Clinical trial NCT03192202
Conditions: Lymphoma, T-Cell, Cutaneous
Keywords: Lymphoma Cutaneous Lymphoma cutaneous T-cell lymphoma (CTCL) CD30-Positive Cutaneous Lymphoma T-cell lymphoma PTCL CTCL CD30 immunotherapy
Sponsor: Ahmed Sawas
Start date: 2017-07-17; Completion date: 2020-04-01
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The investigators plan to investigate AFM13 and evaluate its ability to facilitate and redirect the Natural Killer (NK) cells in eliminating CD30-positive lymphoma targets in the skin and, by inference, other organs involved by the lymphoma.

Detailed description:
This is an open label, Phase Ib/IIa study designed to evaluate the biologic activity of AFM13 in patients with relapsed or refractory CD30-positive lymphomas with cutaneous involvement. Primary cutaneous CD30-positive lymphoproliferative disorders (LPD) represent a spectrum from lymphomatoid papulosis (LyP), to primary cutaneous anaplastic large cell lymphoma (C-ALCL), to transformed mycosis fungoides (TMF).

The most indolent form of primary cutaneous CD30-positive LPD is LyP, which is usually well controlled with low dose oral methotrexate, but control of the disease frequently requires life-long therapy. In contrast, TMF is an aggressive disease which does not have a standard of care, as patients are treated with various modalities of care with variable outcomes). The spectrum of other CD30-positive lymphomas with cutaneous presentation is very broad and involves systemic B and T cell lymphomas with various clinical behaviors.

Redirecting Natural Killer (NK) cells towards these CD30-positive malignancies through direct engagement with AFM13 is expected to induce tumor cell killing through NK cell-mediated and T cell-mediated cytotoxicity (i.e., cytotoxic T lymphocytes (CTL)).

The primary objective of this trial is to study the biologic and immunologic effects induced by the administration of various doses of AFM13, when given as a single agent.

Arms: arm 1: 1.5 mg/kg of AFM13 once weekly for weeks 1-8. arm 2: 7 mg/kg of AFM13 once weekly for weeks 1-8. arm 3: 7mg/kg CIVI for weeks 1-8. arm 4: 200mg flat dose once weekly for 8 weeks.
Interventions: intervention 1: AFM13
Intervention descriptions: intervention 1: AFM13 is a recombinant antibody construct against human CD30 and CD16A. It will be given to patients intravenously at the dose and schedule applicable to the cohort the patient was enrolled in specified in the various arms listed.

Protocol documents:
Prot_SAP_000.pdf: 
 
Columbia University Medical Center 
CONFIDENTIAL 
Protocol 
AFM13 
NCT03192202 
 
 
 
Protocol Version 1.4 February 1st , 2019 
Page 1 of 88 
 
 
 
 
Clinical and Biological Evaluation of the Novel CD30/CD16A 
Tetravalent Bispecific Antibody (AFM13) in Relapsed or Refractory 
CD30-Positive Lymphoma with Cutaneous Presentation: A Biomarker 
Phase Ib/IIa Study 
 


 
Columbia University Medical Center 
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Protocol 
AFM13 
NCT03192202 
 
 
 
Protocol Version 1.4 February 1st , 2019 
Page 2 of 88 
 
1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
Clinical and Biological Evaluation of the Novel CD30/CD16A Tetravalent Bispecific 
Antibody (AFM13) in Relapsed or Refractory CD30-Positive Lymphoma with Cutaneous 
Presentation: A Biomarker Phase Ib/IIa Study 
 
Protocol No.:   
CUMC 
Study identifier CUMC: 
AAAP4461  
Test Product: 
AFM13 
Indication: 
Relapsed or refractory CD30-Positive Lymphoma with 
Cutaneous Presentation 
Sponsor: 
Columbia University Medical Center (CUMC) 
Development Phase: 
Ib/IIa 
Sponsor Signatory: 
CUMC 
Sponsor Medical Expert: 
Ahmed Sawas, MD 
Principal Investigator: 
Ahmed Sawas, MD 
 
Assistant Professor of Medicine 
 
Columbia University Medical Center 
Date of the Protocol: 
February 1st , 2019 
Version of the Protocol: 
1.4 
ClinicalTrials.gov Identifier:           NCT03192202 
 
 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator or consultant for review by you, your staff and applicable Institutional Review 
Board. It is understood that the information will not be disclosed to others without written 
authorization from Columbia University Medical Center except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered. 


 
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Protocol 
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NCT03192202 
 
 
 
Protocol Version 1.4 February 1st , 2019 
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2 
SIGNATURE PAGES 
 
SPONSOR SIGNATURE PAGE 
 
PROTOCOL TITLE: Clinical and Biological Evaluation of the Novel CD30/CD16A 
Tetravalent Bispecific Antibody (AFM13) in Relapsed or Refractory CD30-Positive 
Lymphoma with Cutaneous Presentation: A Biomarker Phase Ib/IIa Study 
 
CUMC PROTOCOL NUMBER:  AAAP4461 
 
IND #129679 
 
 
Columbia University Medical Center 
Center for Lymphoid Malignancies 
51 West 51st Street, Suite 200 
New York, NY 10019 
 
 
 
 
 
 
Ahmed Sawas, M.D.  
 
Date (day/month/year) 
 


 
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Protocol 
AFM13 
NCT03192202 
 
 
 
Protocol Version 1.4 February 1st , 2019 
Page 4 of 88 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
PROTOCOL TITLE: Clinical and Biological Evaluation of the Novel CD30/CD16A 
Tetravalent Bispecific Antibody (AFM13) in Relapsed or Refractory CD30-Positive 
Lymphoma with Cutaneous Presentation: A Biomarker Phase Ib/IIa Study 
 
PROTOCOL NUMBER:  AAAP4461 CUMC 
I agree to conduct the study outlined above in accordance with the terms and conditions of the 
protocol, ICH guidelines on GCP and with applicable regulatory requirements. All information 
pertaining to the study shall be treated in a confidential manner. 
 
 
 
 
 
 
Ahmed Sawas, M.D. 
 
 
 
 
 
Date (day/month/year) 
 
 


 
Columbia University Medical Center 
CONFIDENTIAL 
Protocol 
AFM13 
NCT03192202 
 
 
 
Protocol Version 1.4 February 1st , 2019 
Page 5 of 88 
 
3 
GENERAL INFORMATION 
PROTOCOL TITLE: Clinical and Biological Evaluation of the Novel CD30/CD16A 
Tetravalent Bispecific Antibody (AFM13) in Relapsed or Refractory CD30-Positive 
Lymphoma with Cutaneous Presentation: A Biomarker Phase Ib/IIa Study 
 
Protocol No.: 
AAAP4461 CUMC/AFM13 
Protocol Version and Date: 
v1.2, January 31, 2018 
 
Sponsor: 
Columbia University Medical Center 
 
Principal Investigator: 
Ahmed Sawas, MD 
Sponsor Medical Expert 
Assistant Professor of Medicine 
 
Columbia University Medical Center 
 
Center for Lymphoid Malignancies  
 
 
51 West 51 St, Suite 200 
 
New York, NY 10019 
 
 
Co-Investigators:  
Owen A. O’Connor, MD, Ph.D. 
 
Professor of Medicine and Experimental 
Therapeutics, 
 
Director, Center for Lymphoid Malignancies 
 
oo2130@columbia.edu 
 
 
Jennifer E. Amengual, MD 
 
Assistant Professor of Medicine 
 
jea2149@columbia.edu 
 
 
 
Changchun Deng, MD, Ph.D. 
 
Assistant Professor of Medicine 
 
cd2448@columbia.edu 
 
 
Jennifer Lue, MD 
 
Assistant Professor of Medicine  
 
JKL2160@columbia.edu 
 
 
 
Francesca Montanari, MD 
 
Assistant Professor of Medicine 
 
fm2290@cumc.columbia.edu 
 
 
 
 
 Larisa Geskin M.D 
 
 
 
 Associate Professor of Dermatology 
 
ljg2145@ Columbia.edu  


 
Columbia University Medical Center 
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Protocol 
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NCT03192202 
 
 
 
Protocol Version 1.4 February 1st , 2019 
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George Vlad, Ph.D 
 
Assistant Professor of Clinical Pathology and Cell 
Biology 
 
gv2010@ columbia.edu 
 
 
 
 
Bin Cheng, PhD. 
 
Associate Professor  
 
bc2159@cumc.columbia.edu 
 
 
Covance Laboratories Limited 
 
Otley Road, Harrogate, North Yorkshire, HG3 1PY, UK 
 
Email: HarrogateBioASIC@Covance.com 
 
Tel No: +44 (0)1423 635696 
 
Fax No: +44 (0) 1423 569595  
 
 
 
 
 
Drug Supply:  
 
Marken – Clinical Trial Logistics 
 
Farmingdale Depot 
 
123 Smith Street Farmingdale 
 
NY 11735, USA 
 
Tel No.: +1 631 396 7454 
 
FAX No.: +1 631 396 7412 
 
 


 
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Protocol 
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NCT03192202 
 
 
 
Protocol Version 1.4 February 1st , 2019 
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4 
STUDY SYNOPSIS 
Sponsor:  
Columbia University Medical Center 
Center for Lymphoid Malignancies 51 West 51st Street, New York, NY 10019 
Title of Study: 
Clinical and Biological Evaluation of the Novel CD30/CD16A Tetravalent Bispecific Antibody (AFM13) in 
Relapsed or Refractory CD30-Positive Lymphoma with Cutaneous Presentation: A Biomarker Phase Ib/IIa Study 
Phase: Ib/IIa 
Principal Investigator: 
Ahmed Sawas, MD 
Name of Investigational Product: 
AFM13, Recombinant antibody construct against human CD30 and CD16A (TandAb®) 
Study Center: 
Columbia University Medical Center, 51 West 51st St., Suite 200, New York, N.Y. 
Publications: 
None. 
Planned Study Period: 
Q3 2017 to Q4 2019 (first patient first visit to last patient last visit) 
Objectives: 
The primary objectives are to: 
1. Determine the intratumoral NK-cell and T-cell infiltrate and density 
2. Determine the immunophenotype of immune cells (NK cells, T cells and others) in tumor and peripheral 
blood 
3. Quantitate the plasma cytokine production and release in tumor and peripheral blood as a function of 
treatment. 
 
Secondary objectives are to: 
1. Evaluate the safety and toxicity of AFM13 
2. Determine the clinical efficacy, namely objective response rate (ORR), [including complete response (CR) 
and partial response (PR)], duration of response (DOR) and progression-free survival (PFS) as defined in 
the Revised Response Criteria for Malignant Lymphoma 2007 and modified Severity-Weighted 
Assessment Tool (mSWAT)  
3. Evaluate the pharmacokinetic profile (PK) of AFM13. 
 
Exploratory objectives are to: 
1. Determine the immunogenicity of AFM13 
2. Detect and quantify circulating tumor cells (CTC). 
Methodology: 
This is an open label, Phase Ib/IIa study designed to evaluate primarily the biological and immunological activity 
of AFM13 in tumor and blood when administered as monotherapy to patients with CD30-positive lymphomas 
with cutaneous presentation. Four cohorts of 3 patients will be treated with different doses of AFM13 and dose 
regimens. 
Number of Patients: 
It is planned that at least 15 eligible patients will be accrued. 
Diagnosis and Main Eligibility Criteria: 
This study will enroll patients with relapsed or refractory CD30-positive lymphoma with cutaneous presentation. 


 
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Sponsor:  
Columbia University Medical Center 
Center for Lymphoid Malignancies 51 West 51st Street, New York, NY 10019 
Inclusion criteria: 
1. Age ≥18 years 
2. Histologically confirmed CD30-positive lymphoma with cutaneous involvement 
3. Failure or intolerance to at least one prior therapy for the current disease  
4. Presence of one or more cutaneous lesions (measuring at least 1 cm x 1 cm in size; if only one lesion is 
present it should be up to the investigator discretion to determine eligibility)  
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2  
6. Adequate organ and marrow function 
a) 
Platelets ≥50,000/µL 
b) 
Absolute neutrophil count ≥ 1,000/μL 
c) 
Bilirubin < 1.5 x institutional upper limit of normal (ULN) or < 3 x ULN in patients with Gilbert's 
disease or liver involvement 
d) 
Serum albumin ≥ 2.0 g/dL 
e) 
Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤2.5 × institutional ULN or, in the 
case of liver involvement by the primary disease AST/ALT ≤ 5 x ULN 
f) 
Creatinine≤1.5 x institutional ULN or estimated creatinine clearance of ≥45 mL/min by the Cockcroft-
Gault equation or measured creatinine clearance >45 mL/min 
7. Females of child bearing potential must have a negative serum pregnancy test with 7 days prior to first 
dose of treatment. Female patients of childbearing potential and all male partners must agree to use double 
barrier methods of contraception throughout the study period and for at least 30 days following 
investigational product discontinuation.  
8. Ability to understand and the willingness to sign a written informed consent document. 
 
Exclusion criteria: 
1. Any cancer-related therapy for the current disease within 2 weeks of screening (all supportive care 
measures are allowed) 
2. Major surgery within 2 weeks prior to first dose of study drug 
3. Evidence of active central nervous system (CNS) involvement 
4. Requirement for systemic immunosuppressive therapy (e.g. Graft-versus-Host Disease [GVHD] therapy 
within 12 weeks before the first dose of study drug) 
5. Uncontrolled concurrent serious illness. 
6. Concurrent malignancy requiring cytotoxic or immunotherapy based treatment.  
7. Active infections including hepatitis B carrier status, hepatitis C virus (HCV) infection (patients with 
positive serology must have a negative Hep B and Hep C viral load at screening) 
8. Known HIV-positive status 
9. Any significant medical conditions, laboratory abnormality, or psychiatric illness that would exclude the 
subject from participation or interfere with study treatment, monitoring and compliance such as: 
a) unstable angina pectoris, symptomatic congestive heart failure (NYHA III or IV), myocardial infarction 
≤ 6 months prior to first study drug, clinically significant and uncontrolled cardiac arrhythmia (e.g. atrial 
fibrillation/flutter ventricular cardiovascular physiology is allowed), cerebrovascular accidents ≤ 6 
months before study drug start 
b) severely impaired lung function 
10. Serious, systemic infection requiring treatment ≤7 days before the first dose of study drug 
11. Any severe, uncontrolled disease or condition which in the investigator's opinion, may put the subject at 
significant risk, may confound the study results, or impact the subject's participation in the study. 
Test Product, Dose and Mode of Administration: 


 
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Protocol Version 1.4 February 1st , 2019 
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Sponsor:  
Columbia University Medical Center 
Center for Lymphoid Malignancies 51 West 51st Street, New York, NY 10019 
All patients will receive AFM13, administered by intravenous infusion according the schema shown for cohorts 
below. Dose administered will be determined according to cohort and treatment day: 
• 
Cohort 1: 
1.5 mg/kg weekly for 8 weeks 
• 
Cohort 2: 
7.0 mg/kg weekly for 8 weeks 
• 
Cohort 3: 
7.0 mg/kg weekly for 8 weeks (1 mg/kg applied as loading dose 
and 6mg/kg as continuous infusion for 5 days per week) 
• 
Cohort 4:                                             200 mg weekly for 8 weeks 
Reference Therapy, Dose and Duration of Administration: 
None 
Intended Duration of Treatment: 
All patients will receive at least 1 cycle of treatment (8 weeks). Patients with clinical benefit (CR, PR, or SD) are 
eligible to receive a 2nd cycle of treatment (lasting 8 weeks). Patients can receive a maximum of 2 cycles of 
treatment. 
 
Assessments: 
Biological and immunological effects (primary endpoint) 
• 
Intratumoral natural killer (NK)-cell and T-cell infiltrate and density 
• 
Phenotypic characterization of immune cells (NK cells, T cells and other) in tumor and peripheral blood 
• 
Cytokine production and release in tumor and peripheral blood 
 
Safety Assessments (secondary endpoint) 
• 
Determine the safety profile as a function of dose and schedule.  
• 
Establish vital signs for each treatment 
• 
Intermittent ECG monitoring 
 
Activity Assessments (secondary endpoint) 
• 
ORR (CR, PR)  
• 
DOR 
• 
PFS 
 
Pharmacokinetic  Assessments (secondary endpoint) 
• 
Maximum measured plasma concentration (Cmax)  
 
Other descriptive variables may be applied accordingly such as: 
• 
Area under the curve (AUC) 
• 
Distribution volume (VD) 
• 
Terminal half-life (t1/2) 
• 
Clearance 
 
AFM13 immunogenicity (exploratory endpoint) 
• 
Screen for presence of anti-drug antibodies (ADAs) 
• 
Neutralizing potential of ADAs 
• 
NK cell cytotoxicity against CD30-positive targets and cytotoxic T lymphocyte (CTLs) function 
Statistical Methods: 


 
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Sponsor:  
Columbia University Medical Center 
Center for Lymphoid Malignancies 51 West 51st Street, New York, NY 10019 
As this is an exploratory study, no hypothesis will be tested and thus no formal sample size calculation has been 
undertaken. The response rate will be estimated and their respective exact 95% confidence intervals will be 
constructed based on Binomial distribution.  
Based on the prior Phase 1 study of AFM13, it is expected that approximately 78% of the patients will show 
immunological and biological activity. Observing 12 patients out of 15 with immunological and biological 
response would lead to 95% exact binomial confidence interval of 52%-96% showing activity. The lower bound 
of 52% is assumed to be sufficient for evidence of activity in this exploratory study. 
No formal interim analysis is planned, however a safety committee (not a formal data safety monitoring board) 
will review the safety data from each cohort and advise on opening the next cohort. 
Version and date of the Protocol: 1.4 February 1st, 2019 
 


 
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5 
TABLE OF CONTENTS 
1 
TITLE PAGE ......................................................................................................... 2 
2 
SIGNATURE PAGES ........................................................................................... 3 
3 
GENERAL INFORMATION ................................................................................ 5 
4 
STUDY SYNOPSIS .............................................................................................. 7 
5 
TABLE OF CONTENTS .................................................................................... 11 
5.1 
List of Tables ..................................................................................... 16 
5.2 
List of Figures .................................................................................... 16 
5.3 
List of Appendices and Supplements ................................................. 16 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................ 17 
7 
INTRODUCTION ............................................................................................... 20 
7.1 Background .................................................................................................... 22 
7.1 
Targeting Unique Cell-Surface Proteins in Lymphoma .................... 22 
7.2 
CD30-Positive Lymphoid Malignancies ........................................... 22 
7.3 
AFM13 ............................................................................................... 23 
7.4 
Pharmaceutical and Therapeutic Background ................................... 23 
7.4.1 
Antibody generation and folding pathway ......................... 23 
7.4.2 
Mode of action.................................................................... 24 
7.5 
Non-clinical studies ........................................................................... 25 
7.5.1 
Characterization of affinity and specificity ........................ 25 
7.5.2 
Primary pharmacodynamic activity .................................... 25 
7.5.3 
Secondary pharmacodynamic activity ................................ 26 
7.6 
Safety pharmacology ......................................................................... 26 
7.6.1 
Tissue cross-reactivity ........................................................ 26 
7.7 
Phase I clinical trial in relapsed or refractory Hodgkin lymphoma ... 27 
7.7.1 
Results of the AFM-101 phase I trial ................................. 27 
7.8 
Rationale ............................................................................................ 29 
8 
STUDY OBJECTIVES ....................................................................................... 31 
8.1 Primary Objectives ........................................................................................ 31 
8.2 Secondary Objectives .................................................................................... 31 
8.3 Exploratory Objectives .................................................................................. 31 
9 
INVESTIGATIONAL PLAN .............................................................................. 32 
9.1 Overall Study Design and Plan ...................................................................... 32 
9.1 
Description ......................................................................................... 32 
9.2 
Dose Rationale ................................................................................... 34 
9.3 
Number of Centers ............................................................................. 38 


 
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9.4 
Number of Subjects ........................................................................... 38 
9.5 
Schedule of Assessments ................................................................... 38 
9.6 
Study Assessments ............................................................................. 42 
9.6.1 
Registration Procedures ...................................................... 42 
9.6.2 
Screening Period (Day -28 to Day 0) ................................. 42 
10 
INFORMED CONSENT AND OTHER STUDY PROCEDURES .................... 44 
Study Informed Consent ................................................................................... 44 
10.1 
Consent and Use of Tissue Specimens for Research ......................... 44 
10.2 
Treatment Period (8 weeks) ............................................................... 45 
10.3 
Week 1 ............................................................................................... 45 
10.4 
Week 2, 3, 4, 5, 6, 7 and 8, Day 1 Visits ........................................... 47 
10.5 
Week 11, Day 1- Follow-up Period ................................................... 50 
10.6 
Restaging Visit ................................................................................... 50 
10.7 
End of Study Visit (last dose + 4 weeks) ........................................... 51 
10.8 
Duration of Follow Up ....................................................................... 51 
10.9 
Discussion of Study Design ............................................................... 51 
10.10 
Risk/Benefit and Ethical Assessment ................................................ 52 
10.11 
Selection of Study Population............................................................ 53 
10.11.1 Inclusion Criteria ................................................................ 53 
10.11.2 Exclusion Criteria ............................................................... 54 
10.12 
Inclusion of Women and Minorities .................................................. 54 
10.13 
Withdrawal of Patients....................................................................... 54 
10.14 
Replacement of Subjects .................................................................... 55 
11 
INVESTIGATIONAL PRODUCT ..................................................................... 56 
11.1 
Identity of Study Treatment ............................................................... 56 
11.2 
Treatment Storage .............................................................................. 56 
11.3 
Treatment Packaging and Labeling ................................................... 57 
11.4 
Preparation of Study Treatment ......................................................... 57 
11.5 
Administration of Study Treatments .................................................. 57 
11.6 
Study Treatment Accountability ........................................................ 58 
12 
STUDY ASSESSMENTS ................................................................................... 59 
12.1 
Informed Consent .............................................................................. 59 
12.2 
Medical History and Physical Examinations ..................................... 59 
12.3 
Documentation of Side-effects .......................................................... 59 
12.4 
Reported Undesirable Effects ............................................................ 59 


 
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12.5 
Management of Infusion-related Reactions ....................................... 59 
12.6 
Management of Other AFM13-related Side Effects .......................... 60 
12.7 
Study drug adjustments ...................................................................... 61 
12.8 
Treatment Schedule Interruptions (Delayed or Skipped Doses) ........ 61 
12.9 
Study Drug Discontinuation .............................................................. 61 
12.10 
Concomitant Therapy ........................................................................ 61 
13 
ASSESSMENT OF EFFICACY ......................................................................... 63 
13.1 
Measurement of Biological Effects in Tumor and Blood .................. 63 
13.2 
Measurement of Clinical Efficacy ..................................................... 63 
13.3 
Definitions ......................................................................................... 63 
13.4 
Skin Biopsy ........................................................................................ 64 
13.5 
Objective Response Rate ................................................................... 64 
13.6 
Modified Severity-Weighted Assessment Tool ................................. 64 
13.7 
Computerized Tomography/Magnetic Resonance Imaging .............. 65 
13.8 
Whole body 18FDG-PET Scan ........................................................... 65 
13.9 
Exploratory Studies ........................................................................... 66 
14 
ASSESSMENT OF SAFETY.............................................................................. 67 
14.1 
Adverse Events .................................................................................. 67 
Definitions ......................................................................................................... 67 
14.2 
Unexpected Adverse Reaction ........................................................... 68 
14.3 
Suspected Unexpected Serious Adverse Reaction ............................. 68 
14.4 
Causality/Relationship ....................................................................... 68 
14.5 
Recording of Adverse Events ............................................................ 69 
14.6 
Expedited Adverse Event Reporting .................................................. 70 
14.7 
Adverse Event Updates/IND Safety Reports ..................................... 72 
14.8 
IND  Reporting .................................. Error! Bookmark not defined. 
14.9 
Pregnancy .......................................................................................... 72 
14.10 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms ......... 73 
14.11 
Deaths ................................................................................................ 73 
14.12 
Overdose ............................................................................................ 73 
14.13 
Laboratory Assessments .................................................................... 73 
14.14 
Biological Parameters/Markers .......................................................... 74 
14.15 
Electrocardiogram Assessments ........................................................ 74 
14.16 
Physical Examination ........................................................................ 74 
14.17 
Vital Signs ......................................................................................... 74 


 
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14.18 
Assessment of Pharmacokinetics ....................................................... 75 
15 
STATISTICAL EVALUATION ......................................................................... 76 
15.1 
Statistical Methods ............................................................................. 76 
15.2 
Sample Size and Power...................................................................... 76 
15.3 
Study Populations .............................................................................. 76 
15.4 
Demographics, Baseline Characteristics and Medical History .......... 76 
15.5 
Treatment, Compliance, Disposition, Concomitant Therapies, Protocol 
Deviations .......................................................................................... 77 
15.6 
Primary Objective .............................................................................. 77 
15.7 
Secondary Objectives ........................................................................ 77 
15.7.1 
Efficacy .............................................................................. 77 
15.7.2 
Duration of response .......................................................... 78 
15.7.3 
Progression-Free Survival .................................................. 78 
15.7.4 
Pharmacokinetics................................................................ 78 
15.8 
Safety Objectives ............................................................................... 78 
15.8.1 
Adverse Events ................................................................... 78 
15.8.2 
Laboratory Abnormalities .................................................. 78 
15.8.3 
Vital Signs .......................................................................... 79 
15.8.4 
Other Safety Parameters ..................................................... 79 
15.9 
Exploratory Objectives ...................................................................... 79 
15.9.1 
Presence of Anti-AFM13 Antibody ................................... 79 
15.9.2 
Interim Analysis ................................................................. 79 
16 
SOURCE DOCUMENTATION ......................................................................... 80 
17 
QUALITY CONTROL AND QUALITY ASSURANCE .................................. 81 
17.1 
Conduct of the Study ......................................................................... 81 
17.2 
Study Monitoring ............................................................................... 81 
17.3 
Study Auditing ................................................................................... 81 
17.4 
Protocol Amendments........................................................................ 81 
17.5 
Protocol Deviations/Violations .......................................................... 82 
17.6 
Institutional Review Board ................................................................ 83 
17.7 
Written Informed Consent ................................................................. 83 
18 
DATA HANDLING AND RECORD KEEPING ............................................... 84 
18.1 
Responsibility for Data Submission .................................................. 84 
18.2 
Data Safety Monitoring Board ........................................................... 84 
18.3 
Investigator Reporting Responsibilities ............................................. 84 


 
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19 
REFERENCE LIST ............................................................................................. 85 
20 
APPENDICES ..................................................................................................... 88 
 
 


 
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5.1 
List of Tables 
Table 1:  Treatment Cohorts and Dosing Schedule (one cycle of treatment)………....32 
Table 2:  Schedule of Assessments……………………………………………………39 
Table 3:  Composition of AFM13 for Injection……………………………………….56 
Table 4:  Management of AFM13-associated Infusion-related Reactions…………….59 
Table 5:  Management of Other AFM13-associated Adverse Events…………………59 
Table 6:  Global Response Score………………………………………………………64 
Table 7:  Modified Severity-Weighted Assessment Tool……………………………...65 
 
5.2 
List of Figures 
 
Figure 1: Folding pathway of AFM13………………………………………………….24 
Figure 2: Correlation Between NK Cell Activation and PK of AFM13……………….34 
Figure 3: PK profile for 1.5 mg/kg AFM13 administered weekly……………………...35 
Figure 4:Simulated pKprofile 1.5 mg/kg AFM13 administered three times per week…35 
Figure 5: Simulated PK profile 1.5 mg/kg AFM13 administered weekly q 2wks followed 
by 7 mg/kg weekly over 6 weeks…………………………………………36 
 
5.3 
List of Appendices and Supplements 


 
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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADAs 
Anti-Drug Antibodies 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
AE 
Adverse Event 
ALCL 
Anaplastic Large Cell Lymphoma 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATL 
Adult T-cell Leukemia/Lymphoma 
AUC 
area under the curve 
B-ALL 
B -Cell Acute Lymphoid Leukemia 
BiKE 
Bispecific Killer Engagers 
BiTE 
Bispecific T-cell engager 
C-ALCL 
Cutaneous Anaplastic Large Cell Lymphoma 
CAR-T 
Chimeric Antigen Receptor activated T cell 
CFR 
Code of Federal Regulations 
CIVI 
Cmax 
Continuous Intravenous Infusion 
maximum plasma concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computerized Tomography 
CTC 
Circulating Tumor Cell 
CTCAE 
Common Terminology Criteria for Adverse 
Events 
CTCL 
Cutaneous T cell lymphoma 
CTL 
Cytotoxic T Lymphocyte 
CUMC 
Columbia University Medical Center 
DLBCL 
Diffuse Large B-cell Lymphoma 
DLT 
Dose Limiting Toxicity 
DNAM1 
DNAX accessory molecule 1 
DOR 
Duration of Response 
DSMB 
Data/Safety Monitoring Board 
EBV 
Epstein-Barr Virus 
EC50 
Effective Concentration 50 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram  


 
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EoS 
End of Study 
EoT 
End of treatment 
FDA 
Food and Drug Administration 
18FDG-PET 
fluorodeoxyglucose-positron 
emission 
tomography 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GR  
Global Response  
GVHD 
Graft-Versus-Host Disease 
HCV 
Hepatitis C Virus 
HIPAA 
Health Insurance Portability and Accountability 
Act 
HIV 
Human Immunodeficiency Virus 
HL 
Hodgkin Lymphoma 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IDMC 
Independent Data Monitoring Committee 
IFN-γ 
Interferon  gamma 
IRB 
Institutional Review Board 
IRR 
Infusion-Related Reaction 
IV 
Intravenous 
KIR 
Killer cell Immunoglobulin-like Receptor 
LILRB1 
Leukocyte 
Immunoglobulin-Like 
Receptor 
subfamily B member 1 
LPD 
Lymphoproliferative Disorder 
LyP 
Lymphomatoid Papulosis 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Mycosis Fungoides 
mSWAT 
modified Severity-Weighted Assessment Tool 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCR 
Natural Cytotoxicity Receptor 


 
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NF-κB 
Nuclear Factor kappa-Beta 
NGS 
Next Generation Sequencing 
NHL 
Non-Hodgkin Lymphoma 
NK  
Natural Killer  
NKG2D 
Natural Killer group 2, member D 
NYHA 
New York Heart Association 
ORR 
Overall Response Rate  
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PMBL 
Primary Mediastinal (thymic) large B-cell 
Lymphoma 
pM 
Picomolar 
PR 
Partial Response 
PTCL 
Peripheral T-cell Lymphoma 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
scFv 
Single chain fragment variable 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBSA 
Total Body Surface area 
TMF 
Transformed Mycosis Fungoides 
TNF 
Tumor Necrosis Factor  
TNFRSF 
Tumor Necrosis Factor Receptor Super Family 
TRAF 
Tumor Necrosis Factor receptor-associated factor 
Tregs 
T cells (regulatory) 
TriKE 
Trispecific Killer Engagers 
t1/2 
 Half-life  
ULN 
Upper Limit of Normal 
VD 
Volume of Distribution 
WHO 
World Health Organization 
 
 
 
 


 
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7 
INTRODUCTION 
Natural killer (NK) cells represent approximately 15% of circulating lymphocytes and are 
considered one of the key innate effectors in host immune defense [1]. Although NK cells are 
primarily found in the blood, liver, spleen, bone marrow and, to a lesser extent, lymph nodes, 
inflammation and other factors can trigger NK cell migration into almost any tissue. NK cells 
were identified on the basis of their ability to lyse tumor cells without prior sensitization. In 
contrast to B- and T- lymphocytes, NK cells do not rearrange genes to acquire antigen-specific 
receptors. Instead, NK cells target tumor cells via an array of germ line-encoded cell surface 
receptors. Based on this characteristic, NK cells have traditionally been considered to be part 
of the innate immune response [1]. New observations that some NK cell subsets can be long-
lived and show recall responses to certain stimuli has recently challenged this view, as these 
are properties characteristic of adaptive immunity [2-8]. 
NK cells can mediate cytotoxicity via several distinct mechanisms. The most studied pathway 
is degranulation, whereby NK cells inject perforin-1, and granzyme B into the cytoplasmic 
compartment of the target cell. This pathway is triggered by signals from activating cell surface 
receptors such as NK group 2 member D (NKG2D), DNAX accessory molecule-1 (DNAM1 
or CD226), 2B4 (CD244), a member of the SLAM-related receptor family, and the natural 
cytotoxicity receptors (NCR), including NKp30, NKp44 and NKp46, counterbalanced by 
signals from inhibitory receptors, most of which bind to major histocompatibility complex 
(MHC) class I molecules [9]. Subsequent research has not only provided further insights into 
the intricate regulation of NK cell degranulation but also revealed that their functional capacity 
is tuned by interactions with self-MHC class I molecules [10-12]. In humans, killer cell 
immunoglobulin-like receptors (KIRs) and the CD94–NKG2A receptor are the only receptors 
known to mediate functional tuning (also referred to as NK cell education). However, the role 
for other receptors, such as leukocyte immunoglobulin-like receptor subfamily B member 1 
(LILRB1), in this process remains to be established. One receptor that can trigger potent 
degranulation without the need for simultaneous co-activation signals from other NK cell 
receptors is the Fc receptor CD16 which, upon interacting with antibody-coated cells, mediates 
antibody-dependent cellular cytotoxicity (ADCC). 
Over the past few decades, drugs and cell-based therapies developed to bolster humoral and 
T-cell immunity represent an established and growing component of cancer therapeutics. 
Examples include: the engineering of T-cells with chimeric antigen receptors (CAR-T cells) in 
leukemia [13], and the recently approved bispecific T-cell engager (BiTE) molecule, 
blinatumomab for patients with Philadelphia chromosome-negative precursor B-cell acute 
lymphoblastic leukemia (B-cell ALL) [14], which recruits cytotoxic T-cells to target tumor B-
cells by linking the CD3 and CD19 antigens. Although NK cells have long been believed to 
have advantages over T lymphocytes in terms of their capacity to induce antigen-independent 
host immune responses against malignancies, their therapeutic potential in the clinic has been 
limited. A growing number of scientific discoveries into pathways that both activate and 
suppress NK cell function, as well as methods to sensitize malignancies to NK cell cytotoxicity, 


 
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have led to the development of numerous pharmacological and genetic methods to enhance NK 
cell antitumor immunity. These findings, as well as advances in the ability to expand NK cells 
ex vivo and manipulate their capacity to home to malignant tumors, have now provided 
investigators with a variety of new methods and strategies to harness the full potential of NK 
cell-based cancer immunotherapy in the clinic. 
Bispecific antibodies and bispecific or trispecific killer engagers (BiKEs or TriKEs) are 
engineered molecules that exclusively act via ADCC by crosslinking epitopes on malignant 
cells with the CD16 receptor on NK cells. These molecules have advantages over monoclonal 
antibodies (mAbs) because they bind to a different epitope of the CD16 molecule, resulting in 
stronger NK cell ADCC [15]. In vitro, the CD16–CD33 BiKE seems to overcome inhibitory 
KIR signaling, leading to robust NK cytokine production and killing of myeloid malignancies. 
Several BiKEs and TriKEs are currently being developed and evaluated for targeting of various 
malignancies [16]. AFM13 is a bispecific mAb designed to bind to both CD16A on NK cells, 
and CD30 on malignant cells. A Phase I trial of AFM13 in relapsed and refractory Hodgkin 
Lymphoma (HL) patients has shown promising results [29, 34]


 
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7.1 Background 
7.1 
Targeting Unique Cell-Surface Proteins in Lymphoma  
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoproliferative malignancies 
with multiple histological subtypes. It is estimated that approximately 65,540 new cases of 
NHL were diagnosed in 2010 and 20,210 patients died of their disease [17]. Based on the World 
Health Organization (WHO) classification of hematological and lymphoid tumors, NHL can 
be broadly classified as B or T/NK cell neoplasms [18]. In the United States, about 85% of 
cases are categorized as B cell lymphomas and 15% are categorized as T/NK cell lymphomas 
[17]. 
The expression of unique proteins on the cell surface allows for the identification and diagnosis 
of different malignancies. These cell markers have been exploited as targetable treatment by 
immunotherapeutics, such as Rituximab, a genetically-engineered chimeric IgG1 mAb that 
targets CD20. CD30 was identified in the early 1980s as a protein recognized by mAb Ki-1 
[19] and abundantly and selectively expressed on the surface of Hodgkin and Reed-Sternberg 
cells. Later on, its expression in other neoplastic cells was demonstrated such as anaplastic 
large cell lymphomas (ALCLs), and other lymphoid malignancies as well as on several non-
lymphoid malignancies including selected germ cell tumors. Expression of CD30 on normal 
cells is highly restricted, thereby allowing differential targeting of malignant cells. CD30, a 
member of the tumor necrosis factor (TNF)-receptor superfamily (TNFRSF) has pleiotropic 
biologic functions, and antibodies targeting CD30 and other TNF family receptors can exhibit 
both agonistic and antagonistic signaling functions. Recently, antibody-drug conjugates 
targeting CD30, such as brentuximab vedotin, have shown striking activity in phase I and II 
trials, with manageable toxicity. This has defined an important emerging role for targeting of 
CD30 in the setting of HL, ALCL, and possibly other CD30-positive malignancies. 
Primary cutaneous T-cell lymphomas (CTCL) represent a heterogeneous group of neoplasms 
derived from skin-homing T cells. Apart from mycosis fungoides (MF), primary cutaneous 
CD30-positive lymphoproliferative disorders (LPDs) are the most common group, accounting 
for approximately 25% of all CTCL. This group includes primary cutaneous CD30-positive 
(anaplastic) large T-cell lymphomas (LTCL) and lymphomatoid papulosis (LyP), a chronic 
recurrent, self-healing papulonodular skin eruption with histologic features of a CD30-positive 
CTCL [20]. 
 
7.2 
CD30-Positive Lymphoid Malignancies 
In hematologic malignancies, CD30 expression is strongly increased in HL and ALCL, but has 
also been noted in other lymphoid malignancies, such as diffuse large B-cell lymphoma 
(DLBCL), including primary mediastinal (thymic) large B-cell lymphoma (PMBL), peripheral 
T-cell lymphoma (PTCL), Lyp, MF, and Epstein-Barr Virus (EBV)-driven clonal LPD 
enteropathy-associated T-cell lymphoma type I, human T-cell lymphotropic virus type 1 


 
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(HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL), primary effusion lymphoma 
harboring human herpes virus-8 [21- 25]. Additionally, CD30 expression is regularly observed 
in primary CTCL.  
 
7.3 
AFM13 
The target of AFM13 is CD30, which is a 120-kDa type I transmembrane protein that contains 
six cysteine-rich pseudo-repeat motifs in its extracellular domain and a cytoplasmic tail with 
several TNF receptor-associated factor (TRAF)-binding sequences that mediate activation of 
nuclear factor kappa-B (NF-κB) [26, 27]. CD30 has a broad spectrum of biologic effects 
depending on the cellular context, including induction and regulation of cytokine secretion and 
inflammation, induction of apoptosis, and promotion of cell survival and proliferation [28] 
Please refer to the Investigator’s Brochure (IB) for more details of non-clinical and clinical 
studies conducted with AFM13. 
 
7.4 
Pharmaceutical and Therapeutic Background 
7.4.1 
Antibody generation and folding pathway 
The investigational medicinal product AFM13 is a tetravalent bispecific chimeric (anti-human 
CD30 x anti-human CD16A) recombinant antibody construct (TandAb®) for the treatment of 
HL. 
AFM13 is constructed by means of recombinant technology as a homodimer of a polypeptide 
comprising four antibody variable domains, each one being separated from the neighboring 
domains by a glycine-serine linker of nine amino acids.  The four-domain gene product is 
unable by itself to bind antigen, since the lengths of the linkers between the domains are too 
short for intramolecular pairing of the corresponding heavy and light chains.  However, they 
are arranged in an order that permits formation of the corresponding antibody VH/VL domains 
after non-covalent dimerization.  The result of this folding process is a homodimer molecule 
with a molecular weight of 104-kDa as outlined in Figure 1. 


 
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Figure 1:  Folding pathway of AFM13 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
The tetravalent bispecific format, as represented by AFM13, is designed to recruit cytotoxic 
effector cells of the immune system effectively against pathogenic i.e. tumor target cells. 
 
7.4.2 
Mode of action 
The tetravalent bispecific antibody AFM13 is designed to re-direct cytotoxic effector cells of 
the immune system against CD30-positive malignant cells.  
Natural killer cells are cytotoxic effector cells and represent a potent subset of lymphocytes for 
targeting and killing tumor cells. In contrast to T-lymphocytes, they do not need to be pre-
activated. Their inherent cytotoxic activity is stimulated by the FcγRIIIA (CD16A), which is 
expressed on the surface of NK cells as well as on macrophages, and activated monocytes. 
Interestingly, recent studies have provided evidence that NK cell can be pre-activated prior to 
cytolysis. More important observations have been made regarding the development of a 
memory NK cell that can be primed prior to cytotoxicity against stressed cells (i.e., infected or 
transformed cells) [2-8].  
Regarding AFM13-mediated NK cell-directed cytotoxicity, in vitro studies have shown that 
AFM13 simultaneously binds to CD16A on NK cells and CD30 on Hodgkin- and Reed-


 
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Sternberg cells and that this leads to the lysis of Hodgkin and Reed-Sternberg cells by the NK 
cells via cellular cytotoxicity. 
 
7.5 
 Non-clinical studies 
Of the CD30-positive lymphomas, HL has been targeted for the development of AFM13. Due 
to the lack of an appropriate animal model of HL, most primary and secondary 
pharmacodynamic data of AFM13 have been generated in vitro.  
The pharmacokinetic behavior of AFM13 has been investigated in stand-alone studies in mice, 
and in cynomolgus monkeys as the only relevant species.  Furthermore, toxicokinetic data were 
generated in cynomolgus monkeys in parallel with the toxicological assessment of AFM13. 
Further details of all non-clinical studies are provided in the IB.   
 
7.5.1 
 Characterization of affinity and specificity 
The affinity and specificity of AFM13 to its nominal ligands CD30 and CD16A have been 
extensively characterized.  The results demonstrate high affinity of AFM13 to both of its 
ligands.  AFM13 binds to human CD16A with an affinity of ~ 1.6 x 10-9 M and to human CD30 
with an affinity of ~ 1.3 x 10-9 M.  The experiments using different isoforms of CD16 also 
confirmed the specificity of AFM13 for CD16A, and revealed comparable binding to both 
tested CD16A allelic variants.  No binding of AFM13 to different variants of CD16B was 
detectable.  Using flow cytometry, cell surface binding of AFM13 on CD30-positive and 
CD16-positive cells could be unequivocally demonstrated. The flow cytometry data using cell 
lines transfected with different CD16 isoforms also clearly confirmed specificity of AFM13 
for the A isoform of CD16. CD30- and CD16-specific tissue binding of AFM13 could be well 
demonstrated.  Staining patterns of AFM13 on selected frozen human tissue sections 
corresponded to those seen with control mAbs directed against either CD16 or CD30.  
 
7.5.2 
Primary pharmacodynamic activity 
In vitro AFM13 induces specific and selective killing of CD30-positive target cells by NK cells 
with an EC50 typically seen in the order of ~ 5 – 250 pM (depending on the target cell line and 
effector cells used). AFM13-induced target cell lysis is specific since AFM13-activated killing 
of CD30-positive target cells by NK cells does not affect CD30-negative bystander cells. The 
onset of AFM13-mediated target cell lysis is immediate and does not require pre-activation of 
NK cells. AFM13 which is already bound to CD30-positive target cells or CD16A-positive 
effector cells is able to mediate target cell lysis even in the absence of free soluble AFM13. 
The data suggests a difference between PK and pharmacodynamic half-life in vivo. There is 
substantial inhibition of the AFM13-mediated cytolytic response by human IgG and soluble 
human CD30.   


 
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7.5.3 
Secondary pharmacodynamic activity 
Secondary pharmacodynamic properties of AFM13 were investigated in several in vitro 
systems. These in vitro studies encompassed the ability to induce cytokine release in human 
peripheral blood mononuclear cells (PBMCs) and the ability to induce proliferation in CD30-
positive and CD16A-positive cells.  The ability of free soluble AFM13 to induce cytokine 
release from human PBMC is minimal.  Nevertheless, it is not possible to claim that AFM13 
is free of cytokine releasing potential.  Measurement of plasma concentrations of IL-2, IL-6, 
TNF-α, and IFN-γ, which are known to be most relevant for cytokine-related adverse reactions, 
did not indicate cytokine release in the pivotal 28-day repeated dose toxicity study in 
cynomolgus monkeys up to a dose level of 10 mg/kg. 
Additional data do not indicate strong induction of cytokine release from human PBMC by 
immobilized AFM13 or AFM13 in the presence of physiological and non-physiological cross-
linkers.  The most effective cross-linker with regard to induction of cytokines (especially TNF-
α and IFN-γ) by AFM13 seems to be CD30-positive target cells.  This may be part of the mode 
of action since activation of NK cells is normally associated with release of IFN-γ. Binding of 
AFM13 to CD16A-positive cells in cultures of human PBMC or binding to CD30-positive on 
HL cells does not trigger or affect proliferation. 
 
7.6 
Safety pharmacology 
A number of safety pharmacology end-points concerning the central nervous system (CNS), 
cardiovascular system, respiratory system, gastrointestinal system, renal/urinary system, and 
hematopoietic system, have been integrated into standard toxicity studies of AFM13 in 
cynomolgus monkeys. No alerts with regard to safety pharmacology arose from these studies 
that might call for additional in-depth investigations of AFM13. 
 
7.6.1 
Tissue cross-reactivity 
In human non-epithelial tissues the staining pattern shown by AFM13 is consistent with its 
specificity, detecting only CD16- and CD30-positive cells. However, AFM13 shows strong 
immunostaining of a number of secretory-type human epithelia, including those of breast ducts, 
pancreatic ducts, acinar cells of the prostate, sweat glands of skin, and glandular epithelium of 
the uterine cervix. Furthermore, AFM13 shows staining of some non-secretory epithelia, 
including those of the urinary bladder, the fallopian tube, the ureter, and epididymal epithelial 
cells in the testis. The relevance of these findings is unclear. However, the same pattern of 
epithelial binding has been observed in cynomolgus monkeys without adverse toxicity. 
Overall, AFM13 has a low toxic potential but potentially adverse hematological effects have 
to be taken into account.  


 
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7.7 
Phase I clinical trial in relapsed or refractory Hodgkin lymphoma 
A clinical phase I study, AFM13-101, was conducted in patients with heavily pre-treated 
relapsed/refractory HL [29]. The trial results are summarized in the sections below. 
 
7.7.1 
Results of the AFM-101 phase I trial 
7.7.1.1 
Patient population and treatment 
Twenty-eight patients with HL including 16 males and 12 females were enrolled in the 
AFM13-101 trial. The median age was 38.5 years. The patients had a median of 6 (range 3-11) 
previous lines of therapy for HL including ASCT in 22/28 patients and previous radiotherapy 
in 24/28 patients. Fourteen of 28 patients were refractory to the most recent therapies, 9/28 
patients had received brentuximab vedotin.  
The included patients received treatment with AFM13 in the planned 8-dose cohorts. In the 
dose escalation part, 24 patients received increasing doses of AFM13 ranging from 0.01 mg/kg 
to 7.0 mg/kg on a weekly dose schedule for 4 weeks. In addition, 4 patients were treated with 
AFM13 at a dose of 4.5 mg twice weekly for 4 weeks. Nineteen of 28 patients completed the 
study; the remaining 9 patients discontinued the treatment due to disease progression (n=2), 
adverse events (AEs) (n=1), withdrawal of consent (n=3) and other reasons (n=3). Eight of the 
9 patients who discontinued had received at least one complete treatment cycle and an imaging 
after the last dose before being withdrawn.  
All 28 patients were included in the safety analysis. Two patients were excluded from the 
efficacy population: patient 001-03 in Cohort 1 (0.01 mg/kg) completed cycle1, but left the 
study to start another treatment before completing the final study visit. Patient 002-01 in Cohort 
4 (0.5 mg/kg) discontinued due to AEs (hemolytic anemia followed by aspergillus pneumonia 
and multi-organ failure) before completing cycle 1. 
7.7.1.2 
Safety results of AFM13-101 trial 
Twenty-three of 28 patients experienced at least AE which was evaluated as treatment-related 
by the investigator. Most AEs were mild or moderate; only 18 of 196 documented AEs were 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
grade 3 AEs; in only 1 patient (patient 002-01) a dose-limiting toxicity (DLT), a hemolytic 
anemia CTCAE grade 4, possibly related to AFM13, was documented. The patient 
subsequently died due to aspergillus pneumonia and multi-organ failure which was assessed as 
not or unlikely related to the study drug.  
The most frequent AEs were infusion-related reactions (IRR) including pyrexia, chills, 
headache, nausea and other IRRs. Treatment-associated infections were rare; nasopharyngitis 
was noted in 5 patients and pneumonia in 4. 


 
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After review of the safety data, the independent data monitoring committee (IDMC) concluded 
that the maximum dose of 7 mg/kg in the weekly dose schedule was reached without any 
toxicity concerns and without reaching the maximum tolerated dose (MTD). Additionally, the 
4 patients treated with 4.5 mg/kg twice weekly completed the treatment without toxicity 
concerns of the IDMC. Apart from the documented DLT in patient 002-01 the administration 
of AFM13 was not associated with clinically significant changes in any laboratory parameters, 
nor was it associated with clinically significant changes in any vital signs or electrocardiogram 
(ECG) parameters.  
Thus, the AFM13-101 trial showed that AFM13 is safe and well tolerated at the examined 
doses and dose schedules.  
7.7.1.3 
Efficacy analyses of the AFM13-101 trial 
All 28 patients had measurable levels of sCD30 at the start of cycle 1 and in 24 patients the 
sCD30 level was decreased at the end of the first cycle. All patients treated in the dose cohorts 
of 1.5 mg/kg AFM13 experienced a marked decrease of sCD30. Furthermore, 
immunophenotypic analyses showed that AFM13 resulted in an increase of activated NK cells 
in the peripheral blood as measured by CD69 expression on their surface. 
Of the 26 patients who were eligible for efficacy assessment, 3 patients achieved a partial 
response (PR), and 13 patients experienced a stable disease (SD) as documented at the final 
study visit. More detailed efficacy analyses indicate that the clinical activity is more 
pronounced at or above a dose of 1.5 mg/kg. Of the 13 patients treated at or above a dose level 
of 1.5 mg/kg, 7 patients experienced a SD and only 3 patients developed a progressive disease 
(PD) at the end of the trial. Two of the reported PRs were documented at a dose level of 1.5 
mg/kg and one PR at the dose level of 4.5 mg/kg given twice a week. A waterfall plot analysis 
showed a reduction of the tumor volume in 8 patients treated at a dose level of 1.5 mg/kg or 
above [29, 34]. 
7.7.1.4 
Pharmacokinetic analyses of the AFM13-101 trial 
Pharmacokinetic analyses revealed that weekly dosing is suboptimal because the documented 
half-life of AFM13 was between 9 - 19 h in the dose cohorts ≥ 1.5 mg/kg and because the 
serum levels in the weekly dose schedule were mostly below the serum level of 400 ng/ml 
which was defined as trough blood level as a result of in vitro data. Also, the bi-weekly regimen 
did not result in adequate trough levels at the end of the infusion intervals.  
Furthermore, the measurement of NK cell activation with immunophenotypic analysis of 
CD69+ cells in the peripheral blood showed a correlation between the biological activity of 
AFM13 and its PK (Figure 2).   
 


 
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Figure 2:  Correlation between NK Cell Activation and PK of AFM13  
 
 
 
 
Thus, these PK data indicate that the dosing has to be done more frequently than bi-weekly at 
least for some defined period of time. 
7.8 
 Rationale 
Natural killer cells play an important role in tumor immune-surveillance [8, 10, 30]. Their 
function is regulated by a repertoire of inhibitory and activating surface receptors. NK 
cell-mediated cytotoxicity can occur through distinct mechanisms: (1) by activating the 
receptor NKG2D and NCR, and (2) through the potent activating receptor CD16 (FcγRIII) 
which mediates ADCC [8].  Enhanced expression of NK cell antigens has been shown to 
correlate with systemic anti-tumor response in early primary CTCL [31]. Further, phase I 
clinical data with AFM13 indicate that engagement of NK cells results in pharmacodynamic 
and clinical activity in relapsed/refractory HL. However, NK cell migration into the tumor, 
cytokine release in the tumor, potential effects on the adaptive immune response and other 
biological processes triggered by NK cell activation have not been investigated and are not 
understood so far.  
Thus, we hypothesize that if we are able to engage the innate immune system through a specific 
activation and recruitment of NK cells via CD16A to tumors expressing CD30, then we intend 
to demonstrate an immunological and/or tumor response that might be broadly described in 
relation to dosing/PK parameters and could serve as a good and useful parameter in predicting 
clinical response. 


 
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The therapeutic potential of manipulating NK cell function via CD16 for the treatment of 
cancer has been previously demonstrated through the use of mAbs [32]. Presently, novel single 
chain fragment variable (scFv) recombinant reagents (BiKE and TriKE), which specifically 
target CD16 expressed on effector NK cells and antigens-of-interest on tumor cells, are being 
developed and tested for clinical use [33]. Further, a novel tetravalent bispecific CD30/CD16A 
antibody, AFM13, was investigated in a phase I study in HL patients and was demonstrated to 
be safe and active [29, 34]. We plan to investigate AFM13 and evaluate its ability to facilitate 
and redirect the NK cells in eliminating CD30-positive lymphoma targets in the skin and, by 
inference, other organs involved by the lymphoma.  
Primary cutaneous CD30-positive lymphoproliferative LPD represent a spectrum from LyP, to 
primary cutaneous anaplastic large cell lymphoma (C-ALCL), to transformed mycosis 
fungoides (TMF). The most indolent form of primary cutaneous CD30-positive LPD is LyP, 
which is usually well controlled with low dose oral methotrexate, but control of the disease 
frequently requires life-long therapy. In contrast, TMF is an aggressive disease which does not 
have a standard of care, as patients are treated with various modalities of care with variable 
outcomes [20]). The spectrum of other CD30-positive lymphomas with cutaneous presentation 
is very broad and involves systemic B and T cell lymphomas with various clinical behaviors. 
Again, redirecting NK cells towards these CD30-positive malignancies through direct 
engagement with AFM13 is expected to induce tumor cell killing through NK cell-mediated 
and T cell-mediated cytotoxicity (i.e., cytotoxic T lymphocytes [CTL]).  


 
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8 
STUDY OBJECTIVES 
8.1 Primary Objectives 
The primary objectives of this study are to: 
1. Determine the intratumoral NK-cell and T-cell infiltrate and density 
2. Determine the immunophenotype of immune cells (NK cells, T cells and others) in 
tumor and peripheral blood 
3. Quantitate the plasma cytokine production and release in tumor and peripheral blood as 
a function of treatment. 
8.2 Secondary Objectives 
Secondary objectives are to: 
1. Evaluate the safety and toxicity of AFM13 
2. Determine the clinical efficacy, namely objective response rate (ORR), [including 
complete response (CR) and partial response (PR)], duration of response (DOR) and 
progression-free survival (PFS) as defined in the Revised Response Criteria for 
Malignant Lymphoma 2007 and modified Severity-Weighted Assessment Tool 
(mSWAT)  
3. Evaluate the pharmacokinetic profile (PK) of AFM13. 
 
8.3 Exploratory Objectives 
Exploratory objectives are to: 
1. Determine the immunogenicity of AFM13 
2. Detect and quantify circulating tumor cells (CTC). 


 
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9 
INVESTIGATIONAL PLAN 
9.1 Overall Study Design and Plan 
9.1 
Description 
This is an open label, Phase Ib/IIa study designed to evaluate the biologic activity of AFM13 
in patients with relapsed or refractory CD30-positive lymphomas with cutaneous involvement. 
The primary objective of this trial is to study the biologic and immunologic effects induced by 
the administration of various doses of AFM13, when given as a single agent. The study will 
enroll at least 9 patients with CD30-positive cutaneous lymphoma. Patients will be assigned to 
3 dose cohorts of 3 patients each. As this is not a dose-finding study, there are no stringent 
criteria for initiation of subsequent cohorts: subsequent cohorts will be progressively enrolled 
after all 3 patients from the previous dose cohort have received their first planned treatment 
dose(s) during the first week of the cycle, and the safety of the patients on Week 2 Day 1 of 
the first cycle is deemed acceptable by involved investigators (Table 1). 
After preliminary analysis of Cohorts 1-3, input from a scientific advisory board and the 
companies own experience in the Hodgkin’s Study of AFM-13, it was decided to investigate 
an intermediate dose of 4.5mg/kg. Studying the intermediate dose may optimize some of the 
efficacy seen in Cohort 1 while reducing steroid use seen in Cohort 2 to manage infusion related 
reactions. An additional 3 patients will be recruited into Cohort 4. Afterwards a three patient 
expansion will be planned to confirm efficacy and tolerability of the selected cohort for a phase 
2 study.  
Table 1:  Treatment Cohorts and Dosing Schedule (one cycle of treatment) 
Cohort 
Dose regimen 
Total exposure 
Dose 
Timing 
Period 
Cohort 1 
1.5 mg/kg 
weekly 
weeks 1-8 
12 mg/Kg 
Cohort 2 
7.0 mg/kg 
weekly 
weeks 1-8 
56 mg/Kg 
Cohort 3 
7.0 mg/kg  
(1 mg/kg applied as 
loading dose and 
6mg/kg as 
continuous infusion 
for 5 days per 
week) 
weekly  
weeks 1-8 
56 mg/Kg 
Cohort 4 
200mg 
weekly 
weeks 1-8 
1600mg 
 
Prior to recruitment into this trial, all patients will be assessed individually to document 
eligibility into the trial according to the Inclusion and Exclusion Criteria. Additionally, 
documentation of patient briefing and signed informed consent form (ICF) are mandatory 
requirements for trial participation. The protocol mandates that the primary diagnosis of CD30-


 
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positive lymphoma be confirmed by the Department of Pathology at Columbia University 
Medical Center (CUMC). Patients whose diagnosis was made at a different institution will 
consent to have their biopsy material forwarded to CUMC for confirmation. CD30 expression 
will be confirmed using the BerH2 antibody. To date, there is a suggestion that the level of 
CD30 may not be important in predicting response; it is unclear what the lower limit should 
be. The data from Kim et al. [37] suggest that patients with <5% positivity for CD30 respond 
less well than patient who have more than 5%. Although this is the first paper to suggest a 
relationship on a lower level of expression and response.. 
Each patient eligible for the study will be asked to give consent for the collection of fresh tumor 
material. The completion of all staging assessments is also mandatory before registration into 
this trial. The patient will receive one 8-week cycle of protocol treatment followed by 3 weeks 
off and will be assessed for treatment/tumor response thereafter at week 11. All patients who 
achieve at least SD will receive a second cycle of protocol treatment at the same dose 
administered during Cycle 1, starting in what would be considered Week 12. During treatment 
and follow-up, patients will be closely monitored for safety. The biological and immunological 
effects of the treatment will be assessed in Cycle 1 only.  A schematic overview of treatment, 
interventions and assessments (safety, feasibility, and efficacy) is given in Table 2. 
In cohort 1 and 2 AFM13 will be administered in all patients as a slow intravenous (IV) infusion 
over 4 hours. The duration of the infusions will be stepwise shortened by 30 minutes to a 
minimum infusion rate of 1 hour if well tolerated by the patient. In cohort 3 weekly treatment 
will consists of a loading AFM13 dose of 1 mg/kg to be applied on day1 as 1-hour infusion, 
followed by a 6 mg/kg AFM13 as continuous infusion over 5 days. For further specifications 
please refer to the pharmacy manual. Cohort 4 will use the same dosing schedule as cohorts 1 
and 2. 
The biological and immunological studies will investigate the NK cell phenotypic 
characteristics, proliferative response (Ki-67), activation status (CD69), and density in the 
peripheral blood. The same analyses will be conducted in the tumor tissue collected from all 
patients at different time points. In addition, tumor cell infiltrate by NK cell and their spatial 
distribution in the tumor and its microenvironment will be studied. NK effector function will 
be assessed in both compartments (peripheral blood and tumor) by assaying for ADCC, 
presence of cytolytic proteins (granzyme B, perforin-1), and the production and release of 
cytokines and chemokines. T cells phenotype and effector function (CTL) will also be studied. 
Additionally, tumors obtained from study participants will be analyzed for expression of CD30, 
major histocompatibility antigens (MHC Class-I), other immune cell infiltrates, and resident 
immune cells (myeloid-derived suppressor cells, regulatory T cells (Tregs). 
The presence of anti-AFM13 antibody will be investigated, and their neutralizing ability 
assayed. 
Continuous safety analyses (AEs, safety clinical laboratory assessments, vital signs, ECGs) 
will be regularly performed by a Principal Investigator-led safety team to ensure the safety of 


 
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the patients.in the case of a potential significant safety problem the Principal Investigator in 
consultation with groups such as the FDA, IRB, data monitoring committee and/or statisticians 
may decide on the termination or temporary cessation of the trial. 
 
9.2 
Dose Rationale 
Different doses and dose regimens are investigated in this translational research study aiming 
to understand the impact of the dose regimen on the biological and immunological effects of 
AFM13 in the tumor. The selected dose regimens of the 3 cohorts are based on the target dose 
and dose regimen of AFM13 being investigated in a Phase II proof-of-concept study in 
relapsed/refractory HL. In the Phase II study, 2 dose regimens are investigated which are 
identical to dose Cohorts 1 and 2 of this study. A third cohort of continuous intravenous 
infusion was added which is identical to Cohort 3 of the HL study. A fourth cohort, of an 
intermediate dose between Cohort 1 and 2 was also added. 
The rationale for the selection of dose and dose regimen 
 in Phase II is based on data from 
the phase I trial including a PK modeling as well as pre-clinical cytotoxicity data. 
In the phase I study, it was shown that pharmacodynamics and clinical effects are more 
pronounced at AFM13 doses ≥1.5 mg/kg without having a negative effect on the safety profile. 
It was therefore concluded that the dose in future studies should be at least 1.5 mg/kg (Cohort 
1 of the current study). 
Phase I PK data have been collected and analyzed after weekly doses of AFM13. Data revealed 
that a defined minimum trough plasma level of AFM13 could not be maintained with weekly 
infusions (Refer to Figure 1). This minimum plasma level of 400 ng/mL, indicated by the 
dotted line in Figure 2, was calculated based on the EC50 of in vitro cytotoxicity assays and 
considering physiological conditions like the presence of IgG in blood as well as the barrier 
from the vascular compartment to the HL lesion.  
In parallel to the AFM13 plasma levels, the portion of activated NK cells (relative to the total 
number of NK cells) increased after AFM13 infusion but dropped during the weekly infusion 
period back to baseline prior to the next infusion. This finding supports that more frequent 
dosing is needed at least in the initial phase of treatment.  PK modeling revealed that 1.5 mg/kg 
AFM13 administered 3x per week succeeds in maintaining AFM13 plasma levels above 400 
ng/mL (Figure 2). Therefore, this dose regimen was defined for the initial 2-week treatment 
phase with AFM13.  
Considering clinical feasibility aspects, it was decided for the Phase II study that, after the 
initial treatment phase, AFM13 will be dosed 7 mg/kg weekly (Cohort 2 of the current study). 
The dose regimen of 1.5 mg/kg 3x per week over 2 weeks followed by 7 mg/kg weekly over 6 
weeks (Figure 3) is currently in Phase II clinical development. AFM13 is administered in 8-
week cycles.  
PK modelling based on the data gathered from the phase I study and as well from the currently 
ongoing phase II study revealed that a more stable serum levels of AFM13 can be achieved 


 
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with continuous infusion (CIVI) of 6mg/kg over 5 days after a loading dose of 1 mg/kg. 
Therefore, a new cohort is currently being investigated with the German Hodgkin Study Group 
to assess efficacy of a CIVI dosing scheme identical as planned in this study. (Cohort 3 of the 
current study) 
 
Figure 1: PK profile for 1.5 mg/kg AFM13 administered weekly 
 
 
Figure 2: Simulated PK profile for 1.5 mg/kg AFM13 administered three times per week 
 
 
1
10
100
1000
10000
100000
0
96
192
288
384
480
576
672
Concentration (ng/mL)
Time post-start infusion (h)
100
1000
10000
100000
0
48
96
144
192
240
288
336
Concentration (ng/mL)
Time post-start infusion (h)


 
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Figure 3: Simulated PK profile for 1.5 mg/kg AFM13 administered weekly over 2 weeks 
followed by 7 mg/kg weekly over 6 weeks 
 
 
Figure 4: Simulated PK profile for 7.0 mg/kg AFM13 administered weekly by continuous 
infusion 
 
1
10
100
1000
10000
100000
1000000
0
48
96
144 192 240 288 336 384 432 480 528 576 624 672
Concentration (ng/mL)
Time post-start infusion (h)


 
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For Cohort 4: The rationale for the selected dose and schedule of 200 mg is based on an 
updated analysis of the overall pre-clinical and clinical experience from the completed 
AFM13-101 Phase I study and the other ongoing AFM13 clinical studies ( including present 
study). An exposure-response analysis was completed based on the data from the AFM13-
101 Phase I study.  
 
The PK data from the AFM13-101 showed that overall, the systemic exposure to AFM13 
increased in a slightly greater than dose proportional fashion (an increase of 2.14 and 2.30-
fold for Cmax and AUC0-∞, respectively), the systemic exposure increase from the  dose 1.5 
mg/kg to 7 mg/kg (4.7-fold), geometric mean Cmax and AUC0-∞ increased 9.6-fold and 13.2-
fold, respectively i.e. approximately 2- to 3-fold greater than expected based on a 
proportional relationship.  
 
Exposure-response analyses for the study showed that achieving an AUC0-∞ of at least 
100,000 h*ng/mL appears to be important to increase the likelihood of achieving clinical 
benefit and the proposed stratified flat dose of 200 mg corresponded to a dose of 


 
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approximately 3 mg/kg; which is also significantly lower than the dose of 7 mg/kg, a dose 
level that was associated with increased incidence and severity of AFM13-associated IRRs.  
 
Completed population PK analysis using data from AFM13-101 and the current study, there 
were three variables that had a statistically significant impact on PK parameters as listed 
below:   
 
• 
Dose: higher doses had a greater effect on the central volume of distribution (i.e. with 
higher doses, more of the drug stays within the central compartment) 
• 
Body surface area (BSA): higher BSA had proportionately lower Cmax; however, BSA 
had no significant impact on the AUC 
• 
Albumin: lower albumin led to faster clearance, thereby impacting the AUC. 
 
While these results do not alter the proposed dose selection of 200 mg, an interim PK 
analysis using further PK data from patients treated in this study will be utilized to 
determine if the above described effect on albumin is confirmed and to determine if a higher 
dose of AFM13 is warranted for patients with very low albumin.  
 
9.3 
Number of Centers 
This study will be conducted at CUMC in the United States of America (USA). 
 
9.4 
Number of Subjects 
The study will enroll 15 evaluable subjects. Evaluable patients are defined as having 1 biopsy 
pre-treatment and at least 1 biopsy post treatment. 
 
9.5 
Schedule of Assessments 
See Table 2 for Schedule of Assessments. The details for blood draw per assay are given in the 
Immunobiology Research Manual.  
 
 


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Table 2:  Schedule of Assessments 
Week 
Screening 
1 
2 
3 
4 
5 
6 
7 
8 
11 
 
EoS/PDp 
Day 
-28 to 0 
1 
5  
1 
1 
1 
1 
1 
1 
1 
1§ 
 
AFM13 Administrationa 
Cohort 1 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
  
Cohort 2 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
  
Cohort 3 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
  
Cohort 4 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
x 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
x 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
x 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testb   
x 
 
 
 
 
 
 
 
 
 
 
 
Histology CD30+ lymphomac 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG (rest 12-lead) e 
x 
 
 
x 
 
x 
 
x 
 
x 
 
x 
Vital signsf 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical chemistry  
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
 
 
 
x 
 
 
 
 
x 
x 
Urinalysis 
x 
 
 
 
 
x 
 
 
 
 
x 
 
Trough serum levelsg,j* 
  
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Full AFM13 PK samplingh, j 
  
xh 
 
 
 
 
xh 
 
 
 
 
 
Skin biopsyi  
  
x 
x 
 
 
x 
 
 
 
x 
 
xn 
Blood immunology 
  
x 
x 
 
 
x 
 
 
 
x 
 
x 
Blood cytokinesj,k  
  
x 
x 
 
 
x 
 
 
 
x 
 
x 
sCD30j 
  
x 
x 
 
 
x 
 
 
 
x 
 
x 
ADAsj 
  
x 
 
 
x 
 
 
 
 
 
 
x 
Tumor assessmento : 
(m)SWATm 
Flow Cytometry 
18FDG-PET and CT-Scansl 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
Concomitant medication 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse event 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


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Optional 8 Week Schedule 
 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
11 
EoS/PDp 
Day 
1 
1 
1 
1 
1 
1 
1 
1 
1§ 
 
AFM13 Administrationa 
Cohort 1 
x 
x 
x 
x 
x 
x 
x 
x 
 
  
Cohort 2 
x 
x 
x 
x 
x 
x 
x 
x 
 
  
Cohort 3 
x 
x 
x 
x 
x 
x 
x 
x 
 
  
Cohort 4 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Physical examinationc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ECG (rest 12-lead) d 
x 
x 
 
x 
 
x 
 
x 
 
x 
Vital signse 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical chemistry  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation 
x 
 
 
x 
 
 
 
 
x 
x 
Tumor assessmento : 
18FDG-PET and CT-Scansl  
 (m)SWATm 
Flow Cytometry 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse event 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 


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 ADA=anti-drug antibody; CT=computerized tomography; CTC=circulating tumor cells; ECOG=Eastern Cooperative Oncology Group; ECG=electrocardiogram; EoS=end of study; 
18FDG-PET=fluorodeoxyglucose-positron emission tomography; MRI=magnetic resonance imaging; m(SWAT)=modified Severity-Weighted Assessment Tool; PD= progression of disease. 
PK=pharmacokinetics; SD=stable disease;  
Additional assessments may be conducted as clinically indicated 
Assessments made on drug administration days are to be conducted prior to the start of study medication infusion, unless specified otherwise 
Patients with clinical benefit (SD, PR, CR) will receive a second cycle starting after week 11. 
All study procedures have a +/- 3 day window, unless otherwise specified. 
§ 
Restaging is to be done at each Week 11 Visit  +/- 2 weeks. 
a. 
AFM13 is infused over 4 hours at the first infusion day. Infusion duration is to be stepwise reduced by 30 min to a minimum of 1 hour at the following infusion days. Cave: measures related 
to infusion duration in case of adverse events. In cohort 3 weekly treatment will consists of a loading AFM13 dose of 1 mg/kg to be applied on day1 as 1-hour infusion, followed by a 6 
mg/kg AFM13 as continuous infusion over 5 days.  
b. 
Pregnancy test done at screening must be within 7 days of treatment initiation. 
c. 
A histological confirmation of CD30-positive lymphoma can be made using the previous tumor biopsy (paraffin-embedded tissue block and slides).  
d. 
Physical examination will include recording the patient's weight and height at Screening and weight at the End of Study visit. Symptom-directed physical examinations at other time points 
are to be done as needed. 
e. 
Additional ECGs will be obtained if clinically indicated. All ECGs will be done on local equipment.  
f. 
Vital signs include temperature, systolic blood pressure, diastolic blood pressure, heart rate and respiratory rate.  
g. 
Collected prior to all infusions, during Cycle 1 only  
h. 
Blood samples for full PK to be taken for cohort 1, 2 and 4 prior to infusion and at the following times points after end of first infusion on Week 1 Day 1 and Week 5 Day 1 only: 0, 2, 4, 
and 24 +/- 4 hours, for cohort 3: prior to infusion and at the following time points after end of the loading dose on Week 1 Day 1 and Week 5 Day 1 only: 0,2,4, and 24 +/- 4 hours  
i. 
Skin biopsies on Day 1, pre-treatment (can be taken -7 days from day 1) and 5 (can be taken -1 day from day 5 or up to +3 days) should be taken from different lesions, if possible. If this is 
not possible, the biopsy on Day 5 should be taken from as far away as possible from the first one (at least 3 cm).  
j. 
Blood needs to be centrifuged and serum to be frozen. 
k. 
Blood for cytokines has to be taken prior to infusion, at the end of infusion and 2 hours after end of infusion on Week 1 Day 1, Week 4 Day 1 and Week 8 Day 1. Optional sample will be 
collected upon PD or EoS. 
l. 
18FDG-PET and CT-Scans carried out within 4 weeks prior to the first dose. 
m. 
Skin examination with photo-documentation (part of SOC); evaluation using mSWAT Tool 
n. 
Optional biopsy investigator discretion 
o. 
All assessments will be performed at screening, only positive assessment needs to be followed for response 
p. 
Follow up guidelines per section 10.11 
 
 
 


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9.6 
Study Assessments 
This study comprises a screening period of up to 28 days, an 8-week treatment period, during 
which patients attend at least 1 weekly visit depending on the dose cohort (see Table 1), and a 
3-week treatment-free follow-up/rest period, with visits held at week 11. Patients achieving a 
CR, PR, or SD will be allowed to receive a second cycle of therapy at the same dose and 
schedule as their Cycle 1 treatment. Patients will then have an end-of-study (EoS) visit at week 
11 or after their last treatment. 
The assessments to be carried out at each visit are described below. Details of the procedures 
to be carried out are presented in Sections 0 through 10.7. 
All study visits are allowed ±3 day window. All visits should occur as close as possible to the 
protocol specified time. All assessments pre- and post-treatment have a window of ±15 
minutes.  
 
9.6.1 
 Registration Procedures 
Eligible patients will be enrolled by the study team.  
To register a patient, the following documents should be completed by a member of the 
research staff and delivered to the study coordinator: 
• Eligibility Screening Worksheet  
• Copy of required laboratory results and imaging tests 
• Signed patient ICFs 
• Signed Health Insurance Portability and Accountability Act (HIPAA) form. 
The Study Coordinator will verify eligibility. To complete the registration process, the 
Coordinator will: 
• Assign a patient study number 
• Register the patient on the study 
• Confirm registration with the Principal Investigator and treating physician. 
 
Following enrollment, patients will be screened and should begin protocol treatment within 28 
days. If a patient does not receive the study drug within 28 days of enrollment, the patient will 
be replaced at the discretion of the Principal Investigator. 
 
9.6.2 
Screening Period (Day -28 to Day 0) 
Subjects are to undergo a screening visit 28 days prior to the planned first day of study 
treatment. Prior to conducting any Screening activities that are not considered standard of care, 
the investigator or designee is responsible for obtaining signed and dated written ICF and 
HIPAA authorization from the patient (Sections 9.6.1& 10). 


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Screening assessments are as follows: 
• Check eligibility against study Inclusion and Exclusion Criteria (Sections 10.11.1 and 
0, respectively) 
• Record demographic information (age, race, gender, ethnicity) 
• Record medical and surgical history 
• Assess ECOG performance status 
• Perform a pregnancy test on women of childbearing potential; negative results must 
be confirmed within 7 days prior to administration of first treatment (pregnancy 
testing must use same test format for all patients) 
• Histological confirmation of CD30-positive lymphoma  
• Physical examination (including weight and height) 
• 12-lead ECG 
• Vital signs (temperature, systolic blood pressure, diastolic blood pressure, respiratory 
rate) 
• Clinical laboratory tests (chemistry, hematology, coagulation and urinalysis)  
• Tumor assessment (fluorodeoxyglucose-positron emission tomography [18FDG-PET] 
and computerized tomography (CT) scans not older than 4 weeks prior to the first dose 
can be used as baseline). 
• mSWAT skin examination with photo-documentation (part of SOC) 
• Documentation of concomitant medications and AEs. 
 


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10 
INFORMED CONSENT AND OTHER STUDY PROCEDURES 
Study Informed Consent 
Before beginning of trial-specific screening examinations described in Section 9.6.1 and 9.6.2, 
the patient will be informed about the trial, including the following main points: title and aim 
of the trial, procedures, nature of treatment, duration, side-effects, risks, discomforts, benefits, 
incentives, passing on of data and material samples, confidentiality, alternatives to 
participating, insurance, the ethics committee’s approval, patient’s freedom to decide, and who 
to contact. Independent of the consent to the treatment with AFM13 within the trial and to 
treatment-related diagnostics, the patient will be informed about the scientific research project. 
She/he will receive the respective patient information and will be asked for the informed 
consent to the laboratory research project (biological and immunological analyses).  
Study personnel must obtain documented consent from each potential patient prior to entering 
in the clinical study. Consent must be documented on the Institutional Review Board (IRB) 
approved ICF by obtaining the dated signature both of the patient and of the investigator 
conducting the consent discussion. If the patient is unable to sign the ICF, then oral consent, 
attested to by the dated signature of an impartial witness (someone not involved with the 
conduct of the study), is the required alternative. 
If the patient is illiterate, an impartial witness should be present during the entire informed 
consent reading and discussion. Afterward, the patient should sign and date the ICF, if capable. 
The impartial witness should also sign and date the ICF along with the individual who read and 
discussed the informed consent (i.e., study staff personnel). 
The information from the ICF should be translated and communicated to the subject in 
language understandable to the subject. ICFs will be available in English and Spanish. When 
the study participant is non-English and non-Spanish speaking the CUMC IRB short form will 
be utilized and the consent process followed and documented as per CUMC IRB policy. A 
copy of the signed and dated ICF should be given to the patient before participation in the 
study. 
The initial informed ICF and any subsequent revised written informed ICF, and written 
information will receive the IRB approval. The patient or his/her legally acceptable 
representative will be informed in a timely manner if new information becomes available that 
may be relevant to the patient’s willingness to continue participation in the trial. The 
communication of this information will be documented. 
10.1 
Consent and Use of Tissue Specimens for Research 
The study ICF will be inclusive for the collection of tumor tissue biopsy and blood specimens 
for the correlative laboratory research (biological and immunological analyses) will be 
explained to each patient, and, if willing to participate in this sub-part of the study, must be 
signed by the patient. The investigator or designee is responsible for explaining and verifying 
the subject’s consent before obtaining any biopsy.  


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An additional biopsy may be requested from the patient at the EoS visit (4 weeks following the 
last dose of treatment). This biopsy is optional. Patients are required to undergo skin biopsies 
of the cutaneous tumor at no more than 6 different time points during the course of the study. 
Blood specimens will be obtained from patients for the study of the immunological and 
biological effects of AFM13. For each patient, the analyses of the peripheral blood will be 
paired with those of the tumor tissue obtained at the time of the cutaneous biopsies. 
 
10.2 
Treatment Period (8 weeks) 
One treatment cycle is 8 weeks, though prolongation of this period may occur due to safety 
reasons or unforeseen circumstances. This treatment period will be followed by 3 weeks of rest 
during each cycle.  Study visits will be done according to the schedule of assessments (Table 2). 
These visits will be referred to according to the treatment Week (W1-8) and day of the 
treatment week (D1, 3 or 5/6), e.g. the first visit during the treatment period will be W1D1.  
 
10.3 
Week 1 
During Week 1, the following will be performed: 
W1D1: 
On Day 1, the following assessments will be performed prior to treatment infusion: 
• physical examination 
• vital signs 
• skin biopsy can be up to a week prior to therapy 
• blood sampling for the following: 
o clinical chemistry and hematology 
o PK assessment of AFM13 trough serum levels (Cycle 1 only) 
o full AFM13 PK sampling (Cycle 1 only) 
o blood for immunology 
o blood cytokines 
o sCD30 
o anti-drug antibodies (ADAs) 
• Review of concomitant medications. 
Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. 
After the end of treatment infusion (after the loading dose in cohort 3), the following will be 
done: 


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• blood samples will be taken for: 
o full AFM13 PK sampling at the following time points: 0, 2, 4, and 24 hours. 
o blood cytokines at the following time points: at the end of infusion and 2 hours 
post-infusion. 
• Review of AEs. 
On W1D5 the following will be carried out: 
• blood samples (cycle 1 only) will be taken to assess: 
o blood for immunology  
o blood cytokines  
o sCD30 
• skin biopsy (from different lesions than those on Day 1 if possible, or at least 3 cm 
from the Day 1 biopsy for larger cutaneous lymphoma (at least 5 cm in the greatest 
diameter ; Section 13.4) 
 
 


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10.4 
Week 2, 3, 4, 5, 6, 7 and 8, Day 1 Visits 
On W2D1 the following assessments will be performed prior to treatment infusion: 
• physical examination 
• 12-lead ECG 
• vital signs 
• blood sampling for the following: 
o clinical chemistry and hematology 
o PK assessment of AFM13 trough serum levels (cycle 1 only) 
• Review of concomitant medication. 
• Review of AEs. 
Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. Occurrence of any AEs will be actively sought after completion of 
treatment. 
On W3D1, the following assessments will be performed on all patients, prior to treatment 
infusion: 
• physical examination 
• vital signs 
• blood sampling for the following: 
o clinical chemistry and hematology 
o PK assessment of AFM13 trough serum levels (Cycle 1 only) 
o ADAs. 
Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. 
Concomitant medications and AEs will be documented after completion of treatment infusions. 
On W4D1, the following assessments will be performed on all patients, prior to treatment 
infusion: 
• physical examination 
• 12-lead ECG 
• vital signs 
• skin biopsy  
• blood sampling for the following: 
o clinical chemistry and hematology 


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o PK assessment of AFM13 trough serum levels (cycle 1 only, not repeated if 
patients receive a second cycle of treatment) 
o coagulation 
o blood for immunology 
o blood cytokines  
o sCD30 
• urinalysis. 
Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. 
After the end of treatment infusion (end of loading dose infusion in cohort 3), blood samples 
will be taken for assessment of blood cytokines at the end of infusion and 2 hours post-infusion. 
Concomitant medications and AEs will be documented after completion of treatment infusions. 
On W5D1, the following assessments will be performed on all patients, prior to treatment 
infusion: 
• physical examination 
• vital signs 
• blood sampling for the following: 
o clinical chemistry and hematology 
o PK assessment of AFM13 trough serum levels (Cycle 1 only) 
o Full AFM13 PK sampling. 
Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. 
Concomitant medications and AEs will be documented after completion of treatment infusions. 
After the end of treatment infusion (end of loading dose infusion in cohort 3), blood samples 
will be taken for full AFM13 PK sampling at the following time points: 0, 2, 4, 20 and 24 hours 
post-infusion, in Cycle 1 only. 
On W6D1, the following assessments will be performed on all patients, prior to treatment 
infusion: 
• physical examination 
• 12-lead ECG 
• vital signs 
• skin biopsy 


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• blood sampling for the following: 
o clinical chemistry and hematology 
o immunology 
o PK assessment of AFM13 trough serum levels (Cycle 1 only). 
Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. 
Concomitant medications and AEs will be documented after completion of treatment infusions. 
On W7D1, the following assessments will be performed on all patients, prior to treatment 
infusion: 
• physical examination 
• vital signs 
• blood sampling for the following: 
o clinical chemistry and hematology 
o PK assessment of AFM13 trough serum levels (cycle 1 only, not repeated if 
patients receive a second cycle of treatment). 
Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. 
Concomitant medications and AEs will be documented after completion of treatment infusions. 
On W8D1, the following assessments will be performed on all patients, prior to treatment 
infusion: 
• physical examination 
• vital signs 
• 12-lead ECG 
• skin biopsy  
• blood sampling for the following: 
o clinical chemistry and hematology 
o PK assessment of AFM13 trough serum levels (cycle 1 only, not repeated if 
patients receive a second cycle of treatment) 
o blood for immunology 
o blood cytokines  
o sCD30 
 


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Once the above assessments have been carried out, patients from all 3 cohorts will receive an 
infusion of study drug. 
Concomitant medications and AEs will be documented after completion of treatment infusions. 
After the end of treatment infusion (end of loading dose infusion in cohort 3), blood samples 
will be taken for assessment of blood cytokines at the following time points: at the end of 
infusion and 2 hours post-infusion. 
 
10.5 
Week 11, Day 1- Follow-up Period 
All patients are to return to the study site for a follow-up visit in Week 11. At this visit, the 
following will be performed: 
• physical examination (including weight and height) 
• vital signs  
• clinical laboratory tests (chemistry, hematology, coagulation and urinalysis)  
• concomitant medication 
• tumor assessment CT/18FDG-PET plus CT 
• (m)SWAT skin examination with photo-documentation (part of SOC) 
• restaging. 
If a second treatment cycle is administered, tumor assessments will also be performed at Week 
11 of the Cycle 2.  
If a serious and persistent side-effects of CTCAE grade 3 or grade 4 occur and the patient could 
not continue study drug, the assessment of treatment response should be performed within 4 
weeks of the last dose of study drug. 
 
10.6 
Restaging Visit 
Restaging is done concurrently with the tumor assessment for response (Week 11 of each 
cycle). 
Assessments will include: 
• interim case history (symptoms)  
• physical examination  
• laboratory assessments (clinical chemistry and hematology) 
• (m)SWAT skin examination with photo-documentation (part of SOC) 
• CT/MRI monitoring (if applicable)  
• 
18FDG-PET mandatory  
 


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10.7 
End of Study Visit 
Subjects will return to the study site for an EoS visit after the last treatment or during week 11. 
At this visit the following will be performed: 
• physical examination 
• vital signs 
• 12-lead ECG 
• Optional skin biopsy, if requested by the investigator and agreed upon by the patient 
• concomitant medication 
• blood sampling for the following: 
o clinical chemistry, hematology and coagulation 
o blood for immunology 
o sCD30 
o ADAs 
Patients who discontinue the study for any reason should undergo EoS assessments, if at all 
possible. 
 
10.8 
Duration of Follow Up 
Patients will have an end of study visit after their last dose of drug to evaluate safety.  Patients 
will be further followed every three months by phone call after the 4-week safety evaluation 
for one year, or until they begin a new treatment for their disease, for evaluation of delayed 
toxicity. Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
10.9 
Discussion of Study Design 
This is an open label, Phase Ib/IIa study designed to evaluate the biological and immunological 
activity of AFM13 in the tumors and peripheral blood of lymphoma patients treated with this 
drug.  
This study is to be carried out in patients with histologically-confirmed CD30-positive 
lymphoma with cutaneous presentation who have failed or have been intolerant to at least one 
prior therapy for the current disease with no further standard therapy available. AFM13 has 
shown preliminary anti-tumor activity in a Phase I study in patients with relapsed or refractory 
HL; a Phase II proof-of-concept study is underway in relapsed/refractory HL.   
In the current study, doses of AFM13 will be administered to patients (Table 1). These doses 
have been chosen based on the results of the Phase I trial of AFM13 in patients with relapsed 
or refractory HL (see 10.10). Results from the Phase I study showed that AFM13 was safe 
across the dose range tested, with the MTD not reached. The safety profile was acceptable for 


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AFM13 doses in the range from 0.05 mg/kg to 7 mg/kg (i.e., over a 140-fold dose increase), 
and a more dose-intense, twice-weekly regimen of 4.5 mg/kg did not result in increased risk. 
Based on the safety data of the Phase I trial, it can therefore be anticipated that the 
administration of AFM13 at the proposed dose levels and drug exposure should also be safe 
and feasible. Anti-tumor responses were observed in patients who had received at least 1.5 
mg/kg. A range of different dose regimens are being tested in the present study to try to gather 
as much information as possible about the optimum dosing regimen for AFM13.  
The use of a placebo control would neither be considered ethical nor scientifically necessary 
in this exploratory study.  
Activity assessments (response rate, response duration and PFS) will be assessed according to 
global assessment consensus recommendations for standardization of definition of response in 
skin, nodes, blood and viscera, GR (global response) score, and other endpoints in MF and 
Sezary syndrome. These recommendations are outlined in the consensus statement of The 
International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma 
Consortium, and the Cutaneous Lymphoma Task Force of the European Organization for 
Research and Treatment of Cancer in 2011[36], and the Revised Response Criteria for 
Malignant Lymphoma [35]. 
 
10.10 
Risk/Benefit and Ethical Assessment 
The field of immune-oncology has been fueled by recent approvals of biological agents (i.e., 
mAbs,) for therapy of malignant melanoma, lung cancer, ovarian cancer so far (ipilimumab, 
nivolumab, pembrolizumab) [38-40]. Because tumor development and growth is known to be 
associated with failure of the immune system in its surveillance capacity, it has become 
increasingly clear that immunological and biological factors must exist in the body that either 
promote tumor development, provide growth advantage and survival, and/or abrogate the 
ability of the nascent malignant cell or that of the established tumor to survive the 
immunological attack. Knowledge of these factors is crucial to our understanding of how to 
refine the dose and schedule of our current drugs and drug candidates in order to develop more 
efficacious therapies. The main aim of this study is to identify and characterize immunological 
and biological factors that may correlate with clinical activity or resistance to therapy. Again, 
this knowledge is vital to our future efforts to design rationally drugs that are likely to have a 
positive clinical outcome for patients with lymphoma.   
This study is to be conducted in patients with histologically-confirmed CD30-positive 
lymphoma with cutaneous presentation that has relapsed or is refractory to at least 1 prior 
therapy for the current disease, and has no further standard therapy available (Brentuximab 
Vedotin is only FDA approved in HL and ALCL with no approval in other lymphomas). 
AFM13 is a bispecific tetravalent CD30/CD16A chimeric antibody (TandAb) developed for 
the treatment of CD30-positive malignancies, and has shown promising anti-tumor responses 
in HL patients with relapsed or refractory HL [29, 34]. AFM13 is a novel drug candidate for 
CD30-positive lymphoma, which restricts its use in the current study to patients who have no 
further standard therapy available.  


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In the Phase I study in relapsed or refractory HL, treatment with AFM13 was well tolerated; 
AEs were mainly mild to moderate, with fever and chills being the most frequently reported 
events [29, 34]. One patient in the 0.5-mg/kg dose cohort developed a possibly drug-related 
grade 4 hemolytic anemia. Preclinical data did not indicate increased risk of hemolytic anemia, 
but autoimmune hemolytic anemia has been described in HL, in particular in patients with 
stages III and IV disease [41]. There were no signs of hemolytic anemia noted in other patients 
treated with AFM13, even at doses that were up to 14 times higher. The MTD was not reached, 
and an IDMC did not have safety concerns regarding AFM13 clinical development. 
In conclusion, AFM13 has a well acceptable safety profile and demonstrated preliminary 
activity in CD30-positive HL. Patients in this translational study will also have a CD30-positive 
lymphoma. Again no further standard treatment options are available to them. Hence, there is 
a huge medical need for safe and effective therapies in this patient population. Therefore, it is 
not unreasonable to conclude that the benefits may outweigh the risks, especially given the 
clinical experience with AFM13 in the previous Phase I trial in patients with heavily pre-treated 
relapsed or refractory HL [29, 34]. 
 
10.11 
 Selection of Study Population 
10.11.1 
Inclusion Criteria 
Both men and women of all races and ethnic groups are eligible for this trial. 
Patients eligible for enrolment in the study must meet all of the following criteria: 
1. Age ≥18 years 
2. Histologically confirmed CD30-positive lymphoma with cutaneous presentation 
3. Failure or intolerance to at least one prior therapy for the current disease  
4. Presence of one or more cutaneous lesions (measuring at least 1 cm x 1 cm in size; if only 
one lesion is present it should be up to the investigator discretion to determine eligibility)  
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤2  
6. Adequate organ and marrow function 
a. Platelets ≥50,000/µL 
b. Absolute neutrophil count ≥ 1,000/μL 
c. Bilirubin < 1.5 x institutional upper limit of normal (ULN) or < 3 x ULN in 
patients with Gilbert's disease or liver involvement 
d. Serum albumin ≥ 2.0 g/dL 
e. Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤2.5 × 
institutional ULN or, in the case of liver involvement by the primary disease 
AST/ALT ≤ 5 x ULN 
f. Creatinine≤1.5 x institutional ULN or estimated creatinine clearance of ≥45 
mL/min by the Cockcroft-Gault equation or measured creatinine clearance >45 
mL/min 
7. Females of child bearing potential must have a negative serum pregnancy test with 7 days 
prior to first dose of treatment. Female patients of childbearing potential and all male 
partners must agree to use double barrier methods of contraception throughout the study 
period and for at least 30 days following investigational product discontinuation.  


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8. Ability to understand and the willingness to sign a written informed consent document. 
10.11.2 
Exclusion Criteria 
Patients meeting any of the following criteria are ineligible the study: 
1. Any cancer-related therapy for the current disease within 2 weeks of screening (all 
supportive care measures are allowed) 
2. Major surgery within 2 weeks prior to first dose of study drug 
3. Evidence of active central nervous system (CNS) involvement 
4. Requirement for systemic immunosuppressive therapy (e.g. Graft-versus-Host Disease 
[GVHD] therapy within 12 weeks before the first dose of study drug) 
5. Uncontrolled concurrent serious illness. 
6. Concurrent malignancy requiring cytotoxic or immunotherapy based treatment.   
7. Active infection including hepatitis B-carrier status,  hepatitis C virus (HCV) infection 
(patients with positive serology must have a negative Hep B and Hep C viral load at 
screening) 
8. Known HIV-positive status 
9. Any significant diseases medical condition, laboratory abnormality, or psychiatric illness 
that would exclude the subject from participate or interfere with study treatment, 
monitoring and compliance such as: 
a. unstable angina pectoris, symptomatic congestive heart failure (NYHA III or 
IV), myocardial infarction ≤ 6 months prior to first study drug, clinically 
significant and uncontrolled cardiac arrhythmia (e.g. atrial fibrillation/flutter 
ventricular cardiovascular physiology is allowed), cerebrovascular accidents ≤ 
6 months before study drug start 
b. severely impaired lung function 
10. Serious, systemic infection requiring treatment ≤7 days before the first dose of study drug 
11. Any severe, uncontrolled disease or condition, which in the investigator's opinion, may 
put the subject at significant risk, may confound the study results, or impact the subject's 
participation in the study. 
10.12 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
10.13 
Withdrawal of Patients 
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to future medical care by the physician or at the institution. 
Any subject who withdraws consent to participate in the study will be removed from treatment 
and/or study observation immediately upon the date of request. All subjects who withdraw 
from treatment prematurely before completion of the protocol-specified tests and procedures 
are strongly encouraged to complete the safety follow-up visit. 
If a patient’s participation is terminated prematurely, the cause for the early termination and 
the date and time of the termination will be documented in the patient’s case report form (CRF) 
and in the final Clinical Study Report (CSR).  


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Patients will be withdrawn from treatment for the following reasons: 
1. Disease progression 
2. Unacceptable toxicity, as defined by the CTCAE Version 4 and in the determination of 
the Principal Investigator 
3. Withdrawal of consent 
4. General or specific changes in the patient's condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
Female patients of childbearing potential will be asked to adhere to the requirements of not 
becoming pregnant and using an acceptable method of contraception as specified in Section 0. 
If a patient withdraws or is dismissed from the study, all procedures planned for the EoS visit 
(Section 10.7) will be completed, where possible. If a patient is withdrawn or dismissed from 
the study, all ongoing AEs should be followed up for 30 days after the last administration of 
study drug, with the exception of any ongoing study drug-related AEs, which should be 
followed until resolution or stabilization (if in the investigator's opinion, the AE is unlikely to 
resolve due to the patient's underlying disease).  
 
10.14 
Replacement of Subjects 
Patients whose mandatory biopsies are not obtained during cycle 1, will be replaced, though 
the individual patient may continue their therapy if it is deemed that they are deriving benefit 
from it. 
 
 


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11 
INVESTIGATIONAL PRODUCT 
11.1 
 Identity of Study Treatment 
AFM13 is a bispecific tetravalent CD30/CD16A chimeric antibody (TandAb) developed for 
the treatment of CD30-positive malignancies. It was developed to promote the recruitment of 
NK cells through the binding to CD16A, and through this engagement, the killing of 
CD30-expressing tumors. AFM13 is being manufactured in compliance with Current Good 
Manufacturing Practice (CGMP) regulations enforced by the United States (US) Food and 
Drug Administration (FDA). AFM13 was studied in a pilot Phase I trial in patients with 
relapsed or refractory HL, using a dose-escalation (3+3) design to evaluate the safety, 
tolerability, and determine the MTD [34].  
Affimed will supply AFM13 for IV infusion to the investigator as a sterile lyophilized solid 
powder for reconstitution for infusion. Each 20 mL clear glass type I vial contains 10 mg 
AFM13. Excipients contained in AFM13 are listed in Table 3.  
IL-CSM (Lörrach, Germany), Affimed’s clinical supplies logistics partner, will send the 
study drug to the responsible pharmacist at the trial center through a third party drug warehouse 
and distribution contractor approved by the US government and/or the State of New York for 
drug storage and distribution. 
One vial of study treatment contains 10 mg AFM13. 
 
Table 3:  Composition of AFM13 for Injection  
Component  
 
Excipients 
Polysorbate 20 0.01% (w/v) 
Trehalose dihydrate 8.0% (w/v) 
Sodium dihydrogen phosphate dihydrate 13.5 mM 
Di-Sodium hydrogen phosphate dihydrate 1.5 mM  
Solvent  
Water for Injection: 7.5 mL/vial  
Stability 
Stability testing of AFM13 revealed a shelf-life of 48 months  
Storage and handling:  
The investigational medicinal product AFM13 is stored at 2-8°C: 
After preparation, the solution may be stored at 2-8°C for a 
maximum of 24 hours before start of infusion. 
No special storage or handling instructions are required. 
The Quality Control Standards and requirements for the study medication are described in 
separate release protocols/Certificate of Analysis. 
 
11.2 
Treatment Storage 
As described in Table 3, AFM13 is to be kept at 2-8°C. After preparation, the solution may be 
stored at 2-8°C for a maximum of 24 hours before start of infusion.  


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All medications must be stored in a safe and locked place with no access for unauthorized 
personnel. 
 
11.3 
Treatment Packaging and Labeling 
Clinical trial supplies will be provided in cartons containing single-use glass vials (20 mL vials) 
of lyophylized AFM13 for infusion (10 mg). 
All vials and secondary packaging will be labeled for the purpose of the clinical trial in 
accordance with applicable regulatory requirements. 
 
11.4 
Preparation of Study Treatment 
The solid is to be reconstituted with 7.5 mL of sterile water for injection to give a total volume 
of 8 mL at a concentration of 1.25 mg/mL AFM13, with a pH specification of 6.0 ±0.5 and 
isoosmolarity (300 ±50 mOsmol/kg). Details on the further dilution in sterile 0.9% saline to 
produce the final volume for infusion and the drug shipment and re-supply process are 
described in a separate Pharmacy Manual. 
For a dose of 1.5 mg/kg, a patient with a body weight of 70 kg receives an absolute dose of 105 
mg AFM13 which is equivalent to 10.5 vials. The solution of these vials will be further diluted 
in sterile 0.9% saline to a final volume of 500 ml. 
 
11.5 
Administration of Study Treatments 
AFM13 is administered by IV infusion. For cohort 1 and 2 the first dose will be given over 4 
hours; if the first dose is well tolerated, the subsequent infusion periods may be reduced by 
30 minutes per infusion to minimum infusion duration of 1 hour. In cohort 3 weekly treatment 
will consists of a loading AFM13 dose of 1 mg/kg to be applied on day1 as 1-hour infusion, 
followed by a 6 mg/kg AFM13 as continuous infusion over 5 days. Cohort 4 will use the same 
dosing schedule as cohorts 1 and 2.  
On Day 1 each treatment week, patients should receive premedication with antihistamines (e.g. 
4 mg dimetindene) before AFM13 infusion start. 
Treatment should begin immediately after the patient has been enrolled and in- and exclusion 
criteria are checked.  
All patients should receive at least one 8-week cycle of AFM13. For those patients with a 
documented response or SD in Cycle 1 Week 11, a second cycle of AFM13 will be 
administered.  
Before the administration of AFM13, rescue medication should be prepared for the case of 
AFM13 IRRs.  


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In order to assess protocol adherence during treatment and to evaluate dose reductions, 
treatment delays, early treatment terminations and reasons, the following measures have to be 
documented in the patient’s CRF on each treatment day:  
• date of treatment 
• AFM13 dose 
• reason for treatment delay or dose deviation (if applicable) 
• date and reason for early treatment termination (if applicable).  
 
11.6 
Study Treatment Accountability 
Records shall be maintained of the delivery of study treatments to the study center, the 
inventory at the study center, the use of each subject and the return of unused to the study center 
pharmacy. 
These records shall include dates, quantities, batch numbers, expiry dates and the unique code 
numbers assigned to the study medication and to the study subjects. 
The investigator shall be responsible for ensuring that the records adequately document that 
the subjects were provided the doses specified in the protocol and that all study medication 
received from the Sponsor is reconciled.  
 
 


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12 
STUDY ASSESSMENTS 
12.1 
Informed Consent 
Details for obtaining informed consent are provided in Section 10 
 
12.2 
Medical History and Physical Examinations 
Vital signs including temperature, systolic blood pressure, diastolic blood pressure, heart rate 
and respiratory rate are to be taken as per institutional standard of care prior to, during, and 
after each dosing.  
Physical examinations are to be performed as clinically indicated 
 
12.3 
Documentation of Side-effects 
Exact documentation of side-effects by the treating physician is necessary. The evaluation 
should be based on the NCI-CTCAE version 4.0. The treating physician evaluates the 
side-effects during each cycle according to these criteria. Side-effects of grade 3 and grade 4 
are documented. The documentation of SAEs is described in Section 0. 
 
12.4 
Reported Undesirable Effects 
Adverse events most frequently observed with AFM13 in the Phase I trial included IRRs of 
mild or moderate severity. Infectious complications such as nasopharyngitis or pneumonia 
were significantly less frequent and were probably related to prior heavy chemotherapies. Only 
one DLT, a hemolytic anemia CTCAE grade 4, was reported; the patient subsequently died 
due to aspergillus pneumonia and multi-organ failure which was not assessed as drug-related. 
No further cases of anemia were documented; neither were other relevant laboratory findings 
reported. 
 
12.5 
Management of Infusion-related Reactions 
AFM13 should be administered with antihistamine (H1/H2 antagonists) premedication as 
described in Section 11.5 
The management of IRRs is described in detail in Table 4 In the case of the manifestation of 
an IRR, the AFM13 infusion should be stopped and, dependent on the severity of the reaction, 
the treating physician should decide about the application of an H1/H2 antagonist and 
corticosteroids. If fever or chills occur, the administration of acetaminophen is recommended. 
Dyspnea or hypertensive/hypotensive blood pressure dysregulation might require an intensive 
care treatment. The AFM13 infusion can be continued as described in Section 11.5 when the 
IRRs have resolved. Subjects in Cohort 4 may be dose reduced to 1.5 mg/kg if they encounter 
persistent IRRs at 4.5 mg/kg. 
 


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Table 4:  Management of AFM13-associated Infusion-related Reactions 
 
CTCAE 
Grade 
Management of 
reaction 
Current AFM13 dose 
Any subsequent AFM13 doses 
0 
- 
Premedication with H1 and H2 antagonist e.g. 4 mg dimetindene 
1 
Additional medication not 
indicated 
No change 
Consider reducing the 
infusion rate by ≥25%* 
Premedication with H1 and H2 antagonists  
Consider reducing the infusion rate by 
≥25% especially when Grade 1 IRR re-
occurs* 
2 
Additional therapy with 
corticosteroids e.g. 150-
200 mg iv prednisolone or 
equivalent 
Consider further 
antihistamines, NSAIDS,  
iv fluids, and narcotics 
Stop infusion until symptoms 
resolved 
Continue infusion on same 
day. Reduce infusion rate by 
≥25%*  
If patient does not tolerate 
AFM13 with reduced infusion 
rate omit dose 
First occurrence: Premedication with H1 and 
H2 antagonist 
Re-occurrence: Premedication with H1 and 
H2 antagonist and corticosteroid 
Consider reduction of infusion rate by 
≥25%* 
If Grade 2 events re-occur despite 
premedication (and reduced infusion 
rates), consider dose reduction to 
1.5mg/kg  or discontinue AFM13 
treatment 
3 
Additional therapy with 
corticosteroids e.g. 150-
200 mg iv prednisolone or 
equivalent 
Consider further 
antihistamines, NSAIDS,  
iv fluids, and narcotics 
Cohort 1 and 2: stop and 
omit the rest of infusion 
Cohort 3 loading dose: stop 
and omit the rest of infusion, 
continue with CIVI at the 
next day 
If patient received CIVI, 
suspend CIVI for min. 24 
hours. 
 
Premedication with H1 and H2 antagonist 
and corticosteroid 
Reduce infusion rate by ≥25%* 
If Grade 3 events re-occur despite 
premedication and reduced infusion rates 
consider dose reduction to 1.5 mg/kg or 
permanently discontinue AFM13 treatment 
 
4 
Consider intensive care 
Additional therapy may 
include (but not limited to) 
corticosteroids, 
antihistamines, NSAIDs, iv 
fluids, narcotics, pressors, 
ventilation, epinephrine 
Permanently stop AFM13 treatment 
*not applicable for the CIVI 
 
12.6 
Management of Other AFM13-related Side Effects 
The management of other AFM13-related AEs is described in Table 5. . If a patient presents 
with symptoms indicative for nasopharyngitis or pneumonia, samples for microbiological 
diagnostics should be obtained. The patient should be admitted to hospital and an empirical 
antibiotic treatment should be immediately started in the case of pneumonia or if the infection 
is associated with a significant impairment of the general condition.  
Continuous safety analyses (AEs, safety clinical laboratory assessments, vital signs, ECGs) 
will be regularly performed by a Principal Investigator-led safety team to ensure the safety of 
the patients. In the case of a potential significant safety problem the Principal Investigator in 
consultation with groups such as the FDA, IRB, data monitoring committee and/or statisticians 
may decide on the termination or temporary cessation of the trial. 
 
 


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Table 5:  Management of Other AFM13-associated Adverse Events 
 
CTCAE grade 
Management of other AFM13-associated AEs 
Grade 1 
Symptomatic treatment as applicable 
Grade 2 or 3 
Interruption of AFM13 infusion if event develops during infusion; 
symptomatic treatment as applicable 
Delay next AFM13 dose until the AE has recovered to CTCAE Grade 0 or 1; if 
delay was more than 21 days, permanently discontinue AFM13 treatment 
Exception: in the case of documentation of a CTCAE Grade 2 or 3, non-
clinically significant, laboratory value or non-clinically significant AE e.g. 
Grade 2 fatigue, the treatment can be continued under close monitoring of the 
laboratory changes (suggest two-day intervals) 
Grade 4 
Permanent discontinuation of AFM13, symptomatic treatment as applicable 
 
AE=adverse event, CTCAE=Common Terminology Criteria for Adverse Events 
 
12.7 
Study drug adjustments 
No study drug adjustment is permitted in the trial, except for the management of IRR as 
explained in Table 4. Adjustment in this case involves infusion rate. 
 
12.8 
Treatment Schedule Interruptions (Delayed or Skipped Doses) 
The treatment with AFM13 should be interrupted, if an AE occurs according to Table 4 and 5.  
Any skipped dose will not be made up. If there is a delayed of more than 3 weeks, the patient 
will be removed from study.  
 
12.9 
Study Drug Discontinuation 
The study drug must be discontinued if a drug-related CTCAE Grade 4 AE occurs at any time.  
Patients who discontinue study drug should be scheduled for an end-of-treatment (EoT) visit 
one week after the last dose of study drug, at which time all of the assessments listed for the 
EoS visit (Section 10.7) will be performed. A form should be completed, giving the date and 
reason for stopping the study drug. It is recommended to have these patients return for the 
Restaging Visit on what would have been their Week 11 of that cycle after the last AFM13 
dose for post-treatment safety evaluations, for tumor assessments and restaging (Section 10.6). 
If a new therapy is planned to be started before Week 11, the final restaging visit should be 
performed before administration of this therapy. 
 
12.10 
Concomitant Therapy 
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial.  If there is a clinical indication for any medication specifically prohibited during the trial, 
discontinuation from trial therapy may be required.  The final decision on any supportive 
therapy rests with the Principal Investigator in consultation with the patient and/or the patient's 
primary physician.   


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All treatments considered necessary for a patient’s welfare may be administered at the 
discretion of the Principal Investigator in keeping with the community standards of medical 
care.  All concomitant medications will be recorded on the CRF including all prescriptions, 
over-the-counter (OTC) medications, herbal supplements, and IV medications and fluids.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF. All concomitant medications received within 30 days before 
the first dose of trial treatment and 30 days after the last dose of trial treatment should be 
recorded.   
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial with exception of the treatment of AEs occurring during the study: 
• 
antineoplastic systemic chemotherapy or biological 
therapy, including 
immunotherapy not specified in this protocol;  
• 
investigational agents other than AFM13;  
• 
radiation therapy;  
• 
systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  The use of 
physiologic doses of corticosteroids may be approved at the Principal 
Investigator’s discretion. However, chronic use of systemic steroids is not allowed. 
Note:  Inhaled steroids are allowed for management of asthma. 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Patients may receive 
other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications that are prohibited on entry to this trial. 
There are no prohibited therapies following withdrawal of study treatment. 
Treatment for IRRs is provided in Table 4. Dependent on the symptoms and the severity of the 
infusion-related reaction the additional application of acetaminophen, and 100 mg prednisone 
as well as epinephrine and/or bronchodilators might be indicated.  
No drug interactions of AFM13 have been observed so far or are likely due of the biological 
nature of AFM13. The treating physician should carefully conduct a risk assessment based on 
the severity of clinical symptoms, and prepare a high-risk patient for intensive care 
management in an intensive care unit (ICU). 
 


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13 
ASSESSMENT OF EFFICACY 
13.1 
Measurement of Biological Effects in Tumor and Blood 
The primary objective of this study is to evaluate the immunological and biological effects of 
the study drug. Key analyses will be conducted by CUMC and contract clinical laboratory 
services providers. Details of the assays will be provided in the study Laboratory Manual 
Manual. 
 
13.2 
Measurement of Clinical Efficacy 
Although clinical response is not the primary endpoint of this trial, patients with measurable 
disease will be assessed by standard criteria. Patients will be re-evaluated at the end of each 
cycle. Response will be evaluated with physical examination, Revised Response Criteria for 
Malignant Lymphoma, 2007, mSWAT, CT as defined by the guidelines of the global 
assessment consensus recommendations for standardization of definition of response in skin, 
nodes, blood and viscera, GR score, and endpoints in MF and Sezary syndrome as outlined by 
the consensus statement of The International Society for Cutaneous Lymphomas, the United 
States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the 
European Organization for Research and Treatment of Cancer in 2011 [36]. PET/CT will be 
utilized as recommended by the Revised Response Criteria for Malignant Lymphoma, 2007 
[35]. 
All assessments over all the treatment cycles will use the same definition for measurable 
disease. The measurable disease recorded in screening of the trial prior to treatment 
administration will be utilized as the reference for response. 
 
13.3 
Definitions 
Evaluable for objective response. Patients who complete 1 cycle of therapy according to the 
study protocol, and have had their disease re-evaluated will be considered evaluable for 
response. When no imaging/measurement is done at all at a particular time point, the patient is 
not evaluable at that time point. Similarly, patients whose tumour assessments are not 
repeated/incomplete will also be considered non evaluable for response. Patients evaluable for 
response will have their response classified according to the definitions stated below. Patients 
who exhibit objective disease progression prior to the end of Cycle 1 will also be considered. 


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Table 6:  Global Response Score 
Global 
Score* 
Definition 
Skin 
Nodes/Blood/Viscera 
CR 
Complete disappearance of all 
clinical evidence of disease 
CR 
All categories have CR/NI 
PR 
Regression 
of 
measurable 
disease 
CR 
 
 
PR 
All categories do not have a CR/NI 
and no category has a PD 
 
No category has a PD and if any 
category involved at baseline, at least 
one has a CR or PR 
SD 
Failure to attain CR, PR, or PD 
representative of all disease 
PR 
 
 
 
SD 
No category has a PD and if any 
category involved at baseline, no CR 
or PR in any 
 
CR/NI, PR, SD in any category and 
no category has a PD 
PD 
Progressive disease 
PD 
PD in any category 
Relapse 
Recurrence disease in prior CR  
Relapse in any category 
CR=complete response; NI=noninvolved; PD=progressive disease; PR=partial response; SD=stable disease 
*It is recommended that not only the proportion of patients who achieve a response or an unfavorable outcome be calculated 
but a life table account for the length of the interval during which each patient is under observation also be generated. 
 
13.4 
Skin Biopsy 
Skin biopsies should be taken from different lesions if possible. Examples where lesions may 
be excluded from biopsy might include those lesions where the patient does not consent due to 
cosmesis or pain, where palliative radiotherapy has been administered, skin infection or trauma 
has arisen. If this is not possible, the second biopsy should be taken as far as possible away 
from the first one, preferably at least 3 cm away. Handling of tumor samples is described in a 
separate Immunobiology Research Manual. Patient inclusion criteria describe eligibility based 
on the number of cutaneous neoplastic lesions (see section 10.11.1: Inclusion Criteria). 
 
13.5 
Objective Response Rate 
Objective Response Rate (ORR) = CR + PR based on evaluation of best response in each 
patient. 
 
13.6 
Modified Severity-Weighted Assessment Tool 
The SWAT is an objective, quantitative, severity-weighted method to assess the extent of skin 
lesions. A SWAT score is derived by measuring each lesion as a percentage of total body 
surface area (%TBSA) and multiplying it by a severity-weighting factor (1=patch, 2=plaque, 
4=tumor). All individual numbers are then added to produce a total score. 


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The body is divided into 12 regions with percentage of total body surface area (%TBSA) based 
on methodology used to assess burns. The extent of skin disease is assessed for each region 
and quantified by using the subject's palm as a “ruler” to measure the %TBSA involvement 
within each region.  
Subject’s palm with 4 fingers, excluding the thumb and measured from wrist to fingertips, is 
1% of TBSA. Subject’s palm without fingers is 0.5% of TBSA. 
 
Table 7:  Modified Severity-Weighted Assessment Tool 
Skin Lesion Definitions 
Lesion Type  
Abnormal Skin 
Erythema 
Patch  
not elevated from normal skin 
flat or with mild infiltration 
Plaque  
elevated from normal skin by < 5 mm 
elevated or with moderate infiltration 
Tumor  
elevated from normal skin by ≥ 5 mm 
with fissuring, ulceration, or tumor 
SWAT Score Calculation 
Total mSWAT (maximum score = 400) = sum of %TBSA from all body regions affected by 
patches x severity-weighting factor of 1 + sum of %TBSA from all body regions affected by 
plaques x severity-weighting factor of 2 + Sum of %TBSA from all body regions affected by 
tumors x severity-weighting factor of 4 
Objective response rates will be evaluated using the global assessment consensus 
recommendations for standardization of definition of response in skin, nodes, blood and 
viscera, GR score, and endpoints in MF and Sezary syndrome as outlined by the consensus 
statement of The International Society for Cutaneous Lymphomas, the United States Cutaneous 
Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European 
Organization for Research and Treatment of Cancer in 2011 [36] and the Revised Criteria for 
Malignant Lymphoma [35]. 
 
13.7 
Computerized Tomography/Magnetic Resonance Imaging 
If CT with contrast medium was used for disease measurement for initial staging, then the same 
modality must be used for restaging. The imaging modality used to assess the stage of disease 
and the target lesions used at baseline must be used again for response assessment, and for 
restaging. Additional imaging technique may be used to diagnose a new lesion (i.e. CNS 
involvement) when deemed appropriate. 
The CT/MRI will be done per the facility’s standard procedures. 
 
13.8 
Whole body 18FDG-PET Scan 
Tumor assessments will be done via whole body 18FDG-PET scan. 


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The investigator will check the patient’s fasting blood glucose prior to the 18FDG-PET scan 
and ensure that the fasting blood glucose is below 200 mg/dL. The investigator should also 
ensure that the patient is able to lie down for 60 minutes. 
 
13.9 
Exploratory Studies 
Exploratory analyses will be conducted on stored tissues and blood at a later time to investigate 
molecular profiling of the tumors using cytogenetics (using fluorescence in situ hybridization 
or FISH), gene profiling by New Genome Sequence (NGS) or other molecular techniques.  
Finally, CTCs will be analyzed at the same time points as those for the analysis of the biological 
effects, and will be determined during Cycle 1 only. 
A comprehensive analysis of NK cell function may require as little as 3.5 ml of heparinized 
whole blood. We will conduct similar analysis in tissue samples. This will help in the 
characterization of NK cell subsets and assessment of NK cell activation in the peripheral 
blood. In addition, phenotypic and functional characterization of other immune cells, including 
T cells, MDSCs, Tregs and tumor cell surface and internal proteins identification and their role 
in specific pathways may be explored to gain potential insights into the key biochemical and 
molecular drivers of response or resistance to AFM13 therapy. 
Anti-drug antibodies will be analyzed at an Affimed-contracted laboratory facility in UK. 
These assessments and the assessment schedule are described in detail in the Immunobiology 
Research Manual. 


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14 
ASSESSMENT OF SAFETY 
The timing and frequency of safety assessments are described in Section 9.5.  
All patients will be evaluated for safety if they have received any study drug. The start and stop 
time of each AFM13 infusion must be documented. Toxicity assessments will be continuously 
performed during the treatment phase. Some of the assessments listed below may not be 
captured as data in the CRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically indicated. 
 
14.1 
Adverse Events 
Definitions 
The definitions for AEs and SAEs are given below. It is of the utmost importance that all staff 
involved in the study is familiar with the content of this section. The principal investigator is 
responsible for enduring this. 
Evaluable for toxicity.  
All patients who have received at least one dose of study drug will be evaluable for toxicity 
starting from Day 1 of Cycle 1. 
Adverse Event 
An AE is defined as any untoward medical occurrence in a subject, or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
Adverse Reaction 
An adverse reaction is any detrimental and unintentional reaction to an investigational drug, 
independent of the administered dose. 
Serious Adverse Event 
An SAE is defined as, but is not limited to, one that: 
• Results in death 
• Is life-threatening (Report if suspected that the patient was at substantial risk of 
dying at the time of the adverse event, or use or continued use of the device or other 
medical product might have resulted in the death of the patient.) 
• Requires in-patient hospitalization or prolongs existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
 


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Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered a serious adverse drug experience, when based on 
appropriate medical judgment, they may jeopardize the subject or the subject may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
A hospital stay is any stay in a hospital as an in-patient for at least one night. A hospitalization 
that has already been planned before the first administration of the investigational drug is not 
considered as an SAE. 
 
14.2 
Unexpected Adverse Reaction 
An unexpected adverse reaction is an adverse reaction that does not correspond to the existing 
investigator brochure detailed information on the investigational drug in terms of the nature 
and severity of this reaction. 
The existing information on the investigational product is stated in the current version of the 
AFM13 IB, which is to be used as a reference. 
 
14.3 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a case in which the occurrence 
of a serious adverse reaction that could not be expected is suspected (there is a certain or 
possible relation to the administered protocol medication), and the nature and severity of this 
reaction do not correspond to the existing information on the respective investigational drug. 
The reaction is rated as serious and a relation between the investigational drug and the reaction 
is considered to be possible. If the relation between adverse reaction and protocol medication 
is not evaluable or not evaluated, the relation is regarded as possible in context of the SUSAR. 
The existing information on the respective investigational drug can be found in the IB. 
 
14.4 
Causality/Relationship 
For each event that occurs, an assessment of causality has to be performed. 
• Not Evaluable 
It is not possible to assess whether there is a relation with the administered 
investigational drug(s) or not. 
• Not Evaluated 
An event that was reported as AE, but for which a relation with the administered 
investigational drug(s) was not established at the time of reporting because further 
data were necessary or is currently being compiled. 
• No Relation 
An event on which there is sufficient information available to assume that there is 
no relation with the investigational drug. 
• Possible Relation 


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An event that follows a matching chronological course after administration of the 
investigational drug, or that follows a known or expected scheme of response to the 
suspect investigational drug, but which could also have been caused by a number 
of other factors. 
• Probable Relation 
An event that follows a matching chronological course after administration of the 
investigational drug, or that follows a known or expected scheme of response to the 
suspect investigational drug, and that disappears after the administration is 
discontinued or reduced to a lower dose, and that cannot be explained by the known 
clinical condition of the patient. 
• Certain Relation 
An event that follows a matching chronological course after administration of the 
investigational drug, or an event due to which the concentration of the 
investigational drug in the body tissues or fluids is measured, that follows a known 
or expected scheme of response to the suspect investigational drug, and that 
disappears after the administration is discontinued or reduced to a lower dose and 
reappears after repeated exposure. 
 
14.5 
Recording of Adverse Events 
For the purposes of this study, any detrimental change in the patient's condition, after signing 
the informed ICF and up to completion of the EOS assessments should be considered an AE. 
Adverse events will be recorded the signing of informed consent until the EOS visit. 
Every grade 3/4 AE must be documented, independent of the investigator’s opinion whether 
there is a causative relation with therapy or not.  
Unexpected AEs are to be documented on the respective CRF form (AE form). Documentation 
includes the nature of the event, beginning, duration, intensity/stage and causality. 
All AEs have to be tracked until they have subsided or stabilized.  
All AEs that are not rated as unexpected have to be documented. 
All ongoing AEs should be followed up for 30 days after the last administration of study drug, 
with the exception of any ongoing study drug-related AEs, which should be followed until 
resolution, unless in the investigator's opinion, the AE is unlikely to resolve due to the patient's 
underlying disease. Any new SAEs occurring up to 60 days after the last administration of 
study drug should be reported to spm2 – safety projects & more GmbH, the Affimed ‘s safety 
Clinical Research Organization (CRO) according to Section 14.3 
At any time after the follow-up visit, if an investigator learns of an SAE that can be reasonably 
related to study drug, he/she should promptly notify the IRB/EC and FDA according to 
institutional and federal guidance, respectively. Affimed’s safety CRO spm2 shall also be 
notified. The reports will be sent to  


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spm2 – safety projects & more GmbH 
Aurum 05 
Goldbeckstr. 5 
69493 Hirschberg a. d. Bergstraße, Germany 
Safety Fax: +49 621 - 5 70 59 71 
Email: Affimed-PHV@spm2-safety.com 
 
The investigator will assess the degree of severity as follows: 
• mild  
• moderate  
• severe  
• immediately life-threatening 
The evaluation is to be based on the official CTCAE version 4.0. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 14. 
An AE of severe intensity need not necessarily be considered serious. For example, nausea that 
persists for several hours may be considered severe nausea, but not an SAE. On the other hand, 
a stroke that results in only a limited degree of disability may be considered a mild stroke but 
would be an SAE. 
For an AE to be a suspected drug-related event, there should be at least a reasonable possibility 
of a causal relationship between the study drug and the AE. 
 
14.6 
Expedited Adverse Event Reporting 
The Principal Investigator agrees to provide appropriate parties with copies of all serious 
adverse events within two working days. Reportable information should always be reported by 
the Principal Investigator directly to the IRB within 5 working days from when the Principal 
Investigator learns of the event or new information. Additionally, the Principal Investigator 
agrees to report any pregnancy occurring in association with use of study drug to the 
appropriate parties. 
Serious adverse events (SAE) are defined above. The investigator must inform spm2 in writing 
using a spm2 SAE form or MEDWATCH 3500A form of any SAE within 24 hours of being 
aware of the event. The written report must be completed and supplied to spm2 by facsimile 
within 24 hours/1 business day. The initial report must be as complete as possible, including 
as assessment of the casual relationship between the event and the investigation product, if 
available. Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a follow-
up report. A final report to document resolution of the SAE is required. The institutional 
protocol number should be included on the SAE reports (or on the fax cover letter) sent to 


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spm2. A copy of the fax transmission confirmation of the SAE report to spm2 should be attached 
to the SAE and retained with the patient records 
 
NAME OF SAE REPORTING 
ADDRESS (as appropriate) 
spm2 – safety projects & more GmbH 
Aurum 05 
Goldbeckstr. 5 
69493 Hirschberg a. d. Bergstraße, Germany 
Safety Fax: +49 621 - 5 70 59 71 
Email: Affimed-PHV@spm2-safety.com 
 
The investigator is responsible for reporting any SAEs to the FDA. Serious AEs that are 
unlisted/unexpected, and at least possibly associated to the drug, and that have not 
previously been reported in the IB, or reference safety information document should be 
reported promptly to the FDA by telephone (1-800-332-1088), fax (1-800-FDA-0178), or via 
MedWatch Online. Fatal or life-threatening SAEs that meet the criteria for reporting to the 
FDA must be reported to the FDA within 7 calendar days after awareness of the event. All 
other SAEs that meet the criteria for reporting to the FDA must be reported to the FDA within 
15 calendar days after awareness of the event. A clear description of the suspected reaction 
should be provided along with an assessment as to whether the event is drug or disease related. 
Note:  All deaths on study require expedited reporting regardless of causality. Attribution to 
treatment or other cause must be provided. 
 
Expedited AE Reporting Timelines 
One business day; 5 calendar days – The investigator must initially report the AE within 
1 business day of learning of the event followed by a complete report within 5 calendar days 
of the initial 24-hour report. 
10 calendar days - A complete report on the AE must be submitted within 10 calendar days of 
the investigator learning of the event. 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited AE reporting exclusions. 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported if the event occurs following treatment. 
 


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14.7 
Adverse Event Updates/IND Safety Reports 
The Principal Investigator shall notify FDA via an IND Safety Report of the following 
information: 
• Any AE associated with the use of drug in this study or in other studies that is both 
serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for 
human 
subjects 
including 
reports 
of 
mutagenicity, 
teratogenicity, 
or 
carcinogenicity. 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects. 
The Investigator must keep copies of all AE information, including correspondence with 
Affimed and/or spm2 – safety projects & more GmbH and the IRB. 
 
14.8 
IND Reporting 
During the course of the study, the Sponsor may determine that certain safety reports are 
required to comply with regulations. The Sponsor is responsible for submission of such reports 
to their IND. The Investigator may receive a letter called an “IND Safety Report” from this 
study and/or other Affimed sponsored studies (cross reports). These reports must be submitted 
to the IRB/EC as required. 
Annual IND Report as well as any IND amendments will be to the reported to the CUMC IRB 
as well as the FDA.  
 
 
14.9 
Pregnancy 
AFM13 might cause harm when administered to a pregnant woman. There are no adequate and 
well-controlled studies in pregnant women. 
Women of childbearing potential will be advised to avoid becoming pregnant while receiving 
treatment. Women enrolled in this study should either be post-menopausal, free from menses 
for >2 years, surgically sterilized, or willing to use 2 adequate barrier methods of contraception 
to prevent pregnancy or agree to abstain from heterosexual activity throughout the study, 
starting with Visit 1. Women of childbearing potential must have a negative serum pregnancy 
test (β-hCG) within 7 days prior to receiving the first dose of study drug. Men enrolled in the 
study must also agree to an adequate method of contraception for the duration of the study. 
If a patient or their partner inadvertently becomes pregnant while on study, the patient will 
immediately be removed from the study and the drugs will be discontinued. Investigators will 
follow the patient monthly and document the patient’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to appropriate parties 


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within 24 hours if the outcome is an SAE (i.e. death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). If a male patient’s partner 
becomes pregnant on study, the pregnancy will be reported to appropriate parties. Reporting of 
pregnancy will follow the guidelines outlined in Section 14.3. 
 
14.10 
Abnormal Laboratory Values/Vital Signs/Electrocardiograms 
Signs and symptoms as well as changes in the laboratory values should be documented in 
summary as one AE. Unusual laboratory values have to be assessed by the investigator 
regarding their clinical relevance and – only if they are assessed to be relevant – they have to 
be documented as an AE. Changes in the peripheral blood count are within the scope of this 
trial. Therefore, every grade 3/4 anemia, neutropenia, lymphopenia or thrombocytopenia has 
to be documented as AE. 
 
14.11 
Deaths 
Should a death occur within the study period or within 60 days after the last administration of 
study drug an AE form and an SAE form should be completed, detailing the AE that resulted 
in the death (NB, death is an outcome, not an event). The SAE must be reported to the IRB 
according to institutional guidelines and FDA within 24 hours. The report should contain a 
comment regarding the co-involvement of progression of disease, if appropriate, and should 
assign main and contributory causes of death. 
 
14.12 
Overdose 
Drug 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 patient should 
be observed closely for signs of toxicity.  Appropriate supportive treatment should be provided 
if clinically indicated. 
AFM13 overdose is defined as any dose administration where > 10% over 7 mg/kg is 
administered whether or not associated with an AE.  
If the pharmacy discovers that an overdose has or may have been administered, they should 
contact the Study Investigator and Study Coordinator 
.  
 
14.13 
Laboratory Assessments 
Blood and urine samples will be collected for the following analyses: 
• Complete Blood Count 
• Serum Chemistry 
• Urinalysis 


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A serum pregnancy test will be done on all women of childbearing potential; a negative test 
result must be obtained prior to the first administration of study treatment. 
Samples will be collected per institutional procedures and analyzed in the local laboratory. 
 
14.14 
Biological Parameters/Markers 
Specifications for collection and handling of samples for the assessment of biological 
parameters/markers, are included in the Immunobiology Research Manual.  
Biological parameters/markers will be analyzed according to the scope of work and laboratory 
capabilities at Principal Investigator’s study center. Additional analyses will be performed at 
contract service laboratory facilities as detailed in the Immunobiology Research Manual.  
 
14.15 
Electrocardiogram Assessments 
A resting 12-lead ECG will be done to assess the patient’s general suitability for therapy as 
well as to record her/his initial status to enable assessing treatment-related toxicities that may 
occur later on. 
ECGs will be performed after 5 minutes rest, in the supine position.  
In case of pathological findings a printout of ECG is required. 
Additional cardiac function tests may be required in case of suspected cardiac malfunction that 
warrants further investigation. 
 
14.16 
Physical Examination 
Physical examinations shall include those areas of general physician assessment including but 
not limited to the skin, lymph nodes, spleen, and liver. Performance status and body weight 
should be assessed once weekly. 
Further examinations may be necessary based on the patient’s condition and are in the 
responsibility of the investigator. 
Any new or worsening clinically significant changes have to be reported on the appropriate AE 
or SAE form. 
 
14.17 
Vital Signs 
Assessment of vital signs will include temperature, systolic blood pressure, diastolic blood 
pressure, heart rate and respiratory rate per institutional standard of care prior to, during, and 
after each dosing. 
Vital signs will be measured after 5 minutes rest, in the supine position 
 


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14.18 
Assessment of Pharmacokinetics 
Specifications for collection and handling of samples for PK assessments are included in the 
Immunobiology Research Manual. For adequate analysis of PK at one time point a blood 
sample of approx. 3 ml is required for analyses at CUMC. Additionally, PK assessments will 
be performed at Affimed’s contract laboratory services in Germany. 
PK analyses will be done in the center laboratory at CUMC, for analyses done locally. 
Full PK assessments will include but may not be limited to estimates/calculations of: 
• maximum measured plasma concentration (Cmax) 
• area under the curve  (AUC) 
• distribution volume VD 
• terminal half-life 
• clearance 


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15 
 STATISTICAL EVALUATION 
15.1 
Statistical Methods 
The data will be analyzed by the Columbia University Medical Center. This is a single center 
study. The data will be summarized with respect to demographic and baseline characteristics, 
biological activity measurements, safety observations, efficacy observations, PK and potential 
biomarker observations. The data will be presented by dose cohorts and overall. The clinical 
database lock will occur after all data are reconciled (i.e. “cleaned”) for all patients. A single 
clinical study report will be generated for this study. The Statistical Analysis Plan (SAP) will 
be finalized and signed before the database lock.  
The data analysis will take place after the time of database lock when all patients have 
completed 2 cycles or discontinued the study prior and all data is cleaned. Further data for 
patients that are followed up past the two cycles will be summarized in an extension report 
once all patients have discontinued the study. All analyses are of exploratory nature. 
 
15.2 
Sample Size and Power 
The planned total target accrual for this study is 15 subjects. 
As this study is of exploratory nature no formal sample size calculation is done. However based 
on the prior phase I study of AFM13, it is expected that approximately 78% of the patients will 
show biological activity. Observing 12 patients out of 15 with biological response would lead 
to 95% exact binomial confidence interval of (52%, 96%). The lower bound of 52% is assumed 
to be sufficient for evidence of biological activity in this exploratory study. 
 
15.3 
Study Populations 
Since this study is of exploratory nature only one data set is defined for all analysis. 
The safety set consists of all patients that have received at least one dose of AFM13. 
Patients will be analyzed in the cohort of the treatment they have actually received. Cohorts 
will be disjoint sets; each Patient will belong only to one cohort. For the primary outcome the 
analysis population will be a subgroup of the safety set, only patients with baseline 
measurements and have completed cycle 1 will be considered. 
 
15.4 
Demographics, Baseline Characteristics and Medical History 
Demographics, baseline characteristics and medical history will be analyzed for the safety set 
by cohort and overall. For continuous variables, descriptive statistics will be presented 
including: mean, standard deviation, median and range. For categorical variables frequency 
and percentages will be presented. All data will be listed. 
 


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15.5 
Treatment, Compliance, Disposition, Concomitant Therapies, Protocol 
Deviations 
As a compliance measure the actual number of doses of AFM13 received will be summarized 
by dose cohort. The reason for discontinuation of study treatment and study including study 
completed as per protocol will be presented. Concomitant medication will be coded by ATC 
terminology and summarized by frequencies. Patients with major protocol deviations as 
defined by the study team prior to database lock will be summarized. The safety set will be 
used. All data will be listed. 
 
15.6 
Primary Objective 
The primary objective of the study is to evaluate the biological effects of AFM13 in tumor and 
peripheral blood. For this, NK immunophenotypic characterization, proliferation, density, 
activation and effector function (cytokine production and release, ADCC) will be measured in 
peripheral blood. More importantly, intratumoral NK-cell infiltrate and density, phenotypic 
characterization, cytokine production and release will also be analyzed in the tumor. Similarly, 
T cells will be assessed for the same phenotype, activation and effector function (including 
CTL) both in the peripheral blood and the tumor tissue. Finally, cancer cells will be studied for 
CD30 expression, immunological receptors and other tumor markers. Other tumor resident 
immune cells will also be characterized (myeloid-derived suppressor cells, Tregs). Details of 
immunological and biological studies to be conducted in this protocol appear in the 
Immunobiology Research Manual. 
These endpoints will be assessed by visit and presented by change from baseline. Mean, 
standard deviation, median and range will be calculated for continues measurements, frequency 
and percentages for categorical data.  Correlation of biological and clinical outcome will be 
assed graphically. Non-parametric tests for change over time such as the Friedman-test and the 
signed rank test might be facilitated, however no adjustment for multiplicity is planned. All 
data will be listed. Only patients in the safety set that have also completed cycle 1 and have 
biopsies obtained at 2 scheduled time points for biopsy collection will be assessed and 
presented. No imputation of missing values is planned. 
 
15.7 
Secondary Objectives 
15.7.1 
Efficacy 
Clinical efficacy will be estimated by ORR defined by achieving CR and/or PR, as defined in 
Section 13.3. For the overall cohort 95% exact binomial confidence intervals will be presented. 
The safety set will be used. All data will be listed. 
 


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15.7.2 
Duration of response 
The DOR defined as time from improved baseline tumor assessment achieved on study drug 
(CR and/or PR) to worsening will be estimated and summarized by descriptive statistics and 
listed. 
 
15.7.3 
Progression-Free Survival 
Progression-free survival will be estimated only for the overall cohort. Patients with no event 
will be censored at their study discontinuation visit, including study completion. Kaplan-Meier 
estimates for the 25%, median and 75% quartiles with respective 95% confidence intervals will 
be presented and graphically displayed. The safety set will be used. All data will be listed. 
 
15.7.4 
Pharmacokinetics 
A descriptive PK analysis will be conducted, Mean, standard deviation, median and range will 
be calculated for continues measurements, frequency and percentages for categorical data.  
Only patients in the safety set that have a respective baseline and at least one post-baseline 
measurement will be used 
 
15.8 
Safety Objectives 
15.8.1 
Adverse Events 
All AEs recorded during the study will be coded by MedDRA (Medical Dictionary for 
Regulatory Activities). The incidence of AEs will be summarized by cohort, overall, primary 
system organ class, preferred terms and severity based on CTCAE version 4.0. Relationship to 
study drug, AEs leading to discontinuation of study drug, death and SAEs, will be summarized.  
Infusion-related AEs will be summarized by preferred term and severity. A list of AEs related 
to skin disease using pre-defined MedDRA preferred terms will be used to identify any AEs of 
special interest. All AEs will be listed. The safety set will be used. 
 
15.8.2 
Laboratory Abnormalities 
Laboratory values and severity grades will be calculated using CTCAE version 4.0. For those 
parameters where there is no CTCAE grading defined a classification into lower limit, normal 
and higher limit will be used. Shift tables for change from baseline will be presented as well as 
descriptive statistics mean, standard deviation, median, and range for absolute values by visit 
and change from baseline will be summarized. All lab values, abnormalities will be listed. The 
safety set will be used. 
 


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15.8.3 
Vital Signs 
Vital signs will be summarized by mean, standard deviation, median and range for absolute 
values by visit and change from baseline. The number of abnormal vital signs will be 
summarized by visit. All values will be listed. The safety set will be used. 
 
15.8.4 
Other Safety Parameters 
All other safety parameters such as ECG will be listed for the safety set. 
 
15.9 
Exploratory Objectives 
15.9.1 
Presence of Anti-AFM13 Antibody 
The presence of anti-AFM13 antibodies and their neutralizing function will be assessed by 
descriptive statistics (mean, standard deviation, median and range). The safety set will be used. 
All data will be listed. 
 
 
15.9.2 
Interim Analysis 
No formal interim analysis is planned, however, an internal review by the PI and study team 
will be conducted 8 days after last patient of the cohort has received their first dose, and decide 
on enrolling the next cohort. 
 


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16 
SOURCE DOCUMENTATION  
Source data is all information contained in original records and certified copies of original 
records of clinical findings, observations or other activities in a clinical trial necessary for the 
evaluation of the trial. Source data are contained in source documents, which may include 
hospital records, clinical and office charts, laboratory reports, memoranda, subjects’ diaries, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, radiology and other ancillary service reports, subject files, patient visit notes, 
encounter forms, operative notes, patient medication diaries and electronic medical records.  
 
For FDA-regulated trials, adequate and accurate source documentation is required. According 
to 21 CFR 312.62(b), an investigator is required to prepare and maintain adequate and 
accurate case histories that record all observations and other data pertinent to the 
investigation on each individual administered the investigational drug or employed as a 
control in the investigation. Case histories include the CRFs and supporting data including, 
for example, signed and dated consent forms and medical records including, for example, 
progress notes of the physician, the individual’s hospital chart(s) and the nurses’ notes. The 
case history for each individual shall document that informed consent was obtained prior to 
participation in the study.  
 
 
CRCs must provide direct access to source data and documents for trial-related monitoring, 
audits, IRB reviews and regulatory inspection.  
 
 


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17 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1 
Conduct of the Study 
Columbia University Medical Center (Sponsor) shall implement and maintain quality control 
and quality assurance procedures with written standard operating procedures (SOPs) to ensure 
that the study is conducted and data are generated, documented and reported in compliance 
with the protocol, International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 1996) and all revisions thereof, and in accordance with FDA regulations [US Code 
of Federal Regulations (CFR), Sections 312.50 and 312.56] and with ICH GCP 
(CPMP 135/95). 
The investigator may not deviate from the protocol without a formal protocol amendment 
having been established and approved by an appropriate IRB, except when necessary to 
eliminate immediate hazards to the subject or when the change involves only logistical or 
administrative aspects of the study. Any deviations may result in the subject having to be 
withdrawn from the study and render that subject non-evaluable. 
 
17.2 
Study Monitoring 
The IRB  at CUMC will monitor this study. Monitoring will be conducted in accordance with 
the Center for Lymphoid Malignancies 
Data Safety Monitoring Plan.  
 
17.3 
Study Auditing 
Investigator responsibilities are set out in the ICH guideline for GCP and in the US CFR. 
Investigators must enter study data onto CRFs or other data collection system. The Investigator 
will permit study-related audits by the CUMC IRB and CUMC regulatory  representatives, IRB 
review, and regulatory inspections, providing direct access to the facilities where the study took 
place, to source documents, to CRFs, and to all other study documents. 
 
17.4 
Protocol Amendments 
Any amendment to this protocol must be agreed to by the Principal Investigator and reviewed 
by Affimed. Written verification of IRB approval will be obtained before any amendment is 
implemented. 
 


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17.5 
Protocol Deviations/Violations 
All deviations from and violations of Columbia policies or IRB determinations, including 
departures from the requirement for adherence to the approved protocol, must be reported to 
the IRB.  
 
A protocol deviation is defined as a variation from the approved protocol for one subject or to 
address a temporary situation that is identified by the research team and approved by the IRB 
before implementation.  
 
A protocol violation is defined as a variation from the approved protocol that was 
implemented without prospective approval by the IRB and was not implemented to avoid or 
minimize imminent harm. Protocol violations may be considered noncompliance with the 
federal regulations and institutional policies for the protection of the IRB Noncompliance 
Policy apply.  
 
Requests for Protocol Deviations should be submitted to the IRB via the Modification 
module in Rascal as soon as the study team becomes aware of the need for the deviation. 
When applicable, the sponsor’s concurrence (e.g., that an individual who does not meet 
eligibility criteria may be enrolled) should be provided with the submission. The IRB 
recognizes that some deviations regarding inclusion/exclusion criteria are identified shortly 
before the subject is scheduled for randomization or entry into the study and that a quick 
review by the IRB is important for the study. In time-sensitive situations, the PI should 
follow his/her submission to the IRB with an e-mail outside of Rascal to the Manager of the 
IRB that the approved the study. Please note that repeated Protocol Deviation requests related 
to eligibility suggest that the PI should revised the protocol to reflect more appropriate 
eligibility criteria for the study consistent with research participant safety and preservation of 
the scientific integrity of the data.  
 
If a Protocol Violation is unanticipated, at least possibly related to the research, and involves 
risks to subjects or others, it should be reported to the IRB within one week (5 business days) 
via an Unanticipated Problem (UP) report in Rascal. Protocol violations related to medication 
dose errors should also be submitted as a UP whether the error involves an over- or under-
administration of medication. If the error occurred within NYP, the situation should be 
discussed with the subject, in accordance with the underlying philosophy of NYPs Disclosure 
Policy (Policy #E145); discussion with the subject may also be appropriate for medication 
dose errors that occur outside of NYP in clinical studies under the purview of the IRB.  
 
Violations other than UPs of the rights or welfare of subjects, negatively affect the integrity 
of the study, or require a change to the protocol or consent document(s) are considered to be 
major violations and require prompt reporting to the IRB as a Modification.  
 
Minor violations are violations that are not UPs and do not meet the criteria to be considered 
major violations. These should be reported to the IRB at the time of continuing review, in a 
list or log that includes all UPs, deviation or major violation were made.  
 
The description of the circumstances surrounding the deviation or violation should be clearly 
stated in the UP, in the summary section of the Modification Information Form or in the 
Renewal Form, as applicable.  
The following information should be included:  


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• a complete description of the deviation or violation;  
• an explanation of why the deviation is necessary, or why the violation occurred;  
• whether the deviation affects, or the violation affected, the risk/benefit ratio for 
subjects, integrity of the research data and subjects willingness to continue study 
participation;  
• for protocol violations, a description of the corrective measures that will be taken to 
prevent a recurrence of the same or similar violations; and  
• for protocol deviations, a plan to inform the subject if the deviation may change the 
subject’s willingness to participate in the research study.  
 
17.6 
 Institutional Review Board 
Prior to the start of the study, the investigator is responsible for ensuring that the protocol and 
ICF have been reviewed and approved by the CUMC IRB. The IRB shall be appropriately 
constituted and perform its functions in accordance with FDA ICH GCP and local requirements 
as applicable. 
The IRB shall approve all protocol amendments (except for logistical or administrative 
changes), written informed consent documents and document updates, subject recruitment 
procedures (e.g., advertisements), written information to be provided to the subjects, 
Investigator's Brochure, available safety information, information about payment and 
compensation available to subjects, the investigator's curriculum vitae and/or other evidence 
of qualifications and any other documents requested by the IRB and Regulatory Authority as 
applicable. 
 
17.7 
Written Informed Consent 
The nature and purpose of the study shall be fully explained to each subject.  
Written informed consent must be obtained from each subject prior to any study procedures 
being performed. 
The consent documents to be used for the study shall include all the elements of informed 
consent shall be reviewed and approved by the appropriate IRB prior to use. 
 


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18 
DATA HANDLING AND RECORD KEEPING 
18.1 
Responsibility for Data Submission 
The Study Coordinator is responsible for compiling data for all participants and for providing 
the data to the Principal Investigator for review.   
 
18.2 
Data Safety Monitoring Board 
The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center’s 
Data Safety Monitoring Board (DSMB) will oversee conduct of the study, patient safety and 
all interim analyses as specified in the data analysis plan.  Detailed guidelines regarding the 
structure, function and decision-making mechanisms for the Data Safety Monitoring Board are 
provided in the DSMB charter. 
 
18.3 
Investigator Reporting Responsibilities 
The conduct of the study will comply with all FDA safety reporting requirements.   
During the course of the study, the Sponsor may determine that certain safety reports are 
required to comply with regulations. Columbia University Medical Center will cross-
reference Affimed’s AFM13 Investigational New Drug (IND) Application, and will hold 
the IND for this trial). These reports are required to be submitted to the IRB/EC. 
 
 
 


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19 
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20 
APPENDICES 
 There are no Appendices planned to be added to this study protocol.