 46 
3.9 
Period of Observation .................................................................................................. 46 
3.10 
Number of Subjects ...................................................................................................... 47 
3.11 
Study Initiation and Completion .................................................................................. 48 
4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS .......................................... 48 
4.1 
Subject Inclusion Criteria ............................................................................................. 48 
4.2 
Subject Exclusion Criteria............................................................................................ 51 
4.3 
Subject Withdrawal from Study ................................................................................... 53 
4.4 
Subject Compliance ..................................................................................................... 53 
5.0 
TREATMENT OF SUBJECTS ................................................................................ 54 
5.1 
Description of Study Drug ........................................................................................... 54 
5.2 
Study Drug Administration .......................................................................................... 54 
5.3 
Premedication Regimen and Post-Dose Observation................................................... 55 
5.4 
Dose Interruptions or Delays ....................................................................................... 56 
5.5 
Dose Modification ........................................................................................................ 57 
5.6 
Permitted and Restricted Concomitant Medications .................................................... 57 


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5.6.1 Acceptable Concomitant Medications ......................................................................... 57 
5.6.1.1 COVID-19 Vaccination ............................................................................................... 57 
5.6.2 Prohibited Concomitant Medications ........................................................................... 58 
5.7 
Blinding and Procedures for Unblinding the Study ..................................................... 59 
5.8 
Management of AFM24-Related Toxicities ................................................................ 59 
6.0 
STUDY DRUG MATERIALS AND MANAGEMENT ......................................... 60 
6.1 
Provision and Replacement of AFM24 ........................................................................ 60 
6.2 
Labeling of AFM24...................................................................................................... 60 
6.3 
Storage of AFM24........................................................................................................ 60 
6.4 
Drug Accountability ..................................................................................................... 60 
7.0 
STUDY PROCEDURES............................................................................................ 61 
7.1 
Volume of Blood Sampling ......................................................................................... 61 
7.2 
Description of Study Interventions and Assessments .................................................. 61 
7.2.1 Informed Consent, Medical History, and Demographics............................................. 62 
7.2.2 Pregnancy and FSH tests .............................................................................................. 62 
7.2.3 ECOG Performance Score ........................................................................................... 62 
7.2.4 Vital Signs .................................................................................................................... 62 
7.2.5 Physical Examinations ................................................................................................. 63 
7.2.6 Clinical Chemistry, Hematology, Urinalysis, Coagulation .......................................... 63 
7.2.7 Electrocardiogram ........................................................................................................ 64 
7.2.8 Pharmacokinetic Assessments ..................................................................................... 64 
7.2.9 Pharmacodynamic Assessments................................................................................... 65 
7.2.10 CD16A Receptor Occupancy ....................................................................................... 65 
7.2.11 Disease Response Assessment ..................................................................................... 65 
7.2.12 Tumor Genomics and Tumor Biopsy ........................................................................... 65 
7.2.13 Cytokines...................................................................................................................... 66 
7.2.14 Antidrug Antibodies ..................................................................................................... 66 
8.0 
ASSESSMENT OF SAFETY .................................................................................... 67 
8.1 
Adverse and Serious Adverse Events........................................................................... 67 
8.1.1 Definition of Adverse Events ....................................................................................... 67 
8.1.2 Importance of Adverse Event Reporting...................................................................... 68 
8.1.3 Evaluating Adverse Events .......................................................................................... 68 
8.1.4 Definition of Serious Adverse Events .......................................................................... 69 
8.1.5 Severity ........................................................................................................................ 70 
8.1.6 Unexpected Adverse Events......................................................................................... 70 
8.1.7 Causality Assessments ................................................................................................. 70 
8.2 
Reporting Serious Adverse Events and Adverse Events of Special Interest................ 72 
8.3 
Other Important Events for Immediate Reporting ....................................................... 72 
8.3.1 Adverse Events of Special Interest............................................................................... 73 
8.3.2 Exposure During Pregnancy or Lactation .................................................................... 73 
8.3.3 Misuse, Medication Error, and Overdose..................................................................... 74 
8.3.4 Investigational Product Complaints ............................................................................. 74 
8.4 
Follow-Up Information on an SAE .............................................................................. 74 
8.5 
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.Reporting of Serious Adverse Events to 
Regulatory Authorities ................................................................................................. 74 
9.0 
STATISTICS .............................................................................................................. 75 


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9.1 
Analysis Sets ................................................................................................................ 75 
9.2 
Missing Data/Discontinuation ...................................................................................... 76 
9.3 
Statistical Analyses ...................................................................................................... 76 
9.3.1 Characteristics Demographics, Medical History, Prior Medication, and Other Baseline
 
76 
9.3.2 Study Drug ................................................................................................................... 76 
9.3.3 Concomitant Medication .............................................................................................. 76 
9.3.4 Primary Analysis .......................................................................................................... 76 
9.3.4.1 Phase 1 (Dose Escalation) ............................................................................................ 76 
9.3.4.2 Phase 2a (Dose Expansion) .......................................................................................... 79 
9.3.5 Secondary Analyses ..................................................................................................... 80 
9.3.5.1 Phase 1 (Dose Escalation) & Phase 2a (Dose Expansion) ........................................... 80 
9.3.6 Safety Analyses ............................................................................................................ 81 
9.3.6.1 Adverse Events............................................................................................................. 81 
9.3.6.2 Safety Laboratory ......................................................................................................... 81 
9.3.6.3 Vital Signs .................................................................................................................... 81 
9.3.6.4 Electrocardiogram ........................................................................................................ 81 
9.3.7 Exploratory Analysis .................................................................................................... 81 
9.3.8 Interim Analyses .......................................................................................................... 81 
9.3.8.1 Phase 1 (Dose Escalation) ............................................................................................ 81 
9.3.8.2 Phase 2a (Dose Expansion) .......................................................................................... 82 
9.4 
Sample Size .................................................................................................................. 82 
9.4.1 Phase 1 (Dose Escalation) ............................................................................................ 82 
9.4.2 Phase 2a (Dose Expansion) .......................................................................................... 82 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 83 
10.1 
Data Recording, Monitoring of the Study, and Regulatory Compliance ..................... 83 
10.2 
Study Monitoring ......................................................................................................... 84 
10.3 
Clinical Study Audit ..................................................................................................... 84 
10.4 
Clinical Study Report ................................................................................................... 84 
10.5 
Data Availability .......................................................................................................... 84 
10.6 
Curricula Vitae and Financial Disclosure of Investigators .......................................... 85 
10.7 
Protocol Modifications ................................................................................................. 85 
10.8 
Study or Site Termination ............................................................................................ 85 
11.0 
ETHICAL CONSIDERATIONS .............................................................................. 86 
11.1 
Ethical Conduct of the Study ....................................................................................... 86 
11.2 
Informed Consent ......................................................................................................... 86 
11.3 
Subject Participation Card............................................................................................ 87 
11.4 
Insurance ...................................................................................................................... 87 
11.5 
Institutional Review Board/Independent Ethics Committee ........................................ 88 
11.6 
Subject Privacy............................................................................................................. 88 
12.0 
DATA HANDLING AND RECORDKEEPING ..................................................... 88 
12.1 
Recording of Data ........................................................................................................ 88 
12.2 
Study Record Retention ............................................................................................... 88 
12.3 
Data Confidentiality and Publication Policy ................................................................ 88 
13.0 
LIST OF REFERENCES .......................................................................................... 90 
14.0 
APPENDICES ............................................................................................................ 94 
14.1 
APPENDIX A: Weekly Dosing Regimen (q1w) – Phase 1 and Phase 2a ................... 95 
14.2 
APPENDIX B: Every-2-Weeks Dosing Regimen (q2w) –Phase 2a Only................. 106 
14.3 
APPENDIX C: Eastern Cooperative Oncology Group Performance Score .............. 113 
14.4 
APPENDIX D: Local Laboratory Parameter ............................................................. 114 


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14.5 
APPENDIX E: Statistical Appendix including Model Performance and Data 
Scenarios .................................................................................................................... 115 
14.5.1 Phase 1 (Escalation) ................................................................................................... 115 
14.5.1.1 
Hypothetical Data Scenarios .............................................................................. 115 
14.5.1.2 
Operating Characteristics ................................................................................... 116 
14.6 
APPENDIX F: Grading and Management of Infusion-related Reactions, including 
Anaphylaxis, Allergic Reaction, and Cytokine Release Syndrome ........................... 118 
14.6.1 Monitoring for IRR/CRS............................................................................................ 118 
14.6.2 Grading and Reporting of IRR/CRS .......................................................................... 118 
14.6.3 IRR/CRS Management............................................................................................... 121 
 
LIST OF TABLES 
Table 1: 
Human-equivalent Doses Corresponding to Benchmarks Derived from in vivo 
and in vitro Studies of AFM24 ............................................................................. 33 
Table 2: 
Study Objectives and Endpoints ........................................................................... 37 
Table 3: 
Definition of Dose Limiting Toxicity................................................................... 42 
Table 4: 
Provisional Dose-Escalation Levels ..................................................................... 44 
Table 5: 
Recording Schedule of Vital Sign Parameters ..................................................... 63 
Table 6: 
Reporting of Adverse Events................................................................................ 69 
Table 7: 
Relationship to Study Drug .................................................................................. 71 
Table 8: 
Summary of Prior Distribution ............................................................................. 78 
Table 9: 
Prior Probabilities of DLT at Selected Doses....................................................... 78 
Table 10: 
Sample Size Consideration for Expansion Cohorts.............................................. 82 
Table 11: 
General Schedule of Assessment for Weekly AFM24 Dosing Regimen- For both 
Phase 1 and Phase 2a ............................................................................................ 96 
Table 12: 
Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and 
Translational Assessments for Weekly AFM24 Dosing Regimen (Without Split 
Dosing) - For Phase 1 ......................................................................................... 100 
Table 13: 
Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and 
Translational Assessments for Weekly AFM24 Dosing Regimen (Split Dosing) - 
For Phase 1 ......................................................................................................... 101 
Table 14: 
Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and 
Translational Assessments for Weekly AFM24 Dosing Regimen (Without Split) 
- For Phase 2a ..................................................................................................... 103 
Table 15: 
Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and 
Translational Assessments for Weekly AFM24 Dosing Regimen (Split Dosing) - 
For Phase 2a........................................................................................................ 104 
Table 16: 
General Schedule of Assessments for Every-2-Weeks AFM24 Dosing- For Phase 
2a only ................................................................................................................ 107 
Table 17: 
Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and 
Translational Assessments for Every 2 Weeks AFM24 Dosing Regimen (Without 
Split) - Phase 2a Only ......................................................................................... 110 
Table 18: 
Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and 
Translational Assessments for Every 2 Weeks AFM24 Dosing (Split Dosing) - 
For Phase 2a Only............................................................................................... 111 
Table 19: 
Hypothetical Data Scenarios .............................................................................. 115 
Table 20: 
Assumed True Dose-Toxicity Scenarios ............................................................ 117 
Table 21: 
Hypothetical Data Scenarios .............................................................................. 117 
Table 22: 
Grading System for IRR and Related Events According to CTCAE v5.0 ......... 120 


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Table 23: 
Summary of Management of Infusion Related Reactions, including Anaphylaxis, 
Allergic Reactions, and Cytokine Release Syndrome* ...................................... 121 
 


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LIST OF FIGURES 
Figure 1: 
Overall Study Design.............................................................................................. 8 
Figure 2: 
Overall Study Design............................................................................................ 39 
Figure 3: 
Prior Medians and 95% Credible Intervals........................................................... 79 
Figure 4: 
Sample Subject Participation Card ....................................................................... 87 
Figure 5: 
Study Scheme for Each Subject in Weekly Dosing Regimen .............................. 95 
Figure 6: 
Study Scheme for Each Subject in Every-2-weeks Dosing Regimen ................ 106 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Explanation 
ADCC 
antibody-dependent cellular cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
AE 
adverse event 
AESI 
adverse event of special interest 
BLRM 
Bayesian logistic regression model 
BRAF 
v-raf murine sarcoma viral oncogene homolog B1 
ccRCC 
clear cell renal cell carcinoma 
CD16A 
Fcγ receptor IIIA 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CR 
complete response 
CRA 
clinical research associate 
CRC 
colorectal cancer 
CRS 
cytokine release syndrome 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DDS 
dose-determining set 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
EC 
Ethics Committee 
EC50 
half maximal effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EGFR 
epidermal growth factor receptor 
EOI 
end of infusion 
EWOC 
escalation with overdose control 
Fc 
fragment crystallizable 
FcRn 
neonatal Fc receptor 
FDA 
Food and Drug Administration 
FIH 
first in human 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HER 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IDMC 
Independent Data Monitoring Committee 
IgG 
immunoglobulin G 


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Abbreviation 
Explanation 
IL 
interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
iRECIST 
Response Evaluation Criteria in Solid Tumors for 
immunotherapy 
IRR 
infusion-related reaction 
i.v. 
intravenously 
KRAS 
Kirsten rat sarcoma genes 
LOEL 
lowest observed effect level 
mAb 
monoclonal antibodies 
MABEL 
minimum anticipated biological effect level 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NK 
natural killer 
NOAEL 
no observed adverse effect level 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
PD 
pharmacodynamic(s) 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
q7d 
every 7 days 
q1w 
every 1 week 
q2w 
every 2 weeks 
RAS 
rat sarcoma gene 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SoA 
schedule of assessments 
SOC 
standard of care 
SRC 
Safety Review Committee 
SUSAR 
suspected unexpected serious adverse reaction 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor and its receptor 
 
 
 


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1.0 
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 was designed to specifically utilize the cytotoxic potential of NK cells and 
macrophages for the specific, potent, and efficient 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 antitumor immune response.  
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 those cancers that have 
intrinsic or acquired resistance to EGFR targeting monoclonal antibodies (mAbs) and tyrosine 
kinase inhibitors (TKIs). Therefore, AFM24 has the potential to overcome the limitations of 
EGFR-targeting standard of care (SOC) agents, such as mAbs and TKIs that target EGFR.  
In addition, AFM24 may offer an improved safety profile compared with current 
EGFR-targeting SOC agents. At high concentrations, AFM24 can also down-modulate 
ligand-induced EGFR signaling. However, the inhibitory effect of AFM24 on ligand-induced 
EGFR signaling is substantially lower relative to the anti-EGFR-targeting mAb cetuximab. 
Patients with previously treated advanced or metastatic solid tumor malignancies that express 
EGFR represent patient populations with high unmet medical need due to the associated poor 
prognosis and limited number of 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 antitumor potential of a patient’s own innate immune system to 
effectively control their cancers. 
AFM24 may offer a much-needed alternative to current therapeutic approaches for patients 
with a variety of solid cancers with high unmet needs, such as colorectal, lung, gastric, 
esophageal, pancreatic, head and neck, breast, ovarian, cervical, urothelial and renal cancers, 
and glioblastoma multiforme (AFM24 also binds to EGFR variant III with similar affinity). 
1.1 
EGFR and Description of Disease 
EGFR is a member of the human epidermal growth factor receptor (HER) 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 (eg, colorectal cancer [CRC], 
non-small cell lung 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., 


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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. 
1.2 
Mode of Action of AFM24 
AFM24 is a first-in-class, tetravalent, bispecific, Fc-silenced antibody designed to target 
EGFR+ solid tumors. Of its 4 binding sites, 2 binding sites are specific for EGFR and the other 
2 binding sites are specific for CD16A, which is the Fcγ receptor mainly expressed by NK cells 
and macrophages. The antigen binding domains are fused to a human Fc portion to facilitate 
neonatal Fc receptor (FcRn) binding and to achieve serum half-life comparable to classical 
immunoglobulin G (IgG) antibodies. The Fc portion was engineered to eliminate binding to all 
Fcγ receptors but allows fixing of complement and complement-dependent cytotoxicity (CDC) 
on EGFR+ cells. 
By design, AFM24 binds to both EGFR+ cancer cells and CD16A+ NK cells and macrophages 
with strong avidity, thus creating an immunological synapse. This results in ADCC (induced 
by NK cells) and ADCP (induced by macrophages) of EGFR+ tumor cells, thereby activating 
a potent antitumor immune response.  
It is anticipated that AFM24 would be active in patients who harbor EGFR+ cancers, including, 
but not limited to those cancers that have intrinsic or acquired resistance to EGFR targeting 
mAbs and TKIs. AFM24 has also the potential to overcome the limitations of EGFR-targeting 
standard of care (SOC) mAbs and TKIs.  
In addition, it is anticipated that AFM24 would demonstrate an improved safety profile 
compared with these SOC agents. At high concentrations, AFM24 can also down-modulate 
ligand-induced EGFR signaling. However, the inhibitory effect of AFM24 on ligand-induced 
EGFR signaling is substantially lower relative to the anti-EGFR-targeting mAb cetuximab. 
1.3 
Nonclinical Studies 
The preclinical characterization of AFM24 described below demonstrates the ability of AFM24 
to redirect innate immune cells to EGFR+ malignancies through a mutation-independent 
mechanism of action to be active across a range of human cancers as well as to overcome 
resistance to current SOC therapies, while conferring a favorable safety profile. Please refer to 
the Investigator’s Brochure (IB) for additional details. 
1.3.1 
Pharmacology 
1.3.1.1 
Primary Pharmacodynamics 
Binding of AFM24 to effector cells (NK cells and macrophages) via CD16A has been 
demonstrated. The EGFR binding specificity of AFM24 was established by demonstrating the 
inability of AFM24 to bind to other members of the EGFR family (HER2, HER3, and HER4). 
Binding was shown to recombinant human CD16A, cynomolgus CD16, as well as human and 
cynomolgus recombinant EGFR, human and cynomolgus NK cells, human macrophages, and 
human tumor cell lines with low and high EGFR copy number. Furthermore, AFM24 was 
shown to bind to EGFR in the presence of the ligands EGF and TGF-α. In line with the silenced 
Fc region of AFM24, no binding to Fcγ receptors other than CD16A was observed. 
In the presence of NK cells, AFM24 induced ADCC in all investigated human tumor cell lines 
expressing EGFR, including those bearing the Kirsten rat sarcoma genes (KRAS) or BRAF 


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(v-raf murine sarcoma viral oncogene homolog B1) mutation. In the presence of macrophages, 
AFM24 induced ADCP of EGFR+ tumor cells. In addition, complement-dependent 
cytotoxicity of EGFR+ cells could be induced in the presence of complement factors. 
Dose-dependent in vivo efficacy was demonstrated using the A-431 mouse tumor model 
growing in humanized mice (ie, mice engrafted with human CD34+ cells, forming human 
immune cells) in both the prophylactic and therapeutic settings. AFM24-treated mice 
frequently showed increased intratumoral NK cell numbers when compared with 
vehicle-treated control animals. 
1.3.1.2 
Secondary Pharmacodynamics 
In line with the mode of action of AFM24, a dose-dependent cytokine release of interleukin 6 
(IL-6), tumor necrosis factor-alpha, and interferon-gamma, was detected in cultures of 
peripheral blood mononuclear cells in the presence of target cells in vitro. These data are 
consistent with the IL-6 release observed in the nonclinical toxicity studies (Section 1.3.3). 
NK cell fratricide by AFM24 was observed only at high antibody concentrations. Compared to 
daratumumab, an anti-CD38 mAb with reported NK cell fratricide in vitro and in vivo, the half 
maximal effective concentration (EC50) of AFM24-induced NK cell fratricide was 190-fold 
lower. AFM24 increased NK cell activation marker CD69 in the presence of target tumor cells 
with a mean EC50 of 8.3 pM. In the absence of target tumor cells, the EC50 of NK cell activation, 
most likely because of NK-NK cell lysis, was substantially lower (mean EC50: 4545 pM). 
1.3.2 
Pharmacokinetics 
The pharmacokinetics (PK) of AFM24 was investigated in mice and in cynomolgus monkeys. 
Although AFM24 does not bind to mouse CD16A or mouse EGFR, humanized mice bearing 
subcutaneous human EGFR+ tumors were used for pharmacodynamics (PD) experiments. In 
this context, key PK parameters of AFM24 in immunocompetent normal mice were determined 
to better understand the in vivo efficacy (see the IB for details). 
AFM24 binds to human, cynomolgus monkey and mouse FcRn. The half-life of AFM24 in 
tumor-free mice (14 days) is longer than in monkeys (range 33.4 to 154 hours), which is within 
the expectations for a human IgG1 due to the 2.6-fold higher relative binding of human IgG1 
to mouse FcRn versus human FcRn (Ober et al., 2001). 
In cynomolgus monkeys, a more-than-dose-proportional increase in AFM24 exposure was 
noted in a single dose PK study and a pilot toxicity study with low animal numbers. However, 
in a pivotal Good Laboratory Practice (GLP) toxicity study with large animal number (n = 6 or 
n = 10 in recovery-controlled groups), exposure, as assessed by mean AFM24 maximum 
plasma concentration and AUC values, increased dose proportionally with increasing AFM24 
dose level, with dose proportionality ratios between 3.08 and 3.94 for the 3-fold increase from 
8 to 24 mg/kg/week and between 2.43 and 2.95 for the 3.1-fold increase from 24 to 
75 mg/kg/week. 
A slight increase in the terminal half-life value as the dose level increased was observed in all 
studies and a dose-related change in the observed systemic clearance of AFM24. Volumes of 
distribution indicate that AFM24 is mainly located in the plasma volume. 


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1.3.3 
Non-Clinical Toxicity 
Several studies were performed to identify a relevant species for PK and toxicity in vivo studies 
of AFM24. It was demonstrated that the cynomolgus monkey is the only relevant species for 
AFM24, showing similar binding properties to cynomolgus and human EGFR and to 
cynomolgus CD16 and human CD16A. As a result, mice and dogs were excluded as relevant 
species for toxicity testing. 
Two repeat dose toxicity studies were performed with AFM24 in cynomolgus monkeys, using 
identical treatment dose levels and schedules: a maximum tolerated dose (MTD) pilot toxicity 
study followed by a pivotal GLP toxicity study. The results of the 2 studies were very similar. 
The GLP toxicity study is described below. Further details are provided in the IB. 
In the GLP toxicity study, monkeys were dosed weekly at 7, 24, and 75 mg/kg over 4 weeks 
(5 doses in total, every 7 days [q7d] × 5) by a 2-hour infusion followed by a 4-week recovery 
phase. Assessment of toxicity was based on clinical observations, body weights, body 
temperature, ophthalmic examinations, and clinical and anatomic pathology. Complete 
necropsies were performed on all animals, and macroscopic and microscopic examinations 
were conducted. Blood was collected for toxicokinetic, immunogenicity, and immunotoxicity 
evaluation of AFM24. Safety pharmacology endpoints comprised complete blood counts, 
clinical chemistries, electrocardiograms (ECGs), blood pressure, respiratory rate, and 
neurological behavior. Additionally, cytokine levels (IL-2, IL-6, IL-8, tumor necrosis factor-
α, interferon-γ), and lymphocyte numbers and phenotypes were determined.  
AFM24-related clinical findings were limited to emesis in 2 animals in the high dose group 
(75 mg/kg on Day 1 only). AFM24 caused non-dosedependent-, marked but transient increases 
in white blood cell counts, particularly neutrophil counts, at 4 hours after the completion of 
dosing on Day 1 of the dosing phase. Absolute neutrophil counts were approximately 3-fold 
higher compared with mean pre-dose values or vehicle treated control animals. These findings 
were reversible, returning to baseline 24 hours post-dose in the highest dose group (no sample 
was collected for other groups at this timepoint) and by Day 8 at the low and intermediate dose 
groups. A transient reduction in absolute NK cell counts (CD3-CD20-CD159a+) at a dose 
≥8 mg/kg, 4 hours after dosing on Day 1 (P ≤0.05) in both males and females was observed. 
The reduction on Day 1 was for males and females -84%/-59% at 8 mg/kg and -57%/-67% at 
24 mg/kg and -81%/-84% at 75 mg/kg when compared with data generated on Day 1 before 
dosing. All values returned to pre-dose levels by Day 8 in nearly all animals. 
The first administration of AFM24 had a temporary effect on circulating IL-6 levels 2 hours 
after start of infusion of AFM24 dosing in all dose groups, which reached maximum levels of 
602 pg/mL in the 24 mg/kg dose group and 416 pg/mL in the 75 mg/kg dose group. No clear 
dose response was observed. Four hours after start of infusion, IL-6 levels were strongly 
reduced in all animals and returned to normal within 24 hours. No clinical signs were associated 
with the increase of IL-6. As expected for the species, high heterogeneity was observed for 
IL-8 levels in all tested animals but no clear pattern of AFM24-mediated IL-8 release was 
apparent. All other cytokines assessed were below the limit of quantification. 
No adverse effects were observed for standard parameters as clinical observations, body 
weights, body temperature, ophthalmic examinations, and clinical and anatomic pathology. No 
findings were reported during necropsies, macroscopic and microscopic examinations. No 
AFM24-related effects on safety pharmacology endpoints comprising ECGs, blood pressure, 
respiratory rate and neurological behavior were noted. Therefore, the no observed adverse 


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effect level (NOAEL) was 75 mg/kg under the conditions of the MTD pilot toxicity study and 
the pivotal GLP study.  
Binding of AFM24 to normal human and cynomolgus monkey tissues was investigated in a 
full panel of human and cynomolgus monkey tissues in a GLP tissue cross reactivity study. In 
both species a congruent binding pattern was observed, further identifying human and 
cynomolgus monkeys as a relevant species. AFM24 produced membranous and/or cytoplasmic 
staining in various epithelia (eg, skin, cervix) and in mononuclear immune cells consistent with 
macrophages. The staining pattern and distribution were consistent with on-target binding of 
AFM24.  
1.3.4 
AFM24 Clinical Experience 
This is a first in human (FIH) Phase 1/2a study. The preliminary safety and efficacy data from 
the AFM24-101 study is available in the current Investigator’s Brochure.  
1.4 
Study Rationale  
The introduction of TKI targeting the EGFR intracellular kinase domain and mAbs targeting 
the extracellular domain of EGFR have resulted in improvements in clinical outcomes for 
patients with NSCLC, CRC, and head and neck squamous cell carcinoma; however, treatment 
is associated with significant toxicities in organs where EGFR is expressed (mainly skin) which 
limits the therapeutic utility of these agents (Morgillo et al., 2007). 
In contrast, the mode of action of AFM24 is primarily through ADCC and ADCP, and not 
through inhibition of signaling. Therefore, it is expected that AFM24 will potentially have less 
adverse effects on healthy tissues and result in a wider therapeutic window. 
Additionally, there remains a high unmet medical need due to the limited efficacy of currently 
available SOC agents for patients with EGFR+ cancers and to the occurrence of either intrinsic 
or acquired resistance to EGFR-targeted inhibitors in patients (Morgillo et al., 2007; Mirone et 
al., 2016). In addition, existing agents offer little to no benefit in other patient groups whose 
tumors express EGFR, such as gastric, pancreatic and biliary cancers, bladder and renal 
cancers, and glioblastoma multiforme. 
Intrinsic resistance to EGFR-targeting therapies, such as the marketed anti-EGFR mAbs 
cetuximab and panitumumab, includes mutations in downstream signaling factors such as 
KRAS and BRAF, which are negative predictive biomarkers for clinical response to marketed 
anti-EGFR mAbs (Reddi, 2013). Cetuximab and panitumumab bind with high specificity to 
EGFR preventing ligand-induced homo- or heterodimerization of the receptors and subsequent 
EGFR activation; however, this mode of action is ineffective in tumors bearing KRAS 
mutations (Jorge et al., 2014; Pines et al., 2010; Reddi, 2013). For patients with EGFR mutated 
NSCLC, mechanisms of resistance to EGFR-targeted TKIs include secondary mutations (eg, 
T790M, C797S), activation of alternative signaling pathways (eg, c-MET, HGF, AXL, 
IGF-1R), mutations in downstream pathways (eg, BCL2-like 11 deletion polymorphism), and 
histological transformation (Morgillo et al., 2016). AFM24 binds to both EGFR+ cancer cells 
and CD16A+ NK cells and macrophages thereby creating an immunological synapse resulting 
in ADCC induced by NK cells and ADCP induced by macrophages as primary modes of action. 
These modes of action are independent of the blockade of the EGFR downstream signaling 
pathway. AFM24 can also down-modulate ligand-induced EGFR signaling, but only at high 
concentrations, and therefore this effect is not considered its primary mode of action. It is 
anticipated that the AFM24-induced ADCC and ADCP cannot be evaded by the presence of 


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existing or acquired mutations in the EGFR downstream signaling pathway. Therefore, all 
patients with tumors expressing EGFR could potentially benefit from AFM24 treatment 
regardless of the mutational status of the tumors. 
1.5 
Rationale for Starting Dose Selection in Phase 1 
Selection of a safe clinical starting dose considers international guidance for starting dose 
selection for agents in cancer patients which include the: 
• revised 2017 European Medicines Agency guideline on ‘Strategies to identify and 
mitigate risks for first-in-human and early clinical trials with investigational medicinal 
products’ (EMEA/CHMP/SWP/28367/07 Rev. 1). 
• 2005 Food and Drug Administration (FDA) ‘Guidance for Industry: Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult 
Healthy Volunteers’. 
• International Council for Harmonisation (ICH) Topic S9 – ‘Nonclinical Evaluation 
for Anticancer Pharmaceuticals’ 
In the selection of starting dose for the FIH study, all available nonclinical data were 
considered. These include in vivo data from repeat dose toxicity and PK and toxicokinetic 
studies in cynomolgus monkeys, in vivo antitumoral efficacy data in humanized mice, and in 
vitro PD data of receptor binding and cellular interactions. The nonclinical data were used to 
extrapolate minimum anticipated biological effect levels (MABEL), pharmacologically active 
dose levels, lowest observed effect level (LOEL) and NOAEL and to define a 
pharmacologically active starting dose that is reasonably safe to use in patients with advanced 
cancer. Allometric scaling factors used to derive human equivalent dose levels (HED) were 
those defined in Section V of the 2005 FDA ‘Guidance for Industry: Estimating the Maximum 
Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers’. A 
listing of HEDs corresponding to benchmarks derived from in vivo and in vitro studies of 
AFM24 is provided in Table 1. 
Based on the results of antitumoral efficacy studies in humanized mice and toxicity studies in 
cynomolgus monkeys, a human starting dose of 200 µg/kg is proposed for the planned FIH 
study in cancer patients. This dose level is: 
• by a factor of 2.5 higher than the HED corresponding to the in vivo MABEL of a first 
trend of antitumoral activity against EGFR+ tumors in the mouse model 
(HED≈81 µg/kg).  
• by a factor of approximately 4 lower than the HED corresponding to the murine dose 
level eliciting a statistically significant, antitumor effect against EGFR+ tumors 
(HED≈810 µg/kg). 
• by a factor of approximately 4 lower than the HED corresponding to the adjusted LOEL 
for the onset of IL-6 release in cynomolgus monkeys (HED≈860 µg/kg). 
• by a factor of approximately 40 lower than the HED corresponding to the adjusted 
NOAEL in cynomolgus monkeys (HED≈8060 µg/kg). 


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A clinical starting dose of 200 µg/kg is therefore deemed to be a good compromise between 
expected antitumoral efficacy and safety in cancer patients. 
It is noteworthy that no toxicities were observed in the cynomolgus monkey GLP toxicity 
studies at doses ranging from 8 mg/kg q7d × 5 up to the maximum administered dose level of 
75 mg/kg q7d × 5. The only clinical findings noted in these studies were transient elevations 
of IL-6 levels and neutrophil counts and transient decreases in NK cell counts. These effects 
may be regarded as part of the mode of action of AFM24 and were not considered as adverse 
effects. The IL-6 elevations were seen at all dose levels, and hence, the LOEL (IL-6 release) is 
defined as 8 mg/kg.  
For purposes of benchmarking, the AFM24 dose levels administered to the cynomolgus 
monkey should be considered 3-fold lower than the actual doses administered due to the 
presence of an unanticipated cleaved form of AFM24 in the drug product used only in the GLP 
toxicity study and a correspondingly lower exposure to AFM24 in these animals (refer to IB 
for details). Including an allometric scaling factor (cynomolgus to human) of 3.1, the adjusted 
NOAEL corresponds to a HED of approximately 8 mg/kg, and the adjusted LOEL corresponds 
to a HED of approximately 0.8 mg/kg, approximately 40- and 4- fold higher, respectively, than 
the selected starting dose.  
HED values extrapolated solely from in vitro data were too low for the estimation of a clinical 
starting dose in cancer patients. The lowest relevant benchmark in this context was the MABEL 
extrapolated from in vitro ADCC studies of human NK cells against glioblastoma -derived 
DK-MG target cells using an AUC model. This MABEL corresponds to a HED of 
0.0192 µg/kg and would be by more than 5 orders of magnitude lower than the HED 
corresponding to the adjusted NOAEL determined in the GLP toxicity study in cynomolgus 
monkeys (8060 µg/kg). Such a low starting dose would only be reasonable for high-risk protein 
therapeutics with agonistic properties. 
In this context, the clinical experience with AFM13, a bispecific NK cell engager 
(CD30/CD16A) that contains CD16A binding domains that are identical to AFM24 (Rothe 
2015), was also considered. AFM13 is currently in clinical development for patients with 
CD30+ hematologic malignancies and has shown safety and tolerability in patients at doses up 
to 7 mg/kg weekly.  
Results of serum PK and toxicokinetic studies of AFM24 in cynomolgus monkeys predict a 
serum half-life of 4 to 6 days in humans. Therefore, a weekly dosing schedule is anticipated to 
result in accumulation over the first 3 to 4 doses and achievement of a steady state thereafter. 
Based on preliminary data from the cynomolgus monkey PK studies of AFM24 a fixed dosing 
regimen appears to be associated with less inter-patient variability in exposure compared to 
body size-based dosing. Hence, a fixed dosing scheme was selected to be tested in the FIH 
Phase 1 study, and a fixed, weekly starting dose of 14 mg (0.2 mg/kg × 70 kg of average human) 
is proposed for the planned FIH Phase 1/2a study.  


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Table 1: 
Human-equivalent Doses Corresponding to Benchmarks Derived from in 
vivo and in vitro Studies of AFM24 
Model 
Benchmark 
HED (µg/kg) 
in vivo 
NOAEL (cynomolgus, Pilot-TOX) 
24190 
LOEL (cynomolgus, IL-6 release, Pilot-TOX) 
2580 
adjusted* NOAEL (cynomolgus, GLP-TOX) 
8060 
adjusted* LOEL (cynomolgus, IL-6 release, GLP-TOX) 
860 
PAD (mouse, antitumoral) 
810 
MABEL (mouse, antitumoral) 
81 
in vitro (AUC) 
ADCC (NK vs. DK-MG; AUC) 
0.0192 
NK activation (CD69; AUC) 
2.22 
IL-6 release (PBMC; AUC) 
6.662 
ADCC = antibody-dependent cellular cytotoxicity; AUC = area under the concentration-time curve; 
CD69 = cluster of differentiation 69; GLP = Good Laboratory Practice; HED = human equivalent dose; 
IL-6 = interleukin-6; LOEL = lowest observed effect level; MABEL = minimum anticipated biological effect 
level; NK = natural killer; NOAEL = no observed adverse effect level; PAD = pharmacologically active dose 
level; PBMC = peripheral blood mononuclear cell; TOX = toxicology study. 
Note: * adjusted LOEL and NOAEL refer to benchmarks determined in the GLP toxicity study and include an 
additional correction factor of 3 due to intrinsic properties of the applied bioanalytical assay in the GLP toxicity 
study (see discussion above).  
1.6 
Rationale for the Recommended Phase 2 Dose Selection 
The selection of the recommended phase 2 dose (RP2D) was based on the review of the totality 
of available data including, but not limited to, the observed safety, tolerability and preliminary 
clinical activity of AFM24 as well as the available PK and pharmacodynamic (PD) data for 
AFM24. A brief summary of the data and the RP2D selection is provided below. Please refer 
to the Investigator’s Brochure for more details. 
As of a data cutoff date of 29 October 2021, 29 subjects were enrolled into 6 dose cohorts, with 
AFM24 doses ranging from 14 mg to 480 mg i.v. every 1 week (q1w). AFM24 was generally 
safe and well tolerated across dose levels, with infusion-related reactions (IRRs) (69%) being 
the most frequently reported treatment-emergent adverse events (TEAEs). There were no 
treatment-related deaths. No dose-limiting toxicities (DLTs) were observed in 6 subjects at the 
highest dose of 480 mg. 
Best objective response (BOR) per Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 was stable disease (SD) in 8 of 24 response-evaluable subjects.   
At 480 mg, dose proportional PK was reached, suggesting a peripheral saturation of target 
(EGFR)-mediated elimination. The preliminary exposure-response curve with CD16a RO 
appeared to level off to approximately 30-40% RO at concentrations that were reached with 
480 mg, indicating that higher exposures would not lead to higher CD16a RO. Moreover, 
estimated intra-tumoral AFM24 concentrations and CD16a RO were in the range associated 
with maximum tumor cell killing (SW-982 cells or A-431 cells) in vitro (Affimed Study No. 
AFM24_018).  
Taken together, based on the review of the totality of available data, the Safety Review 
Committee (SRC) (Section 3.6) determined 480 mg i.v. q1w as an acceptable RP2D of AFM24. 
The Phase 1 part of the study was ongoing at the time of selection of this RP2D and Cohort 7 
(720 mg q1w) had been opened for enrollment. 


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1.7 
Safety Guidance Information for Investigators 
Investigators should refer to the current edition of the IB for a full review of the potential risks 
associated with treatment with AFM24 and details of expected AEs. 
1.8 
Benefit-Risk Assessment 
Information gathered to date is limited to nonclinical in vitro pharmacology, in vivo 
pharmacology in mice and cynomolgus repeat dose toxicity studies in cynomolgus monkeys, 
in conjunction with knowledge of the clinical profile of other EGFR targeting agents, and 
preliminary clinical data from this FIH study. Management of possible AFM24 related 
toxicities are described in Section 5.8. 
AFM24 was well tolerated in cynomolgus monkeys, when administered weekly (q7d × 5) up 
to a maximum dose of 75 mg/kg. Findings of note were a temporary, non-dose-dependent 
reduction in absolute peripheral NK counts as well as an increase in neutrophil counts in all 
animals on Day 1. In addition, the first dose of AFM24 caused a transient elevation of 
circulating IL-6 levels 2 hours after administration which reverted to normal after 24 hours. 
These data are supported by in vitro cytokine release studies, where a dose-dependent release 
of IL-6 was detected in the presence of target cells and peripheral blood mononuclear cells as 
described in Section 1.3.1.2. Based on these observations, AFM24 has the potential to induce 
cytokine release in patients.  
Cetuximab, a marketed EGFR-targeting monoclonal antibody, has been tested in cynomolgus 
monkeys, and has been found to induce significant toxicities directed to healthy tissues that 
express EGFR (EPAR, 2004). These toxicity findings were completely lacking in the AFM24 
toxicity studies in cynomolgus monkeys, suggesting that AFM24 may have a more favorable 
safety profile in humans compared with cetuximab. However, it is possible that toxicities 
similar to those of the approved products that target the EGFR (mAbs or TKI small molecules) 
may occur with AFM24 treatment in humans. In addition, clinical experience with AFM13, 
another CD16A-targeted bispecific antibody in clinical studies, may be relevant to the safety 
profile of AFM24. 
EGFR-targeting antibodies, such as cetuximab (EPAR 2019; US package insert 2019), 
panitumumab (US package insert 2015; EPAR 2018), or necitumumab (US package insert 
2015; EPAR 2016) which block cellular signaling through EGFR as their primary mode of 
action, have been clinically validated and are now SOC for patients with advanced head and 
neck cancer and subgroups of patients with advanced colorectal and lung cancers. As the 
primary mode of action of AFM24 is likely not signal inhibition of the EGFR pathway, but 
redirecting NK cells and macrophages to EGFR-positive tumor cells and inducing ADCC and 
ADCP, respectively, the potential for AFM24 to manifest adverse reactions known to be 
associated with EGFR-targeting mAbs may be reduced. However, at high exposures, AFM24 
also blocks EGFR-mediated cellular signaling, and there is a potential that adverse reactions 
seen with EGFR targeting mAbs will also manifest during AFM24 treatment. The most 
common adverse reactions seen in ≥20% of the patients in EGFR targeting monoclonal 
antibody clinical studies were cutaneous adverse reactions, headache, diarrhea, infection, 
nausea, vomiting, paronychia, and fatigue. The most common (≥5% of the patients) severe 
(Grade 3 and above) adverse reactions were dyspnea, skin disorders (erythema, rash, and 
acneiform dermatitis), thromboembolic events, diarrhea, fatigue, pain, nausea, vomiting, 
infections, dehydration, and confusion. 


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There is also potential overlap between the mechanism of action of AFM24 and that of small 
molecules that inhibit the kinase activity of mutated and wild-type EGFR. Such molecules 
include gefitinib (US package insert 2018; EPAR 2019), erlotinib (US package insert 2016; 
EPAR 2019), afatinib (EPAR 2018; US package insert 2018), dacomitinib (US package insert 
2018; EPAR 2019), and osimertinib (EPAR 2018; US package insert 2018), which are SOC 
for the treatment of patients with NSCLC that harbor activating mutations of EGFR. These 
molecules block the intracellular kinase domain of EGFR and inhibit further downstream 
signaling. There is a potential for adverse reactions seen with EGFR kinase inhibitors to 
manifest during AFM24 treatment. The most common adverse reactions (seen in ≥20% of the 
patients treated) with EGFR-targeted kinase inhibitors in clinical studies were diarrhea, 
asthenia, rash, dry skin, pruritus, paronychia, stomatitis, cough, dyspnea, decreased weight, 
alopecia, nausea, vomiting, decreased appetite, and fatigue. The most common (≥5% of the 
patient) severe, (≥Grade 3) adverse reactions were rash, diarrhea, dyspnea, stomatitis, 
paronychia, and hypertension.  
AFM13 is a CD30/CD16A bispecific (NK cell and macrophage) engager currently in 
development for the treatment of Hodgkin and T-cell lymphomas. Although the molecular 
structure is different, as AFM13 does not have an Fc portion, the mode of action is similar to 
AFM24 as AFM13 redirects CD16A-positive cells to CD30-positive tumor cells to induce 
ADCC and ADCP of the tumor target cells. There is a potential that AFM24 treatment is 
associated with similar adverse reactions as observed for AFM13. AFM13 is generally well 
tolerated; however, mild to moderate IRRs are common and often require premedication with 
acetaminophen and H1/H2 antagonists. Severe IRRs have also occurred, although infrequently 
(Ansell et al., 2019). 
The Phase 1/2a study will evaluate AFM24 in subjects with advanced or metastatic solid 
malignancies that express the EGFR and therefore have the potential to respond to AFM24-
induced tumor target cytotoxicity. The subject population selected have advanced or metastatic 
disease which has progressed during or after treatment with SOC therapies. In the dose 
escalation phase (Phase 1), subjects with a variety of advanced solid malignancies are eligible, 
whereas in the dose expansion phase (Phase 2a), subjects with advanced CRC, clear cell renal 
cell carcinoma (ccRCC), and NSCLC are eligible. Effective treatment options for subjects with 
these advanced cancers after disease progression are extremely limited and new therapies are 
urgently needed. The choice of subject population is further supported by nonclinical testing 
which has demonstrated significant antitumor activity in EGFR+ tumor cell lines and in vivo 
models. 
The primary objective of the Phase 1 dose escalation portion of this Phase 1/2a study is to 
determine the MTD and/or to select one or more recommended phase 2 doses (RP2Ds), and 
generally investigate safety and tolerability of AFM24. The nonclinical toxicity studies have 
not identified any risks that would preclude investigation of AFM24 in the advanced cancer 
setting, although the safety profile of AFM24 is difficult to predict. Based on the identified and 
potential risks associated with AFM24 treatment, this clinical study protocol incorporates 
mandatory and thorough safety monitoring procedures and additional guidance documents to 
assist with early diagnosis and rapid management of potential treatment related toxicities. The 
safety monitoring plan takes into consideration the results of AFM24 toxicity studies as well 
as the known safety profile of other EGFR targeting or NK-cell engager drugs. 
The Phase 1 dose escalation portion of the study is designed to maximize safety while 
minimizing the number of subjects treated at subtherapeutic dose levels. The first 2 cohorts 
will enroll a minimum of 2 subjects, whereas subsequent cohorts will enroll a minimum of 3 


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and up to 6 subjects. Dose escalation will be guided by an adaptive Bayesian logistic regression 
model (BLRM) following the dose escalation with overdose control (EWOC) principle. This 
design uses all accumulating toxicity data to assign enrolling subjects to doses that have a 
higher chance of targeted toxicity (close to the MTD), while controlling the risk of excessive 
toxicity. To further ensure safety, the safety findings of each cohort will be carefully reviewed 
by the Safety Review Committee (SRC) prior to dose escalation decisions for the subsequent 
dose cohort. 
During Phase 1, if a subject is tolerating AFM24 without significant evidence of disease 
progression or AFM24-related toxicity, the subject 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. This intra-subject dose escalation 
may allow subjects a greater possibility of benefit from treatment with AFM24 than might be 
achieved at the starting dose in his/her assigned dose cohort. 
Risks of the tumor biopsy (mandatory for the subjects in the dose escalation phase [Phase 1]) 
include pain and tenderness at the tumor biopsy site and potential bleeding complications, 
which will be minimized by inclusion of subjects who have at least 1 site of tumor that is 
accessible to biopsy and that is considered by the Investigator to be low risk and of sufficient 
size to undergo a biopsy procedure, and monitoring per institutional practice. 
No reproductive toxicity or carcinogenicity studies have been conducted with AFM24 to date. 
Both women and men should be fully informed of the lack of reproductive toxicity testing. 
Women of childbearing potential and men must agree to use adequate contraception from 
14 days prior to the first dose of study drug up to 120 days after the last dose of study drug. 
Women must have a negative pregnancy test within 7 days prior to first dose of AFM24. It is 
unknown whether the drug is excreted in human milk, and women who are breast feeding are 
excluded from the study. 
The study design for this FIH Phase 1/2a dose escalation/expansion study of AFM24 aims to 
minimize potential risks and offer the potential to benefit subjects with advanced or metastatic 
solid tumors. Although the potential benefits to subjects are unknown at this time, nonclinical 
data demonstrate evidence of potent antitumor efficacy, and the potential toxicities can be 
monitored and managed appropriately. The benefit/risk assessment for this study was based on 
the lack of effective alternative treatments, the limited life expectancy of the subject population, 
and the strength of the nonclinical data in support of potent antitumor activity. The preliminary 
safety, tolerability, and clinical activity data from the first cohorts of the Phase 1 part of study 
AFM24-101 are described in Section 1.6 of this protocol and in the Investigator’s Brochure. 
The risk/benefit assessment remains unchanged. 
 
 


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2.0 
STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and their respective endpoints for assessment are described in Table 2. 
Table 2: 
Study Objectives and Endpoints 
Objective 
Endpoint(s) 
Phase 1 (Dose Escalation) 
Primary Objective 
Primary Endpoint 
Determine the MTD, and/or to select one or more 
RP2Ds, and investigate the safety and tolerability 
of AFM24 in subjects with advanced or metastatic 
solid malignancies 
The incidence of DLTs (during DLT observation 
period) 
Secondary Objectives 
Secondary Endpoints 
Characterize the safety and tolerability of AFM24, 
including both acute and chronic toxicities 
Incidence of subjects with TEAEs and SAEs 
Characterize the PK of AFM24 administered i.v. 
Serum PK parameters: AUCtau, Cmax, Tmax, Cmin 
Characterize the immunogenicity of AFM24 
Incidence of subjects who develop ADAs during 
treatment with AFM24 (by measurement of ADA 
before and throughout treatment with AFM24) 
Assess the preliminary antitumor efficacy of 
AFM24 
OR (CR + PR), DOR, and disease control (CR + 
PR + SD) assessed by:  
• Local RECIST v1.1 
Exploratory Objectives 
Exploratory Endpoints 
Assess the preliminary antitumor efficacy of 
AFM24, using iRECIST tumor response criteria 
OR (CR + PR), DOR, and disease control (CR + 
PR + SD) assessed by:  
• Local iRECIST; 
• Central RECIST v1.1; and 
• Central iRECIST. 
PFS measured by local and central assessments  
Overall survival 
Assess AFM24 pharmacodynamics 
 
Phase 2a (Expansion) 
Primary Objective 
Primary Endpoint 
Assess the preliminary antitumor efficacy of 
AFM24, by local RECIST v1.1 
Overall response (CR + PR) assessed by local 
RECIST v1.1.  
Secondary Objectives 
Secondary Endpoints 
Characterize the safety and tolerability of AFM24, 
including both acute and chronic toxicities 
Incidence of subjects with TEAEs and SAEs  
Characterize the PK of AFM24 administered i.v. 
 AFM24 serum concentrations will be included in 
a population PK analysis 
Characterize the immunogenicity of AFM24 
Incidence of subjects who develop ADAs during 
treatment with AFM24 (by measurement of ADA 
before and throughout treatment with AFM24) 
Assess the preliminary antitumor efficacy of 
AFM24 
OR (CR + PR) assessed by 
• Central RECIST v1.1;  


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Objective 
Endpoint(s) 
DOR, and disease control (CR + PR + SD) 
assessed by  
• Local RECIST v1.1; 
• Central RECIST v1.1;  
PFS measured by local and central assessments 
Overall Survival 
Exploratory Objectives 
Exploratory Endpoints 
Assess the preliminary antitumor efficacy of 
AFM24, using iRECIST tumor response criteria 
OR (CR + PR) assessed by 
• Local iRECIST 
• Central iRECIST 
DOR (CR + PR + SD) assessed by  
• Local iRECIST 
• Central iRECIST 
Assess AFM24 pharmacodynamics 
 
Explore the predictive potential of biomarkers 
measured in blood and/or tumor tissue in response 
to AFM24 
 
ADA = antidrug antibody; AUCtau = area under the concentration-time curve over the dose interval; 
Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; CR = complete response; 
DLT = dose-limiting toxicity; DOR = duration of response; iRECIST = Response Evaluation Criteria in Solid 
Tumors for immunotherapy; i.v.= intravenously; MTD = maximum tolerated dose; OR = overall response; 
PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; RP2D = recommended phase 2 
dose; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse events; SD = stable 
disease; TEAE = treatment-emergent adverse events; Tmax = time to Cmax. 
 
 


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3.0 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
AFM24-101 is a FIH Phase 1/2a open-label, non-randomized, multicenter, multiple ascending 
dose escalation/expansion study evaluating AFM24 as monotherapy in subjects with advanced 
or metastatic solid malignancies whose disease has progressed after treatment with previous 
anticancer therapies. 
An overview of overall study design is provided in Figure 2. 
There will be 2 parts to this study: a dose escalation phase (Phase 1) and a dose expansion 
phase (Phase 2a). The aim of the dose escalation phase (Phase 1) is to determine the MTD 
and/or establish at least one RP2D. An adaptive 2-parameter BLRM guided by the EWOC 
principle will be used in the escalation phase to guide determination of the MTD and/or RP2D 
in subjects with advanced or metastatic solid malignancies (Section 9.3.4.1). 
The dose escalation phase (Phase 1) will be followed by the dose expansion phase (Phase 2a) 
once the MTD and/or one or more RP2Ds of AFM24 monotherapy has been determined. The 
dose expansion phase (Phase 2a) of the study is intended to collect preliminary evidence of 
efficacy and to further confirm the safety of AFM24 as a monotherapy in distinct patient 
populations. The expansion phase will have 3 cohorts based on tumor type, as described in 
Figure 2. The expansion cohorts may be opened in parallel or subsequently.  
Figure 2: 
Overall Study Design 
 
approx. = approximately; CRC = metastatic colorectal cancer; ccRCC = clear cell renal cell carcinoma; 
EGFR = epidermal growth factor receptor; MTD = maximum tolerated dose; NSCLC = non-small cell lung 
cancer; RAS = rat sarcoma gene; RP2D = recommended phase 2 dose; wt = wild type. 
The study scheme, including pre-screening/screening, treatment, and follow-up, for each 
subject receiving study drug as weekly dosing regimen is described in Figure 5.  
Based on the findings in the dose escalation phase (Phase 1) part of the study, additional 
treatment schedules (i.e., every 2 weeks [q2w] dosing) may be explored in the dose expansion 
phase cohorts (Phase 2a). The study scheme, including pre-screening/screening, treatment, and 
follow-up, for each subject receiving study drug as q2w dosing regimen is described in 
Figure 6. 
 
 


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3.2 
Pre-screening and Screening 
Pre-screening: 
Pre-screening is required for subjects in Phase 2a only. EGFR expression is to be assessed as 
per inclusion criterion #1) before the subject enters the screening phase. Archived paraffin 
embedded tumor tissue is acceptable for EGFR determination; otherwise, a fresh tumor biopsy 
must be performed. Local EGFR assessment is acceptable. 
Subjects 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 the screening phase (Note: if a positive EGFR test has been performed from a 
subject’s tumor tissue, and the EGFR laboratory report is available, the subject 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). 
For patients in Phase 2a, the screening phase starts only after the subject has met the eligibility 
criterion for EGFR expression and has signed the Main ICF. 
Screening: 
For each subject in the escalation phase (Phase 1), the study starts with a screening phase. The 
screening phase lasting up to 21 days begins for all subjects (in Phase 1 and 2a) when the 
(Main) ICF is signed and ends on the day before the first dose of study drug. Before entering 
the (main) study, all study procedures and possible risks will be explained to each subject who 
is asked to participate in the study. After provision of written informed consent for the study, 
screening assessments will include a careful review of the subject’s medical history, 
assessment of Eastern Cooperative Oncology Group (ECOG) performance score (PS), physical 
examination, ECGs, laboratory assessments, and tumor assessments by computed tomography 
(CT) or magnetic resonance imaging (MRI), and tumor histopathology. Eligible subjects in 
dose escalation must have a tumor site that is accessible to biopsy and be willing to undergo at 
least 2 biopsy procedures (ie, 1 prior to and at least 1 during treatment with AFM24); see 
Section 4.1, inclusion criterion #9). Screening assessments are to be performed within 21 days 
of the first study drug dose, except for CT/MRI studies and tumor biopsies which may be 
performed within 28 days of the first study drug dose. Subjects who do not meet 1 or more 
eligibility criteria may be re-screened. The assessments for hepatitis C, hepatitis B, and human 
immunodeficiency virus (HIV) do not need to be repeated for re-screened subjects if it was 
done within 3 months before first dose of AFM24. 
3.3 
Treatment Assignment 
Subjects will be enrolled in the study based on their eligibility criteria confirmed by the 
Sponsor’s medical monitor. 
3.4 
Dose Escalation Phase (Phase 1) 
Phase 1 will employ an adaptive BLRM with 2 parameters guided by the EWOC principle to 
make dose recommendations and estimate the MTD (Section 9.3.4.1). It is estimated that 
approximately 25 to 41 subjects will be enrolled into Phase 1 of the study. The number of 
subjects is dependent on the tested dose cohorts and safety profile of AFM24. As multiple 
centers will contribute to the enrollment a communication plan will be established to ensure 
distribution of safety data and study progress amongst the participating centers. 


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Dose-limiting toxicities (DLTs) will be assessed in the first treatment cycle (ie, the first 
4 weeks of treatment for each subject), referred to as the DLT observation period. 
The starting dose of AFM24 in the first dose cohort is 14.0 mg administered as an i.v. infusion 
on a once weekly dosing schedule divided into 4-week cycles.  
Dose Cohorts 1 and 2: 
To minimize the number of subjects treated at potentially subtherapeutic dose levels in the dose 
escalation phase (Phase 1), the first 2 dose cohorts will enroll a minimum of 2 subjects. The 
first 2 subjects of each dose cohort will begin treatment in a staggered approach with at least 
7 days between first dosing of these 2 subjects. After the first subject in each cohort has begun 
treatment and been observed for at least 7 days, additional subjects within the cohort may begin 
treatment concurrently. All subjects who start treatment need to complete the 28-day DLT 
observation period or experience a DLT before the SRC meeting and dose escalation decision. 
A minimum of 2 subjects needs to be evaluable for DLT assessment (Section 3.4.2) to allow 
for a dose escalation decision by the SRC. If none or only 1 of the subjects is evaluable for 
DLT assessment, replacement subject(s) will be enrolled. The dose cohorts might be extended 
to up to 6 subjects based on the SRC decision.  
Dose Cohort 3 and any Subsequent Cohorts: 
Dose Cohort 3 and any subsequent cohorts will enroll at least 3 subjects. A fourth subject may 
be enrolled if treatment of the fourth subject is anticipated to begin within 14 days of treatment 
initiation of the third subject in the cohort. The first 2 subjects of each dose cohort will begin 
treatment in a staggered approach with at least 7 days between first dosing of these 2 subjects. 
Subsequent subjects may be enrolled concurrently. All subjects who start treatment need to 
complete the 28-day DLT observation period or experience a DLT before the SRC meeting 
and dose escalation decision. A minimum of 3 subjects need to be evaluable for DLT 
assessment (Section 3.4.2) to allow for a dose escalation decision by the SRC. If less than 3 
subjects are evaluable for DLT assessment, replacement subject(s) will be enrolled. The dose 
cohorts might be extended to up to 6 subjects based on the SRC decision.  
The BLRM will be assessed for those subjects who are evaluable for DLT assessment in the 
dose-determining set (DDS) consisting of all subjects who received at least 1 dose of AFM24, 
and either experienced a DLT at any time during Cycle 1 or met the minimum treatment and 
safety evaluation requirements without experiencing a DLT within Cycle 1. After completion 
of a given dose cohort, or at any time the BLRM is updated, the decision to dose escalate and 
the actual dose chosen will be based on the recommendation of the BLRM regarding the highest 
admissible dose according to the EWOC principle (Section 9.3.4.1) and the medical review of 
all available clinical, laboratory, and PK data. The outcome of these analyses and the respective 
datasets will be reviewed by the SRC consisting of the Principal Investigators at each study 
center and the Sponsor’s Medical representative(s), and additional clinical experts, as needed. 
The SRC will confirm the dose level selection of the next dose cohort prior to enrollment. Dose 
escalation will continue until the MTD and/or at least one RP2D is determined. 
In the event of a Common Terminology Criteria for Adverse Events (CTCAE) Grade 5 adverse 
event (AE) or a second CTCAE Grade 4 AE at least possibly related to AFM24 at any time 
during Phase 1, the Sponsor will suspend further accrual and will perform a safety analysis that 
will be reviewed by an ad-hoc SRC meeting to decide on further progression of the study. 


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3.4.1 
Definition of Maximum Tolerated Dose 
The MTD is defined as the highest dose of AFM24 if both of the following criteria are fulfilled: 
• The posterior probability of the true DLT rate being in the target interval (≥16% to 
<33%) is >50% with less than 25% risk of the true DLT rate being above 33%; and 
• At least 6 subjects have been treated at that cohort in the first cycle of AFM24 
treatment under that dosing schedule. 
As described in Section 3.4.3, an RP2D can be declared if: 
• The MTD criteria are not met on any dose level and/or clinical and laboratory data 
indicate an optimal biologically active dose has been reached (with less than 25% risk 
of the true DLT rate being above 33%). 
AND 
• At least 6 subjects have been treated at that dose level. 
3.4.2 
Definition of Dose-Limiting Toxicity (DLT) 
Dose-limiting toxicity 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 (Cycle 1) and that meets any of the 
following criteria shown in Table 3. Clinically relevant toxicities will be evaluated according 
to the National Cancer Institute (NCI)/National Institutes of Health CTCAE v5.0. Subjects who 
experience a DLT during Cycle 1 must permanently discontinue AFM24. 
Subjects must receive ≥80% of their assigned AFM24 dose in Cycle 1 and complete the 28-day 
DLT observation period or have had a DLT within the first cycle of treatment to be considered 
evaluable for DLT. 
For dose-escalation decisions, only DLTs occurring during Cycle 1 of treatment will be 
considered in the 2-parameter BLRM. 
Table 3: 
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) 
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 (ie, 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) 


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Toxicity 
Any of the following criteria 
• 
CTCAE Grade 3 hypertension for >14 consecutive days despite 
optimal anti-hypertension therapy 
• 
CTCAE Grade 4 hypertension 
• 
≥CTCAE Grade 3 total bilirubin (>3×ULN) 
• 
≥CTCAE Grade 3 ALT, AST, or ALP (>5×ULN) 
• 
Subjects without hepatic metastasis: subjects fulfilling Hy’s law 
criteria or 1.5 times increase from baseline value of total bilirubin for 
>2 weeksb; 
• 
Subjects with hepatic metastasis: 1.5 times increase from baseline 
value of total bilirubin for >2 weeksb; 
• 
≥CTCAE Grade 3 vomiting or nausea for ≥72 hours despite optimal 
anti-emetic therapy; and/or 
• 
≥CTCAE Grade 3 diarrhea for ≥72 hours despite optimal anti-diarrhea 
treatment 
Any other ≥CTCAE Grade 3 AE not listed above, except for the exclusions 
noted below 
Inability to receive at least 3 of the scheduled doses of AFM24 in Cycle 1 due 
to treatment-related toxicity 
Any other toxicity (irrespective of grade) that:  
• 
Is greater than that at baseline and clinically significant and/or 
unacceptable and/or does not respond to supportive care and judged to 
be a DLT by the SRC; or 
• 
Results in a disruption of AFM24 dosing for more than 2 weeks 
Exceptions to DLT 
criteriac 
Isolated laboratory changes of any grade without clinical sequelae or clinical 
significance with the exception of 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 (ie, improvement to Grade 
2 or better within 6 hours with optimal medical management) 
AE = adverse event; ALT = alanine aminotransferase; ALP = alkaline phosphatase; ANC = absolute 
neutrophil count; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; DLT = dose-limiting toxicity; NCI = National Cancer Institute; QTcF = corrected QT interval by 
Fridericia; SRC = Safety Review Committee; ULN = upper limit of normal. 
a. Subjects may receive supportive care (eg, 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. Subjects fulfilling potential Hy’s law criteria need to have a repeat blood draw immediately and study 
drug withheld while the case is reviewed and follow-up assessments are performed. The Investigator will 
review all previous laboratory data to determine whether potential Hy’s Law criteria were met at any 
study visit prior to or after starting study drug and will review the case with the Medical Monitor and 
agree on the approach for the subjects’ follow-up assessments.  
Investigators should use their best judgment based on clinical and radiological criteria to exclude 
progressive disease as the cause of increased hepatic dysfunction. 
c. The SRC 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 meetings. 
Note: NCI CTCAE v5.0 will be used for all grading. 


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3.4.3 
Estimation of MTD/RP2D 
A 2-parameter BLRM employing the escalation with EWOC principle will be used during the 
escalation phase for selection of doses to investigate and for estimation of the MTD 
(Section 9.3.4.1). The general plan is that cohorts of subjects will receive escalating doses of 
AFM24 until the MTD is reached. Each cohort will consist of newly enrolled subjects. 
Estimation of the MTD during the escalation phase of the study will be based upon the 
estimation of the probability of DLT in Cycle 1 in subjects who are evaluable for DLT 
assessment. If the MTD cannot be reached in the dose escalation phase (Phase 1), one or more 
RP2Ds will be determined as the dose resulting in the best therapeutic window for AFM24 
based on the review of DLTs, AEs, serious AEs (SAEs), and laboratory, PK, and PD data. 
MTD and/or at least one RP2D (as defined in Section 3.4.3) might be determined based on 
dosing schedules and cancer indications. 
At all decision time points, the adaptive BLRM permits alterations in the dose increments based 
on the observed toxicities. It will be possible for additional, intermediate dose levels to be 
added during the study. 
Dose escalation will not exceed a 200% increase from the current dose being studied. Cohorts 
may be expanded at any dose level below the highest dose deemed unacceptable in order to 
better understand safety, tolerability, PK, or PD. 
Provisional dose escalation levels are provided in Table 4; however, dose decisions during 
escalation are not limited to the values provided. Based on the recommendation of the BLRM 
regarding the highest dose that may not be exceeded at any decision point during escalation 
and the maximum increase in dose allowed by the protocol, intermediate doses may be 
administered to subsequent new cohorts of subjects. This includes doses lower than the starting 
dose or intermediate doses between the current and next (lower or higher) provisional doses. 
To further characterize the safety, PK, and/or PD, for a dose of AFM24 that is considered 
acceptably safe, i.e., lower than the MTD, the associated cohort may be expanded. In addition, 
dose escalation may be terminated at any time without establishing the MTD based on 
emerging safety concerns or based on clinical and laboratory data that indicate an optimal 
biologically active dose has been reached. 
Table 4: 
Provisional Dose-Escalation Levels 
Dose Level 
Proposed Dosea (mg) 
Increment from previous 
dose 
-1b 
7 
50% decrease 
1 
14  
Starting dose 
2 
40 
200% 
3 
120 
200% 
4 
360 
200% 
5 
1000 
200% 
a. It is possible for additional, intermediate dose levels to be added during the course of the study.  
b. Dose level -1 represents a dose that may be evaluated if dose level 1 is poorly tolerated. No dose de-
escalation below this level is planned for this study. If dose level -1 is poorly tolerated the study will be 
terminated. 


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3.4.4 
Replacement of Subjects 
In the first 2 cohorts of the dose escalation phase (Phase 1) a subject will be replaced (ie, an 
additional subject will be added to the cohort) if only 1 or none of the treated subjects is 
evaluable for DLT assessment.  
In the subsequent cohorts a subject will be replaced (ie, an additional subject will be added to 
the cohort) if less than 3 subjects are evaluable for DLT assessment. 
In the dose expansion phase (Phase 2a) all patients in the safety set will not be replaced, 
independent of the availability of their post-baseline disease assessments. 
3.5 
Dose and Schedule Modifications 
The BLRM will be updated with the newly accumulated data. The overdose risk will then be 
calculated for each dose, and escalation will be permitted to all doses, which fulfill the EWOC 
criterion (Section 9.3.4.1).  
If DLTs are observed in the first 2 consecutive subjects receiving a dose level that has not been 
cleared for safety, subsequent enrollment to that cohort will be stopped. The BLRM will be 
re-run to confirm that the dose-level still fulfills the EWOC criterion. Based on this 
information, the SRC will evaluate whether the next subjects will be enrolled on the same dose 
level, or if they will be enrolled to a lower dose level.  
Dose decisions for dose escalation cohorts (Phase 1) and additional dosing schedules to be 
explored in the expansion cohorts (Phase 2a) will be based on all relevant data available 
including safety information, DLTs, all ≥CTCAE Grade 2 toxicity data during Cycle 1 and PD 
and PK data, as available, from evaluable subjects in any cohort. 
3.6 
Safety Review Committee 
The SRC will consist of the Sponsor’s medical representative and the Principal Investigator or 
delegate from each active study center. The SRC will be co-chaired by 1 of the participating 
Principal Investigators and the Sponsor’s medical representative. The study statistician will 
participate in the SRC. Ad hoc participants such as the clinical pharmacology scientist and 
clinical operations leader may be invited as appropriate. Additional experts may be consulted 
by the SRC as needed. Appropriate representatives of the coordinating contract research 
organization will also attend and minute the meeting. 
The SRC has the responsibility for monitoring the clinical study’s progress and the safety of 
the participating subjects. After there are 2 evaluable subjects for the first 2 cohorts and at least 
3 evaluable subjects for subsequent cohorts at each dose level during Phase 1 of the study, the 
SRC will review and assess all available safety data from the cohort together with available 
PK data and recommendations from the BLRM to make a decision on the dose for the next 
cohort of subjects. The decision may be to: 
• Proceed with dose escalation; 
• Expand the cohort to a maximum of 6 evaluable subjects; 
• De-escalate the dose to a lower dose level or to an intermediate lower dose level; or 
• Stop the dose escalation. 


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The decisions and decision-making of the SRC will be documented and will be provided to the 
Investigators before dosing any new subjects on the next dose level. 
During the dose expansion phase (Phase 2a) of the study, an Independent Data Monitoring 
Committee (IDMC) will periodically review all safety data generated throughout the dose 
expansion phase (Phase 2a) part of the study on a regular basis (Section 3.7). 
All details regarding the SRC composition, meetings, reviewed data and the decision-making 
process will be documented in the study-specific SRC Charter. 
3.7 
Independent Data Monitoring Committee 
Prior to initiation of dose expansion phase (Phase 2a), an Independent Data Monitoring 
Committee (IDMC) will be established consisting of clinical experts who are not directly 
involved in this clinical study. The IDMC will review all safety data generated throughout the 
dose expansion phase (Phase 2a) part 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. 
3.8 
Dose Expansion Phase (Phase 2a) 
Once at least one RP2D dose has been determined, then enrollment into 1 or more expansion 
cohorts for selected cancer indication in the dose expansion phase (Phase 2a) will begin. Other 
expansion cohorts may follow with the same or a different RP2D dose level. An optimum 
Simons two-stage design will be applied for the preliminary efficacy analyses for the following 
expansion cohorts (Figure 2): 
• Expansion Cohort A will enroll up to a total of 39 subjects with microsatellite stable 
CRC with rat sarcoma gene (RAS) wild-type tumor, the interim analysis (IA) will be 
conducted after 11 subjects. 
• According to Simons two-stage design it was planned that Expansion Cohort B will 
enroll up to a total of 41 subjects with ccRCC, and the IA will be conducted after 15 
subjects. After conducting the interim analysis for Cohort A and C and stopping these 
cohorts for futility, it was considered unlikely that the continuation criteria can be met 
in Cohort B. Hence it was decided to prematurely stop enrollment after 8 patients in 
Cohort B.  
• Expansion Cohort C will enroll up to a total of 41 subjects with advanced or metastatic 
NSCLC with an EGFR mutation, the IA will be conducted after 15 subjects. 
3.9 
Period of Observation 
After completion of study drug, subjects will enter follow-up and will be contacted regularly 
by the Investigator or study personnel to collect information about subsequent therapies, 
disease status, and survival. Subjects will be followed for safety, duration of response (DOR), 
progression f-ree survival (PFS), and overall survival (OS) until the end of the study, (see 
below). 


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Observation Visits: 
• End of Treatment visit: Visit to be performed 14 days (±2 days) from last drug intake 
or before start of any new anti-cancer treatment whichever is sooner. For subjects 
who discontinue prematurely before disease progression it must be performed as the 
last visit. 
• Safety Follow Up visit: All subjects will undergo one Safety Follow-up visit 30 days 
(±5 days) after the last AFM24 infusion or before start of any new anti-cancer 
treatment whichever is sooner.  
• Long-term Follow Up: Additional follow-up (phone contact) will take place at 
3-month intervals (±2 weeks) after end of treatment visit until death, lost to follow-
up- or mutual decision between PI and sponsor to discontinue Long-term Follow Up 
of the patient, whichever is sooner. 
• End of Study: The study will be terminated as soon as all subjects have completed the 
first Long-term Follow-Up interval, withdrawn, or died, whichever occurs first.  
The study will be analyzed and reported once the last subject of the study has experienced at 
least one of the following: 
• Has been treated till 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 subjects are still being treated with study medication at the primary analysis cut-off 
date for this study, such subjects 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. 
3.10 
Number of Subjects 
The study will enroll subjects with advanced or metastatic solid malignancies whose disease 
has progressed after treatment with previous anticancer therapies. 
It is estimated that approximately 25 to 41 subjects will be enrolled into Phase 1 (dose 
escalation) of the study. The number of subjects is dependent on the tested dose cohorts and 
safety profile of AFM24. 
Additionally, 3 expansion cohorts (in Phase 2a [Expansion Phase]), with up to a total of 39, 41, 
and 41 subjects in Cohorts A, B, and C, respectively, for a maximum of 121 subjects, will be 
enrolled to assess the preliminary efficacy of AFM24 in 3 different subject populations. 
Depending on the preliminary efficacy observed in the dose escalation phase (Phase 1) of the 
study, additional expansion cohorts may be added by a protocol amendment. 


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3.11 
Study Initiation and Completion 
The start of this clinical study is defined as the first act of screening (signing of the Main 
ICF) for a potential subject. 
The end of the study is defined as when all subjects have completed the first Long-term 
Follow-Up interval, withdrawn, or died, whichever occurs first. 
 
4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects will be considered eligible to be enrolled in the study if ALL the inclusion criteria 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 (eg, NCCN Guidelines: Cancer and COVID-19 Vaccination [NCCN 2021] and 
MHRA Guidance on Coronavirus [COVID-19] [MHRA 2021]), COVID-19 vaccination 
should be prioritized for subjects with cancer with the understanding that there are limited 
safety and efficacy data in this subject 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 (ie, Cycle 1). Therefore, for any new subjects to be enrolled 
in the study, every effort should be made to vaccinate subjects prior to being considered for 
this study based on the Investigator’s risk/benefit analysis for each subject. Any COVID-19 
vaccination should be at least 2 weeks prior to C1D1; live attenuated vaccines at least 4 weeks 
prior to C1D1. For subjects whose opportunity for COVID-19 vaccination arrives during 
the conduct of the study (ie, ongoing subjects in the study), see instructions for COVID-19 
vaccination provided in Section 5.6.1.1. 
4.1 
Subject Inclusion Criteria 
The study will enroll subjects with advanced or metastatic solid malignancies whose disease 
has progressed after treatment with previous anticancer therapies. 
Subjects are eligible only if all the following criteria are met: 
1) For the dose escalation phase (Phase 1): histologically or cytologically confirmed 
advanced or metastatic solid malignancies that are known to express EGFR. 
For the dose expansion phase (Phase 2a): histologically or cytologically confirmed 
advanced or metastatic EGFR+ malignancies. EGFR expression is defined as positive 
staining for EGFR in ≥1% of tumor cells determined by a validated 
immunohistochemistry assay. Archived paraffin embedded tumor tissue is acceptable 
for EGFR determination – otherwise a fresh tumor biopsy must be performed. Local 
laboratory EGFR assessment is acceptable. 


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2) For dose escalation phase (Phase 1): Subjects must have been previously treated with 
1 or more lines of anticancer therapy and have documented disease progression 
during or after their most recent line of anticancer therapy. In addition, either there is 
no further SOC therapy for the subject or the remaining SOC therapies are deemed 
not appropriate for the subject by the Investigator. 
3) Subjects must have documented radiological progression during or after their latest 
therapy for all phases. 
4) Voluntary provision and understanding of signed and dated, written informed consent 
prior to any mandatory study-specific procedures, sampling, or analysis. 
5) Male or female aged ≥18 years on the day of signing informed consent (or of an 
acceptable age according to local regulations, whichever is older). 
6) Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) 0 or 1. 
7) Adequate organ function, assessed within 14 and within 7 days before first AFM24 
infusion, defined as follows: 
Note: Transfusions and hematopoietic growth factors to help meet eligibility are 
not allowed.  
• Bone marrow: Absolute neutrophil count ≥1.5×109/L, platelet count 
≥100×109/L, and hemoglobin ≥8 g/dL; 
• Hepatic: total bilirubin ≤1.5×upper limit of normal (ULN) (or ≤3×ULN in 
participants with Gilbert’s syndrome), alanine aminotransferase and aspartate 
aminotransferase ≤2.5×ULN for subjects without liver metastasis and alanine 
aminotransferase and aspartate aminotransferase ≤5×ULN for subjects with 
liver metastasis;  
• Renal: If serum creatinine concentration ≥1.5×ULN, then estimated creatinine 
clearance must be ≥50 mL/min (Cockcroft-Gault formula). 
8) Serum potassium, calcium, magnesium, and phosphate within normal limits or not 
worse than CTCAE v5.0 Grade 1 and asymptomatic. If values are low on the initial 
screening assessment, supplements may be given, if clinically appropriate, and values 
repeated to confirm within CTCAE v5.0 Grade 1 limits.  
9) For dose escalation phase (Phase 1): Subjects must have (mandatory) at least 1 tumor 
site that is accessible to biopsy and that is considered by the Investigator to be low 
risk and of sufficient size to undergo a core biopsy procedure on at least 2 separate 
occasions. 
10) For the dose expansion phase (Phase 2a) only: Subjects must have measurable disease 
per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (ie, 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 assessed 
by CT scan), with the last imaging performed within 28 days before Cycle 1 Day 1 
(C1D1). 
11) Subjects in dose expansion phase (Phase 2a) must have histologically confirmed 
advanced or metastatic EGFR-positive malignancy for each expansion cohort as listed 
below: 
• Cohort A: Subjects with RAS wild type, microsatellite stable CRC whose 
disease has progressed after having received ≥2 prior lines of therapy, which 


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must have included oxaliplatin, irinotecan, and fluoropyrimidine. If available, 
prior therapy must also have included an anti-vascular endothelial growth factor 
(anti-VEGF) or anti-vascular endothelial growth factor and its receptor (anti-
VEGFR) therapy (eg, bevacizumab, aflibercept, or ramucirumab), and an anti-
EGFR therapy (eg, cetuximab or panitumumab).  
• Cohort B: Subjects with ccRCC whose disease has progressed after having 
received ≥1 prior line(s) of therapy, which must have included a TKI (eg, 
sunitinib, pazopanib) and a checkpoint inhibitor (eg, pembrolizumab, 
avelumab, nivolumab). 
• Cohort C: Subjects 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 for advanced disease including 
≥1 prior TKI approved for EGFR mutated NSCLC, such as gefitinib, erlotinib, 
afatinib, dacomitinib, or osimertinib. Subjects who were treated with a 1st or 2nd 
generation TKI in 1st line and developed a documented T790M mutation must 
have received a TKI targeting this mutation such as osimertinib or lazertinib to 
be eligible. Subjects must have documentation of EGFR mutated NSCLC as 
assessed by an approved test using genomic sequencing of tumor or circulating 
free tumor DNA.  
12) Female subjects must have a negative urine or serum pregnancy test within 7 days 
prior to first dose of AFM24 if of childbearing potential or be of non-childbearing 
potential. 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 subject to be eligible. Non-childbearing potential is defined as: 
• 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. 
• Surgically sterile. Surgical sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
13) 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 120 days after the last 
dose of study drug. Acceptable highly effective birth control methods include: 
• Oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation; 
• Oral, injectable, or implantable progestogen-only hormonal contraception 
associated with inhibition of ovulation; 
• Intrauterine device; 
• Intrauterine hormone-releasing system; 
• Bilateral tubal occlusion; 


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• 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 
• 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 120 days 
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 subject. 
14) Males who have female partners of childbearing potential must agree to use a highly 
effective method of contraception as described in inclusion criterion 13, starting with 
the first dose of study drug through 120 days after the last dose of study drug. 
4.2 
Subject Exclusion Criteria 
Subjects are eligible only if none of the following criteria are met: 
1) Currently participating in a study and receiving study therapy or participated in a study 
of an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of study drug. 
2) Treatment with systemic anticancer therapy within 4 weeks (6 weeks if therapy was 
mitomycin C and/or nitrosoureas), or within 5 half-lives of the agent if half-life is 
known and it is shorter, before first dose of study drug. Anticancer therapies include 
cytotoxic chemotherapy, targeted inhibitors, and immunotherapies, but do not include 
hormonal therapy or radiotherapy. 
3) Radiation therapy within 2 weeks before first dose of study drug or unresolved (NCI 
CTCAE v5.0 >Grade 1) toxicity from previous radiotherapy (e.g., radiation dermatitis). 
Note: Palliative (limited field) radiotherapy for managing pain associated with bone 
metastases present at baseline is permitted during the study. 
4) Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks 
before first dose of study drug or anticipation of need of a major surgical procedure 
during the course of study. Note: Procedures that are considered to be minimally 
invasive (e.g., peripherally inserted central catheters lines and/or port placements) will 
be exceptions. 
5) Subjects with toxicities (as a result of prior anticancer therapy) which have not 
recovered to baseline or CTCAE v5.0 ≤Grade 2, except for AEs not considered a likely 
safety risk (e.g., alopecia, specific laboratory abnormalities). 
6) History of any other invasive malignancy, unless previously treated with curative intent 
and the subject has been disease free for 3 years or longer. Examples for acceptable 
previous malignancies include: completely removed in situ cervical intra-epithelial 
neoplasia, non-melanoma skin cancer, ductal carcinoma in situ, and early-stage prostate 
cancer that has been adequately treated. 
7) One or more of the following cardiac criteria: 
• Unstable angina; 
• Myocardial infarction within 6 months prior to screening; 
• New York Heart Association Class III to IV heart failure; 


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• Corrected QT interval >470 msec obtained as the mean from 3 consecutive 
resting ECGs using the Fridericia’s formula; 
• Clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG (e.g., complete left bundle branch block or third-degree heart 
block); 
• Congenital long QT syndrome; 
• Uncontrolled hypertension (≥150/100 mmHg based on accurate measurement 
and average of ≥2 readings which are ≥5 minutes apart on ≥2 occasions) 
despite maximum antihypertensive therapy. 
Note: Patients who initially fail screening due to uncontrolled hypertension as 
defined above, but who then attain controlled hypertension with intensified 
antihypertensive therapy are allowed to undergo rescreening. 
8) Stroke or transient ischemic attack within 6 months prior to screening. 
9) History of leptomeningeal disease or spinal cord compression. 
10) Known brain metastases unless asymptomatic and not requiring steroids for at least 
4 weeks prior to start of study drug. 
11) Subjects with primary brain tumor who require high dose steroids (defined as ≥30 mg 
prednisolone or equivalent per day) or who received high dose steroids within 4 weeks 
prior to first dose of study drug. 
12) Diagnosis of immunodeficiency or active infection including known hepatitis B, 
hepatitis C, or HIV. A negative confirmatory test within 3 months of treatment start 
does not have to be repeated during the screening period. 
13) Active autoimmune disease that requires systemic treatment with steroids or other 
immunosuppressive agents, or subjects who have received such agents within 4 weeks 
prior to first dose of study drug: 
Exceptions: 
• Topical (≤20% of the skin surface area), ocular, intra-articular, intranasal, or 
inhalation corticosteroids with minimal systemic absorption 
• A short course (≤7 days) of corticosteroids prescribed prophylactically (e.g., for 
contrast dye allergy or antiemetic therapy) or for treatment of non-autoimmune 
causes (e.g., delayed hypersensitivity reaction caused by contact allergen)  
• Physiological replacement doses of corticosteroids for adrenal or pituitary 
insufficiency 
14) Has received a live vaccine administered within 28 days of planned treatment start 
(C1D1) or while participating in the study. Seasonal vaccines for influenza are 
generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines 
and are not allowed. 
15) Subjects who require systemic steroid treatment or any other immunosuppressive 
therapy, or subjects who received such therapy within 4 weeks prior to the first dose of 
study drug, with the exceptions as outlined under exclusion criterion #13). 
16) Pregnant, breastfeeding, or expecting to conceive or father children within the projected 
duration of the study, starting with the Screening visit (females) or first dose of study 
drug (males) through 120 days after the last dose of study drug. 


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17) Subject’s unwillingness to comply with the protocol or inability to appreciate the 
nature, meaning, and consequences of the study and to formulate his/her own wishes 
correspondingly. 
18) Any medical, psychological, or social condition that would interfere with the subject’s 
participation in the study. 
4.3 
Subject Withdrawal from Study  
Throughout the study, treatment with AFM24 may continue until the occurrence of 1 of the 
following events, whichever comes first: 
• Subject withdrawal of consent; 
• Disease progression (if initial radiological progressive disease is observed, while the 
clinical condition of the subject is stable, treatment continuation is allowed at the 
discretion of the Investigator. If treatment is continued after initial progressive disease, 
a confirmatory scan should be acquired within 4 to 6 weeks); 
• Occurrence of intolerable toxicity; 
• DLT during Cycle 1 in the Phase 1 part; 
• Subject non-compliance and the need for withdrawal for this reason as assessed by the 
Investigator; or 
• Investigator decision that it is in the subject’s best interest to withdraw from the study. 
Upon withdrawal from study drug, the reason for withdrawal should be sought and recorded in 
the subject file and the withdrawal will be captured in the electronic case report form (eCRF). 
Every effort will be made to complete the End of Treatment visit, the Safety Follow-up visit 
and for the subject to be followed up every 3 months thereafter. Where a subject withdraws 
his/her consent to participate in the study, such follow-up assessments cannot be conducted. 
The management and holding of data around subject withdrawal will be described in the subject 
ICF. 
4.4 
Subject Compliance 
Subjects 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 subject 
fails to return to the clinic for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study; 
• Before a subject is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a registered letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
medical record; and 
• Should the subject 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 subject withdrawal from treatment and/or the study, where 
appropriate. 
5.0 
TREATMENT OF SUBJECTS 
5.1 
Description of Study Drug 
AFM24 is a member of a new class of antibody drugs that recruits NK cells to eliminate cancer 
cells. AFM24 is a tetravalent, bispecific Fc-containing antibody that is bivalent for CD16A on 
NK cells and macrophages, and bivalent for EGFR on EGFR+ tumor cells. The antigen binding 
domains are fused to a human Fc portion to facilitate FcRn binding and to achieve a serum 
half-life comparable to classical IgG antibodies. The Fc portion was engineered to eliminate 
binding to all Fcγ receptors but allows fixing of complement and CDC on EGFR+ cells. AFM24 
mediates specific, potent, and efficient lysis of human tumor cell lines that express EGFR 
solely by binding to CD16A+ on NK cells or macrophages (ADCC and ADCP). 
AFM24, constructed by means of recombinant technology, is expressed from 2 different genes 
(codon optimized for expression in Chinese hamster ovary cells) encoding 2 polypeptide chains 
(heavy chain 75 kDa and light chain 23 kDa) that subsequently form an IgG-like molecule 
consisting of 2 identical heavy and light chains at the size of about 196 kDa. 
Please refer to the current version of the IB for additional information on the physical, 
chemical, and pharmaceutical properties of AFM24. 
5.2 
Study Drug Administration 
All doses of AFM24 will be administered as an i.v. infusion. During the dose escalation phase 
(Phase 1), subjects will receive AFM24 as a weekly infusion. As mentioned in Section 3.1, 
additional dosing regimen (i.e., q2w) may be explored in the dose expansion phase (Phase 2a) 
only. 
For dose escalation phase (Phase 1) and dose expansion phase (Phase 2a) 
• Weekly dosing regimen (q1w): i.e., on Day 1, Day 8, Day 15, and Day 22 of a 28-day 
cycle (see APPENDIX A [Section 14.1]).  
For dose expansion phase (Phase 2a) only 
In addition to the weekly dosing regimen mentioned above, the following dosing regimen may 
be used: 
• Every-2-weeks dosing regimen (q2w): i.e., on Day 1 and Day 15 of a 28-day cycle (see 
APPENDIX B [Section 14.2]). If the drug is given on a q2w schedule, the daily dose 
will not be higher than the highest daily dose that was tested in Phase 1 part of the study 
and was considered safe. 
The baseline infusion time should not take less than approximately 4 hours for at least the first 
2 AFM24 infusions (Note: infusion time is approximately 4 hours, any infusion time ≥3 hour 
50 minutes will not be a deviation). It should also be noted that as the dose escalation continues 
into the higher dosing cohorts, the baseline infusion time may increase to >4 hours and as long 
as over 2 days (ie, split day dosing) based on a given subject’s tolerability as detailed in the 
Pharmacy Manual for each cohort. For infusion times that span over 2 days (i.e., split day 
dosing), timepoints for different assessment may be affected and the Schedule of Assessment 
(SoA) tables should be referenced for details (See Section 14.1 and Section 14.2 for SoA tables 


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for weekly and q2w dosing schedules, respectively). If the first 2 consecutive AFM24 infusions 
are well tolerated (defined as no IRR/cytokine release syndrome (CRS) Grade >1), then the 
infusion time may be decreased to <4 hours to a minimum of 1 hour starting with the third 
subsequent infusion (ie, C1D15 for weekly dosing regimen and C2D1 for q2w dosing regimen) 
at the discretion of the Investigator along with a potential reduction of post 
infusion- observation period (with regular checks of vital signs, please refer to Table 5 for 
detailed description) from 4 hours to a minimum of 2 hours and a taper of corticosteroid 
premedication. Investigators should only make 1 modification per infusion at 1 time. 
See APPENDIX F (Section 14.6) for details regarding treatment management for symptoms of 
IRR/CRS due to study drug). Refer to the Pharmacy Manual for full details regarding study 
drug administration. 
Subjects may receive AFM24 as long as they continue to show clinical benefit, as judged by 
the Investigator, or until disease progression, other treatment discontinuation criteria are met, 
or withdrawal of consent (Section 4.3).  
5.3 
Premedication Regimen and Post-Dose Observation 
Subjects are required to receive premedication with the following medications approximately 
1 hour before each dose of AFM24: 
• i.v dexamethasone 20 mg (or equivalent long-lasting steroid dose) 
• i.v. H1 antagonist (e.g., diphenhydramine 50 mg or similar medication as used per 
local institutional practice) with or without an H2 antagonist (e.g., famotidine or 
similar medication as used per local institutional practice), and 
• acetaminophen dosage as per local institutional practice (e.g., 650 mg to 1000 mg or 
equivalent). 
Note: For infusion times that span over 2 days (i.e., split day dosing), subjects must receive 
premedication on Day 1 and as well on Day 2. This includes the H1 antagonist (with or without 
an H2 antagonist), acetaminophen, and dexamethasone. For Day 2, dexamethasone dose can 
be reduced to a minimum of 8 mg, according to local standards at the discretion of the 
Investigator/treating physician. 
Subjects may also be administered prophylactic antiemetic medications as indicated. 
Additional oral premedication will be allowed on the day before each dose of AFM24 at the 
discretion of the Investigator, in particular for those subjects who may experience persistent 
IRR.  
If the first 2 subsequent infusions are well tolerated (defined as no Grade >1 IRR/CRS), then 
the medication(s) within the premedication regimen can be tapered/decreased. 
Clinicians should be prepared for an IRR or CRS to occur during or shortly after each AFM24 
drug administration, with frequent monitoring of vital signs and medical equipment and 
supplies readily available and standing orders in place for immediate intervention. Please see 
APPENDIX F (Section 14.6) for details regarding treatment management for symptoms of 
IRR/CRS due to study drug. 
After the first 2 subsequent doses of AFM24 subjects must be observed for at least 4 hours 
after the end of infusion (EOI), with regular checks of vital signs as described in Section 7.2.4. 


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In case of a split day dosing (over 2 days) subjects must be observed for at least 4 hours after 
the end of AFM24 infusion on each day. In this scenario, the split day dosing AFM24 infusion 
is considered 1 dose. If no signs or symptoms of CRS or an IRR (no Grade >1) are observed 
during or after the first 2 subsequent doses of AFM24 then the observation period following 
each AFM24 dose may be reduced from 4 hours to at least 2 hours after the end of infusion.  
5.4 
Dose Interruptions or Delays 
AFM24 dosing delays may be permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, subject 
vacation and/or holidays). Subjects should re-commence study therapy within 3 weeks of the 
interruption, unless otherwise discussed and agreed with the Sponsor. Every effort should be 
made to avoid dose delays during the DLT observation period (Cycle 1 of the dose escalation 
phase).  
Dose delays of up to 3 weeks (≤21 days between 2 consecutive doses) are allowed for subjects 
to recover from any AE and return to baseline or Grade ≤1 (except for fatigue or anorexia).  
Subjects who do not recover from any AE and return to baseline or Grade ≤1 (except for fatigue 
or anorexia) within 3 weeks (≤21 days between 2 consecutive doses) must discontinue AFM24 
permanently.  
Please refer to APPENDIX A (Section 14.1) and APPENDIX B (Section 14.2) for more details 
of weekly and q2w AFM24 dosing schedules, respectively. 
Weekly dosing schedule: 
If the subject recovers from an AE and is able to continue study drug within 72 hours of the 
originally scheduled dosing day, then the subject should receive the delayed dose and continue 
treatment as per the original schedule, by not shifting any later doses. There should be at least 
4 days without treatment before the subject receives the next dose. An example: if the subject 
has an AE on C1D15 and recovers in time and can receive the missed dose on C1D18, then the 
next dose for the subject is on C1D22. 
If the subject does not recover from an AE within 72 hours, the missed dose(s) should be 
skipped and the subject should receive the next dose as per original schedule. An example: a 
missed dose on C2D1 and the subject recovered on C2D9, the next dose for this subject is on 
C2D15. 
Every-2-weeks dosing schedule: 
If the subject recovers from an AE and is able to continue study drug within 1 week from the 
original scheduled dosing day then the subject 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 subject receives the next dose. An example: if the subject 
has an AE on C1D1 and recovers in time and can receive the missed dose latest on C1D8, then 
the next dose for the subject is on C1D15. 
Further dose delays or skipping is not allowed for subjects to recover from any AE. 
Further note, if an AE happens during the infusion, and the dose is interrupted, the subject can 
restart upon recovery to baseline or CTCAE v5.0 ≤Grade 1 within the same day of the event 
while keeping in mind the stability data of the AFM24 dose in the infusion bag (please refer to 


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the Pharmacy Manual for details as a new dose may have to be prepared depending on when 
the infusion was interrupted). If the subject already received ≥80% of the prescribed dose of 
that day at the time of the interruption or cannot recover within the same day of the event, the 
rest of the dose should be omitted. 
5.5 
Dose Modification 
During Phase 1, if a subject is tolerating AFM24 well (ie, no drug-related Grade ≥2 toxicity) 
without evidence of disease progression following 2 cycles, the subject 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.  
Subjects who experience a DLT during Cycle 1 must permanently discontinue AFM24. 
Dose reductions are not allowed. 
5.6 
Permitted and Restricted Concomitant Medications 
5.6.1 
Acceptable Concomitant Medications 
All treatments and supportive care that the Investigator considers necessary for a subject’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 5.6.2. All concomitant medication will be recorded in the subject’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 as mentioned in the SoA tables (see APPENDIX A [Section 14.1] and APPENDIX B 
[Section 14.2]). Concomitant medications administered after the Safety Follow-up visit should 
be recorded for SAEs which are considered related to study drug (Section 8.1). 
5.6.1.1 
COVID-19 Vaccination 
Various guidelines (eg, NCCN Guidelines: Cancer and COVID-19 Vaccination [NCCN 2021] 
and MHRA Guidance on Coronavirus [COVID-19] [MHRA 2021]) have noted that COVID-19 
vaccination should be prioritized for subjects with cancer with the understanding that there are 
limited safety and efficacy data in this subject 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 (ie, 20 mg 
of i.v. dexamethasone) for at least the duration of the first cycle (ie, Cycle 1). Therefore, for 
new subjects to be enrolled in the study, every effort should be made to vaccinate subjects 
prior to being considered for this study based on the Investigator’s risk/benefit analysis for 
each subject. Any COVID-19 vaccination should be at least 2 weeks prior to C1D1; live 
attenuated vaccines at least 4 weeks prior to C1D1. 


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For subjects whose opportunity for COVID-19 vaccination arrives during the conduct of 
the study (ie, ongoing subjects in the study), the following should be noted: 
• COVID-19 vaccination should be avoided during the DLT period or Cycle 1 of the 
study period. 
• As stated in Section 5.3, Investigators may taper premedication with corticosteroids for 
those subjects who do not experience IRR/CRS symptoms Grade >1 during the 
previous infusion starting with the third subsequent infusion (C1D15 for weekly dosing 
schedule and C2D1 for q2w schedule).  
• If the vaccination opportunity falls within the mandatory corticosteroid premedication 
period, there should be a consideration by the Investigator for holding or tapering the 
corticosteroid to prioritize vaccination on a case-by-case basis based on the risk/benefit 
analysis by the Investigator/treating MD.  
• COVID-19 vaccination is not permitted on AFM24 dosing days. Vaccination should be 
administered at least 3 days before or 3 days after the AFM24 treatment administration 
day. 
• It should be noted that no planned dose delays for study drugs are allowed during the 
DLT period (ie, Cycle 1).  
5.6.2 
Prohibited Concomitant Medications 
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
study. If there is a clinical indication for any medication specifically prohibited during the 
study, discontinuation from study drug may be required. The Investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the Investigator and/or the subject’s primary physician. However, in such cases, the 
decision to continue the subject on AFM24 study drug requires the mutual agreement of the 
Investigator, Sponsor, and subject. 
Apart from the exceptions listed in the inclusion/exclusion criteria, subjects are prohibited from 
receiving the following therapies during the Screening (see Exclusion Criteria Section 4.2) and 
Treatment periods of this study, with exception of the treatment of AEs occurring during the 
study: 
• Antineoplastic systemic chemotherapy or biological therapy;  
Exceptions: LHRH agonists/antagonists, bisphosphonates, and RANK ligand 
inhibitors will only be allowed during the study provided that the treatment was 
started prior to the study and the subject has been on a stable dose for at least 3 
months (i.e., ≥3 months) from first day of study drug. Additionally, LHRH 
agonists should not be discontinued during the study. 
• Immunotherapy not specified in this protocol; 
• Investigational agents other than AFM24; 
• Radiation therapy; 
• Immunosuppressant drugs such as systemic glucocorticoids (high-dose steroids 
defined as ≥10 mg prednisone or equivalent per day, exceptions see below), Janus 
kinase inhibitors (e.g., tofacitinib), calcineurin inhibitors (e.g., cyclosporine), mTOR 
inhibitors (e.g., sirolimus), IMDH inhibitors (e.g., azathioprine), biologics (e.g., 


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etanercept), monoclonal antibodies (e.g., infliximab); 
• Systemic glucocorticoids for any purpose other than to prevent IRR/CRS and/or to 
modulate symptoms from an AE of suspected immunological etiology.  
Exceptions:  
• Topical (≤20% of the skin surface area), ocular, intra-articular, intranasal, 
or inhalation corticosteroids with minimal systemic absorption 
• A short course (≤7 days) of corticosteroids prescribed prophylactically (e.g., 
for contrast dye allergy or antiemetic therapy) or for treatment of non-
autoimmune causes (e.g., delayed hypersensitivity reaction caused by 
contact allergen)  
• Physiological replacement doses of corticosteroids for adrenal or pituitary 
insufficiency 
• Corticosteroid use for the management of symptoms of IRR/CRS is 
permitted 
Subjects who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
Subjects may receive other medications that the Investigator deems to be medically necessary. 
5.7 
Blinding and Procedures for Unblinding the Study 
This is an open-label study, and there are no procedures for blinding and unblinding. 
5.8 
Management of AFM24-Related Toxicities 
Any DLT during Cycle 1 in the Phase 1 part: Permanently discontinue AFM24.  
Please see APPENDIX F (Section 14.6) for a summary of management of IRR/CRS, and other 
AFM24-related AEs. 
Fever: Subjects who develop fever during AFM24 treatment should be supported with 
antipyretic medications such as paracetamol or metamizole-sodium. If the subject develops 
high fever (above 40°C body temperature) physical cooling of the body, e.g., with cold packs 
should be considered. AFM24 treatment is recommended to be held for subjects who have 
body temperature ≥38°C until temperature normalizes below 38°C. 
Cytokine release syndrome: See APPENDIX F (Section 14.6; grading and management of 
IRRs, CRS, and other AFM24-related AE) for detailed grading criteria and detailed guidance 
on management.  
Dermatological toxicities: Investigators are asked to pay special attention to ALL 
dermatological toxicities and consult with a dermatologist if needed. In cases of ≥Grade 3 skin 
toxicity, AFM24 treatment should be interrupted or postponed until the reaction resolves to 
≤Grade 1 or baseline. Subjects should be asked to limit direct sunlight exposure and apply 
protective sun cream during treatment with AFM24. A rechallenge should be considered at the 
discretion of the Investigator but AFM24 should be permanently discontinued with a 
recurrence of Grade 3 skin toxicity. 
IRRs: See APPENDIX F (Section 14.6; grading and management of IRs, CRS, and other 
AFM24-related AEs) for detailed grading criteria and detailed guidance on management. 


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Electrolyte abnormalities: Consider withholding AFM24 for ≥Grade 2 electrolyte 
abnormalities and resume when resolved. Replenish electrolytes as medically appropriate.  
Pulmonary symptoms: In the event of acute onset or worsening of pulmonary symptoms, 
interrupt AFM24 therapy. Discontinue AFM24 therapy if interstitial lung disease is confirmed. 
Hepatotoxicity: If severe (CTCAE Grade ≥3) hepatic impairment develops for subject 
with/without liver metastasis, AFM24 should be discontinued permanently.  
Gastrointestinal Perforation: Permanently discontinue AFM24 in subjects 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. 
6.0 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1 
Provision and Replacement of AFM24 
Sufficient doses of AFM24 study drug will be supplied. Where study 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 study drug at site will be 
described in the Pharmacy Manual. 
6.2 
Labeling of AFM24 
AFM24 clinical study supplies will be labeled in compliance with Good Manufacturing 
Practice Annex 13 requirements, United States (US) FDA requirements, and any other 
applicable local regulatory guidelines. 
6.3 
Storage of AFM24 
AFM24 study drug 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.  
6.4 
Drug Accountability 
The Investigator is obliged to keep sufficient documentation of the delivery, use, and 
destruction or return of unused, used, or partially used AFM24 study drug. The documentation 
must include dates, quantities, subject numbers, batch numbers, 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 subjects were 
administered the doses specified in the protocol and reconcile all AFM24 study drug 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. 


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AFM24 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 AFM24 are correctly received by a responsible person; 
• 
Such deliveries are recorded; 
• 
Study drug is handled and stored safely and properly as stated on the label; 
• 
Study drug is only dispensed to study subjects in accordance with the protocol; and 
• 
Any unused study drug 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. To help with 
compliance checks, records of usage should include an appropriate form of identification of 
the subject to whom the study drug was dispensed (using an indirect form to allow cross 
reference to the subjects’ 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. 
7.0 
STUDY PROCEDURES 
The schedule of assessments to be followed for weekly and q2w dosing regimens are provided 
in APPENDIX A [Table 11 through Table 15] and APPENDIX B [Table 16 through Table 18], 
respectively.  
Safety will be assessed by periodic vital signs, physical examinations, ECOG PS, 12-lead 
ECGs, clinical laboratory assessments, and monitoring of AEs. AEs will be graded using the 
NCI CTCAE, v5.0 (NCI 2017). 
All AEs and SAEs that are related to study procedures occurring during pre-screening as well 
as all AEs and SAEs occurring from the time the subject signs the main ICF up to and including 
the Safety Follow-up visit (30 days [±5 days] after the last administration of AFM24) or until 
the start of a new anti-cancer treatment, whichever is sooner, will be collected. Adverse events 
occurring after signing of the Main ICF but prior to the first dose of study drug shall be recorded 
on the Medical History eCRF page (Note: any SAEs which are related to study procedures and 
occur during pre-screening and any SAEs that occur after the subject signs the Main ICF and 
prior to the first dose of study drug will still be reported using the SAE form). 
7.1 
Volume of Blood Sampling 
Total blood volumes required during study participation will be provided in the ICF provided 
to each subject. Efforts will be made to limit blood sampling to avoid any redundancy. The 
requirements for blood sampling will be described and maintained in the Lab Manual. 
7.2 
Description of Study Interventions and Assessments 
Details of the procedures to be followed for specified study assessments for weekly and q2w 
dosing regimens are provided in APPENDIX A (Section 14.1) and APPENDIX B 


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(Section 14.2), respectively. During the study, additional assessments may be carried out as 
clinically indicated. 
7.2.1 
Informed Consent, Medical History, and Demographics 
Before starting the pre-screening process (for subjects in Phase 2a) or screening process, 
written informed consent will be obtained. Demographic information will be collected during 
the Screening visit. There will be a baseline assessment of relevant medical history and cancer 
history conducted at Screening to confirm eligibility and to record significant medical history 
and concurrent illnesses. Concurrent illnesses recorded at Screening (excluding the primary 
disease under evaluation) that worsen in severity or frequency from this baseline assessment 
during the study should be reported as AEs (see Section 8.1). 
7.2.2 
Pregnancy and FSH tests 
Female subjects of reproductive potential will have a pregnancy test carried out at Screening 
and at time points specified in the SoA tables (APPENDIX A [Section 14.1] and APPENDIX B 
[Section 14.2] for weekly and q2w, dosing regimens, respectively). This test must be carried 
out within 7 days prior to first AFM24 administration. A urine test is acceptable; however, 
where a urine test is equivocal, a blood test must be performed to confirm the result. Subjects 
confirmed as pregnant will be excluded from participation in the clinical study. 
Female subjects of reproductive potential with a negative pregnancy test at screening will 
continue to have pregnancy tests conducted at least every 4 weeks during the study and at the 
End of Treatment visit. 
Female subjects who require documented confirmation of post-menopausal status will have 
their FSH levels assessed at Screening. Where post-menopausal status is not confirmed, 
subjects will be required to undergo pregnancy testing per protocol to confirm suitability to 
proceed. 
7.2.3 
ECOG Performance Score 
ECOG PS will be assessed at Screening and Day 1 of each treatment cycle. Details of the 
ECOG PS categories are presented in APPENDIX C (Section 14.3). Subjects must be 
confirmed as ECOG PS 0 or 1 to be eligible for study participation and then reconfirmed at 
Day 1 of each cycle. 
7.2.4 
Vital Signs 
Frequent monitoring of the subject’s vital signs during and after AFM24 infusion is 
implemented as a precautionary measure in this protocol. 
Vital sign parameters will be taken at Screening and at timepoints specified in the Schedule of 
Assessments Tables (APPENDIX A [Section 14.1] for weekly dosing schedule; APPENDIX B 
[Section 14.2] for q2w dosing schedule). The date and time of collection will be recorded in 
the source document and in the eCRF. 
Vital sign parameters will consist of measurements of temperature, resting heart rate, seated 
blood pressure (systolic/diastolic) after 5 minutes resting, oxygen saturation, and respiratory 
rate (Table 5).  
If no signs or symptoms of CRS or IRR (no >Grade 1) are observed during or after the first 2 
infusions of AFM24, beginning from the third subsequent infusion (i.e., C1D15 for weekly 


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schedule and C2D1 for every-2-weekly schedule) the observation period after the end of 
infusion may be reduced from 4 hours to a minimum of 2 hours post infusion. The recording 
schedule of vital signs parameters is described in Table 5. 
Table 5: 
Recording Schedule of Vital Sign Parameters 
 
Vital sign timepoints for first 2 
consecutive AFM24 dosing days 
(i.e., Cycle 1 Day 1 and Day 8) 
Vital sign timepoints for subsequent 
AFM24 dosing days  
(i.e., Cycle 1 Day 15 and beyond) a,b 
Before 
infusion 
Baseline (within 1 hour before start of 
the infusion) 
Baseline (within 1 hour before start of 
the infusion) 
During 
infusion 
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 b  
As clinically indicated b 
 
After infusion 
+60 (±10) minutes post EOI 
Every 60 (±10) minutes thereafter until 
the end of the observation period 
As clinically indicated b 
CRS = cytokine release syndrome; EOI = end of infusion; IRR = infusion related reaction. 
Note: in addition to the above listed time points, subjects should be additionally monitored in accordance with 
the institutional guidelines/clinical practice and as clinically indicated. 
In case of split dosing, vital signs assessments at similar timepoints need to be done on both days. 
a  If no CRS or IRR (no Grade >1) events are observed during or after the first 2 consecutive AFM24 dosing days, 
then a reduced schedule of vital signs assessments may be followed as indicated for Cycle 1 Day 15 and beyond.  
b  In case of the occurrence of Grade >1 events of CRS or IRR at a later infusion (ie, on Cycle 1 Day 15 or beyond), 
then the same schedule for increased vital signs assessments should be performed as done for Cycle 1 Day 1 
and Cycle 1 Day 8. If, after two consecutive infusions, the patient does not have an IRR event Grade > 1, then 
a reduced schedule of vital signs assessments may be followed. 
7.2.5 
Physical Examinations 
A physical examination will be performed at screening and at timepoints specified in the SoA 
tables (APPENDIX A [Section 14.1] for the weekly dosing regimen; APPENDIX B 
[Section 14.2] for q2w dosing regimen). 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 and at timepoints specified in the SoA tables 
(APPENDIX A [Section 14.1]; APPENDIX B [Section 14.2]). Weight will be measured within 
24 hours of administration of AFM24 on Day 1 of each cycle. Height and body weight will be 
obtained while the subject 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. 
7.2.6 
Clinical Chemistry, Hematology, Urinalysis, Coagulation 
Blood and urine samples for determination of clinical chemistry, hematology, urinalysis, and 
coagulation parameters will be taken as described in the SoA tables (APPENDIX A 
[Section 14.1] for weekly dosing schedule and APPENDIX B [Section 14.2] for q2w dosing 
schedule). Subjects must demonstrate adequate organ function when assessed within 14 and 
7 days before first AFM24 infusion to remain eligible as outlined in the inclusion criteria 
(Section 4.1). Clinical chemistry, hematology, urinalysis, and coagulation samples must be 


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taken within 24 hours of AFM24 infusion start on days when AFM24 is administered. In case 
a subject receives AFM24 as a split dose then the time period ‘within 24 hours’ refers to the 
first day of infusion onset (ie, if infusion is given as split dose on both Day 1 and Day 2 [in 
weekly dosing regimen], then these samples need to be collected within 24 hours of AFM24 
infusion start on Day 1). 
Hepatitis B, hepatitis C, and HIV serology testing will be performed at Screening. 
The laboratory variables to be measured are described in APPENDIX D [Section 14.4]. 
Copies of laboratory accreditation certificates and reference ranges will be obtained from each 
study site prior to analysis of their first subject 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. 
7.2.7 
Electrocardiogram 
A resting 12-lead ECG will be performed at timepoints specified in the SoA tables 
(APPENDIX A [Section 14.1] for weekly dosing schedule and APPENDIX B [Section 14.2] 
for q2w dosing schedule). For Phase 1 only, triplicate 
 
 ECGs should be taken at least 5 minutes apart before infusion and within approximately 15 
minutes after the end of infusion (note plus only). For Phase 2a, ECGs will be performed in 
triplicate at least 5 minutes apart at the Screening visit only; all subsequent ECGs will be 
performed as single ECGs.  
For those occasions when both an ECG and peripheral blood sample (PK and PD [cytokines]) 
collection are required at the EOI of AFM24 (ie, Cycle 1 Day 1 and Day 22), the blood draw 
must be completed first, as close to the EOI as possible, followed by the ECG. Both procedures 
should be completed within approximately 15 minutes after the EOI (note plus only). 
All 12-lead ECGs should be recorded while the subject 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 subjects. 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. 
In addition, an unscheduled ECG might be performed at any time if clinically indicated. 
7.2.8 
Pharmacokinetic Assessments 
The PK profile will be assessed by determining serum levels of AFM24 at intervals throughout 
the study, as described in the Schedules of Pharmacokinetic, Pharmacodynamic, 
Immunogenicity, and Translational Assessments (APPENDIX A, Section 14.1 [Table 12 
through Table 15] for weekly dosing regimen schedule and APPENDIX B, Section 14.2 [Table 
17 and Table 18] for q2w dosing schedule). 


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The nominal PK blood sampling times requested should be adhered to as closely as possible. 
It is essential that the actual date and time of collection of each blood sample is recorded in the 
subject’s records and the eCRF. 
The pre-dose PK sample collected on C1D1 may also be used for the determination of 
soluble EGFR; high soluble EGFR levels at baseline might lead to faster AFM24 clearance. 
Full details of the PK blood sample collection, processing, and handling for PK samples will 
be described in the Lab Manual for the study.  
7.2.9 
Pharmacodynamic Assessments  
Serum and peripheral blood mononuclear cells will be collected as described in the Schedule 
of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and Translational Assessments 
(APPENDIX A, Section 14.1 [Table 12 through Table 15] for weekly dosing schedule; 
APPENDIX B, Section 14.2 [Table 17 and Table 18] for q2w dosing schedule). PD 
assessments will be performed by measuring cytokine levels (see Section 7.2.13) and various 
lymphocyte subsets including NK cells, activated NK cells, and macrophages. 
Blood PD markers will be assessed as described in the Schedule of Pharmacokinetic, 
Pharmacodynamic, Immunogenicity, and Translational Assessments (APPENDIX A 
[Section 14.1] for weekly dosing schedule and APPENDIX B [Section 14.2] for q2w dosing 
schedule). Please see the Lab Manual for full details of sample collection and handling. 
7.2.10 
CD16A Receptor Occupancy 
CD16A receptor occupancy by AFM24 on NK cells in the peripheral blood will be measured 
in Phase 1 subjects only as described in the Schedule of Pharmacokinetic, Pharmacodynamic, 
Immunogenicity, and Translational Assessments (APPENDIX A [Section 14.1] for weekly 
dosing schedule and APPENDIX B [Section 14.2] for q2w dosing schedule). 
7.2.11 
Disease Response Assessment 
Disease response will be assessed by the Investigator, using local RECIST v1.1 (Eisenhauer et 
al., 2009; Schwartz et al., 2016) and Response Evaluation Criteria in Solid Tumors for 
immunotherapy (iRECIST) (Seymour et al., 2017). In Phase 1 and 2a, imaging results will also 
be sent for independent central review. Tumor assessment with CT and/or MRI will occur at 
Screening as well as at timepoints specified in the SoA tables (APPENDIX A [Section 14.1] 
for weekly dosing schedule and APPENDIX B [Section 14.2] for q2w dosing schedule). Partial 
or complete response needs to be confirmed with repeated assessment at least 4 weeks after the 
initial assessment.  
If initial radiological progressive disease is observed, while the clinical condition of the subject 
is stable, treatment continuation is allowed at the discretion of the Investigator. If treatment is 
continued after initial progressive disease, a confirmatory scan should be acquired within 4 to 
6 weeks. However, the first successive scheduled timepoint after the confirmatory scan may 
be skipped if the window is considered not clinically relevant (up to the discretion of the 
Investigator). 
7.2.12 
Tumor Genomics and Tumor Biopsy 
Blood samples for the assessment of tumor genomics from circulating tumor DNA will be 
taken as described in the Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, 


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and Translational Assessments (see APPENDIX A [Section 14.1] for weekly dosing schedule 
and APPENDIX B [Section 14.2] for q2w dosing schedule). Analysis will measure 
quantitatively the amount of circulating tumor DNA and a search will be done for known 
targetable tumor mutations (such as but not limited to known mutations in EGFR, anaplastic 
lymphoma kinase, BRAF genes). Full details of sample collection and handling of the sample 
will be described in the Lab Manual for the study.  
For Phase 1 only: An initial tumor biopsy will be performed at Screening and 1 tumor biopsy 
will be performed during treatment with AFM24 on Day 24 of Cycle 1 (see SoA tables 
APPENDIX A [Section 14.1] for weekly dosing schedule and APPENDIX B [Section 14.2] 
for q2w dosing schedule). Tumor biopsies are mandatory for subjects in escalation phase 
(Phase 1). Tumor samples will be evaluated centrally to assess EGFR positivity of cancer cells, 
infiltrating NK cells and macrophages and their subpopulations, and additional markers.  
For Phase 2a only: for diagnostic purposes, a tumor biopsy at pre-screening is needed for EGFR 
assessment if there is no archived tumor tissue available. Tumor biopsies for central lab 
analysis are not collected in the expansion phase. 
Samples will be used only for purposes related to this research. Unused samples of subjects 
who separately consented to long-term storage will be stored up to maximum of 15 years or 
until the Sponsor has determined that specimens are no longer needed, and the decision has 
been made that none of the samples needs to be reanalyzed, whichever is sooner. In addition, 
samples can be destroyed at any time at the request of the subject.  
7.2.13 
Cytokines 
All subjects will have blood samples taken to assess cytokine levels as part of the PD 
assessment at the time points described in the Schedule of Pharmacokinetic, 
Pharmacodynamic, Immunogenicity, and Translational Assessments (APPENDIX A 
[Section 14.1], for weekly dosing schedule and APPENDIX B [Section 14.2] for q2w dosing 
schedule). Samples collected for cytokine analysis may also be used for measurement of 
chemokines and/ or soluble receptors. 
In case of suspected CRS or IRR or any anaphylactic reaction during or close to AFM24 
infusion, a sample for central laboratory testing should be drawn. Sampling should occur at the 
first sign of the AE and 1 hour later to assess cytokine changes. In addition, local cytokine 
testing is recommended as clinically indicated and in accordance with institutional treatment 
guidelines. 
Full details of sample collection and handling of cytokine samples will be described in Lab 
Manual for the study. 
7.2.14 
Antidrug Antibodies 
All subjects will have blood samples drawn to assess for antidrug antibodies as described in 
Schedule of Pharmacokinetic, Pharmacodynamic, Immunogenicity, and Translational 
Assessments (APPENDIX A [Section 14.1] for weekly dosing schedule and APPENDIX B 
[Section 14.2] for q2w dosing schedule). Antidrug antibody samples should be taken just 
before administration of AFM24. 
Full details of sample collection and handling of antidrug antibody samples will be described 
in the Lab Manual. 


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8.0 
ASSESSMENT OF SAFETY 
All subjects who receive treatment with AFM24 will be considered evaluable for safety. All 
AEs and SAEs that are related to study procedures occurring during pre-screening as well as 
all AEs and SAEs occurring from the time the subjects sign the Main ICF up to and including 
the Safety Follow-up visit (30 days [±5 days] after the last administration of AFM24 or before 
start of any new anti-cancer treatment whichever is sooner) will be collected. Detailed 
instructions on how to record/report AEs are provided in Section 8.1.3. 
8.1 
Adverse and Serious Adverse Events 
8.1.1 
Definition of Adverse Events  
An AE is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a subject or clinical investigation subject 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, whether considered related or unrelated to 
AFM24. 
During clinical studies, AEs can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. To prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of 1 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) 
Adverse Events Expected Due to Disease Progression 
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.  
Example, a subject 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) event.  
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. 


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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. 
8.1.2 
Importance of Adverse Event Reporting 
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 subjects; 
• 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. 
8.1.3 
Evaluating Adverse Events 
During pre-screening, only AEs which are related to study procedures (e.g., a biopsy) should 
be collected. The AEs must be recorded and described on the appropriate AE page of the eCRF 
Following the subject’s written Main consent to participate in the study and up to the 30-day 
Safety Follow-up Visit, all AEs should be collected.  
Adverse events that occur following signing of the Main ICF but prior to the first dose of study 
drug shall be recorded on the Medical History page of the eCRF.  
Adverse events occurring after the subject signs the Main ICF and at/after the first dose of 
study drug and up to the 30-day Safety Follow-up Visit must be recorded and described on the 
appropriate AE page of the eCRF. (Note: any SAEs that are related to study procedures and 
occur during pre-screening and any SAEs that occur following signing the Main ICF and prior 
to the first dose of study drug will still be reported using the SAE form). Where known, the 
diagnosis of the underlying illness or disorder shall be recorded, rather than listing individual 
symptoms. 
Please refer to Table 6, which describes the timelines of AE/SAE reporting and documentation 
in the eCRF. 
The following information shall be captured for all AEs: date of onset and resolution, 
seriousness and seriousness criteria, severity of the event, causality assessment, treatment 
required for the AE, action taken with study drug, and information regarding 
resolution/outcome. 


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Table 6: 
Reporting of Adverse Events 
 
… between Pre-
Screening ICF and 
Main ICF 
… between Main ICF 
and first infusion 
… at/after first 
infusion 
AE unrelated to Study 
Procedure occurs … 
no documentation 
needed 
document in medical 
history 
document as AE 
AE related to Study 
Procedure occurs … 
document as AE 
document in medical 
history 
document as AE 
SAE unrelated to 
Study Procedure 
occurs … 
no documentation 
needed 
document as SAE 
document as SAE 
SAE related to Study 
Procedure occurs … 
document as SAE 
document as SAE 
document as SAE 
Abbreviations: AE = adverse event; ICF = informed consent form; SAE = serious adverse event 
8.1.4 
Definition of Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose causes or qualifies as 
the following: 
• Results in death; 
• Is life-threatening; 
o “Life-threatening” means that the subject 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 
subject or may require intervention to prevent 1 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 


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emergency room or at home, blood dyscrasias, convulsions that do not result in 
inpatient hospitalization, or repeated IRRs. 
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 3.4.2) are considered as important 
medical events and should be reported as an SAE. 
All SAEs will be followed until resolution, the condition stabilizes or is considered chronic, 
the event is otherwise explained, or the subject is lost to follow-up or withdraws consent. 
8.1.5 
Severity 
All AEs (including SAEs) are to be accurately recorded on the AE page of the subject’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. 
8.1.6 
Unexpected Adverse Events 
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 IB. 
8.1.7 
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 using the following definitions described in Table 7. 
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 study drug. In case of disagreement between the Investigator and the Sponsor, 
the more conservative assessment will determine the reportability of the case. 


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Table 7: 
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 subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject. 
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 subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject. 
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 
subject’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the subject. 
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 (eg, 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 
subject’s clinical state, environmental or toxic factors, or other modes of 
therapy administered to the subject. 
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 subject, however, a category of definitely related can only be used when 
a recurrence is observed.)  


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Relationship 
Description 
4. It follows a known pattern of response to the test drug. 
AE = adverse event. 
8.2 
Reporting Serious Adverse Events and Adverse Events of Special Interest  
Investigators must report SAEs which are related to study procedures and occur during 
prescreening and SAEs/adverse events of special interest (AESIs) occurring from the time the 
subject signs the Main ICF up to 30 days after the last administration of AFM24 or until the 
start of a new anti-cancer treatment, whichever is sooner, to the Sponsor or delegate within 24 
hours of becoming aware of the event, by entering all required information in to the Electronic 
Data Capture (EDC) system by completing an electronic Case Report Form (eCRF) in 
accordance with the eCRF completion guidelines. Upon completion of the eCRF and 
submission of the eCRF, an automated notification will be triggered and will be received by 
the safety service provider and Sponsor.   
In the unlikely event of a malfunction of the eCRF, sites are provided with paper-based 
SAE/AESI reporting forms; forms will be completed by the study Investigator and e-mailed 
within 24 hours to Affimed-PhV@spm2-safety.com. The Investigator shall ensure that the 
information is entered in the eCRF as soon as the eCRF technical issues are resolved.  
(Note: Any SAEs that are related to study procedures and occur during pre-screening and any 
SAEs that occur following signing the Main ICF and prior to the first dose of study drug will 
still be reported using the SAE form). 
Other supporting documentation of the event may be requested by the Sponsor or delegate and 
should be provided as soon as possible in an anonymized manner. Follow-up information about 
a previously reported SAE/AESI must be reported within the same applicable timeframe of 
receiving it. All SAEs/AESIs will be followed up until resolution or stabilization at a level 
acceptable to the Investigator and/or the Sponsor.  
The Investigator is not responsible for actively seeking new SAEs after the follow-up period; 
however, if the Investigator becomes aware of an SAE that is reasonably associated with 
study treatment after the study period including follow up, this must be reported to the 
Sponsor.  
8.3 
Other Important Events for Immediate Reporting 
Adverse events meeting the following criteria, although not categorized as ‘serious’ per 
International Council for Harmonisation (ICH) definition, are reportable to the Sponsor in the 
same timeframe as SAEs to meet certain local requirements and the study needs: 
• A new cancer (that is not a condition of the study); 
• A reported pregnancy or lactation after receipt of study drug and for ≤60 days from last 
dose; and 
• An overdose (defined as a dose of AFM24 which is ≥10% above the intended daily 
dose or a dose interval <4 days between 2 consecutive doses). 
Such events must be reported within 24 hours to the Sponsor either by electronic report or 
paper.  


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8.3.1 
Adverse Events of Special Interest 
Infusion-Related Reactions  
The occurrence of IRRs is within the anticipated safety profile of AFM24, considering 
experiences with other EGFR and CD16 targeting agents.  
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. 
In order to increase the understanding of IRRs, these events are considered to be AESIs. This 
means:  
• Any of these events should be reported within 24 hours of occurrence. 
• The SAE form should be used. 
• All symptoms suggesting an IRR should be mentioned. 
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.  
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 SAE. 
8.3.2 
Exposure During Pregnancy or Lactation 
Pregnancy and breastfeeding are considered exclusion criteria for this study (Section 4.2). 
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 subject (spontaneously 
reported to them) or pregnancy in a subject’s partner that occurs during the study. Immediately 
discontinue AFM24 treatment permanently in case of pregnancy. 
Pregnancies and lactations that occur in subjects after the ICF is signed but before starting 
study drug must be reported by the Investigator if they cause the subject to be excluded from 
the study. Pregnancies and lactations that occur in a study subject or a pregnancy in a subject’s 
partner from the time of first study drug through to 60 days following cessation of AFM24 
study drug, 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 ie, 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 via email, fax, or telephone. The 
reporting procedures can be found in the SAE completion guidelines located in the Study 
Operations Manual (or equivalent). 


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8.3.3 
Misuse, Medication Error, and Overdose 
Study drug misuse, medication error, or overdose should be reported in the same format and 
within the same timelines as an SAE, even if they may not result in an adverse outcome. In the 
event of overdose, the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
Overdose is defined as: >10% above the intended AFM24 planned dose is given or a dose 
interval <4 days between 2 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. 
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 subject. 
Misuse is defined as: Situations where an investigational medicinal product is intentionally 
and inappropriately used not in accordance with the terms of the current protocol. 
8.3.4 
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. 
8.4 
Follow-Up Information on an SAE 
Collection of complete information concerning SAEs is extremely important. Thus, follow-up 
information that becomes available as the SAE evolves, as well as supporting documentation 
(eg, hospital discharge summaries and autopsy reports), should be collected subsequently if not 
available at the time of the initial report and immediately sent using the same procedure as the 
initial SAE report. The Sponsor (or their delegate) will also review SAE reports for missing 
information and send queries to the site for resolution as appropriate. 
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. 
Reporting of Serious Adverse Events to Regulatory Authorities 
In accordance with the US Code of Federal Regulations (CFR), Title 21 CFR Part 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 relationship. In case of 


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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 (eg, 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 
should 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. 
 
9.0 
STATISTICS 
9.1 
Analysis Sets 
The safety set will consist of all subjects who received at least 1 dose of AFM24. The safety 
set will be the primary population for all safety-related endpoints except determination of the 
dose-DLT relationship, and for all efficacy related endpoints. 
The DDS will consist of all subjects in the safety set who have either (a) experienced a DLT at 
any time during Cycle 1, or (b) met the minimum treatment and safety evaluation requirements 
without experiencing DLT within Cycle 1 (DLT evaluation period). 
At least 2 subjects will be treated in each of the first 2 dose cohorts of AFM24. For all other 
dose cohorts, at least 3 subjects per cohort will be treated. The DDS will be used for 
determination of the MTD. The minimum treatment and safety evaluation requirements will 
have been met if the subject received ≥80% of their assigned AFM24 dose in Cycle 1 and 
completed the 28-day DLT observation period or have had a DLT within the first cycle of 
treatment to be considered evaluable for DLT. For the first 2 dose cohorts, at least 2 subjects 
are required to be evaluable for DLT for dose escalation to occur. For subsequent cohorts, at 
least 3 subjects are required to be evaluable for dose escalation to occur. 
The DDS will be used in the BLRM to estimate the dose-DLT relationship. 
The PK set consists of all subjects who have received at least 1 adequately documented dose 
of study drug and have at least 1 adequately documented post-dose PK measurement. 
Subjects who were screened and have signed the informed consent but did not receive any 
treatment will be listed including reason for screening failure and any SAE that is related to 
study procedure. These subjects will not be part of any summary table except for summarizing 
disposition. 


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9.2 
Missing Data/Discontinuation 
Due to the dose escalation design of Phase 1 and the exploratory design of Phase 2a of the 
study, no imputation of missing values will be done for any analysis (except the imputation for 
missing partial dates of AEs, response assessments and concomitant medications). Reasons for 
discontinuation from the study and the study drug will be listed and summarized. 
Currently, no drop out during the treatment period is foreseen. However, in the first 2 cohorts 
of Phase 1 (dose escalation), subjects will be replaced (ie, additional subjects will be added to 
the cohort) if <2 subjects are evaluable for DLT assessment. In the subsequent cohorts subjects 
will be replaced if <3 subjects are evaluable for DLT assessment. In the dose expansion phase 
(Phase 2a). all patients in the safety set will not be replaced, independent of the availability of 
their post-baseline disease assessments. 
9.3 
Statistical Analyses 
9.3.1 
Characteristics Demographics, Medical History, Prior Medication, and 
Other Baseline  
Demographic characteristics, prior anti-cancer therapies and surgeries, medical history, prior 
medication, and other baseline data will be listed and summarized using descriptive statistics 
for numerical data and contingency tables for categorical data. Medical history and prior 
medication will be listed. Prior anti-cancer therapies will be coded by World Health 
Organization Anatomical, Therapeutic and Chemical terms and summarized. Prior cancer 
surgeries will be summarized. 
9.3.2 
Study Drug 
Exposure to AFM24 will be summarized with descriptive statistics for the total number of 
infusions received. The total amount of time on AFM24 (duration of dosing in weeks) will also 
be derived and summarized. The number of infusions with interruptions (regardless of reason) 
will be summarized by dose cohorts and total.  
9.3.3 
Concomitant Medication 
Concomitant medication and significant non-drug therapies after the start of study drug will be 
listed and summarized by World Health Organization Anatomical, Therapeutic and Chemical 
term in contingency tables. 
9.3.4 
Primary Analysis 
9.3.4.1 
Phase 1 (Dose Escalation) 
An adaptive BLRM guided by the EWOC principle will be used in the dose escalation. The 
use of Bayesian response adaptive models for Phase 1 studies has been advocated by the 
European Medicines Agency adopted guideline on small populations (EMA, 2006) and by 
(Rogatko et al., 2007) and is one of the key elements of the FDA’s Critical Path Initiative. 
A 2-parameter BLRM (Neuenschwander et al., 2008) will be used for dose escalation of the 
monotherapy. Standardized doses will be used such that 1 of the doses (d*) equals 1, eg, doses 
are rescaled as d/d*. Consequently, α is equal to the odds of the probability of toxicity at d*. 
All information currently available about the dose-DLT relationship of AFM24 is summarized 
in a prior distribution. For this study, this includes preclinical data about the starting dose and 
predicted MTD of AFM24 within different animal species. This prior distribution is then 
updated after each cohort of subjects with all the DLT data available in the DDS from the 


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current study. Once updated, the distribution summarizes the probability that the true rate of 
DLT for each dose lies in the following categories: 
• 0% to <16%: under-dosing; 
• ≥16% to <33%: targeted toxicity; and 
• ≥33% to 100%: excessive toxicity. 
The EWOC principle (Babb et al., 1998; Neuenschwander et al., 2008) mandates that any dose 
of AFM24 that has more than a 25% chance of being in the excessive toxicity category is not 
considered for the next dose cohort. A clinical synthesis of the available toxicity information 
(including AEs that are not DLTs), PK, PD, and efficacy information as well as the 
recommendations from the Bayesian model, and the SRC will be used to determine the dose 
regimen for the next cohort at a dose-escalation teleconference. In any case where there is a 
change in dose schedule, a new model will be defined using a Meta-Analytic-Predictive prior, 
based on the observed data. 
The frequency of DLTs will be tabulated by dose for subjects in the dose escalation phase 
(Phase 1) (especially for Cycle 1 and subjects in the DDS as the primary endpoint tabulation) 
and information about all DLTs will be listed by dose. 
Bayesian Logistic Regression Model for MTD/RP2D Determination 
The objective of the design is to determine the MTD defined as the highest dose with less than 
25% risk of the true DLT rate being above 33%. The escalation Phase 1 dose-finding will be 
guided by a Bayesian 2-parameter logistic regression model with overdose control. These 
designs have been shown to be superior regarding the precision of MTD determination 
compared with 3+3 designs.  
The model is formulated as follows: 
logit(p(d)) = log(α) + β*log(d/d*), 
where logit(p) = log(p/(1-p)). p(d) represents the probability of having a DLT in the first cycle 
at dose d, d* =180 mg is the reference dose, allowing for the interpretation of α as the odds of 
a DLT at dose d*, and θ = (log(α), log(β)) with α, β >0 is the parameter vector of the model. 
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a multivariate normal 
distribution, ie, 
π(θ) = MVN(μ, Σ) 
the multivariate normal distribution with mean vector μ and covariance matrix Σ, with 
 
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Prior derivation 
For the current study, data from the non-clinical animal studies were available. Therefore, the 
observed toxicity data from a study in animals is used to derive the prior.  
Prior from nonclinical data: 
The starting dose of AFM24 will be 14.0 mg (200 µg/kg × 70 kg body weight), which is 
presumed to be at the lower end of the pharmacologically active dose range. No critical 
toxicities were observed in the cynomolgus toxicity studies up to the maximum applied AFM24 
dose level of 75 mg/kg and furthermore, the bispecific NK engagers (in contrast to bispecific 
T cell engagers) tested so far by Affimed in nonclinical and clinical studies, were all well 
tolerated up to high dose levels. It is therefore highly unlikely that a severe toxicity defined as 
DLT in this study would occur at this starting dose, leading to the prior assumption that the 
median DLT rate at 14 mg is 0.1%. On the other hand, assuming dose-proportionality in 
humans using a cautious approach, the median DLT rate at the highest planned dose = 1000 mg 
was therefore assumed 25%. 
Table 8: 
Summary of Prior Distribution 
Mean vector 
STD vector 
Correlation 
-1.983 -0.217 
2.000, 1.000 
0 
STD = standard deviation. 
A summary of the prior probabilities of DLT at different doses, as well as the corresponding 
probability of under-, targeted, and overdosing, are shown in Table 9. Graphically, the prior 
medians with accompanying 95% credible intervals are shown in Figure 3. As can be seen from 
both Table 9 and Figure 3, the prior medians of the DLT probabilities are in line with the prior 
median derived from the non-clinical studies.  
Table 9: 
Prior Probabilities of DLT at Selected Doses 
Dose 
Probability of true DLT rate in 
Mean 
STD 
Quantiles 
[0–0.16) 
[0.16–0.33) 
[0.33–1] 
2.5% 
50% 
97.5% 
7a mg 
0.888 
0.058 
0.054 
0.061 
0.138 
0.000 
0.006 
0.533 
14 mg 
0.859 
0.072 
0.069 
0.075 
0.153 
0.000 
0.011 
0.597 
40 mg 
0.795 
0.097 
0.108 
0.108 
0.182 
0.000 
0.026 
0.699 
120 mg 
0.655 
0.148 
0.196 
0.178 
0.227 
0.001 
0.074 
0.821 
360 mg 
0.538 
0.175 
0.288 
0.244 
0.261 
0.003 
0.134 
0.892 
1000 mg 
0.415 
0.166 
0.419 
0.342 
0.311 
0.005 
0.236 
0.974 
DLT = dose-limiting toxicity; STD = standard deviation. 
Doses printed in bold type meet the overdose criterion, P(overdose) <0.25.  
a Dose level -1 represents a dose that may be evaluated if dose level 1 is poorly tolerated. No dose de-escalation 
below this level is planned for this study. If dose-level -1 is poorly tolerated the study will be terminated. 
 


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Figure 3: 
Prior Medians and 95% Credible Intervals 
 
 
CrL = credible interval; MTD = maximum tolerated dose; RP2D = recommended Phase 2 dose. 
For MTD and/or RP2D definition, please refer to Section 3.4.3. 
Statistical model assessment 
The single agent model was assessed using 2 different metrics: 
Hypothetical data scenarios: for various potential data constellations as they could occur in 
the actual study, the maximal next doses as allowed by the model and by the 200% escalation 
limit are investigated. Data scenarios thus provide a way to assess the “on-study” behavior 
of the model. 
2. Simulated operating characteristics: these illustrate for different assumed true dose-toxicity 
relationships, how often a correct dose would be declared as MTD by the model. They are 
a way to assess the “long-run” behavior of the model. 
In summary, the model showed very good behavior as assessed by these metrics. More details 
can be found in Appendix E (Section 14.5). 
9.3.4.2 
Phase 2a (Dose Expansion) 
Once the MTD and/or at least one RP2D is determined, enrollment of subjects into 1 of several 
expansion cohorts for selected tumor indications may begin at the RP2D. The SRC may select 
an RP2D that is below the MTD, or if an MTD is not reached, an RP2D may be selected by 
the SRC after careful review of all available clinical and laboratory data from Phase 1. The 
RP2D will not exceed the MTD. 
The primary objective of the expansion phase is to determine preliminary efficacy as objective 
response (OR) using a Simon's two-stage design. The primary endpoint is based on the 
objective response assessed by local Investigator according to RECIST v1.1 (Eisenhauer et al., 
2009; Schwartz et al., 2016). The primary analysis will take place once all subjects per cohort 
had at least 1 confirmed response assessment (ie, ≥12 weeks post-baseline) or have been 
withdrawn from the study.  


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9.3.5 
Secondary Analyses 
9.3.5.1 
Phase 1 (Dose Escalation) & Phase 2a (Dose Expansion) 
9.3.5.1.1 
Efficacy Analyses 
All efficacy analyses will be done for Investigator assessed RECIST v1.1 (Eisenhauer et al., 
2009; Schwartz et al., 2016), Investigator assessed iRECIST (Seymour et al., 2017), Central 
assessed RECIST v1.1 and Central assessed iRECIST. The local Investigator assessed RECIST 
is the primary endpoint for the Phase 2a. 
9.3.5.1.1.1 
Overall Response Rate 
Overall response as defined by achieving confirmed CR and/or PR assessed by RECIST v1.1 
will be presented by percentage rates and where appropriate the 95% confidence intervals 
(CIs). Partial or complete response needs to be confirmed with repeated assessment at least 
4 weeks after the initial assessment. For changes in solid tumor size waterfall plots will be 
presented. For all response assessments swimmer plots will be presented. All response 
assessments will be listed. 
9.3.5.1.1.2 
Disease Control Rate at Month 3, 6, and 9 
Disease control at months 3, 6, and 9, 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. 
Waterfall plots will be presented. 
9.3.5.1.1.3 
Duration of Response 
The DOR defined as time from first assessment of PR or CR to follow-on first assessment of 
progressive disease will be summarized by descriptive statistics including median DOR and 
where appropriate the respective 95% CIs. DOR will also be listed. 
9.3.5.1.1.4 
Progression Free Survival and Overall Survival  
Time from first treatment received until disease progression or OS will be summarized by 
Kaplan-Meier estimates, median PFS/OS and where appropriate the respective 95% CIs. 
Subjects with no event will be censored at the last available tumor assessment for PFS and at 
the last timepoint known alive for OS. 
9.3.5.1.2 
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 area under 
the concentration-time curve over the dose interval, maximum plasma concentration, time to 
maximum plasma concentration, and minimum plasma concentration will be reported by dose 
group. Additional parameters or model-based analysis may be calculated depending on the 
available data. 
In the expansion cohorts, owing to sparse data sampling population exploratory PK analysis 
may be conducted to provide more comprehensive PK parameters for these subjects. If a 
population PK analysis is conducted, all available AFM24 serum concentrations will be used. 
9.3.5.1.3 
Immunogenicity Analyses 
Immunogenicity parameters will be summarized by descriptive statistics and listed. 


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9.3.6 
Safety Analyses 
9.3.6.1 
Adverse Events 
Adverse events, related AEs, SAEs and related SAEs, AEs with NCI CTCAE Grades ≥3, AEs 
leading to premature discontinuation, interruptions or discontinuation of study drug, and 
standard medical queries will be analyzed descriptively utilizing corresponding Medical 
Dictionary for Regulatory Activities System Organ Classes and Preferred Terms. NCI CTCAE 
v5.0 toxicity Grades will be utilized for classifying severity. 
Deaths within 28 days after the last dose and the corresponding reasons will be summarized. 
Also, all deaths overall will be summarized. 
9.3.6.2 
Safety Laboratory 
Safety laboratory results 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. Each parameter will be 
presented by descriptive statistics at each visit including change from baseline (Screening). 
Shift tables for CTCAE grades and normal ranges will be presented. All laboratory values will 
be listed. A separate listing for abnormal lab values (Grade 3 and higher, and low/high values) 
will be presented. 
9.3.6.3 
Vital Signs 
Vital signs will be summarized by descriptive statistics at each visit including change from 
baseline will be presented and a listing will be provided. 
9.3.6.4 
Electrocardiogram 
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 subjects with notable 
ECGs and newly occurring qualitative ECG abnormalities will be tabulated by cohort. 
9.3.7 
Exploratory Analysis 
Exploratory biomarker analyses will be described in a biomarker statistical analyses plan. 
Exploratory PD and biomarker analyses are dependent upon the availability of appropriate 
assays and may be deferred or not performed if, during or at the end of the study, it becomes 
clear that the analysis will have no scientific value or if there are not enough samples or 
responders to allow for adequate biomarker evaluation. If the study is terminated early or shows 
poor clinical efficacy, completion of biomarker assessments will be based on justification and 
intended utility of the data. 
9.3.8 
Interim Analyses 
9.3.8.1 
Phase 1 (Dose Escalation) 
An interim analysis (IA) will be conducted at each dose escalation step. The BLRM will be 
updated with the respective number of subjects treated and the number of DLTs observed in 
the last cohort. The updated model will then give a statistical recommendation for the next 
escalation step. In addition, a risk-benefit assessment that includes a comprehensive analysis 
of safety and available clinical information will be done to decide on the next escalation steps. 
In the event of a CTCAE Grade 5 AE or a second CTCAE Grade 4 AE at least possibly related 
to AFM24 at any time during Phase 1, the Sponsor will suspend further enrollment and interim 


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analysis will be done. The interim safety analysis will be reviewed by an ad-hoc SRC meeting 
to decide on further progression of the study. 
At least 1 IA (end of Phase 1) will be performed after all subjects treated in Phase 1 have 
completed their first post-baseline disease assessment and its confirmation (2nd post-baseline 
assessment, ie, ≥12 weeks post-baseline) or have withdrawn from the study. In case several 
RP2Ds will be determined, additional IAs might be performed after the respective dose level. 
No formal interim report will be written. All subjects still ongoing at this timepoint will 
continue until disease progression, intolerable toxicity, Investigator discretion, or subject’s 
withdrawal of consent and all assessments will be included in final analysis at the end of study. 
9.3.8.2 
Phase 2a (Dose Expansion) 
An IA will be performed for each cohort independently, once the defined number of subjects 
(11, 15, and 15 subjects for Cohorts A, B, and C, respectively, – see Table 10) in the respective 
cohort have completed their first post-baseline assessment and its confirmation (2nd 
post-baseline assessment, ie, ≥12 weeks post-baseline) to be categorized under the primary 
response endpoint or have withdrawn from the study. Each cohort will be then assessed for 
futility. The results from this IA will be non-binding, unless no signs of efficacy are observed. 
Safety criteria will also be evaluated to decide on the continuation of the cohorts. During the 
conduct of the study, after the interim analysis for Cohort A and C and stopping these cohorts 
for futility, it was considered unlikely that the continuation criteria can be met in Cohort B. 
Hence it was decided to prematurely stop enrollment after 8 patients in Cohort B. 
 
9.4 
Sample Size 
9.4.1 
Phase 1 (Dose Escalation) 
During the study, for the first 2 dose cohorts of the monotherapy, at least 2 subjects need to be 
evaluable. For the remaining cohorts, a minimum of 3 subjects evaluable for the DDS will be 
treated per dose cohort until determination of the MTD and/or one or more RP2Ds. At least 2 
evaluable subjects are planned for the first 2 cohorts and at least 3 evaluable subjects per any 
following dose cohort thereafter. It is estimated that up to 41 subjects will be enrolled taking 
dropouts and additional subjects enrolled for some of the dose groups into account. The actual 
number of subjects will depend on the number of dose levels/cohorts that are tested. 
9.4.2 
Phase 2a (Dose Expansion) 
An optimum Simon's two-stage design will be used for the expansion phase (Simon 1989). The 
assumptions and sample size calculations for different cohorts are summarized in Table 10. 
Table 10: 
Sample Size Consideration for Expansion Cohorts  
Indication 
Objective 
Response Rate 
Interim 
Analysis 
Final Analysis 
One-sided test 
 
Alternative 
hypothesis 
Null 
hypothesis 
Number 
of 
subjects 
OR, 
that 
may 
lead 
to 
stop 
Number 
of 
subjects* 
OR 
(rejection 
of the null 
hypothesis) 
Power 
Type 
I 
error 
rate 
(α) 


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RAS wt, 
microsatellit
e stable CRC 
25% 
5% 
11 
≤1 
39 
≥4 
80% 
5% 
ccRCC 
30% 
14% 
15 
≤2 
41 
≥10 
81% 
5% 
NSCLC 
EGFRmut 
30% 
14% 
15 
≤2 
41 
≥10 
81% 
5% 
Maximum number of subjects:                                             121  
ccRCC = clear cell renal cell carcinoma; CRC = colorectal cancer; EGFRmut = epidermal growth factor 
receptor mutant; NSCLC = non-small cell lung cancer; OR = objective response; RAS = rat sarcoma gene; wt = 
wild type. 
*Up to a total of N~40 subjects per cohort according to the FDA guideline, 2018 
In other words: 
RAS wt, 
microsatellite 
stable CRC: 
The power that is computed at ORR=25% (alternative hypothesis) is 80%. 
If the treatment is actually not effective, there is a 0.05 (α) probability of 
concluding that it is. After testing the treatment on 11 subjects in the first 
stage, the study may be terminated if 1 or fewer responds. At final analysis 
(N=39) if the total number responding is less than or equal to 3, the 
treatment is rejected. 
ccRCC: 
The power that is computed at ORR=30% (alternative hypothesis) is 81%. 
If the treatment is actually not effective, there is a 0.05 (α) probability of 
concluding that it is. After testing the treatment on 15 subjects in the first 
stage, the study may be terminated if 2 or fewer responds. At final analysis 
(N=41), if the total number responding is less than or equal to 9, the 
treatment is rejected. 
NSCLC 
EGFRmut: 
The power that is computed at ORR=30% (alternative hypothesis) is 81%. 
If the treatment is actually not effective, there is a 0.05 (α) probability of 
concluding that it is. After testing the treatment on 15 subjects in the first 
stage, the study may be terminated if 2 or fewer responds. At final analysis 
(N=41), if the total number responding is less than or equal to 9, the 
treatment is rejected. 
The sample size is based on the safety analysis set for all subjects. 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
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 in order to review protocol compliance, examine CRFs and 
individual subject’s medical records, and assure that the study is being conducted according to 
pertinent regulatory requirements including ICH-Good Clinical Practice (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 subject confidentiality 
is maintained. 


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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. 
10.2 
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, subject case notes, administrative 
documentation including the Investigator Site File, and frequent telephone/e-mail 
communications with the 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). 
10.3 
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. 
10.4 
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 reach the primary endpoint assessment 
(see Section 9.3.4.2). 
In case subjects are still being treated with study medication at the primary analysis cut-off 
date for this study, such subjects 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. 
10.5 
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. 


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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 subject must be maintained that includes the 
signed ICF and all source documentation related to that subject. The Investigator must ensure 
the availability of source documents from which the information in the eCRF was derived. 
Please refer to Section 12.2 for details of required record retention for the study. 
10.6 
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. 
10.7 
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 subject’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 subjects, 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. 
10.8 
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 subjects 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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11.0 
ETHICAL CONSIDERATIONS 
The Investigator will obtain written informed consent from each subject, or their authorized 
representative, participating in the study. The ICF must be signed, witnessed, and dated. The 
ICF will contain all the Essential Elements of Informed Consent set forth in 21 CFR, Part 50, 
the ICH Guideline for GCP, and the terms of the Declaration of Helsinki. Copies of the signed 
document should be given to the subject and filed in the Investigator’s Study File, as well as 
the subject’s medical record if in conformance with the institution’s standard operating 
procedures. 
The final study protocol and subject 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 subject safety, which will be 
implemented immediately. 
If an amendment substantially alters the study design, increases the potential risk to the 
subjects, affects the treatment of the subject, or might otherwise influence the willingness of 
the subject 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 subject is currently undergoing study procedures and is affected by the amendment, 
then the subject must be asked to consent again using the new ICF. 
11.1 
Ethical Conduct of the Study 
The study will be conducted in accordance with ICH GCP, the Declaration of Helsinki, the 
European Union 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 Part 50. 
11.2 
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 subjects 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 subject will be informed about the AFM24 study drug and 
anticipated effects and the reason, design, and implication of the study. The subject must give 
consent to participate prior to enrollment in the study. This consent must be given in writing. 
The Investigator who conducts the informed consent discussion must also sign the ICF. The 
Investigator may delegate this responsibility to a suitably qualified member of the study team 
(eg, Sub-Investigator) if permitted by local regulations. This delegation of responsibility must 
be recorded in the Study File. By giving signed consent, the subject 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. 
The signed and dated consent form will be kept by the Investigator. Prior to participation in the 
study, the subject should receive a copy of the signed and dated written ICF. 


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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 subject’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 subjects’ identities 
and Sponsor’s proprietary information. It is the CRA’s responsibility to verify that each subject 
has consented, in writing, to direct access. 
11.3 
Subject Participation Card 
A study participation card will be provided to subjects 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 subject will be 
asked to retain this card while participating in the study and show it to any other medical 
practitioners consulted during this time. Subjects will be advised to contact the 
Investigator/study site if there are any questions. A sample subject participation card is shown 
in Figure 4. 
Figure 4: 
Sample Subject Participation Card 
Dear Subject,  
 
Please inform any physician you visit during the 
study that you are participating in a clinical study by 
presenting this contact card. 
 
Please always carry this card with you until the end 
of the study. 
 
Subject Name:............................................ 
is participating in an open-label study and is 
receiving an investigational product, AFM24, a 
novel, tetravalent bispecific chimeric (anti-human 
EGFR x anti-human CD16A) recombinant antibody 
construct. 
 
 
 
Subject Contact Card Version X/date 
 
Clinical Trial Contact Card 
Study AFM24-101: A Phase 1/2a Open label, 
Multicenter Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Preliminary Efficacy of 
AFM24 in Subjects with Advanced Solid Cancers 
In the case that additional medications must be 
prescribed, you need more information about the 
clinical study, or the subject’s condition has 
worsened, please contact the treating study 
physician: 
 
Name: ..................................................................   
 
Phone: .................................................................. 
 
Address: …………………………………………... 
 
 
11.4 
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. 


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11.5 
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 European Union 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, or the Sponsor, as required by national regulations, as to the 
progress of the study as well as to any serious and unexpected AEs.  
11.6 
Subject Privacy  
The Investigator must ensure that subject privacy is maintained. On the eCRF or other 
documents submitted to the Sponsor, subjects will be identified by a subject number only. 
Clinical study documents that are not submitted to the Sponsor (eg, 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 request access to all study records, including source documentation for 
inspection. Clinical information will not be released without the written permission of the 
subject as outlined in the subject consent form. 
12.0 
DATA HANDLING AND RECORDKEEPING 
12.1 
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.  
12.2 
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 (ie, 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. 
Subjects’ medical files should be retained in accordance with applicable legislation and with 
the maximum period permitted by the hospital, institution or private practice. 
12.3 
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., 


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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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13.0 
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Lee DW, Gardener R, Porter DL, Louis C, Ahmed N, Jensen M, et al. Current concepts in the 
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Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated 
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19#management-of-covid-19-vaccine-deployment-for-ongoing-non-covid-19-clinical-trials. 
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https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick
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NCCN: Cancer and COVID-19 Vaccination. Preliminary Recommendations of the NCCN 
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19_Vaccination_Guidance_V1.0.pdf. (Accessed 19 March 2021). 
Necitumumab (Portrazza). European Public Assessment Report (EPAR). Utrecht, The 
Netherlands: Eli Lilly Nederland B.V.; 2016. 
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Necitumumab (Portrazza). United States package insert. Indianapolis, IN, USA: Eli Lilly and 
Company; 2015. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stat Med. 2008 Jan 15;27(13):2420-39. 
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interactions across species: implications for therapeutic antibodies. International 
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Osimertinib (Tagrisso). European Public Assessment Report. Södertälje, Sweden: 
AstraZeneca AB; 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/tagrisso 
(Accessed 26 June 2019). 
Osimertinib (Tagrisso). United States package insert. Wilmington, DE, USA: AstraZeneca 
Pharmaceuticals LP; 2018. 
Panitumumab (Vectibix). European Public Assessment Report. Breda, The Netherlands: 
Amgen Europe B.V.; 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/vectibix 
(Accessed 26 June 2019). 
Panitumumab (Vectibix). United States package insert. Thousand Oaks, CA, USA: Amgen 
Inc.; 2015. 
Pines G, Koestler W, Yarden Y. Oncogenic mutant form of EGFR: Lessons in signal 
transduction and targets of cancer therapy. FEBS Letters. 2010; 584: 2699–2706. 
Reddi H. Mutations in the EGFR Pathway. Clinical Utility and Testing Strategies. 
https://www.aacc.org/publications/cln/articles/2013/october/egfr-mutations. 2013. (Accessed 
Aug 22, 2016). 
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Robertson K, Reeves J, Smith G, Keith W, Ozanne B, Cooke T, et al. Quantitative estimation 
of epidermal growth factor receptor and c-erbB-2 in human breast cancer. Cancer Res. 1996 
Aug 15;56(16):3823-30. 
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. Translation of 
innovative designs into phase I trials. J Clin Oncol. 2007 Nov 1;25(31):4982-6. 
Rothe A, Sasse S, Topp MS, Eichenauer DA, Hummel H, Reiners KS, et al. A phase 1 study 
of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or 
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Sargent E, Gomella L, Belldegrun A, Linehan W, Kasid A. Epidermal growth factor receptor 
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trials testing immunotherapeutics [published correction appears in Lancet Oncol. 2019 
May;20(5):e242]. Lancet Oncol. 2017;18(3):e143-e152. 
Schwartz LH, Litière S, de Vries E, et al. RECIST 1.1-Update and clarification: From the 
RECIST committee. Eur J Cancer. 2016;62:132-137. doi:10.1016/j.ejca.2016.03.081. 
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10(1). doi: 10.1016/0197-2456(89)90015-9. 


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14.0 
APPENDICES 
 


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14.1 
APPENDIX A: Weekly Dosing Regimen (q1w) – Phase 1 and Phase 2a 
Figure 5: 
Study Scheme for Each Subject in Weekly Dosing Regimen 
 
DLT = dose-limiting toxicity; EOT = end of treatment; FU = follow-up 
* Collection of tumor sample (for central analysis) and DLT observation period is applicable for the dose escalation phase (Phase 1) only.  
Note: If a positive EGFR test has been performed from a subject’s tumor tissue, and the EGFR laboratory report is available, the subject 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. 
 
 
 
 






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General Notes: 
* ---- (demarcated lines) between columns indicate split dosing days (ie, AFM24 infusion time can span over 2 consecutive days). 
#  Pre-Screening Phase: applicable for Phase 2a only. Note: if a positive EGFR test has been performed from a subject’s tumor tissue, and the EGFR laboratory report is available, the subject 
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. 
# # End of Treatment visit is scheduled 14 days (±2 days) after the last administration of AFM24 or before start of any new anti-cancer treatment whichever is sooner. 
# # #  Safety Follow-up visit is scheduled 30 days (±5 days) after the last administration of AFM24 or before start of any new anti-cancer treatment whichever is sooner. 
# # # #  During Long-term Follow-Up interval, subjects are contacted every 3 months (±2 weeks) starting after EOT, to collect data on their subsequent therapies and disease status.  
Study Assessment Notes 
a. 
Only PK sampling is done on this visit, see Table 12 through Table 15. 
b. 
Subjects must demonstrate adequate organ function when assessed within 7 days before first AFM24 infusion to remain eligible (Section 4.1). 
c. 
For Phase 2a only: In case there is no archived tumor tissue, a local tumor biopsy for EGFR determination is required at pre-screening (see Inclusion criteria 1, Section 4.1). Note: if a 
positive EGFR test has been performed from a subject’s tumor tissue, and the EGFR laboratory report is available, the subject 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. 
d. 
The following assessments could be completed within 24 hours prior to the AFM24 infusion at each visit noted in the above table: Pre-dose samples for hematology parameters, clinical 
chemistry parameters and urinalysis parameters, pregnancy test, weight, physical examination, and coagulation parameters. 
e. 
Height and weight will be obtained while the subject is wearing light clothing (without shoes). 
f. 
Female subjects who require documented confirmation of postmenopausal status will have their FSH levels assessed at Screening. Subjects who are not postmenopausal at screening will 
be required to undergo pregnancy testing per protocol to confirm suitability to proceed. Female subjects of reproductive potential will have a pregnancy test carried out at Screening. This 
test must be carried out within 7 days prior to first AFM24 administration. 
g. 
Subjects must be confirmed as ECOG PS 0 or 1 to be eligible for study participation, and then assessed at Day 1 of each cycle. 
h. 
Vital sign parameters will consist of measurements of temperature, resting heart rate, seated blood pressure (systolic/diastolic) after 5 minutes resting, oxygen saturation, and respiratory 
rate. For details, please refer to Table 5. In case of split dosing, vital signs assessments at similar timepoints need to be done on both days. Note: In addition to the above-listed time 
points, subjects should be additionally monitored in accordance with the institutional guidelines/clinical practice and as clinically indicated. 
i. 
An unscheduled ECG might be performed any time if clinically indicated. 
j. 
For the dose escalation phase (Phase 1), ECG is required on Cycle 1 Day 1 and Day 22, before infusion and within 15 minutes after the EOI (+15 minutes, note plus only). When both an 
ECG and peripheral blood sample collection (PK and PD [cytokines]) are required at the EOI of AFM24 (ie, Cycle 1 Day 1 and Day 22), the blood draw must be completed first as close 
to the EOI as possible, followed by the ECG. Both procedures should be completed within 15 minutes after the EOI (+ 15 minutes, note plus only). For Phase 2a, ECG is not required on 
Cycle 1 Day 1 and Day 22. ECG assessments are to be performed with the subject in the supine position. For the dose escalation phase (Phase 1) only, all ECGs should be performed in 
triplicate at least 5 minutes apart. For the dose expansion phase (Phase 2a), ECGs will be performed in triplicate at least 5 minutes apart at the Screening visit only.  All subsequent ECGs 
will be performed as single ECGs. 
k. 
Hematology (including coagulation) parameters include red cell count, mean corpuscular volume, hemoglobin, hematocrit, reticulocyte count, platelet count, white blood cells, leukocyte 
differential count (% and/or absolute), international normalized ratio or prothrombin time, and activated partial thromboplastin time (See APPENDIX D, Section 14.4). 
l. 
Phase 1 without split day dosing: Additional blood sample for hematology on Cycle 1 Day 1 and Day 22 should be collected 1 hour after EOI (±15 minutes). 
Phase 2a without split day dosing: Additional blood samples for hematology on Cycle 1 Day 1 and Day 22 should be collected after EOI (+15 minutes, note plus only) at sites that can 
perform the PBMC isolation according to the lab manual/Sponsor requirements. 
m. Phase 1 and Phase 2a with split day dosing: Blood sample for hematology on Cycle 1 Day 2 and Day 23 should be collected after EOI (+15 minutes) at sites that can perform the PBMC 
isolation according to the lab manual/Sponsor requirements. 
n. 
Clinical chemistry parameters include calcium, total protein, albumin, total bilirubin, alanine transaminase, aspartate transaminase, lactate dehydrogenase, alkaline phosphatase, glucose 
(random), sodium, potassium, bicarbonate, chloride, magnesium, urea (blood urea nitrogen), creatinine, phosphate, uric acid, amylase, lipase, and C-reactive protein (See APPENDIX D, 
Section 14.4). 
o. 
Urinalysis parameters include glucose, protein, bilirubin, ketones, blood, pH, specific gravity (microscopic examination when indicated), FSH (to confirm post-menopausal status 
[Screening], and human chorionic gonadotropin (female pre-menopausal subjects [Screening] (See APPENDIX D, Section 14.4). 
p. 
Coagulation may be assessed from the hematology sample. 


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q. 
Tumor biopsy for central analysis is required for subjects in the dose escalation phase (Phase 1) only. 
r. 
+1 week: The second tumor biopsy will be performed on a non-dosing day during week 3 (+1 week). 
s. 
CT or MRI will be done at Screening and during the last week of cycles 2, 4, 6, 8, and every 3 cycles thereafter. 
t. 
During pre-screening, only AEs which are related to study procedures are to be recorded. AEs occurring after signing of the Main ICF but prior to the first dose of study drug should be 
recorded on the Medical History eCRF page (Note: any SAEs which are related to study procedures and occur during pre-screening and any SAEs that occur following signing the Main 
ICF and prior to the first dose of study drug will still be reported using the SAE form). Please also refer to Section 8.1.3 for detailed description. 
u. 
Concomitant medications administered after the Safety Follow-up visit should be recorded for SAEs which are considered related to study drug. 
 
ADA = anti-drug antibodies; C = cycle; CT = computed tomography; ctDNA = circulating tumor DNA; D = day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
Performance Status; EGFR = epidermal growth factor receptor; EOI = end of infusion; EOT = End of Treatment visit; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; I/E = inclusion/exclusion; ICF = informed consent form; LT-FU = long term follow-up; MRI = magnetic resonance imaging; PD = pharmacodynamics; PK = pharmacokinetics; SCR = 
screening; S-FU = Safety Follow-up visit. 






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c. 
In case of suspected CRS or IRR or any anaphylactic reaction during or close to AFM24 infusion a sample for central laboratory testing should be drawn. Sampling should occur at the 
first sign of the AE and 1 hour later to assess cytokine changes. In addition, local cytokine testing is recommended as clinically indicated and in accordance with institutional treatment 
guidelines. 
d. 
End of Treatment visit is scheduled 14 days (±2 days) after the last administration of AFM24 or before start of any new anti-cancer treatment whichever is sooner. 
ADA = anti-drug antibodies; AE = adverse event; CD16a RO = CD16a receptor occupancy testing; CRS = cytokine release syndrome; ctDNA = circulating tumor DNA; D = day; EOI = end 
of infusion; h = hour(s); EOT = End of Treatment visit; IRR = infusion-related reaction; m = minutes; PD = pharmacodynamics; PK = pharmacokinetic; Pre = pre-dose; SCR = screening visit 
 
 






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d. 
Blood for circulating lymphocytes will not be collected from subjects where the local laboratories of specific sites cannot perform the PBMC isolation according to the lab manual/Sponsor 
requirements. 
e. 
In case of suspected CRS or IRR or any anaphylactic reaction during or close to AFM24 infusion a sample for central laboratory testing should be drawn. Sampling should occur at the first 
sign of the AE and 1 hour later to assess cytokine changes. In addition, local cytokine testing is recommended as clinically indicated and in accordance with institutional treatment 
guidelines.  
f. 
End of Treatment visit is scheduled 14 days (±2 days) after the last administration of AFM24 or before start of any new anti-cancer treatment whichever is sooner. 
 
g.    PK, ADA and cytokines samples for subsequent cycles should be collected until C6 completion. All additional samples collected after this cycle can be used for analysis. However, the 
obligatory samples to be collected only until C6D22 completion. EOT samples are still to be drawn for PK, ADA and ctDNA. 
 
ADA = anti-drug antibodies; AE = adverse event; CRS = cytokine release syndrome; ctDNA = circulating tumor DNA; D = day; EOI = end of infusion; h = hour(s); EOT= End of Treatment 
visit; IRR = infusion-related reaction; m = minutes; PD = pharmacodynamics; PK = pharmacokinetic; Pre = pre-dose; SoI = start of infusion 
 
 
 
 


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14.2 
APPENDIX B: Every-2-Weeks Dosing Regimen (q2w) –Phase 2a Only 
 
Figure 6: 
Study Scheme for Each Subject in Every-2-weeks Dosing Regimen 
 
DLT = dose-limiting toxicity; EOT = end of treatment; FU = follow-up 
* Local tumor biopsy for EGFR determination is required at pre-screening in case there is no archived tumor tissue. 
Note: If a positive EGFR test has been performed from a subject’s tumor tissue, and the EGFR laboratory report is available, the subject 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. 






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m. Urinalysis parameters include glucose, protein, bilirubin, ketones, blood, pH, specific gravity (microscopic examination when indicated), FSH (to confirm post-menopausal status 
[Screening], and human chorionic gonadotropin (female pre-menopausal subjects [Screening] (See APPENDIX D, Section 14.4). 
n. 
Coagulation may be assessed from the hematology sample. 
o. 
CT or MRI will be done every 8 weeks after baseline assessment for first 4 assessments, and every 12 weeks thereafter. 
p. 
Concomitant medications administered after the Safety Follow-up visit should be recorded for SAEs which are considered related to study drug. 
q. 
Only taken in Cycle 2 at sites that can perform the PBMC isolation according to the lab manual/Sponsor requirements. 
r. 
During pre-screening, only AEs that are related to study procedures are to be recorded. AEs occurring after signing of the Main ICF but prior to the first dose of study drug should be 
recorded on the Medical History eCRF page (Note: any SAEs that are related to study procedures and occur during pre-screening and any SAEs that occur following signing the Main 
ICF and prior to the first dose of study drug will still be reported using the SAE form). Please also refer to Section 8.1.3 for detailed description.  
 
ADA = anti-drug antibodies; C = cycle; CT = computed tomography; ctDNA = circulating tumor DNA; D = day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
Performance Status; EGFR = epidermal growth factor receptor; EOI = end of infusion; EOT = End of Treatment visit; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; I/E = inclusion/exclusion; ICF = informed consent form; LT-FU = long term follow-up; MRI = magnetic resonance imaging; PD = pharmacodynamics; PK = pharmacokinetics; 
SCR = screening visit; S-FU = Safety Follow-up visit. 
 






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g.    PK, ADA and cytokines samples for subsequent cycles should be collected until C6 completion. All additional samples collected after this cycle can be used for analysis. However, the 
obligatory samples to be collected only until C6D22 completion. EOT samples are still to be drawn for PK, ADA and ctDNA. 
ADA = anti-drug antibodies; AE = adverse event; CD16a RO = CD16a receptor occupancy testing; CRS = cytokine release syndrome; ctDNA = circulating tumor DNA; D = day; EOI = end 
of infusion; h = hour(s); IRR = infusion-related reaction; m = minutes; PD = pharmacodynamics; PK = pharmacokinetic; Pre = pre-dose; q2w= every 2 weeks. 
 


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14.3 
APPENDIX C: Eastern Cooperative Oncology Group Performance Score 
Grade 
ECOG Performance Score 
0 
Fully active. Able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office 
work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 
Source: Oken et al., 1982. 
 
 
 


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14.4 
APPENDIX D: Local Laboratory Parameter 
Clinical Chemistry 
Hematology (Including Coagulation) 
Calcium 
Red cell count 
Total protein 
Mean corpuscular volume 
Albumin 
Hemoglobin 
Total bilirubin 
Hematocrit 
Alanine aminotransferase 
Reticulocyte count 
Aspartate aminotransferase 
Platelet count 
Lactate dehydrogenase 
White blood cells 
Alkaline phosphatase 
Leukocyte differential count (% and/or absolute) 
Sodium 
International normalized ratio or prothrombin time 
Potassium 
Activated partial thromboplastin time  
Bicarbonate 
Urinalysis 
Chloride 
Glucose  
Magnesium 
Protein 
Urea (Blood urea nitrogen) 
Bilirubin 
Creatinine 
Ketones 
Phosphate 
Blood 
Uric acid 
pH 
C-reactive protein 
Specific gravity (microscopic examination when indicated) 
Amylase 
Follicle-stimulating hormone (to confirm post-menopausal status, Screening)  
Lipase 
Glucose (random) 
Human chorionic gonadotropin (female pre-menopausal subjects, Screening) 
Note: This is the full testing panel to be carried out locally by sites; any exceptions due to local testing 
restrictions must be reported immediately to Sponsor to ensure subject safety assessment is not jeopardized. 
 
 
 


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14.5 
APPENDIX E: Statistical Appendix including Model Performance and Data 
Scenarios 
14.5.1 
Phase 1 (Escalation) 
The model was assessed by 2 different metrics: hypothetical on-study data scenarios and long-run 
operating characteristics.  
14.5.1.1 
Hypothetical Data Scenarios 
Hypothetical data scenarios are shown in Table 19. These scenarios reflect potential on-study data 
constellations and related escalation as allowed by the model and the 200% escalation limit. For 
each scenario, the probability of overdose for the current dose, as well as the next potential dose 
and related probabilities of under-dosing, target dose and over-dosing are shown.  
For example, scenario 1 represents the case that no DLT is observed in the first subject at the 
starting dose of 14 mg. In this case, the next dose permitted by the model and by the 200% 
escalation rule is 40 mg. In scenario 5a, while no DLT was observed at dose 14 mg, 1 DLT is 
observed in the first 2 subjects at 40 mg and the model would then not allow to escalate and would 
require to stay at 40 mg and treat 4 more subjects at 40 mg before escalating to 120mg (scenario 
5b). In scenario 9b, an intermediate dose escalation is show: While no subject experienced a DLT 
at dose levels 14 mg and 40 mg, 1 DLT was observed at 120 mg. The model would require that in 
total 6 subjects are treated at 120 mg and would thereafter only allow to escalate to 200 mg (and 
not to the maximum of the next level, which is 360 mg), to prevent potential overdosing. These 
cases illustrate the adaptive behavior of the model. 
Table 19: 
Hypothetical Data Scenarios 
Scenario 
Dose 
Data - 
#DLT 
Data - 
#Sub 
CD - 
P(OD) 
Next Dose 
ND - 
P(UD) 
ND - 
P(TD) 
ND - 
P(OD) 
1 
14 
0 
2 
0.014 
40 
0.881 
0.085 
0.035 
 
2 
14 
1 
2 
0.322 
7 
0.500 
0.251 
0.249 
 
3 
14 
1 
3 
0.207 
14 
0.524 
0.269 
0.207 
 
4 
14 
0 
2 
0.012 
120 
0.788 
0.135 
0.076 
40 
0 
2 
 
5a 
14 
0 
2 
0.209 
40 
0.506 
0.285 
0.209 
40 
1 
2 
 
5b 
14 
0 
2 
0.041 
120 
0.461 
0.306 
0.233 
40 
1 
6 
 
6 
14 
1 
6 
0.052 
120 
0.486 
0.317 
0.197 
40 
0 
3 
 
7 
14 
0 
2 
0.603 
7 
0.466 
0.299 
0.235 
40 
2 
2 
 


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Scenario 
Dose 
Data - 
#DLT 
Data - 
#Sub 
CD - 
P(OD) 
Next Dose 
ND - 
P(UD) 
ND - 
P(TD) 
ND - 
P(OD) 
8 
14 
0 
2 
0.013 
360 
0.571 
0.184 
0.245 
40 
0 
2 
120 
0 
3 
 
9a 
14 
0 
2 
0.159 
120 
0.526 
0.315 
0.159 
40 
0 
2 
120 
1 
3 
 
 
 
 
 
 
 
 
 
9b 
14 
0 
2 
0.043 
200 
0.471 
0.312 
0.217 
40 
0 
2 
120 
1 
6 
 
10 
14 
0 
2 
0.221 
120 
0.344 
0.434 
0.221 
40 
0 
2 
120 
2 
6 
 
11 
14 
0 
2 
0.062 
360 
0.487 
0.293 
0.220 
40 
0 
2 
120 
1 
6 
200 
0 
3 
 
12 
14 
0 
2 
0.036 
1000 
0.585 
0.190 
0.225 
40 
0 
2 
120 
0 
3 
360 
0 
3 
 
13 
14 
0 
2 
0.280 
200 
0.685 
0.251 
0.063 
40 
0 
2 
120 
0 
3 
360 
1 
3 
CD-P = current dose probability; DLT = dose-limiting toxicity; ND-P = current dose probability; OD = overdosing; 
#Sub = subject number; TD = target dosing; UD = underdosing.  
14.5.1.2 
Operating Characteristics 
Operating characteristics are a way to assess the long-run behavior of a model. Under an assumed 
true dose-toxicity curve, metrics such as the probability of recommending a dose with true DLT 
rate in the target interval can be approximated via simulation Table 20 describes 3 assumed true 
dose-toxicity scenarios which were used to assess the operating characteristics of the model. These 
scenarios reflect a wide range of possible cases as follows: 
Scenario 1 (P): aligned with prior means 
Scenario 2 (H): high-toxicity scenario 
Scenario 3 (LH): low-toxicity followed by high-toxicity 


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Table 20: 
Assumed True Dose-Toxicity Scenarios 
Scenario 
 
 
7 mg 
14 mg 
40 mg 
120 mg 
200 mg 
360 mg 
1000 mg 
1 (P) 
P (DLT) 
0.061 
0.075 
0.108 
0.178 
0.244 
0.342 
0.486 
2 (H) 
0.150 
0.200 
0.250 
0.350 
0.400 
0.450 
0.500 
3 (LH) 
0.005 
0.070 
0.100 
0.300 
0.350 
0.450 
0.500 
DLT = dose-limiting toxicity; H = high toxicity; LH = low-high toxicity; P = assumed true-dose toxicity. 
Bold numbers indicate true DLT rates in the target interval [0.16-0.33). 
For each of these scenarios, 500 studies were simulated. It was then assessed how often a dose 
was declared as MTD with true DLT rate in the under-, targeted or over-dose range. Furthermore, 
the average, minimum, and maximum number of subjects per study and the average number of 
DLTs per study are reported. Results are shown in Table 21. 
Table 21: 
Hypothetical Data Scenarios 
Scenario 
% of studies declaring an MTD with true DLT rate in 
# Subjects 
# DLT 
Underdose 
Target dose 
Overdose 
Stopped 
Mean 
(Min-Max) 
Mean 
(Min- Max) 
1 (P) 
29.0 
51.2 
18.0 
1.8 
18.57 (1-43) 
3.26 (1-11) 
2 (H) 
1.4 
58.6 
17.4 
22.6 
13.90 (1-38) 
3.55 (1-12) 
3 (LH) 
47.2 
33.8 
17.0 
2.0 
17.65 (1-42) 
3.45 (1-10) 
DLT = dose-limiting toxicity; H = high toxicity; LH = low toxicity; Max = maximum; Min = minimum; 
MTD = maximum tolerated dose; P = assumed true dose toxicity. 
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 51.2% 
of the simulated studies declared a dose as MTD with true DLT rate in the targeted dose range. 
Since the dose of 1000 mg has a DLT probability of 48.6% it was identified quite rarely as MTD, 
namely in 4 case of the simulated cases.  
In Scenario 2 (high-toxicity scenario), the starting dose has already 20% probability of observing 
at least 1 DLTs in the first cohort if 2 subjects enrolled. This contributes to the high percentage 
22.6% of all simulated studies for which the study is stopped since none of the doses is considered 
tolerable anymore. This is an expected situation for a high-toxicity scenario. 
In Scenario 3, 33.8% of the simulated studies declared a dose as MTD with true DLT rate in the 
targeted dose range. 
The mean subject numbers range from 13.9 subjects (high scenario) to 18.57 subjects (true dose 
toxicity scenario) and the maximum number of subjects was 43. The low mean number of subjects 
in the high toxicity- scenario is explained by the frequent stopping of the study.  
In summary, the considered data scenarios show a reasonable behavior of the model and the 
operating characteristics demonstrate a good precision of MTD determination. 
 
 


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14.6 
APPENDIX F: Grading and Management of Infusion-related Reactions, 
including Anaphylaxis, Allergic Reaction, and Cytokine Release Syndrome 
Investigators are asked to pay special attention to IRRs, which include hypersensitivity reactions 
and CRS. These reactions may be experienced by subjects during the infusion of investigational 
treatment (uniphasic reaction) and/or within hours of an infusion (biphasic/delayed reaction). The 
reaction may be caused by the therapeutic agent, diluent, or delivery vehicle. IRRs can have a 
broad variety of symptoms; from mild to moderate chills, flushing, itching, skin rashes, heart 
rate/blood pressure alterations, dyspnea, chest discomfort, back/abdominal pain, nausea, vomiting, 
diarrhea to severe and life threatening anaphylactic/anaphylactoid reactions; mostly appearing 
during or immediately after the investigational drug infusion. Special attention must be paid to 
CRS during investigational treatment which can manifest with fever, cardiac dysfunction, acute 
respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated 
intravascular coagulation. Skin rash, as well as gastrointestinal symptoms of nausea, vomiting or 
diarrhea may also occur. Fever is a hallmark for CRS, and many features of CRS can also mimic 
infection.  
The aim of this appendix is to:  
Provide guidance on monitoring for IRR/CRS 
Provide guidance on the grading of IRR/CRS 
Provide guidance on management of IRR/CRS. 
In addition, pre-medication with steroids, antihistamines, and oral acetaminophen is advised to 
minimize the severity of IRR/CRS (see Section 5.3). Other premedication such as antiemetics 
(e.g., ondansetron, metoclopramide hydrochloride) may be administered at the discretion of the 
Investigator/ treating physician. 
14.6.1 
Monitoring for IRR/CRS 
Frequent monitoring of the subject’s vital signs during and after AFM24 infusion is implemented 
as a precautionary measure in this protocol. For the first 2 doses (ie, C1D1 and C1D8 in weekly 
schedule; C1D1 and C1D15 in q2w schedule) of AFM24 subjects must be observed for at least 
4 hours after the end of infusion with regular checks of vital signs as described in Section 7.2.4. 
In case of a split day dosing (over 2 days) subjects must be observed for at least 4 hours after the 
end of AFM24 infusion on each day. In this scenario, the split day dosing AFM24 infusion is 
considered one dose. Starting from the third subsequent dose (ie, at any time point in the study 
starting from the third subsequent dose [C1D15 in weekly schedule, C2D1 in q2w schedule) for 
subjects who do not experience IRR/CRS symptoms >Grade 1 during the previous infusions, the 
infusion time for the next and/or subsequent infusions may be decreased to ≥1 hour (at least 
1 hour), observation period may be reduced from 4 hours to a minimum of 2 hours, and steroids 
and other premedications could be tapered, all at the discretion of the Investigator. However, it 
should be kept in mind that only 1 modification should be made at a time per infusion day. 
Any IRR/CRS occurring should be reported as AESIs using the SAE form within 24 hours (see 
Section 8.3.1). 
14.6.2 
Grading and Reporting of IRR/CRS 
Any treatment-related IRRs are defined according to the NCI CTCAE v5.0 definition (Injury, 
poisoning and procedural complications). Symptoms occurring during or following infusion of 
investigational treatment may also be defined according to AE categories such as allergic reaction, 


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anaphylaxis, or cytokine release syndrome. If an allergic reaction, anaphylaxis or cytokine release 
syndrome is related to the infusion of AFM24, the term “infusion-related reaction” should be 
reported. In addition, Investigators are encouraged to use any additional terms to further describe 
the event (e.g., anaphylaxis, cytokine release syndrome, hypotension, bronchospasm, hypoxia). 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE v5.0) 
contains a grading system for IRR and related events as provided in Table 22. 
 


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Table 22: 
Grading System for IRR and Related Events According to CTCAE v5.0 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Infusion related reaction 
Mild transient reaction; 
infusion interruption not 
indicated; intervention 
not indicated 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, i.v. 
fluids); prophylactic 
medications indicated for 
≤24 hours 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
Life-threatening 
consequences; urgent 
intervention indicated 
 
Death 
Definition: A disorder characterized by an adverse reaction to the infusion of pharmacological or biological substances 
Navigational Note: Not applicable 
Allergic reaction 
Systemic intervention 
not indicated 
Oral intervention indicated 
Bronchospasm; 
hospitalization indicated 
for clinical sequelae; 
intravenous intervention 
indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to allergen. 
Navigational Note: If related to infusion, use Injury, poisoning, and procedural complication: Infusion related reaction. Do not report both 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral intervention 
indicated; allergy related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; urgent 
interventions indicated  
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a 
hypersensitivity immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness, and may lead to death. 
Navigational Note: Not applicable. 
Cytokine release 
syndrome 
Fever with or without 
constitutional symptoms 
Hypotension responding to 
fluids; hypoxia responding 
to <40% oxygen 
Hypotension managed 
with 1 pressor; hypoxia 
requiring ≥40% oxygen 
Life-threatening 
consequences; urgent 
interventions indicated  
Death 
Definition: A disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. 
Navigational Note: Also consider reporting other organ dysfunctions including neurological toxicities such as: Psychiatric disorders: Hallucinations or Confusions; 
Nervous system disorders: Seizure, Dysphasia, Tremor, or Headache 
CTCAE = Common Terminology Criteria for Adverse Events; i.v. = intravenous; NSAID = nonsteroidal anti-inflammatory drug.


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14.6.3 
IRR/CRS Management 
The management of IRR and other related AEs is summarized in Table 23. 
Table 23: 
Summary of Management of Infusion Related Reactions, including 
Anaphylaxis, Allergic Reactions, and Cytokine Release Syndrome*  
CTCAE v5.0 
Grade 
Action to AFM24 
Actions and medication to manage toxicity 
Grade 1  
Continue treatment without modification  Vigilant supportive care and treat in line with 
institutional practice including needed workup to 
rule out other differential diagnoses 
Grade 2  
Interrupt treatment and restart when 
symptoms resolve to ≤CTCAE Grade 1 or 
baseline 
 
Consider infusing the next AFM24 
infusion with a >4-hour infusion time 
 Vigilant supportive care and treat in line with 
institutional practice including needed workup to 
rule out other differential diagnoses 
 Consider symptomatic medication such as 
antihistamines, antipyretics, steroids, i.v. fluids, 
oxygen, as appropriate, and in line with 
institutional practice 
 In case subject of older age and/or with 
extensive co-morbidities and CRS, consider: 
Administer tocilizumab 8 mg/kg (maximum 800 
mg) i.v. over 60 min; may administer up to 3 
additional doses of tocilizumab 8 mg/kg (maximum 
800 mg) if no clinical improvement in 
signs/symptoms of CRS after first dose.  
Start corticosteroid treatment (e.g., 
methylprednisolone 2mg/kg/day) 
Grade 3  
Interrupt treatment 
IRRs 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): 
Discontinue AFM24 permanently 
Any Grade 3 anaphylaxis: 
Discontinue AFM24 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 
subject.  
If re-challenge is considered, 
administer the next AFM24 infusion 
with a >4-hour infusion time.  
 Vigilant supportive care and treat in line with 
institutional practice including needed workup to 
rule out other differential diagnoses 
 Consider symptomatic medication such as 
antihistamines, antipyretics, steroids, i.v. fluids, 
oxygen, vasopressor, as appropriate, and in line 
with institutional practice 
 Consider transfer to intensive care unit or have 
the subject under continuous surveillance. 
Monitor cardiac and other organ functions.  
 In case of CRS: 
Administer tocilizumab 8 mg/kg (maximum 800 
mg) i.v. over 60 min; may administer up to 3 
additional doses of tocilizumab 8 mg/kg (maximum 
800 mg) if no clinical improvement in 
signs/symptoms of CRS after first dose.  
Start corticosteroid treatment (e.g., 
methylprednisolone 2mg/kg/day) 


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CTCAE v5.0 
Grade 
Action to AFM24 
Actions and medication to manage toxicity 
Grade 4  
Discontinue permanently 
 
 Vigilant supportive care and treat in line with 
institutional practice including needed workup to 
rule out other differential diagnoses 
 Consider symptomatic medication such as 
antihistamines, antipyretics, steroids, i.v. fluids, 
oxygen, vasopressor, as appropriate, and in line 
with institutional practice 
 Transfer to intensive care unit or have the subject 
under continuous surveillance. Monitor cardiac 
and other organ functions.  
 In case of CRS: 
Administer tocilizumab 8 mg/kg (maximum 800 
mg) i.v. over 60 min; may administer up to 3 
additional doses of tocilizumab 8 mg/kg (maximum 
800 mg) if no clinical improvement in 
signs/symptoms of CRS after first dose.  
Start corticosteroid treatment (e.g., 
methylprednisolone 2mg/kg/day) 
CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; IRR = infusion 
related reactions; i.v. = intravenous; NSAID = nonsteroidal anti-inflammatory drug. 
*For further reference for management of CRS, please see: Lee DW et al, 2014. (Current concepts in the diagnosis 
and management of cytokine release syndrome. Blood 2014; 124(2):188-195) and Lee DW et al, 2019 (ASTCT 
Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. 
Biol Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758.) 

SAP_001.pdf: 
CONFIDENTAL 
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Statistical Analysis Plan template version 1.0 dated 27-MAR-2019 
Affimed GmbH 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL AFM24-101 
 
A Phase 1/2a Open Label, Multicenter Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Preliminary Efficacy of AFM24 in Patients with Advanced 
Solid Cancers 
 
Protocol code:  
AFM24-101 
SAP Version:  
Final v 3.0 
SAP Date:  
27 January 2023 
Author:  
 
 
 
 


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Statistical Analysis Plan template version 1.0 dated 27-MAR-2019 
DOCUMENT HISTORY 
VERSION HISTORY 
Version # 
Version Date 
Final 1.0 
27 February 2020 
Final 2.0 
08 October 2021 
Final 3.0 
27 January 2023 
REVISION HISTORY 
Version # 
Chapter 
Revision Summary 
Reason(s) for Revision 
2.0 
2.1 
Endpoint list updated as per new 
protocol 
Compliance with the new 
protocol 
2.0 
7.7.1 
Confirmed response definition rules 
updated 
Reviewers request 
2.0 
7.7.2 
PK summaries have been removed.  PK will be summarized in a 
separate report.  
2.0 
7.7.2 
Waterfall and swimmers plots for 
RECIST 1.1 assessments have 
been added. 
Added to better visualize the 
data. 
2.0 
7.7.3 
Clinical Benefit Rate analysis added. Reviewers request 
2.0 
7.7.3 
Kaplan-Meier plots added. 
Added to better visualize the 
data. 
2.0 
7.7.3 
Time to Response analysis added 
To further explore the results 
2.0 
7.8.1 
Treatment compliance analysis 
added 
To further explore the results 
2.0 
7.8.4 
EGC summaries for Phase 2 
removed. 
Too few data expected to be 
collected for a meaningful 
summary 
3.0 
1 
The protocol version used has been 
changed 
To refer to the latest available 
protocol 
3.0 
All 
“KRAS” is replaced with “RAS” 
Reflecting the same change 
made in the protocol 
3.0 
2.2 
List of the exploratory objectives has 
been updated 
Reflecting the same change 
made in the protocol 
3.0 
7.2 
Protocol-defined windows for vital 
signs assessments have been 
updated 
To reflect similar update in the 
new protocol 
3.0 
7.7.1 
Reference to Technical Appendix 
has been removed 
To reflect the change in the 
protocol 


Statistical Analysis Plan: AFM24-101 
Review Status: FINAL 
 
Version: 3.0 
 
Version Date: 27-JAN-2023 
 
 
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Statistical Analysis Plan template version 1.0 dated 27-MAR-2019 
3.0 
7.8.1 
Dose Intensity and Relative Dose 
Intensity definitions and description 
of associated analyses have been 
added.  
To further explore the exposure 
data 
 
 
 
 


Statistical Analysis Plan: AFM24-101 
Review Status: FINAL 
 
Version: 3.0 
 
Version Date: 27-JAN-2023 
 
 
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Statistical Analysis Plan template version 1.0 dated 27-MAR-2019 
APPROVAL SIGNATURES 
STUDY TITLE: A Phase 1/2a Open Label, Multicenter Study to Assess the Safety, 
Tolerability, Pharmacokinetics and Preliminary Efficacy of AFM24 in Patients with 
Advanced Solid Cancers 
PROTOCOL NUMBER: AFM24-101 
SAP Final 3.0, 27 January 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Statistical Analysis Plan: AFM24-101 
Review Status: FINAL 
 
Version: 3.0 
 
Version Date: 27-JAN-2023 
 
 
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Statistical Analysis Plan template version 1.0 dated 27-MAR-2019 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION .....................................................................................................................................................8 
2. 
STUDY OBJECTIVES..............................................................................................................................................8 
2.1 
Phase 1 (Dose Escalation)............................................................................................................................ 8 
2.1.1 
Primary Objective ............................................................................................................................. 8 
2.1.2 
Secondary Objectives ....................................................................................................................... 8 
2.1.3 
Exploratory Objectives ...................................................................................................................... 8 
2.2 
Phase 2a (Expansion) .................................................................................................................................. 8 
2.2.1 
Primary Objective ............................................................................................................................. 8 
2.2.2 
Secondary Objectives ....................................................................................................................... 8 
2.2.3 
Exploratory Objectives ...................................................................................................................... 8 
3. 
STUDY DESCRIPTION ............................................................................................................................................9 
3.1 
Overall Study Design .................................................................................................................................... 9 
3.2 
Phase 1 ....................................................................................................................................................... 9 
3.3 
Phase 2a ..................................................................................................................................................... 9 
3.4 
Study Treatment ........................................................................................................................................ 10 
3.5 
Safety Review Committee (SRC)................................................................................................................. 10 
3.6 
Independent Data Monitoring Committee (IDMC) ......................................................................................... 10 
4. 
SAMPLE SIZE AND POWER CALCULATION ........................................................................................................10 
5. 
ANALYSIS ENDPOINTS........................................................................................................................................10 
6. 
ANALYSIS POPULATIONS ...................................................................................................................................10 
6.1 
Safety Set .................................................................................................................................................. 10 
6.2 
Dose-Determining Set ................................................................................................................................ 10 
6.3 
PK Set ....................................................................................................................................................... 11 
7. 
ANALYTICAL PLAN AND STATISTICAL METHODS .............................................................................................11 
7.1 
General Conventions and Statistical Considerations ..................................................................................... 11 
7.2 
Definition of Baseline, Study Visits, and Visit Windows ................................................................................. 11 
7.3 
Handling of Missing Data ............................................................................................................................ 12 
7.4 
Patient Disposition...................................................................................................................................... 12 
7.5 
Protocol Deviations .................................................................................................................................... 13 
7.6 
Patient Characteristics ................................................................................................................................ 13 
7.6.1 
Baseline and Demographic Characteristics ...................................................................................... 13 
7.6.2 
Medical History and Current Medical Conditions ............................................................................... 13 
7.6.3 
Prior and Concomitant Medications and Procedures ......................................................................... 13 
7.7 
Efficacy Endpoints and Analysis .................................................................................................................. 14 
7.7.1 
Analysis of Primary Endpoint ........................................................................................................... 14 
7.7.2 
Analysis of Secondary Efficacy Endpoints ........................................................................................ 16 
7.7.3 
Analysis of Exploratory Efficacy Endpoints ....................................................................................... 17 
7.8 
Safety Endpoints and Analysis .................................................................................................................... 19 
7.8.1 
Exposure to Study Treatment .......................................................................................................... 19 
7.8.2 
Adverse Events .............................................................................................................................. 20 
7.8.3 
Laboratory Data ............................................................................................................................. 20 
7.8.4 
Vital Signs and Other Safety Parameters ......................................................................................... 20 
7.9 
Exploratory Analysis ................................................................................................................................... 21 
7.9.1 
Biomarker and Genomic Data Analysis ............................................................................................ 21 
8. 
INTERIM ANALYSES ............................................................................................................................................21 
9. 
DEVIATIONS FROM ANALYSIS AS DESCRIBED IN THE PROTOCOL ..................................................................22 
10. 
PROGRAMMING SPECIFICATIONS ......................................................................................................................22 
 


Statistical Analysis Plan: AFM24-101 
Review Status: FINAL 
 
Version: 3.0 
 
Version Date: 27-JAN-2023 
 
 
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Statistical Analysis Plan template version 1.0 dated 27-MAR-2019 
LIST OF ABBREVIATIONS 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BLRM 
Bayesian Logistic Regression Model 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CRF 
Case Report Form 
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 
EGFR 
Epidermal growth factor receptor 
EGFRmut 
Epidermal growth factor receptor mutation 
EoI 
End of Infusion 
EWOC 
Escalation with Overdose Control 
FIH 
First-in-Human 
IDMC 
Independent Data Monitoring Committee 
iRECIST 
Response Evaluation Criteria in Solid Tumors for Immunotherapy 
KRAS-w 
Kirsten Rat sarcoma genes-wild type 
i.v. 
Intravenously 
mCRC 
Metastatic Colorectal Cancer 
MedDRA 
Medical Dictionary for Regulatory Activities  
MTD 
Maximum Tolerated Dose 
NCA 
Non-compartmental analysis 
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 
Pharmacodynamics, Progressive Disease 
PE 
Physical Examination 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
QTcF 
Corrected QT interval by Fridericia 
R2PD 
Recommended Phase 2 Dose 
RAS 
Rat sarcoma genes 
RECIST 
Response Evaluate Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 


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SOC 
System Organ Class 
SRC 
Safety Review Committee 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical analysis and reporting for the study 
protocol AFM24-101 (version 9.0) dated 03Nov2022.  
2. 
STUDY OBJECTIVES 
2.1 
PHASE 1 (DOSE ESCALATION) 
2.1.1 PRIMARY OBJECTIVE 
Determine the maximum tolerated dose (MTD), select one or more recommended phase 2 
doses (RP2D), and investigate the safety and tolerability of AFM24 in subjects with advanced or 
metastatic solid malignancies 
2.1.2 SECONDARY OBJECTIVES 
- 
Characterize the safety and tolerability of AFM24, including both acute and chronic 
toxicities 
- 
Characterize the pharmacokinetics (PK) of AFM24 administered intravenously (i.v.) 
- 
Characterize the immunogenicity of AFM24 
- 
Assess the preliminary antitumor efficacy of AFM24 
2.1.3 EXPLORATORY OBJECTIVES 
- 
Assess the preliminary antitumor efficacy of AFM24, using Response Evaluation Criteria in 
Solid Tumors for immunotherapy (iRECIST) tumor response criteria 
- 
Assess AFM24 pharmacodynamics 
2.2 
PHASE 2A (EXPANSION) 
2.2.1 PRIMARY OBJECTIVE 
Assess the preliminary antitumor efficacy of AFM24, by local Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 
2.2.2 SECONDARY OBJECTIVES 
- 
Characterize the safety and tolerability of AFM24, including both acute and chronic 
toxicities 
- 
Characterize the PK of AFM24 administered i.v. 
- 
Characterize the immunogenicity of AFM24 
- 
Assess the preliminary antitumor efficacy of AFM24 
2.2.3 EXPLORATORY OBJECTIVES 
- 
Assess the preliminary antitumor efficacy of AFM24, using iRECIST tumor response criteria 


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- 
Assess AFM24 pharmacodynamics 
- 
Explore the predictive potential of biomarkers measured in blood and/or tumor tissue in 
response to AFM24 
3. 
STUDY DESCRIPTION 
3.1 
OVERALL STUDY DESIGN 
AFM24-101 is a first-in-human (FIH) Phase 1/2a open-label, non-randomized, multicenter, 
multiple ascending dose escalation/expansion study evaluating AFM24 as monotherapy in 
subjects with advanced solid malignancies whose disease has progressed after treatment with 
previous anticancer therapies. 
There will be 2 parts to this study: a dose escalation phase (Phase 1) and a dose expansion 
phase (Phase 2a). The aim of the dose escalation phase (Phase 1) is to determine the MTD 
and/or establish a RP2D. An adaptive 2 parameter BLRM guided by the EWOC principle will be 
used in the escalation phase to guide determination of the MTD and/or RP2D in subjects with 
advanced solid malignancies. 
The dose escalation phase (Phase 1) will be followed by the dose expansion phase (Phase 2a) 
once the MTD and/or 1 or more RP2Ds of AFM24 monotherapy has been determined. The dose 
expansion phase (Phase 2a) of the study is intended to collect preliminary evidence of efficacy 
and to further confirm the safety of AFM24 as a monotherapy in distinct patient populations. The 
expansion phase will have 3 cohorts based on tumor type, as described in Figure 2 in the 
Protocol. The expansion cohorts may be opened in parallel or subsequently. 
The full study scheme can be seen in the Protocol section 3.1. 
3.2 
PHASE 1  
Phase 1 will employ an adaptive BLRM with 2 parameters guided by the EWOC principle to 
make dose recommendations and estimate the MTD (see Section 7.7.1 of the SAP). It is 
estimated that approximately 25 to 35 patients will be enrolled into Phase 1 of the study. The 
number of patients is dependent on the tested dose cohorts and safety profile of AFM24. As 
multiple centers will contribute to the enrollment a communication plan will be established to 
ensure distribution of safety data and study progress amongst the participating centers. 
DLTs will be assessed in the first treatment cycle (i.e., the first 4 weeks of treatment for each 
patient), referred to as the DLT observation period. 
3.3 
PHASE 2A  
Once at least 1 RP2D dose has been determined, then enrollment into 1 or more expansion 
cohorts for selected cancer indication in the dose expansion phase (Phase 2a) will begin. Other 
expansion cohorts may follow with the same or a different RP2D dose level. An optimum 
Simons two-stage design will be applied for the preliminary efficacy analyses for the following 
expansion cohorts: 
• Expansion Cohort A will enroll up to a total of 39 subjects with microsatellite stable CRC with 
RAS wild type tumor, the interim analysis (IA) will be conducted after 11 subjects; 


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• Expansion Cohort B will enroll up to a total of 41 subjects with ccRCC, the IA will be conducted 
after 15 subjects; 
• Expansion Cohort C will enroll up to a total of 41 subjects with advanced NSCLC with an 
EGFR mutation, the IA will be conducted after 15 subjects.  
3.4 
STUDY TREATMENT 
All doses of AFM24 will be administered as an i.v. infusion. During the dose escalation phase 
(Phase 1), subjects will receive AFM24 as a weekly infusion. Additional dosing regimen (ie, 
every 2 weeks) may be explored in the dose expansion phase (Phase 2a) only. Patients may 
receive AFM24 as long as they continue to show clinical benefit, as judged by the Investigator, 
or until disease progression, other treatment discontinuation criteria are met, or withdrawal of 
consent. Refer to the Pharmacy Manual for full details regarding study drug administration. 
3.5 
SAFETY REVIEW COMMITTEE (SRC) 
The SRC will convene to make a decision on the dose escalation.  
All details regarding the SRC composition, meetings, reviewed data and the decision-making 
process will be documented in the study-specific SRC Charter. 
3.6 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) 
Prior to initiation of dose expansion phase (Phase 2a), an Independent Data Monitoring 
Committee (IDMC) will be established consisting of clinical experts who are not directly involved 
in this clinical study. The IDMC will review all safety data generated throughout the dose 
expansion phase (Phase 2a) part 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. 
4. 
SAMPLE SIZE AND POWER CALCULATION 
Please refer to the protocol section 9.4 for sample size justifications. 
5. 
ANALYSIS ENDPOINTS 
 
Please refer to the protocol section 2.0 for Study Objectives and Endpoints. 
6. 
ANALYSIS POPULATIONS 
6.1 
SAFETY SET 
The safety set will consist of all patients who received at least one dose of AFM24. The safety 
set will be the primary population for all safety related endpoints except determination of the 
dose-DLT relationship, and for all efficacy related endpoints. 
6.2 
DOSE-DETERMINING SET 
The Dose-Determining Set (DDS) will consist of all patients in the safety set, who have either (a) 


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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 ≥80% of their assigned AFM24 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 ECG, or have had a DLT within 
the first cycle of treatment to be considered evaluable for DLT. 
6.3 
PK SET 
The PK set consists of all patients who have received at least 1 dose of study drug and have at 
least 1 post dose PK measurement. 
7. 
ANALYTICAL PLAN AND STATISTICAL METHODS 
7.1 
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 and 
standard deviation, median, and 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 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.  
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 summaries 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 Arm. 
7.2 
DEFINITION OF BASELINE, STUDY VISITS, AND VISIT WINDOWS 
Baseline is defined as the last non-missing observation prior to the first dose of study drug 
(screening assessment for most of the parameters, or C1D1 pre-dose, where applicable). 
Data will be analyzed in accordance with the visits recorded in the case report form (CRF), no 
visit reassignment will be done. 
Timepoints for analysis of vital signs will be assigned using protocol-defined windows. The 
windows are shown below: 


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Vital sign timepoints for first 2 
consecutive AFM24 dosing days 
(ie, Cycle 1 Day 1 and Day 8) 
Vital sign timepoints for 
subsequent AFM24 dosing if no 
Cytokine Release Syndrome or 
Infusion-related reaction (no 
Grade >1) observed during or 
after first 2 consecutive AFM24 
dosing days  
(ie, Cycle 1 Day 15 and beyond) 
Before 
infusion 
Baseline (within 1 hour before start of 
the infusion) 
Baseline (within 1 hour before start of 
the infusion) 
During 
infusion 
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 
As clinically indicated 
After infusion 
+60 (±10) minutes post EOI 
Every 60 (±10) minutes thereafter 
until the end of the observation 
period 
As clinically indicated 
EOI = End of Infusion 
7.3 
HANDLING OF MISSING DATA 
The following approach will be used to impute missing start date of Adverse Events and 
Concomitant Medications: 
- 
If only day is missing and the month and the year match the date of the first study drug 
injection, then impute the first date of the study drug injection 
- 
If only day is missing and the month and the year do not match the date of the first study 
drug injection, then impute the first day of the month 
- 
If the day and the month are missing and the year matches the date of the first study drug 
injection, then impute the first date of the study drug injection 
- 
If the day and the month are missing and the year does not match the date of the first study 
drug injection, then impute 01 January of the year 
Details of imputation of missing severity and causality for Adverse Events are given in Section 
7.8.2. No other imputation for the missing data will be done. 
7.4 
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. All patients who have signed the 
informed consent form are considered screened; enrolled refers to the CRF 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, 


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Dose-Determining Set and Safety Set for Phase 1, and for all enrolled patients for Phase 2a. 
Listings of all screened patients, reasons for screen failure, study populations, 
inclusion/exclusion criteria and not met will be created. Study discontinuation data will also be 
listed. 
7.5 
PROTOCOL DEVIATIONS 
Protocol Deviations will be summarized by counts and percentages. 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 or minor, will be 
provided for all screened patients.  
7.6 
PATIENT CHARACTERISTICS 
All summaries in this section will be done for Safety Set for Phase 1 and Phase 2a. 
7.6.1 BASELINE AND DEMOGRAPHIC CHARACTERISTICS 
Following characteristics at Baseline will be summarized: 
- 
Age (years) 
- 
Sex 
- 
Female with childbearing potential (and a reason, if not) 
- 
Race and Ethnicity 
- 
Height 
- 
Weight  
Listings of the baseline demography data will be prepared for the Safety Set. 
7.6.2 MEDICAL HISTORY AND CURRENT MEDICAL CONDITIONS 
Prior Cancer History (Cancer Type, Cancer Stage, Histopathological Type, Extent at Screening, 
Location of Metastases, Mutation/Alteration status) together with the screening ECOG value will 
be summarized for Phase 1. Similar summaries for Phase 2a will also include Tumor Mutation 
Status. 
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 Medical Dictionary for Regulatory Activities (MedDRA) dictionary 
version 22.1 or higher. Summaries will be split by SOC and Preferred Term. A condition will be 
considered prior if its end date is prior to the first date of the study 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. 
7.6.3 PRIOR AND CONCOMITANT MEDICATIONS AND PROCEDURES 
Prior Cancer Related Surgeries (number of surgeries and residual disease), Cancer Related 


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Radiotherapy (number of radiotherapies and total dose) and Prior Cancer Therapy (number of 
regiments, regiment 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 CRF 
page. Prior Cancer Therapies will be coded using 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, Radiotherapies 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. 
7.7 
EFFICACY ENDPOINTS AND ANALYSIS 
All the efficacy tables will be run for Safety Set for Phase 1 and for Phase 2a. Where specified 
additionally, sensitivity analyses on DDS will be run. 
In addition, a sensitivity analysis on ORR (as defined by RECIST by investigator and the 
independent assessor) will be performed for all patients in the safety set for patients receiving at 
least one full planned dose. 
7.7.1 ANALYSIS OF PRIMARY ENDPOINT 
Phase 1 (Dose Escalation) 
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 (Cycle 1) and that meets any of the following criteria 
shown in Table 1. The CRF record of DLT will be used to determine the DLT. 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. 
Patients must receive ≥80% of their assigned AFM24 dose in Cycle 1 and complete the 28-day 
DLT observation period or have had a DLT within the first cycle of treatment to be considered 
evaluable for DLT. The exact definition of the DLT is given in Section 3.4.2 of the Protocol. 
A 2-parameter BLRM (Neuenschwander et al., 2008) will be used for dose escalation of the 
monotherapy. The model will be run in house by Affimed. Detailed description of the process 
can be found in the Protocol. 
The model is formulated as follows: 
logit(p(d)) = log(α) + β*log(d/d*), 
where logit(p) = log(p/(1-p)). p(d) represents the probability of having a DLT in the first cycle at 
dose d, d* =180 mg is the reference dose, allowing for the interpretation of α as the odds of a 


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DLT at dose d*, and θ = (log(α), log(β)) with α, β >0 is the parameter vector of the model. 
Non-clinical data have been used to determine an informative prior distribution for θ. The details 
for the calculation can be found in the Protocol section 9.3.4.2. The resulting distribution is as 
follows:  
The analysis of the primary endpoint will be done on DDS. Number and percentage of the DLTs 
for every dose level will be summarized, together with the predicted DLT probability and 
predicted probability of overdosing. The analysis will be repeated on the updated data before 
each SRC. Final results obtained from complete data from Phase 1 will be reported in the CSR.  
Listing of all the DLTs will be created as a part of AE listings and separately. 
Phase 2a (Dose Expansion) 
Primary endpoint for this phase will be Overall response rate (complete response [CR] + partial 
response [PR]) assessed by local RECIST v1.1. Best confirmed overall response will be used to 
define the ORR. The table below summarizes the confirmation rules: 
Response at first visit 
Response at consecutive visit 
(at least 4 weeks after the 
initial assessment) 
Confirmed Response at visit 
CR 
CR 
CR 
CR 
PR 
PD 
CR 
SD 
SD* 
CR 
PD 
PD 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD* 
PR 
PD 
PD 
SD 
CR 
SD* 


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SD 
PR 
SD* 
SD 
SD 
SD* 
SD 
PD 
PD 
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease 
* - In order to assign Stable Disease as a confirmed response, there has to be another assessment of at 
least SD no less than 7 weeks after the initial visit. If this criterion is not satisfied, assign PD.   
If the closest consecutive visit is closer than 4 weeks, or is not evaluable, use the next available 
assessment for confirmation. The last visit has no confirmed response. For iRECIST data 
similar approach will be used to define the confirmed response at visit.  
Simon’s two-stage design will be used to determine the outcome of the study in each of the 
three cohorts. The table below shows the decision thresholds for the design for all three cohorts: 
Indication 
Interim Analysis 
Final Analysis 
 
Number of 
subjects 
OR, that may 
lead to stop 
Number of 
subjects* 
OR (rejection of the 
null hypothesis) 
RAS-wt, 
microsatellite stable 
CRC 
11 
≤1 
39 
≥4 
ccRCC 
15 
≤2 
41 
≥10 
NSCLC EGFRmut 
15 
≤2 
41 
≥10 
CRC = colorectal cancer; EGFRmut = epidermal growth factor receptor mutant; RAS-wt = rat sarcoma 
genes-wild type; NSCLC = non-small cell lung cancer; OR = objective response 
*Up to a total of N~40 subjects per Cohort 
The final analysis will take place after the last expansion arm was closed for futility or the last 
patient of the last expansion arm had the final end-of-study visit. Summaries will include the 
count and percentages of different best confirmed overall responses for each cancer type and 
observed ORR. In the final analysis, a p-value using the exact binomial test will be calculated 
comparing the response proportion to the probability stated under H0 for each indication 
separately. 
Listing of CT scan data, reporting both confirmed and unconfirmed responses at all visits will be 
created. Additionally, biopsy data will be listed. 
7.7.2 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
Phase 1 (Dose Escalation) 
Non-compartmental analysis (NCA) 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). Plots for individual 
PK concentrations will be generated. PK concentrations will be listed.  
ADA results (both screening and confirmatory results as well as titer) will be summarized by visit 


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and change from baseline to worst-post-baseline. Listing of ADA data will be created. The 
Immunogenicity data will be summarized both for the Safety Set in Phase 1. 
Overall response rate (CR + PR) and disease control rate (CR + PR + stable disease [SD]), 
assessed by Local RECIST v1.1 will be summarized. Best confirmed overall response will be 
used to define the ORR. Best response is defined as the best observed response 
(CR>PR>SD>PD) throughout the study. See Table 1 for rules of response confirmation. 
Summaries will include the count and percentages of different best confirmed overall responses, 
ORR and DCR for each dose level. The percentages will be based on the total number of 
patients in the Safety population 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 (both from the 
central reader and the investigator). 
Phase 2 (Dose Extension) 
The secondary endpoints for Phase 2a match the ones for the Phase 1. Similar analyses will be 
performed, but the presentation will be done by Expansion Arm rather than by dose level. 
Analysis of Adverse Events is described in section 7.8.2. 
Waterfall and swimmer plots will also be created, similar to what is described for Phase 1, but 
additionally color coding the Best confirmed Overall Response. 
7.7.3 
ANALYSIS OF EXPLORATORY EFFICACY ENDPOINTS 
Phase 1 (Dose Escalation) 
Overall response rate (CR + PR) and disease control rate (CR + PR + SD), assessed by: Local 
iRECIST; Central RECIST v1.1 and Central iRECIST will be summarized. 
In addition, Clinical Benefit Rate will be calculated and summarized. It will be defined similarly to 
DCR, but additionally requiring for SD to last at least 24 weeks. 
Duration of Response (DOR) will be defined as (date of first progression or death – date of first 
response (unconfirmed))/30.4375. Patients without response will be excluded from the analysis. 
Patients without progression or death will be censored at the date of the last tumor scan.  
Progression-Free Survival (PFS) will be defined as (date of first progression – date of first study 
drug injection)/30.4375. Patients without progression or death will be censored at the date of the 
last tumor scan.  
Overall Survival (OS) will be defined as (date of death – date of first dose)/30.4375. Patients 
alive at the end of study will be censored on the last date of observation. Separate analyses for 
DOR and PFS will be created for local and central assessments. Censoring rules for all time-to-
event endpoints can be seen in the table below.  
 
 


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Endpoint 
Situation 
Date 
Censored/Event 
Overall Survival 
A death is recorded 
Date of death 
Event 
Overall Survival 
No death is recorded 
Latest available observed 
date 
Censored 
Duration of Response 
A PD is observed 
First date of PD 
Event 
Duration of Response 
No PD is observed, 
but there is a death 
recorded 
Date of death 
Event 
Duration of Response 
Neither PD nor 
Death are observed 
Date of the last Tumor 
scan 
Censored 
Duration of Response 
New anti-cancer 
therapy is started 
before any event is 
recorded 
Date of the new anti-
cancer therapy 
Censored 
Time to Response 
A Response is 
observed 
Date of the earliest 
(unconfirmed) response 
Event 
Time to Response 
No Response is 
observed 
Date of latest tumor 
assessment 
Censored 
Progression-Free 
Survival 
A PD is observed 
First date of PD 
Event 
Progression-Free 
Survival 
No PD is observed, 
but there is a death 
recorded 
Date of death 
Event 
Progression-Free 
Survival 
Neither PD nor 
Death are observed 
Date of the last Tumor 
scan 
Censored 
Progression-Free 
Survival 
New anti-cancer 
therapy is started 
before any event is 
recorded 
Date of the new anti-
cancer therapy 
Censored 
PD = progressive disease 


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DOR, Time to Response (TTR), PFS and OS will be analyzed using Kaplan-Meier model. 
Summaries will include numbers and percentages of events and censored and product limit 
estimates of Median and the first and third Quartiles. Kaplan-Meier plots will also be created to 
support the summaries. 
Listings of Tumor assessment data and of DOR, TTR, PFS and OS data will be created. 
Lymphocyte subset counts, including number of total and activated 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. 
Summaries of the Cytokine values by visit will be created. Cytokine values will be listed. 
Post-hoc subgroup analyses may be performed, where deemed necessary. 
Phase 2 (Dose Extension) 
The exploratory endpoints and assessments for Phase 2a match the ones for the Phase 1. 
Similar analyses will be performed, but the presentation will be done by Expansion Arm rather 
than by dose level. PFS analyses for iRECIST-based outcomes will only be performed if 
deemed necessary based on the interim results. 
In addition, TTR will be summarized similarly to the other survival endpoints. TTR will be defined 
as (date of first (unconfirmed) CR or PR – data of first study drug injection)/30.4375. Patients 
without response of CR or PR will be censored at the last tumor assessment date. Patients with 
no post-baseline tumor assessments will be excluded from the analysis. TTR analyses for 
iRECIST-based outcomes will only be performed if deemed necessary based on the interim 
results. 
 
7.8 
SAFETY ENDPOINTS AND ANALYSIS 
Summaries for safety parameters will be done for the Safety Set for Phase 1 and Phase 2a. 
Tables will be presented by dose level for Phase 1 and by Expansion Arm for Phase 2a.  
7.8.1 EXPOSURE TO STUDY TREATMENT 
Total exposure (planned and actual) to the AFM24 in mg will be summarized by visit and 
overall. Delays, Interruptions, Dose Adjustments and Deviations and reasons for those will be 
summarized as well. Listings of AFM24 exposure data (doses and all dose 
adjustments/deviations) will be created.  
For Phase 2, the overall number of cycles, Duration of Exposure, Dose Intensity and Relative 
Dose Intensity will be summarized. Duration of Exposure in weeks will be defined as (date of the 
last AFM24 injection – date of the first AFM24 injection +7)/7. The above rule applies for weekly 
doses of AFM24, for the biweekly schedule the rule will be (date of the last AFM24 injection – 
date of the first AFM24 injection +14)/7. Dose Intensity will be defined as the total amount of 
AFM24 received by the subject in mg divided by the Duration of exposure. Relative Dose 


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Intensity will be calculated as the total dose of AFM24 received divided by the planned dose per 
cycle times the number of initiated cycles. 
The Exposure data will be summarized both for DDS and the Safety Set in Phase 1. 
7.8.2 ADVERSE EVENTS 
AEs will be summarized with patient counts, percentages and event counts by MedDRA System 
Organ Classes (SOCs) and Preferred Terms (PTs). Following categories of AEs will be 
summarized: AEs, related AEs, SAEs and related SAEs, AEs with NCI CTCAE Grades ≥3, AEs 
leading to premature discontinuation and interruptions or discontinuation of study drug and 
TEAEs on day of dosing (up to 24h after the dose) and on the first day after the dose. An event 
will be considered study drug related if it has ‘possible’, ‘probable’ or ‘definitely’ in relationship to 
study drug CRF field. TEAEs presented by SOC and PT will also be summarized by severity 
grades. 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 (separate for each AE category listed above) 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. 
7.8.3 LABORATORY DATA 
Safety laboratory results (Serum Chemistry, Hematology, and Coagulation) 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. 
7.8.4 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 


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significant ECGs and newly occurring qualitative ECG abnormalities will be tabulated as well. 
The summaries will only be done for Phase 1, Phase 2 ECG data will only be listed. 
Physical Examination data will be summarized by visit. Listing of the PE data will be created. 
7.9 
EXPLORATORY ANALYSIS 
7.9.1 BIOMARKER AND GENOMIC DATA ANALYSIS 
Summary statistics of biomarkers and genomic markers (including ctDNA, Cytokines, CyTOF 
and RO) will be reported by dose group or pooled and examined for possible associations with 
Investigator assessed RECIST efficacy endpoints (this will be done by running analyses of the 
efficacy assessment, grouped by biomarker categories, if deemed relevant and enough data per 
subgroup) and listed.  
A separate plan for Biomarker statistical analysis, containing all the details of the planned 
analyses will be created. 
8. 
INTERIM ANALYSES 
Phase 1 (Dose Escalation) 
Each dose escalation step is considered to be an interim analysis, but without a formal interim 
analyses report. The BLRM will be updated with the respective number of patients treated and 
the number of DLTs observed in the last cohort. The updated model will then give a statistical 
recommendation for the next escalation step. In addition, a risk-benefit assessment that 
includes a comprehensive analysis of safety and available clinical information will be done to 
decide on the next escalation steps. SRC will review the data at this stage and make the final 
decision regarding the dose escalation. A separate SRC charter will be composed to describe 
the SRC activities. 
In case of a CTCAE Grade 5 adverse event or a second CTCAE Grade 4 adverse event at least 
possibly related to AFM24 at any time during Phase 1, the Sponsor will suspend further 
enrollment and an interim safety analysis will be done. The interim safety analysis will be 
submitted to the applicable competent authorities for review prior to resuming the study. 
Phase 2a (Dose Expansion) 
An interim analysis will be performed for each cohort independently, once the defined number of 
subjects (11, 15, and 15 subjects for Cohorts A, B, and C, respectively) in the respective cohort 
have completed their first post-baseline assessment and its confirmation (2nd post baseline 
assessment, ie, ≥12 weeks post-baseline) to be categorized under the primary response 
endpoint or have withdrawn from the study. Each cohort will be then assessed for futility and 
recruitment will not be stopped until the IA is completed. The results from this IA will be non-
binding, unless no signs of efficacy are observed. Safety criteria will also be evaluated to decide 
on the continuation of the cohorts. Since this is a non-comparative multiple arm study no 
adjustment for multiple testing is made.