Conditions: Diffuse Large-cell B-cell Lymphoma
Keywords: DLBCL, NOS Diffuse Large B-cell Lymphoma Transformed indolent Lymphoma
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the safety and effectiveness of plamotamab when it is given with tafasitamab and lenalidomide in participants with relapsed or refractory DLBCL.

Detailed description:
This is a randomized, multicenter, open-label, Phase 2 study of plamotamab combined with tafasitamab plus lenalidomide versus tafasitamab plus lenalidomide in adult participants with DLBCL who have relapsed after or are refractory to at least 1 prior line of therapy, which must have included multi-agent chemoimmunotherapy inclusive of an anti-cluster of differentiation (CD) 20 monoclonal antibody, and who are not candidates for autologous stem-cell transplantation (ASCT), refuse ASCT, or relapse after ASCT.

The study was planned to be performed sequentially, with Part 1A (Safety run-in, with a lower plamotamab dose), Part 1B (Safety run-in, with the target plamotamab dose) and Part 2 (Open-Label, randomized). The study was terminated by the Sponsor during Part 1A of the study. No participants were enrolled in Part 1B or Part 2.

Arms:
arm 1: Drug: Plamotamab will be administered at a lower dose in addition to tafasitamab (12 milligrams \[mg\]/kilograms \[kg\] intravenously) plus lenalidomide (25 mg orally). This cohort was planned to enroll sequentially prior to Part 1B. arm 2: Drug: Plamotamab will be administered at the target dose in addition to tafasitamab (12 mg/kg intravenously) plus lenalidomide (25 mg orally). This cohort was planned to enroll sequentially after Part 1A. arm 3: Drug: Plamotamab will be administered at protocol defined dose in addition to tafasitamab (12 mg/kg intravenously) plus lenalidomide 25 mg (orally). arm 4: Drug: Tafasitamab (12 mg/kg intravenously) plus lenalidomide 25 mg (orally).

Interventions: intervention 1: Plamotamab intervention 2: Tafasitamab intervention 3: Lenalidomide
Intervention descriptions: intervention 1: Biological intervention 2: Biological intervention 3: Drug

Protocol document:
Prot_000.pdf: 
XmAb®13676 (Xencor, Inc.) 
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CLINICAL STUDY PROTOCOL 
A Phase 2 Randomized, Open-Label, Multicenter Study to Evaluate 
the Efficacy and Safety of XmAb®13676 (Plamotamab) Combined 
with Tafasitamab Plus Lenalidomide Versus Tafasitamab Plus 
Lenalidomide in Subjects with Relapsed or Refractory Diffuse 
Large B-Cell Lymphoma
Protocol No.: 
XmAb13676-03 
IND No.: 
IND 129984 
EudraCT: 
Pending 
Test Product: 
XmAb®13676 (Plamotamab) 
Indication: 
Relapsed-refractory diffuse large B-cell lymphoma (R/R 
DLBCL) 
Sponsor: 
Xencor, Inc. 
111 West Lemon Avenue 
Monrovia, CA 91016 
Telephone: 
 
Development Phase: 
Phase 2 
Sponsor Medical Expert: 
 
Xencor, Inc. 
Telephone: 
 
E-mail: 
Version and Date: 
Version 2.0 (08 March 2022) 
Replaces Version and 
Date: 
Version 1.0 (15 December 2021) 
Confidentiality Statement 
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 Independent Ethics Committee and/or Institutional Review 
Board. It is understood that the information will not be disclosed to others without written authorization from 
Xencor, Inc. except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered.  
NCT: NCT05328102


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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Expert 
PROTOCOL TITLE: 
A Phase 2 Randomized, Open-Label, Multicenter Study to 
Evaluate the Efficacy and Safety of XmAb®13676 (Plamotamab) 
Combined 
with 
Tafasitamab 
Plus 
Lenalidomide 
Versus 
Tafasitamab Plus Lenalidomide in Subjects with Relapsed or 
Refractory Diffuse Large B-Cell Lymphoma 
PROTOCOL NUMBER: 
XmAb13676-03 
 
Xencor, Inc. 
 
This clinical study protocol was subjected to critical review. The information it contains is 
consistent with current knowledge of the risks and benefits of the investigational medicinal product 
(IMP), as well as with the moral, ethical and scientific principles governing clinical research as set 
out in the Declaration of Helsinki (Version 2013), and the current guidelines on Good Clinical 
Practices (GCP) applicable to this clinical study. 
 
 
 
 
 
{See appended electronic signature at the end of the document} 
 
 
Xencor, Inc. 
 
 


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INVESTIGATOR PROTOCOL SIGNATURE PAGE 
Protocol No. XmAb13676-03 (Version 2.0) 
A Phase 2 Randomized, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety 
of XmAb®13676 (Plamotamab) Combined with Tafasitamab Plus Lenalidomide Versus 
Tafasitamab Plus Lenalidomide in Subjects with Relapsed or Refractory Diffuse Large 
B-Cell Lymphoma 
08 March 2022 
I have read and understand the protocol and the Investigator’s Brochure, and I agree that they 
contain all the ethical, legal, and scientific information necessary to conduct this study. I will 
conduct this protocol as outlined herein and will make every effort to complete the study within 
the time designated. 
I will provide copies of the protocol and access to all information furnished by the Sponsor to 
study personnel under my supervision. I will discuss this material with them to ensure that they 
are fully informed about the drug and the study. 
The protocol may not be modified without written approval of the Sponsor. All changes to the 
protocol must be submitted to the applicable regulatory authorities, Institutional Review Board 
(IRB), and Independent Ethics Committee (IEC) and must be approved by the IRB/IEC prior to 
implementation except when necessary to eliminate immediate hazards to the subjects or when the 
change(s), as deemed by the Sponsor, involves only logistical or administrative changes. 
Documentation of IRB/IEC approval must be sent to the Sponsor immediately upon receipt. 
By my signature below, I hereby attest that I have read, understood, and agreed to abide by all the 
conditions, instructions, and restrictions contained in Protocol XmAb13676-03 and in accordance 
with International Council on Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) GCP guidelines, the Declaration of Helsinki, and all regulatory requirements 
for protection of human subjects in clinical studies and privacy requirements for the protection of 
individual and company data. 
I understand that the study may be terminated or enrollment suspended at any time by the Sponsor, 
with or without cause, or by me if it becomes necessary to protect the best interest of the study 
subjects. 
 
 
Printed Name of Principal Investigator 
 
 
 
Signature of Principal Investigator 
 
___________________________  
Date 


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LIST OF STUDY STAFF/EMERGENCY CONTACTS 
Sponsor: 
Xencor, Inc. 
111 West Lemon Avenue 
Monrovia, CA. 91016 
Telephone: 
 
Medical Monitor: 
 
 
Xencor, Inc. 
Telephone: 
 
E-mail: 
 
Serious Adverse Event 
Reporting: 
ICON PVSS 
E-mail: 
Fax number: 
Emergency phone number: 
 
 
(toll free within US) or 
 (toll number) 
Back-up number: 
 
Contract Research 
Organization: 
ICON Clinical Research Ltd  
South County Business Park 
Leopardstown, Dublin 18 
Ireland 
Bioanalytical 
Laboratory 
(Pharmacokinetics, 
Anti-Drug Antibodies, 
Cytokine Assays): 
See Laboratory Manual for contact information. 
Bioanalytical 
Laboratory (Flow 
Cytometry, 
Immunohistochemistry, 
and Biobanking): 
See Laboratory Manual for contact information. 
 
 
 


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SYNOPSIS  
Name of Sponsor/Company: 
Xencor, Inc. 
111 West Lemon Avenue  
Monrovia CA 91016 
Name of Investigational Product: 
XmAb®13676 (plamotamab) 
Name of Active Ingredient: 
XmAb®13676 
Title of Study:  
A Phase 2 Randomized, Open-Label, Multicenter Study to Evaluate the Efficacy and Safety of 
XmAb®13676 (Plamotamab) Combined with Tafasitamab Plus Lenalidomide Versus Tafasitamab Plus 
Lenalidomide in Subjects with Relapsed or Refractory Diffuse Large B-Cell Lymphoma 
Study Period: 
Estimated date first subject enrolled: Quarter 1 2022 
Estimated date last subject completed: Quarter 4 2027 
Phase of Development: 2 
Objectives:  
Primary Objectives: 
The primary objective of the study is to: 
Determine the safety and efficacy of the combination of plamotamab, tafasitamab, and lenalidomide 
compared to tafasitamab and lenalidomide in adult subjects with relapsed or refractory diffuse large 
B-cell lymphoma (R/R DLBCL). 
Secondary Objectives: 
The secondary objectives of the study are to compare the combination of plamotamab, tafasitamab, and 
lenalidomide to tafasitamab and lenalidomide for the following assessments: 
1. 
Rates of objective response (ORR = CRR + partial response rate [PRR]) by Blinded 
Independent Review Committee (BIRC) and Investigator per Lugano 2014 criteria 
2. 
Overall survival (OS) 
3. 
Time to treatment failure (TTF) 
4. 
Duration of response (DOR) among subjects achieving an objective response (CR + PR) and 
among subjects achieving a complete response (CR) by BIRC 
5. 
Progression-free survival (PFS), as determined by the Investigator 
6. 
Incidence, timing, and severity of cytokine release syndrome (CRS) by following CRS-related 
adverse events (AEs) including incidence and grade of AEs and incidence of serious adverse 
events (SAEs) 


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7. 
Incidence, timing, and severity of neurological AEs and incidence and grade of immune effector 
cell-associated neurotoxicity syndrome 
8. 
Dose intensity of tafasitamab and lenalidomide in Part 1 when given in combination with 
plamotamab 
9. 
Safety profile of the combination of plamotamab, tafasitamab, and lenalidomide in Part 2, as 
determined by the incidence and severity of treatment-emergent adverse events (TEAEs), in 
adult subjects with R/R DLBCL  
Study Endpoints: 
Primary Efficacy Endpoints: 
The primary endpoints for each part of the study are: 
• 
For Part 1, safety as measured by incidence of CRS and TEAEs; and 
• 
For Part 2, PFS, defined as the time from randomization to first documentation of 
progressive disease or death, whichever comes first, as assessed by the BIRC using 
Lugano 2014 criteria. 
Secondary Endpoints: 
The secondary endpoints of the study are as follows: 
1. 
Best objective response rate (ORR) and CRR, as assessed by Investigator and by the BIRC 
according to Lugano 2014 criteria 
2. 
OS, defined as the time from randomization to death from any cause 
3. 
TTF, defined as the time from randomization to discontinuation of all study treatment for any 
reason, including disease progression (as assessed by Investigator and by BIRC), treatment 
toxicity, and death, whichever comes first 
4. 
DOR, defined as the time from first response to progression or death due to any cause, 
whichever comes first, among subjects achieving an objective response (OR) and among 
subjects with complete response (CR) as assessed by BIRC 
5. 
Progression-free survival (PFS), as assessed by Investigator using Lugano 2014 criteria 
6. 
Incidence, timing, and severity of CRS as assessed by following CRS-related AEs, including 
incidence and grade of AEs and incidence of SAEs, with CRS grading defined by the American 
Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading 
7. 
Incidence, timing, and severity of neurological AEs, and incidence and grade of immune 
effector cell-associated neurotoxicity syndrome 
8. 
Dose intensity of tafasitamab and lenalidomide as measured by planned and actual dose 
administration in Part 1 
9. 
Incidence and severity of TEAEs in Part 2, with severity defined by National Cancer Institute 
(NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
Methodology:  
This is a randomized, multicenter, open-label, Phase 2 study of plamotamab combined with tafasitamab 
plus lenalidomide versus tafasitamab plus lenalidomide in adult subjects with DLBCL who have relapsed 
after or are refractory to at least 1 prior line of therapy, which must have included multi-agent 
chemoimmunotherapy inclusive of an anti-CD20 monoclonal antibody, and who are not candidates for 
ASCT, refuse ASCT, or relapse after ASCT. 


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The study will consist of 2 parts. Part 1 will enroll and evaluate subjects in 2 cohorts (A and B) for safety 
and determination of dose and dose schedule. After dosing has been determined, Part 2, with 2 arms 
(A and B), will begin. 
Part 1 is a single-arm evaluation of the safety of the triple combination of plamotamab combined with 
tafasitamab plus lenalidomide in at least 40 subjects, in 2 cohorts of a minimum of 20 subjects per cohort.  
Part 1, Cohorts 1A and 1B: 
• 
Cohort 1A treats subjects with the triple combination at plamotamab dose level – 1.  
• 
Cohort 1B enrollment starts after Cohort 1A completes enrollment. Cohort 1B treats subjects 
with the triple combination at plamotamab dose level 1.  
• 
An initial safety evaluation is conducted after all subjects in Cohorts 1A and 1B either receive 
treatment, at a minimum, through C4D28 or are discontinued prior to C4D28 due to an AE or 
progressive disease. 
Part 2 is open-label and randomized and begins after an initial safety evaluation of at least 40 subjects 
from Part 1, Cohorts 1A and 1B, after which the pharmacologically optimal dose of plamotamab 
(dose level – 1 or dose level 1) with an acceptable safety profile will be advanced to the randomized 
(Part 2) portion of the study. Prior to the initiation of Part 2, this protocol will be revised with the dosing 
regimen selected from Part 1 and will include adequate justification to support the proposed 
dose/schedule in Part 2. 
During Part 2, subjects are randomized in a 1:1 ratio to the 2 treatment arms, stratified by international 
prognostic index (IPI) risk score at baseline (3 to 5 versus 0 to 2), number of lines of prior therapy 
(1 versus ≥ 2), and primary refractory (yes versus no). Primary refractory enrollment is limited to 36 of 
200 subjects. Part 2 will enroll approximately 200 subjects. The sample size for Part 2 may be adjusted 
based on the results from Part 1. An increase in the enrollment number beyond 200 will be made by a 
protocol amendment prior to the initiation of the randomized portion. An independent data monitoring 
committee (IDMC) will review safety data during Part 2 with meetings scheduled after 50, 100, and 
150 subjects have been randomized. The primary analysis for PFS will occur after 89 disease progression 
and death events. An interim analysis for OS will also be performed at that time. 
All subjects will be treated until progression or withdrawal for other reasons and then followed for OS 
for up to 5 years. 
Of note: A central pathologist reading will confirm the diagnosis of DLBCL retrospectively after 
enrollment, using archival or recently obtained tissue. Central radiology and clinical reviewers will 
assess objective disease response according to the Lugano 2014 guidelines. Details of the central review 
will be provided in an imaging charter outlining functions and processes. In addition, 
Investigator-assessed response will be captured in the clinical database, and concordance analyses will 
be performed.  
Number of Subjects (planned):  
Part 1 will enroll at least 40 subjects into 2 cohorts (1A, 1B) with a minimum of 20 subjects per cohort. 
Part 2 will enroll approximately 200 subjects in 2 arms, A and B. The sample size for Part 2 may be 
adjusted based on the results from Part 1. Any increase in the enrollment number beyond 200 will be 
made by a protocol amendment prior to the initiation of the randomized portion. Primary refractory 
enrollment will be limited in Part 2 to 36 of 200 subjects.  
Total number of subjects planned for the entire study is approximately 240 subjects. 
Of note: Treatment assignment for Part 1 and randomization for Part 2 will be performed via third-party 
randomization and trial supply management (RTSM)/interactive response technology (IRT) system. 


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Number of Clinical Investigational Sites (planned): Up to 120 in the United States and outside the 
United States 
Inclusion Criteria: 
To be eligible for enrollment, subjects must meet all the following criteria: 
• 
Adult (age ≥ 18 years) 
• 
Able to provide written informed consent 
• 
Histologically confirmed diagnosis of DLBCL, not otherwise specified (NOS), including DLBCL 
arising from low-grade lymphoma (ie, an indolent pathology such as follicular lymphoma, or 
marginal zone lymphoma transforming into DLBCL) 
• 
Subjects must have CD20+ and CD19+ lymphoma based on flow cytometric or 
immunohistochemical evaluation of their most recent biopsy 
• 
At a minimum, archival paraffin embedded tumor tissue (preferred) or unstained slides must be 
available for retrospective cell of origin determination by a central independent pathologist. 
Subjects will be consented and may undergo an optional (recommended) biopsy to obtain fresh 
tumor tissue if a peripheral disease site can easily and safely be accessed. A fresh tumor tissue 
sample will satisfy this criterion for those subjects who do not have adequate archival tumor tissue; 
in this case, the fresh tumor biopsy becomes mandatory for participation. 
• 
Subjects must have at least 1 of the following: 
− 
Relapsed disease after standard therapeutic options, as defined below: 
 
Documented progressive disease (PD), according to the Lugano 2014 criteria 
after the most recently administered anti-lymphoma regimen  
− 
Primary refractory DLBCL, defined as follows: 
 
Documented persistent disease (less than a complete remission [PR, SD, or PD], 
according to the Lugano 2014 criteria) at the completion of first-line therapy, or 
 
PD (according to the Lugano 2014 criteria) within 3 months of completion of 
first-line therapy 
• 
Subjects must have received at least 1 prior systemic line(s) of therapy, one of which must have 
included multi-agent chemoimmunotherapy that includes an anti‑CD20 monoclonal antibody. 
DLBCL arising from low-grade lymphoma must have relapsed or refractory disease after at least 
2 prior lines of chemoimmunotherapy (at least one of which must have been directed at the DLBCL 
arising from low grade lymphoma). 
• 
At least 1 bidimensionally measurable disease site. The lesion must have a greatest transverse 
diameter of ≥ 1.5 cm and greatest perpendicular diameter of ≥ 1.0 cm at baseline. The lesion must 
have a positive finding on PET scan. 
• 
Subjects who are ineligible for or refuse hematopoietic stem cell transplantation (HSCT). Subjects 
may be considered ineligible for HSCT for any of the following reasons (Documentation of the 
reason for a subject’s ineligibility must be provided in the subject’s source data and eCRF):  
− 
Age 
− 
Performance status 
− 
Comorbidities 


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− 
Stem cell mobilization failure 
− 
Failure of prior transplant 
− 
Insufficient response to salvage chemotherapy 
− 
Subject refusal 
− 
Logistical reasons 
− 
Other potential reasons not listed above will be considered on a case-by-case basis 
• 
If eligible for chimeric antigen receptor-T cell (CAR-T) therapy, subjects must consent to 
bypassing the approved treatment with demonstrated clinical benefit 
• 
An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2  
• 
Completed vaccination for the SARS-CoV-2 virus prior to study entry is recommended   
Laboratory Values 
• 
Subjects must meet the following laboratory criteria at screening: 
− 
ANC ≥ 1.5 × 109/L (for subject with bone marrow involvement ANC ≥ 0.5 × 109/L) 
− 
Platelet count ≥ 90 × 109/L (for subjects with bone marrow involvement platelet count 
≥ 50 × 109/L) 
− 
Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN), unless secondary to Gilbert’s 
syndrome or documented liver involvement by lymphoma. Subjects with Gilbert’s 
syndrome or documented liver involvement by lymphoma may be included if their total 
bilirubin is ≤ 5 × ULN  
− 
ALT, AST, and alkaline phosphatase ≤ 3 × ULN, or < 5 × ULN in cases of documented 
liver involvement 
− 
Serum creatinine clearance must be ≥ 60 mL/minute calculated using a standard 
Cockcroft and Gault formula or Modification of Diet in Renal Disease (MDRD) 
• 
Willingness to avoid pregnancy or fathering children based on the criteria below. 
− 
Male subjects with reproductive potential must agree to take appropriate precautions to 
avoid fathering children (with at least 99% certainty) from screening through 180 days 
(6 months) after the last dose of study treatment, even if they have undergone a 
successful vasectomy, and must refrain from donating sperm during this period. 
Permitted methods that are at least 99% effective in preventing pregnancy (see section 
“Avoidance of Pregnancy”) should be communicated to the subjects and their 
understanding confirmed. 
− 
Women of childbearing potential subjects: 
 
Must commit either to abstain continuously from heterosexual sexual 
intercourse or agree to take appropriate precautions to avoid pregnancy (by 
using 2 different methods of birth control with at least 99% certainty) starting 
at least 4 weeks before taking the study treatment, while taking the study 
treatment, during breaks (dose interruptions), and for at least 8 months after 
stopping the study treatment. Permitted methods that are at least 99% effective 
in preventing pregnancy (see section “Avoidance of Pregnancy”) should be 
communicated to the subjects and their understanding confirmed. 


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 
Must have a negative serum pregnancy test at screening (within 10 to 14 days 
of Day –8) and before the first dose of lenalidomide on Day 1 (within 24 hours 
of initiating treatment with lenalidomide). 
 
Agree to ongoing pregnancy testing during the course of the study: weekly 
during the first month of study drug treatment, then monthly thereafter for 
women with regular menstrual cycles or every 2 weeks for women with 
irregular menstrual cycles (even if true abstinence is the chosen method of birth 
control) up to and including the end-of-treatment (EOT) visit. 
 
Must refrain from breastfeeding and donating oocytes during the course of study 
and for 8 months after the last dose of study treatment. 
Note: The subjects should be informed about the option of donation and cryopreservation of germ cells 
before the study, if applicable. 
• 
In the opinion of the Investigator, the subjects must: 
− 
Be able and willing to receive adequate prophylaxis and/or therapy for thromboembolic 
events  
− 
Be able to understand, give written informed consent, and comply with all study-related 
procedures, medication use, and evaluations  
− 
Not have a history of noncompliance in relation to medical regimens or be considered 
potentially unreliable and/or uncooperative 
− 
Be able to understand the reason for complying with the special conditions of the 
protocol and supplemental Summary of Pregnancy Prevention Strategies and give 
written acknowledgement of this in the informed consent form (ICF) 
Subject Exclusion Criteria: 
Subjects who meet any of the following criteria will be excluded from the study. 
Exclusionary Diagnosis 
• 
High-grade B-cell lymphoma, including those with MYC and BCL2 and/or BCL6 
rearrangements (double-hit or triple-hit lymphoma) and high grade B-cell lymphoma NOS, 
according to WHO 2016 criteria. 
• 
Any other histological type of lymphoma, including primary mediastinal (thymic) large B-cell 
(PMBL) or Burkitt lymphoma 
• 
A prior diagnosis of chronic lymphocytic leukemia (CLL) (Richter’s Transformation)  
• 
Primary central nervous system (CNS) lymphoma 
• 
A history of secondary CNS involvement by DLBCL are ineligible, unless treated into remission 
Exclusionary Previous and Current Treatment 
• 
Subjects who have previously received treatment with an anti-CD20 × anti-CD3 bsAb 
• 
Subjects who have been previously treated with tafasitamab 
• 
Anti-CD20 therapy (eg, rituximab) within 21 days prior to Day –8, to minimize competition with 
plamotamab binding to CD20 on DLBCL target cells 
• 
Subjects who have, within 14 days prior to Day –8: 


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− 
Chemotherapy, radiotherapy, or other lymphoma-specific therapy not including 
anti-CD20 therapy. Note: palliative local radiotherapy is permitted; however, these 
lesions may not serve as target lesions. 
− 
Small molecule or investigational anticancer agents within 6 elimination half-lives 
prior to Day –8 
− 
Undergone major surgery not related to lymphoma complications or suffered from 
significant traumatic injury 
− 
Received live vaccines within 30 days of Day –8 
− 
Required systemic anti-infective therapy for active, intercurrent infections  
• 
Subjects who have had the following prior therapies or treatments: 
− 
Have, in the opinion of the Investigator, not recovered sufficiently from the adverse 
effects of prior therapy(ies) 
− 
Were previously treated with CD19-targeted therapy, including CAR-T, unless current 
biopsy (after last therapy) is CD19+  
− 
Have known intolerance to CD20 monoclonal antibody therapy 
− 
Have a history of hypersensitivity to compounds of similar biological or chemical 
composition to tafasitamab, immunomodulatory imide drugs (IMiDs), and/or the 
excipients contained in the study drug formulations 
− 
Have undergone autologous stem cell transplantation (ASCT) ≤ 1 month prior to 
signing the informed consent form. Subjects who have a more distant history of ASCT 
must exhibit full hematologic recovery before enrollment into the study.  
− 
Have undergone previous allogenic stem cell transplantation 
− 
Have a history of deep venous thrombosis/embolism, threatening thromboembolism, 
or known thrombophilia, or are at high risk for a thromboembolic event in the opinion 
of the Investigator, and who are not willing/able to take venous thromboembolic event 
prophylaxis during the entire treatment period 
− 
Concurrently use other anticancer or experimental treatments 
Exclusionary Subject’s Medical History 
• 
Prior history of malignancies other than DLBCL, unless the subject has been free of the disease 
for ≥ 3 years prior to screening. Exceptions to the ≥ 3-year time limit include a history of the 
following: 
− 
Basal cell carcinoma of the skin 
− 
Squamous cell carcinoma of the skin 
− 
Carcinoma in situ of the cervix 
− 
Carcinoma in situ of the breast 
− 
Carcinoma in situ of the bladder 
− 
Tumor/Node/Metastasis [TNM] stage of T1a or T1b prostate cancer 
• 
Subjects with the following medical history: 


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− 
Known active hepatitis infection: 
 
Positive test for HBsAg or HBcAb (a subject whose HBsAg or HBcAb is 
positive may be enrolled if an HBV DNA test is negative and either the subject 
is treated with potent antiviral therapy or is re-tested for HBV DNA every 
month) 
 
Positive test for HCV antibodies (a subject whose HCV antibody test is positive 
may be enrolled if quantitative HCV polymerase chain reaction test is negative) 
− 
Known seropositivity for or history of active viral infection with HIV 
− 
Positive SARS-CoV-2 nucleic acid or antigen test 
− 
History or evidence of clinically significant cardiovascular, CNS, and/or other 
systemic disease that would in the Investigator’s opinion preclude participation in the 
study or compromise the subject’s ability to give informed consent 
− 
History of solid organ transplantation 
− 
History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase 
deficiency, or glucose-galactose malabsorption 
− 
Gastrointestinal abnormalities that would interfere with the ability to take or absorb 
oral medication 
Dose, Route of Administration, and Treatment Regimen 
Study Drugs: 
Three study drugs are in use during this study: 1) Xencor study drug product DP /investigational 
medicinal product (IMP), plamotamab, and 2 other drugs previously approved by the FDA, 
2) tafasitamab -cxix and 3) lenalidomide. The drugs will be used in triple combination, plamotamab (+) 
tafasitamab (+) lenalidomide. 
1) Plamotamab (XmAb13676) is a humanized bsAb that binds both CD3 and the tumor antigen 
CD20 in order to recruit cytotoxic T cells to kill CD20 positive tumor cells. IV Solution 
Stabilizer (IVSS) is a concentrated form of the plamotamab (XmAb13676) buffer that also 
minimizes protein binding to the administration equipment when plamotamab is administered at 
lower concentrations. 
2) Tafasitamab (tafasitamab-cxix) is a CD19-directed cytolytic antibody indicated for use in the 
US in combination with lenalidomide for the treatment of adult patients with R/R DLBCL not 
otherwise specified (NOS), including DLBCL arising from low-grade lymphoma, and who are 
not eligible for ASCT. 
3) Lenalidomide, a thalidomide analogue, is an immunomodulatory agent (IMiD®) with 
antiangiogenic and antineoplastic properties. It is indicated for the treatment of adult patients 
with multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma, follicular 
lymphoma, and marginal zone lymphoma. 
Study Drug Dose Administration and Regimen: 
Plamotamab (XmAb13676) – Subjects in Part 1 and those randomized to Arm A in Part 2 will be 
administered plamotamab IV 
 
In Cycle 1, plamotamab will be administered once every 7 days (± 1 day) for 4 doses; beginning with 
Cycle 2, plamotamab will be administered every 2 weeks (Q2W). Doses of plamotamab anticipated for 
use during the study via IV infusions include: 0.8 mg, 2 mg, and 20 mg. Refer to dosing table below. 


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Tafasitamab and plamotamab must not be administered simultaneously. On days when both tafasitamab 
and plamotamab are given, the tafasitamab should be given first followed by plamotamab. It is 
recommended that the infusions are separated by at least 2 hours. 
 
Part 1, Cohort 1A and 1B, Plamotamab Dosing Regimen 
Cohort 
Dose 
Level 
Cycle 1  
Day 1 
(Priming  
Dose) 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 1 
Day 22 
Cycle 2 
 Day 1 
Cycle 2 
Days 1, 
8, 15, 
and 22 
Cycle 3 and 
Subsequent 
Q2W Dosing 
1A 
–1 
0.8 mg 
2 mg 
20 mg 
20 mg 
20 mg 
20 mg 
20 mg 
1B 
1 
0.8 mg 
2 mg 
20 mg 
35 mg 
50 mg 
50 mg 
50 mg 
Q2W= every 2 weeks.  
Tafasitamab: All subjects will receive tafasitamab. Priming doses will be administered on Days –8 and 
–4 of a 1-week run-in period. During the first 3 cycles of the study, tafasitamab will be infused on Day 1, 
Day 8, Day 15, and Day 22 of each cycle. Thereafter, tafasitamab will be administered on a biweekly 
(every 14 days) basis, with infusions on Days 1 and 15 of each 28-day cycle until disease progression, 
unacceptable toxicity, or discontinuation for any other reason, whichever comes first. Refer to dosing 
table below. Tafasitamab and plamotamab must not be administered simultaneously. On days when both 
tafasitamab and plamotamab are given, the tafasitamab should be given first followed by plamotamab. 
It is recommended that the infusions are separated by at least 2 hours. 
Tafasitamab Dosing Regimen 
Day –8 and –4 
(Priming Dose) 
Cycle 1 
Days 1, 8, 15, 22 
Cycle 2 
Days 1, 8, 15, 22 
Cycle 3 
Days 1, 8, 15, 22 
Cycle 4 
and Subsequent 
Q2W Dosing 
12 mg/kg 
12 mg/kg 
12 mg/kg 
12 mg/kg 
12 mg/kg 
Q2W = every two weeks.  
Lenalidomide: All subjects will receive lenalidomide and self-administer a starting dose of 25 mg oral 
lenalidomide daily on Days 1 to 21 of each cycle. No more than 21 doses of lenalidomide will be 
dispensed per cycle; lenalidomide can be given for only up to a total of 12 cycles. Investigators will 
follow the package insert or SmPC for recommended medications for venous thromboembolic event 
prophylaxis and dosing modifications. It is recommended that subjects take oral (PO) lenalidomide in 
the evening about the same time each day, with or without food. Subjects are to swallow lenalidomide 
capsules whole with water. When ingesting, the capsules should not be opened, broken, or chewed. 
Treatment with lenalidomide may be modified in a deescalating fashion or discontinued based upon 
clinical and laboratory findings. Detailed dose modification guidelines to manage hematologic and/or 
other toxicities are provided in the relevant sections of the protocol. 
Study Drug Use in Part 1: Single-arm, Two-cohort, Safety Run-in 
This first part of the study is designed to establish a dose of plamotamab with an acceptable safety profile 
when given in combination with the other 2 drugs. 
• 
Part 1, Cohort 1A treats subjects with the triple combination at plamotamab dose level –1.  
• 
Part 1, Cohort 1B commences enrollment after Cohort 1A completes enrollment. Cohort 1B treats 
subjects with the triple combination at plamotamab dose level 1.  


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• 
An initial safety evaluation is conducted after all subjects in Cohorts 1A and 1B either receive 
treatment, at a minimum, through C4D28 or are discontinued prior to C4D28 due to an AE or 
progressive disease. 
Study Drug Use in Part 2: Two-Arm, Open-label, Randomized, Efficacy and Safety 
After the initial safety evaluation of both Cohorts 1A and 1B, the pharmacologically optimal dose of 
plamotamab with an acceptable safety profile (dose level -1 or dose level 1) will be advanced to the 
randomized, Part 2, of the study. Subjects are randomized in a 1:1 ratio to 2 treatment arms, Arm A and 
Arm B. The subjects are stratified to one arm or the other by using 3 criteria: international prognostic 
index (IPI) risk score at baseline (3 to 5 versus 0 to 2), number of lines of prior therapy (1 versus ≥ 2), 
and primary refractory (yes versus no). 
• 
Part 2: Arm A: 
Treatment consists of the combination of plamotamab, tafasitamab, and lenalidomide 
administered in 28-day cycles, with 2 priming doses of tafasitamab before Cycle 1. Plamotamab 
and tafasitamab can be administered until disease progression, unacceptable toxicity, or 
discontinuation for any other reason, whichever comes first. Lenalidomide can be given for up 
to a total of 12 cycles.  
• 
Part 2: Arm B: 
Treatment consists of the combination of tafasitamab and lenalidomide administered in 28-day 
cycles with 2 priming doses of tafasitamab before Cycle 1. Tafasitamab can be administered 
until disease progression, unacceptable toxicity, or discontinuation for any other reason, 
whichever comes first. Lenalidomide can be given for up to a total of 12 cycles. 
Duration of Treatment: Plamotamab and tafasitamab can be administered until disease progression, 
unacceptable toxicity, or discontinuation for any other reason, whichever comes first; however, 
lenalidomide can be given for only up to a total of 12 cycles. 
Primary Endpoint Assessment Criteria: 
• 
For Part 1, safety as measured by incidence of CRS and TEAEs 
• 
TEAEs are defined as events with onset dates on or after the start of study treatment or 
events that are present before the first infusion of study treatment and subsequently worsen 
in severity. 
• 
AE-related endpoints include: 
o Treatment-emergent AEs 
o Treatment-emergent SAEs 
o Adverse reactions 
o Serious adverse reactions 
o Treatment-emergent AEs by severity, as defined by NCI-CTCAE Version 5.0 
o Treatment-emergent AEs resulting in the permanent discontinuation of plamotamab 
o Other safety variables include vital signs, PE findings, ECGs, laboratory values, medical 
history, and concomitant medications, which will be summarized by Part and by Arm. 
• 
For Part 2, PFS, defined as the time from randomization to first documentation of progressive 
disease or death, whichever comes first, as assessed by the BIRC using Lugano 2014 criteria. 


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The following secondary endpoints will be tested sequentially in the following order, if the test for the 
primary endpoint is positive: 
• 
ORR by BIRC per Lugano 2014 criteria 
• 
OS 
• 
TTF 
Secondary Endpoint Assessment Criteria: 
• 
Best ORR and CRR, as assessed by Investigator and by the BIRC according to Lugano 2014 
criteria 
• 
OS, defined as the time from randomization to death from any cause 
• 
TTF, defined as the time from randomization to discontinuation of all study treatment for any 
reason, including disease progression (as assessed by Investigator and by BIRC), treatment 
toxicity, and death, whichever comes first 
• 
DOR, defined as the time from first response to progression or death due to any cause, whichever 
comes first, among subjects achieving an objective response (OR) and among subjects with CR 
as assessed by BIRC 
• 
PFS, as assessed by Investigator using Lugano 2014 criteria 
• 
Incidence, timing, and severity of CRS as assessed by following CRS-related AEs, including 
incidence and grade of AEs and incidence of SAEs, with CRS grading defined by the ASTCT 
Consensus Grading 
• 
Incidence, timing, and severity of neurological AEs, and incidence and grade of Immune 
Effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
• 
Dose intensity of tafasitamab and lenalidomide as measured by planned and actual dose 
administration in Part 1 
• 
Incidence and severity of TEAEs in Part 2, with severity defined by the National Cancer Institute 
(NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
Statistical Methods and Data Analysis: 
Efficacy Analysis  
The Randomized (intent-to-treat) Analysis Set will be used for primary and secondary efficacy analyses, 
unless otherwise noted. 
Efficacy analysis will utilize hazard ratio based on Cox regression model stratified by IPI risk score, 
number of lines of prior therapy, and primary refractory. KM estimates for median, Q1 and Q3. Stratified 
log-rank test for treatment effect. 
PFS as assessed by the BIRC is the primary endpoint for Part 2 of this study. For determination of the 
sample size, it is assumed that triple combination treatment could improve the median PFS from 
12 months (under treatment with tafasitamab + lenalidomide to 23.5 months under the triple combination 
treatment (plamotamab + tafasitamab + lenalidomide), corresponding to a hazard ratio (HR) of 0.51 with 
all randomized subjects (it is estimated that 90% of subjects will be central pathologically confirmed as 
DLBCL). 


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Safety Analysis  
Safety Analysis will be performed with the Safety Analysis Set. All AE-related endpoints will be 
summarized by SOC and preferred term. At each level of summation, subjects will be counted once, 
under the greatest severity and strongest study-drug relationship.  
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA). 
The verbatim term recorded by the Investigator will be mapped to System Organ Class (SOC) and 
Preferred Term using MedDRA (MedDRA). Additional analysis will be performed for AEs of CRS. 
These will include analyses of time to onset, duration, severity, and associations with laboratory cytokine 
measurements and missed or delayed doses (ie, CRS may be associated with longer intervals between 
doses). Graphical summaries will illustrate the timing relative to dosing, the severity of CRS events and 
cytokine levels. 
Vital sign results (blood pressure, heart rate, respirations, temperature, and blood oxygen saturation by 
continuous pulse oximetry) will be summarized descriptively for each scheduled time point. 
The hematology, chemistry, and other laboratory values and change from baseline values will be 
summarized descriptively for each scheduled assessment time point and grouped by dosing cohort. 
The toxicity grades for laboratory tests will be based on NCI-CTCAE Version 5.0 criteria. 
The extent of exposure to plamotamab and tafasitamab will be summarized based on the number of 
infusions administered and the number of treatment cycles completed, as well as the total dose received. 
Lenalidomide exposure will be summarized similarly, based on number of doses taken.  
Additional summaries of drug exposure will be provided based on the PK parameters described in the 
section “Pharmacokinetic Analysis.”  
Pharmacokinetic Analysis 
Serum concentrations of plamotamab and tafasitamab will be listed, summarized in tabular form by 
dosing visit (including, mean, median, range, and 25th and 75th percentiles). Details of additional analyses 
will be provided in a PK analysis plan.  
Immunogenicity Analysis 
The incidence and titer of anti-plamotamab antibodies and anti-tafasitamab antibodies will be reported 
by sample collection time point and treatment arm, as applicable. 
Biomarker Analyses 
Biomarkers will be analyzed at the central laboratory per instruction in the Laboratory Manual and 
reported per the descriptions in the SAP. Exploratory endpoints will not be reported in the clinical study 
report. Serum cytokine levels will be reported using descriptive statistics and tabular display. 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................ 2 
INVESTIGATOR PROTOCOL SIGNATURE PAGE ................................................................ 3 
LIST OF STUDY STAFF/EMERGENCY CONTACTS ............................................................. 4 
SYNOPSIS ................................................................................................................................. 5 
TABLE OF CONTENTS .......................................................................................................... 17 
LIST OF TABLES .................................................................................................................... 22 
LIST OF FIGURES .................................................................................................................. 23 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 24 
2. 
INTRODUCTION .................................................................................................. 28 
2.1. 
Diffuse Large B-cell Lymphoma ............................................................................ 28 
2.2. 
CD20 as a Therapeutic Target ................................................................................. 28 
2.3. 
Treatment Descriptions ........................................................................................... 29 
2.3.1. 
Plamotamab (XmAb13676) Product Description .................................................... 29 
2.3.2. 
Tafasitamab Product Description ............................................................................ 29 
2.3.3. 
Lenalidomide Product Description .......................................................................... 30 
2.4. 
Human Experience with Plamotamab ..................................................................... 30 
2.4.1. 
Non-Hodgkin’s Lymphoma: Escalation Cohorts ..................................................... 30 
2.4.2. 
Non-Hodgkin’s Lymphoma: Flat-Dosing Cohorts ................................................... 30 
2.4.3. 
Recommended Phase 2 Dose .................................................................................. 33 
2.4.4. 
Benefit/Risk Assessment ........................................................................................ 34 
3. 
TRIAL OBJECTIVES AND PURPOSE ................................................................. 35 
3.1. 
Primary Objectives ................................................................................................. 35 
3.2. 
Secondary Objectives ............................................................................................. 35 
3.3. 
Exploratory Objectives ........................................................................................... 36 
3.4. 
Purpose of Study..................................................................................................... 36 
4. 
INVESTIGATIONAL PLAN ................................................................................. 37 
4.1. 
Overall Study Design .............................................................................................. 37 
4.1.1. 
Part 1: Single-Arm, Safety Run-In .......................................................................... 37 
4.1.2. 
Part 2: Open-Label Randomized ............................................................................. 38 
4.2. 
Endpoints ............................................................................................................... 38 
4.2.1. 
Primary Endpoints .................................................................................................. 38 


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4.2.2. 
Secondary Endpoints .............................................................................................. 38 
4.2.3. 
Exploratory Endpoints ............................................................................................ 39 
4.3. 
Treatment Regimens ............................................................................................... 40 
4.3.1. 
Part 1: Single-Arm, Safety Run-In .......................................................................... 40 
4.3.2. 
Part 2: Open-Label, Randomized ............................................................................ 40 
4.4. 
Number of Subjects ................................................................................................ 42 
4.5. 
Treatment Assignment ............................................................................................ 42 
4.5.1. 
Part 1: Single-Arm Safety Run-In ........................................................................... 42 
4.5.2. 
Part 2: Open-Label Randomized ............................................................................. 42 
4.5.3. 
Subject Screening and Enrollment Numbers ........................................................... 42 
4.6. 
Management of Toxicities ...................................................................................... 43 
4.6.1. 
Cytokine Release Syndrome ................................................................................... 43 
4.6.1.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and 
Lenalidomide) ........................................................................................................ 44 
4.6.1.2. 
Part 2, Arm B (Tafasitamab and Lenalidomide) ...................................................... 44 
4.6.1.3. 
Cytokine Release Syndrome Versus Allergic/ Hypersensitivity/ Infusion-
related Reactions .................................................................................................... 45 
4.6.1.4. 
Management of Cytokine Release Syndrome .......................................................... 45 
4.6.1.5. 
Fluid Management .................................................................................................. 45 
4.6.1.6. 
Cytokine Release Syndrome Treatment Guidelines by ASTCT CRS 
Consensus Grade .................................................................................................... 46 
4.6.1.7. 
Neurotoxicity .......................................................................................................... 48 
4.6.2. 
Allergic/Hypersensitivity/Infusion-related Reactions .............................................. 51 
4.6.2.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and 
Lenalidomide) ........................................................................................................ 52 
4.6.2.2. 
Part 2, Arm B (Tafasitamab and Lenalidomide) ...................................................... 52 
4.6.3. 
Hematologic Toxicities ........................................................................................... 52 
4.6.3.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and 
Lenalidomide) ........................................................................................................ 53 
4.6.3.2. 
Part 2, Arm B (Tafasitamab and Lenalidomide) ...................................................... 53 
4.6.4. 
Tumor Lysis Syndrome .......................................................................................... 53 
4.6.4.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and 
Lenalidomide) ........................................................................................................ 53 
4.6.4.2. 
Prophylaxis, Monitoring, and Treatment of Tumor Lysis Syndrome ....................... 53 


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4.6.4.3. 
Part 2, Arm B (Tafasitamab and Lenalidomide) ...................................................... 54 
4.7. 
Dose Modification Guidelines ................................................................................ 54 
4.8. 
Criteria for Study Modifications ............................................................................. 58 
4.9. 
Independent Committees ........................................................................................ 58 
4.9.1. 
Independent Data Monitoring Committee ............................................................... 58 
4.9.2. 
Blinded Independent Review Committee ................................................................ 59 
4.9.3. 
Independent Confirmation of Histological Diagnosis .............................................. 59 
5. 
STUDY ASSESSMENTS....................................................................................... 59 
6. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................ 68 
6.1. 
Subject Inclusion Criteria ....................................................................................... 68 
6.2. 
Subject Exclusion Criteria ...................................................................................... 71 
6.3. 
Subject Withdrawal Criteria .................................................................................... 73 
6.3.1. 
Criteria for Removal from Study Treatment ............................................................ 73 
6.3.2. 
Criteria for Removal from Study ............................................................................. 74 
6.4. 
Avoidance of Pregnancy ......................................................................................... 74 
7. 
TREATMENT OF SUBJECTS .............................................................................. 76 
7.1. 
Dosing Schedule and Premedications ...................................................................... 76 
7.1.1. 
Plamotamab Dosing Schedule and Premedications ................................................. 76 
7.1.2. 
Tafasitamab Dosing Scheme and Premedications .................................................... 77 
7.1.3. 
Lenalidomide Dosing Scheme ................................................................................ 79 
7.2. 
Concomitant Medications ....................................................................................... 79 
7.3. 
Treatment Compliance ............................................................................................ 80 
7.4. 
Treatment Assignment, Randomization, and Blinding............................................. 80 
7.5. 
Pretreatment Evaluations ........................................................................................ 81 
7.5.1. 
Screening Evaluations (Up to Day –35) .................................................................. 81 
7.5.2. 
Day –8, Day –4, and Day –1 ................................................................................... 83 
7.6. 
Treatment Evaluations ............................................................................................ 84 
7.6.1. 
Treatment Cycles .................................................................................................... 84 
7.6.2. 
End of Treatment Visit ........................................................................................... 87 
7.6.3. 
Ninety (90) Days After the Last Dose of Study Medication..................................... 87 
7.6.4. 
Long-Term Follow-Up Period ................................................................................ 87 
7.7. 
Study Drug ............................................................................................................. 88 
7.7.1. 
Plamotamab (XmAb13676) .................................................................................... 88 


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7.7.2. 
Tafasitamab-cxix (Tafasitamab).............................................................................. 88 
7.7.3. 
Lenalidomide .......................................................................................................... 88 
7.8. 
Study Drug Storage ................................................................................................ 88 
7.8.1. 
Plamotamab ............................................................................................................ 88 
7.8.2. 
Tafasitamab ............................................................................................................ 88 
7.8.3. 
Lenalidomide .......................................................................................................... 89 
7.9. 
Study Drug Preparation .......................................................................................... 89 
7.9.1. 
Plamotamab ............................................................................................................ 89 
7.9.2. 
Tafasitamab ............................................................................................................ 89 
7.9.3. 
Lenalidomide .......................................................................................................... 89 
7.10. 
Study Drug Administration ..................................................................................... 89 
7.10.1. 
Plamotamab ............................................................................................................ 89 
7.10.2. 
Tafasitamab ............................................................................................................ 90 
7.10.3. 
Lenalidomide .......................................................................................................... 90 
7.11. 
Study Drug Accountability, Handling, and Disposal ............................................... 90 
8. 
PHARMACOKINETIC, PHARMACODYNAMIC, AND BIOMARKER 
ASSESSMENTS .................................................................................................... 91 
8.1. 
Serum Assessments for Pharmacokinetic Analyses, Anti-Drug Antibodies, 
Cytokines, and Rituximab Levels............................................................................ 91 
8.2. 
Pharmacodynamics and Biomarker Assessments .................................................... 91 
8.2.1. 
Peripheral Blood Assessments ................................................................................ 91 
8.2.2. 
Tumor Biopsies ...................................................................................................... 92 
8.2.2.1. 
Archival Tissue....................................................................................................... 92 
8.2.2.2. 
Baseline and On-Treatment Tumor Biopsies ........................................................... 92 
9. 
ASSESSMENT OF EFFICACY ............................................................................. 93 
9.1. 
Efficacy Assessments ............................................................................................. 93 
10. 
ASSESSMENT OF SAFETY ................................................................................. 97 
10.1. 
Safety Parameters ................................................................................................... 97 
10.1.1. 
Treatment/Reporting of Overdose or Medication Errors .......................................... 97 
10.2. 
Adverse Events and Serious Adverse Events........................................................... 98 
10.2.1. 
Definition of Adverse Events .................................................................................. 98 
10.2.2. 
Definition of Serious Adverse Events ..................................................................... 98 


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10.2.3. 
Adverse Event Monitoring, Recording, Reporting, Follow-up, and 
Assessments ........................................................................................................... 99 
10.2.3.1. 
AE Severity/Intensity Grading .............................................................................. 101 
10.2.3.2. 
Causality .............................................................................................................. 102 
10.2.3.3. 
Action Taken ........................................................................................................ 103 
10.2.3.4. 
Outcome ............................................................................................................... 104 
10.3. 
Evaluation of Subjects Who Experience an Adverse Event during the Study ......... 104 
10.4. 
Pregnancy and Breastfeeding ................................................................................ 104 
10.4.1. 
Reporting of Pregnancy ........................................................................................ 104 
10.4.2. 
Breastfeeding ........................................................................................................ 105 
10.4.3. 
Embryo-Fetal Toxicity from Lenalidomide WARNINGS AND 
PRECAUTIONS Section ...................................................................................... 105 
11. 
STATISTICS ........................................................................................................ 107 
11.1. 
General ................................................................................................................. 107 
11.2. 
Primary Objective Estimand ................................................................................. 107 
11.3. 
Sample Size and Power ......................................................................................... 108 
11.3.1. 
Progression-Free Survival ..................................................................................... 108 
11.3.2. 
Overall Survival ................................................................................................... 109 
11.3.3. 
Objective Response Rate ...................................................................................... 110 
11.3.4. 
Statistical Testing Sequence .................................................................................. 110 
11.4. 
Independent Data Monitoring Committee ............................................................. 111 
11.5. 
Analysis Sets ........................................................................................................ 111 
11.6. 
Key Subgroups ..................................................................................................... 111 
11.7. 
Subject Characteristics and Disposition ................................................................ 112 
11.8. 
Safety Analysis ..................................................................................................... 112 
11.9. 
Efficacy Analysis.................................................................................................. 113 
11.10. 
Pharmacokinetic Analysis ..................................................................................... 115 
11.11. 
Immunogenicity Assays ........................................................................................ 115 
12. 
STUDY ADMINISTRATIVE STRUCTURE ....................................................... 115 
12.1. 
Study Monitoring.................................................................................................. 115 
12.2. 
Deviation from Protocol ....................................................................................... 116 
12.3. 
Institutional Review Board/Independent Ethics Committee ................................... 116 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................... 117 


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14. 
ETHICS................................................................................................................ 117 
14.1. 
Ethics Review ....................................................................................................... 117 
14.2. 
Ethical Conduct of the Study ................................................................................ 117 
14.3. 
Written Informed Consent .................................................................................... 117 
15. 
DATA HANDLING AND RECORDKEEPING ................................................... 118 
15.1. 
Subject Confidentiality ......................................................................................... 118 
15.2. 
Inspection of Records ........................................................................................... 118 
15.3. 
Retention of Records ............................................................................................ 119 
16. 
PUBLICATION POLICY..................................................................................... 119 
17. 
REFERENCES ..................................................................................................... 120 
18. 
APPENDICES ...................................................................................................... 123 
APPENDIX A. ECOG PERFORMANCE STATUS SCALE ................................................ 124 
APPENDIX B. SUMMARY OF CHANGES FROM PROTOCOL VERSION 1.0, 
DATED 15 DECEMBER 2021, TO VERSION 2.0, DATED 08 MARCH 
2022  .................................................................................................................... 125 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ........................................................................ 24 
Table 2: 
Overall Response Rate, Complete Response and Disease Control Rate for 
Overall Population and by Top Dose Level in Subjects with NHL from 
Study XmAb13676-01 ............................................................................................ 32 
Table 3:  
Cohort 1A and Cohort 1B Plamotamab Dosing Regimen ........................................ 38 
Table 4: 
American Society for Transplantation and Cellular Therapy Cytokine 
Release Syndrome Consensus Grading ................................................................... 44 
Table 5: 
Immune Effector Cell-Associated Encephalopathy Scoring .................................... 49 
Table 6: 
American Society for Transplantation and Cellular Therapy Immune 
Effector Cell-Associated Neurotoxicity Syndrome Consensus Toxicity 
Grading for Adults .................................................................................................. 50 
Table 7: 
Adverse Events of Neutropenia and Thrombocytopenia with 
Tafasitamab/Lenalidomide and Plamotamab (All Grades) ....................................... 52 
Table 8: 
Dose Modifications for Select Toxicities ................................................................ 55 
Table 9: 
Schedule of Assessments ........................................................................................ 60 
Table 10: Sampling for Plamotamab Anti-Drug Antibodies, Cytokines, PK, and ECGs, 
and Rituximab Levels ............................................................................................. 66 


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Table 11: Sampling for Tafasitamab Anti-Drug Antibodies and Pharmacokinetics ................. 67 
Table 12: Cohorts 1A and 1B Plamotamab Dosing Regimen .................................................. 77 
Table 13: Premedications for Plamotamab .............................................................................. 77 
Table 14: Tafasitamab Dosing Scheme ................................................................................... 78 
Table 15: Premedications for Tafasitamab .............................................................................. 78 
Table 16: Assessment of Response ......................................................................................... 94 
Table 17: Investigational Site Recording/Reporting of Adverse Events ................................ 100 
Table 18: Severity Grading Scale ......................................................................................... 102 
Table 19: Causality Assessment Categories .......................................................................... 103 
Table 20: Primary Objective Estimand ................................................................................. 108 
Table 21: Efficacy Boundaries and Properties for Progression-Free Survival Analyses ......... 109 
Table 22: Summary of Interim and Final Analyses Strategy ................................................. 109 
Table 23: Efficacy Boundaries and Properties for Overall Survival Analyses ....................... 110 
 
LIST OF FIGURES 
Figure 1: 
Log Scale Simulated Median Concentrations and 90% Prediction Intervals 
for Flat Dose and Schedule. .................................................................................... 34 
Figure 2: 
Dosing Schema ....................................................................................................... 41 
 


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviations and Specialist Terms 
Explanation 
ABC 
activated B cell 
ADA 
anti-drug antibodies 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
APTT 
activated partial thromboplastin time 
ASCT 
autologous stem-cell transplantation 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy 
β-hCG 
beta human chorionic gonadotropin 
BIRC 
Blinded Independent Review Committee 
bsAb 
bispecific antibody 
CAR-T 
chimeric antigen receptor-modified T-cell therapy 
CBC 
complete blood count 
CI 
confidence interval 
CLL 
chronic lymphocytic leukemia 
COO 
cell of origin assay 
CNS 
central nervous system 
CR 
complete response 
CRS 
cytokine release syndrome 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
Ctrough 
predose or trough concentration 
DCF 
Data Clarification Form 
DICOM 
Digital Imaging and Communications in Medicine 
DLBCL 
diffuse large cell B-cell lymphoma 
DOR 
duration of response 
DP 
drug product 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 


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Abbreviations and Specialist Terms 
Explanation 
EDC 
electronic data capture 
EOI 
end of infusion 
EOS 
end-of-study 
EOT 
end-of-treatment 
FcγR 
Fc gamma receptor 
FDA 
US Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FISH 
fluorescence in situ hybridization  
FSH 
follicle-stimulating hormone 
GCB 
germinal center B-cell 
GCP 
good clinical practice 
GGT 
serum gamma-glutamyl transferase 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
 
hepatitis B virus 
HCV 
hepatitis C virus 
HEENT 
head, eyes, ears, neck, and throat 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HSCT 
hematopoietic stem cell transplantation 
ICANS 
immune effector cell-associated neurotoxicity syndrome 
ICE 
Immune effector cell-associated encephalopathy 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IDMC 
independent data monitoring committee 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IgE 
immunoglobulin E 
IL-6 
interleukin-6 
IMiD 
immunomodulatory agent 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
INR 
international normalized ratio 
IPI 
international prognostic index 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 


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Abbreviations and Specialist Terms 
Explanation 
IV 
intravenous(ly) 
IVSS 
Intravenous Solution Stabilizer 
LEN 
Lenalidomide 
mAb 
monoclonal antibody 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRD 
minimal residual disease 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
NK 
natural killer 
NOS 
not otherwise specified 
OR 
objective response 
ORR 
objective response rate 
OS 
overall survival 
OUS 
outside United States 
PBML 
primary mediastinal large B-cell 
PD 
progressive disease 
PE 
physical exam 
PET/CT 
combined positron emission tomography with computerized 
tomography 
PFS 
progression-free survival 
PI 
package insert 
PK 
pharmacokinetics 
PO 
by mouth 
PR 
partial response  
PRR 
partial response rate 
PT 
prothrombin time 
Q2W 
every 2 weeks 
RBC 
red blood cell 
RDW 
red blood cell distribution width 
RP2D 
recommended Phase 2 dose 
R/R 
relapsed or refractory 
RTSM 
randomization and trial supply management 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 of the genus 
betacoronavirus 
scFv 
single-chain variable fragment (immunoglobulin fusion protein) 


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Abbreviations and Specialist Terms 
Explanation 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBNK 
T-, B-, and NK cells 
TEAE 
treatment-emergent adverse event 
TLS 
tumor lysis syndrome 
TTF 
time to treatment failure 
ULN 
upper limit of normal 
WBC 
white blood cell 
w/v 
weight-to-volume 


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2. 
INTRODUCTION 
2.1. 
Diffuse Large B-cell Lymphoma  
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin’s 
lymphoma (NHL). Since the introduction of the anti-CD20 antibody rituximab, approximately 
50% to 70% of patients may achieve cure with initial standard-of-care immunochemotherapy. 
For patients who are refractory to or relapse after frontline therapy, prognosis is poor. Salvage 
chemotherapy followed by high-dose chemotherapy and autologous stem-cell transplantation 
(ASCT) has some benefit in this setting and is associated with significant toxicities. Moreover, 
most patients are ineligible for this approach and have fewer treatment options. Recent therapeutic 
advances, such as chimeric antigen receptor T-cell therapy (CAR-T) and tafasitamab (US: 
Monjuvi®; EU: Minjuvi®) plus lenalidomide (Revlimid®), have potential to improve patient 
outcomes. Despite these advances, a significant need remains to provide effective treatment 
options for patients with relapsed or refractory (R/R) DLBCL who are ineligible for ASCT 
(Coiffier, 2016).  
2.2. 
CD20 as a Therapeutic Target 
The introduction of the anti-CD20 monoclonal antibody (mAb) rituximab for B-cell lymphoma in 
the late 1990s inaugurated a new era of cancer therapy (Maloney, 1994). In principle, mAbs are 
an amalgamation of 2 desirable characteristics of an anticancer drug, and rituximab exemplifies 
these qualities. First, rituximab is a therapy targeted to the tumor cell and carries fewer side effects 
than chemotherapy. Second, with its ability to directly stimulate the host immune system, it can 
potentially induce stronger, more long-lasting anti-tumor effects that bypass immunosuppressive 
factors. CD20 is an ideal target for monoclonal antibody therapy, since most B-cell neoplasms 
consistently express it, but normal B lineage stem cells and plasma cells do not allow B-cell 
repopulation and immunoglobulin production to continue, at least over several years (Stashenko, 
1980). Rituximab (Rituxan®, Truxima®, MabThera®) and other similar therapeutic anti-CD20 
mAbs such as iodine-131 tositumomab (Bexxar®), ofatumumab (Arzerra® and Kesimpta®), and 
obinutuzumab (Gazyva®) have been largely effective in realizing these aims, with impressive 
efficacy coupled with modest toxicity (Illidge, 2015; Robak, 2016).  
However, there are limitations to these gains. Approximately 30% of cases of B-cell NHL either 
do not respond to rituximab or relapse after initially responding, and eventually become refractory 
to rituximab (Stolz, 2009). Also, rituximab has good activity against tumor masses and circulating 
tumor cells but has significantly less ability to clear tumor from bone marrow and lymph nodes 
(Mraz, 2011). Clearly, the ability of rituximab to strongly activate immune killing of tumor cells 
needs to be improved, especially in certain compartments of the body, while maintaining its 
tolerable side-effect profile. 
Resistance to anti-CD20 monoclonal antibody therapy also remains a problem, although the 
mechanism of this resistance is still somewhat unclear. Recently, new anti-CD20s have entered 
the clinic to address this issue. Ofatumumab (type I) and obinutuzumab (type II) were both 
approved by the United States Food and Drug Administration (FDA) in 2009 and 2013, 


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respectively, for the treatment of chronic lymphocytic leukemia (CLL; Lee [B], 2014; Lemery, 
2010). These antibodies have characteristics that theoretically should improve their efficacy over 
rituximab (Alduaij, 2011; Niederfellner, 2011; Rafiq, 2013; and Teeling, 2004). The hope is that 
the new anti-CD20 mAbs will be more efficacious than rituximab, but the clinical data so far are 
mixed. One study of a head-to-head comparison between rituximab and obinutuzumab in relapsed 
indolent lymphoma showed no difference in progression-free survival (PFS; Sehn, 2007). In a 
head-to-head comparison in patients with CLL (Goede, 2014), obinutuzumab was superior to 
rituximab when combined with chlorambucil, but the doses and schedules of the 2 mAbs were not 
matched. In short, although in vitro and xenograft studies support the potential of the new 
anti-CD20 mAbs over rituximab, the available clinical data are unclear as to whether these new 
mAbs are indeed an advance. 
2.3. 
Treatment Descriptions 
2.3.1. 
Plamotamab (XmAb13676) Product Description 
Plamotamab (XmAb13676) is a humanized bispecific antibody (bsAb) that binds both CD3 and 
the tumor antigen CD20 in order to recruit cytotoxic T cells to kill CD20 tumor cells. Plamotamab 
has been designed to maintain full-length humanized monospecific antibody properties in a bsAb, 
enabling the design of stable molecules with favorable in vivo half-life, and allowing for the use 
of standard antibody production methods.  
 
 
 
 
 
 
 Antibody discovery programs at Xencor have 
demonstrated that several bsAbs based on this format are highly but selectively active towards 
target cells in primate models. See Section 2.4 for human experience with plamotamab.  
2.3.2. 
Tafasitamab Product Description 
Tafasitamab (tafasitamab-cxix) is a CD19-directed cytolytic antibody indicated for use in the US 
in combination with lenalidomide for the treatment of adult patients with R/R DLBCL not 
otherwise specified (NOS), including DLBCL arising from low-grade lymphoma, and who are not 
eligible for ASCT. Tafasitamab is also approved in the EU and is indicated in combination with 
lenalidomide followed by tafasitamab monotherapy for the treatment of adult patients with 
relapsed or refractory DLBCL who are not eligible for ASCT. Tafasitamab is a humanized 
CD19-directed cytolytic monoclonal antibody that contains an IgG1/2 hybrid Fc-domain with 
2 amino acid substitutions to modify the Fc-mediated functions of the antibody. It is produced by 
recombinant DNA technology in mammalian cells (Chinese hamster ovary). Tafasitamab has a 
molecular weight of approximately 150 kDa (see US Monjuvi® PI, 2021; EU Minjuvi® SmPC, 
2021). 


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2.3.3. 
Lenalidomide Product Description 
Lenalidomide, a thalidomide analogue, is an immunomodulatory agent (IMiD®) with 
antiangiogenic and antineoplastic properties. It is indicated for the treatment of adult patients with 
multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma, follicular lymphoma, and 
marginal zone lymphoma. See Revlimid® PI, 2021 or Revlimid® SmPC, 2022 for more 
information. 
2.4. 
Human Experience with Plamotamab 
Plamotamab is being studied in a Phase 1 study, XmAb13676-01 (A Phase 1 Multidose Study to 
Evaluate the Safety and Tolerability of XmAb®13676 in Patients with CD20-Expressing 
Hematologic Malignancies). As of 18 August 2021, a total of 96 subjects have been treated with 
plamotamab in the XmAb13676 01 study at weight-based dose levels of 0.7 to 360 µg/kg and flat 
dose levels of 0.8 to 50 mg. Of those 96 subjects, 80 were in the NHL group and 16 were in the 
CLL group. Adverse events (AEs) have been reported in 100% of the 80 NHL subjects. The most 
frequent AEs (>20%) in the NHL group were cytokine release syndrome (51/80, 63.8%), pyrexia 
(43/80, 53.8%), anemia (34/80, 42.5%), fatigue (24/80, 30.0%), nausea (21/80, 26.3%), diarrhea 
and cough (20/80, 25.0%), constipation (19/80, 23.8%), chills, headache, hypokalemia, and 
thrombocytopenia, (18/80, 22.5%), asthenia, dizziness, dyspnoea, hypotension, and neutropenia 
(17/80, 21.3%). Cytokine release syndrome (CRS), a predicted toxicity for this class of drugs, has 
occurred in subjects treated at 7.5, 10, 20, 25, 45, 50, 80, 125, 170, 250 µg/kg and at 0.8, 2, 20, 
35 mg; however, CRS has not yet been seen at the highest dose levels of 360 µg/kg and 50 mg, in 
this study. The pattern of these events has differed in the NHL versus the CLL cohorts in this 
study. 
2.4.1. 
Non-Hodgkin’s Lymphoma: Escalation Cohorts 
In the NHL escalation cohorts, the events have been predominantly Grade 1 or 2 in severity, with 
the exception of 4 out of 80 (5.0%) subjects who each experienced ≥ Grade 3 CRS, assessed 
according to American Society for Transplantation and Cellular Therapy (ASTCT) 2019 criteria, 
all associated with the first infusion of plamotamab. Manifestations of CRS have included fever, 
hypotension, tachycardia, chills, rigors, hypertension, headache, hypoxia, and elevations of liver 
enzymes. During the XmAb13676-01 study, cases of transaminase elevation, with or without 
bilirubin elevation, have occurred in the setting of CRS. The events were transient and reversible, 
with the transaminase and bilirubin levels returning to normal usually within 5 days. Five subjects 
(5/80, 6.3%) in the NHL cohort died during the study due to AEs, 3 due to COVID-19 (3/80, 
3.8%), one of respiratory failure (1/80, 1.3%), and one due to unknown reasons (1/80, 1.3%). 
2.4.2. 
Non-Hodgkin’s Lymphoma: Flat-Dosing Cohorts 
In the flat-dosing cohort (Cohort 1N-C, weekly titration of 0.8, 2, 20, 35 and 50 mg, followed by 
weekly dosing of 50 mg until Cycle 3 then every-two-week dosing of 50 mg) of NHL subjects, 
data are available for 14 subjects as of 18 August 2021. Of those subjects, the most frequent AEs 
(> 20%) were cytokine release syndrome (8/14, 57.1%), nausea (7/14, 50.0%), pyrexia and anemia 
(6/14, 42.9%), asthenia (4/14, 28.6%), fatigue, diarrhea, headache, dizziness, dyspnoea, 
hypotension, decreased appetite, alanine aminotransferase (ALT), increased back pain, peripheral 


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oedema, and aspartate aminotransferase (AST) increased (3/14, 21.4%). All CRS events, assessed 
according to ASTCT 2019 criteria, were Grade 1 or 2. In this cohort, manifestations of CRS 
occurring in more than 1 subject included pyrexia (7/8, 87.5%), hypotension (5/8, 62.5%), hypoxia 
and tachycardia (3/8, 37.5%), and headache (2/8, 25.0%). Anemia and lymphopenia were the only 
Grade 3 or 4 events reported in more than 1 subject (2/14, 14.3%). A single subject (1/14, 7.1%) 
died of COVID infection in this cohort. 
Efficacy in the NHL population as measured by overall response rate (objective response rate 
[ORR], complete response [CR] plus partial response [PR]) and was observed in nearly all cohorts, 
with responses seen more consistently in cohorts with a top dose of greater than 80 µg/kg. Table 2 
below presents the responses by cohort, as of 18 August 2021, for cohorts with a top dose of greater 
than or equal to 80 µg/kg in the efficacy evaluable population for NHL. The proposed plamotamab 
flat dosing regimen for the XmAb13676-03 study is represented below as “50 mg.” 
 
 


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Table 2: 
Overall Response Rate, Complete Response and Disease Control Rate for 
Overall Population and by Top Dose Level in Subjects with NHL from Study 
XmAb13676-01 
Top Dose/Response 
Efficacy Evaluable Population 
Overall 
ORR 
24/55 (43.6) 
CR 
11/55 (20.0) 
DCR 
32/55 (58.2) 
80 µg/kg 
ORR 
1/5 (20.0) 
CR 
0/5 
DCR 
2/5 (40.0) 
125 µg/kg 
ORR 
6/16 (37.5) 
CR 
5/16 (31.3) 
DCR 
10/16 (62.5) 
170 µg/kg 
ORR 
4/8 (50.0) 
CR 
2/8 (25.0) 
DCR 
5/8 (62.5) 
250 µg/kga 
ORR 
6/12 (50.0) 
CR 
1/12(8.3) 
DCR 
5/12 (41.7) 
360 µg/kg 
ORR 
2/5 (40.0) 
CR 
1/5 (20.0) 
DCR 
4/5 (80.0) 
50 mg 
ORR 
5/9 (55.6) 
CR 
2/9 (22.2) 
DCR 
5/9 (55.6) 
CR = complete response; DCR = disease control rate; ORR = objective response rate. 
a One subject received a single priming dose of 25 μg/kg and achieved a PR. 
Note: Efficacy population is defined as Subjects who did not withdraw prior to 2 cycles and completed at least 75% 
doses (6 out of 8 doses) and have post-baseline response assessment data available; or subjects who withdrew due to 
AEs/death; or subjects who withdrew other than AEs/death and have completed at least 75% doses of the first cycle 
(3 doses out of 4). 


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DCR includes Complete Metabolic Response, Complete Response, Partial Metabolic Response, Partial Response, 
No Metabolic Response, and Stable Disease. 
 
2.4.3. 
Recommended Phase 2 Dose 
The Phase 1 study, XmAb13676-01 demonstrated that plamotamab is well tolerated up to the 
highest dose level tested and has activity in R/R DLBCL. Notably, the flat dosing Cohort 1N-C 
(weekly titration of 0.8, 2, 20, 35, and 50 mg, followed by weekly dosing of 50 mg until Cycle 3 
then every-two-week dosing of 50 mg) had an acceptable rate of CRS, with no Grade 3 or 4 CRS 
and no CRS events after start of every 2-week dosing. Among the subjects in the 1N-C cohort, 
Grade 3 and 4 toxicities were limited to anemia, liver enzyme increases, and cytopenias, all at rates 
of less than 20%. No dose-limiting toxicities were observed among the 14 treated subjects. 
Preliminary exposure-response analysis based on the plamotamab pharmacokinetics (PK) and 
corresponding responses (ORR, CRS, others) in study XmAb13676-01 indicate a target trough 
concentration (Ctrough) threshold of approximately 350 ng/mL (95% CI) to minimize the risk of 
CRS and a target Ctrough threshold of approximately 650 ng/mL (95% CI) to maximize the 
probability of objective response. A population PK model was developed for plamotamab using 
interim data (April 2020) from the Phase 1 Study XmAb13676-01 that included plamotamab 
concentrations, actual sampling times, dosing histories, and baseline body weights from 
53 subjects with NHL. Based on this model, the proposed dosing schemes in Part A of this study 
(XmAb13676-03) were simulated (predictions for high dose group shown in Figure 1). Population 
PK based predictions indicate that at the 20 mg dose, 77% of subjects exceed the safety threshold 
of 350 ng/mL, but only 52% of the subjects exceed the efficacy threshold of 650 ng/mL. At the 50 
mg dose, 93% of subjects exceed the safety threshold of 350 ng/mL and 83% of the subjects exceed 
the efficacy threshold of 650 ng/mL. Based on these results, 50 mg dose group is more likely to 
provide a robust response across the population, but there exists significant variability in the 
estimate for target thresholds, and therefore further characterization of exposure response is 
desired at a range of concentrations in this study. Accordingly, this study evaluates two dose levels 
of plamotamab 20 mg and 50 mg at steady state that have been demonstrated to be well tolerated 
and active in the Phase 1 study.  
This study includes a safety run-in that evaluates 2 dose levels of plamotamab with the standard 
doses of tafasitamab and lenalidomide. In addition to the recommended Phase 2 dose (RP2D), the 
study begins with a regimen that titrates to 20 mg: weekly titration of 0.8, 2, and 20 mg, followed 
by weekly dosing of 20 mg until Cycle 3 then every-2-week dosing of 20 mg. The titration from 
low minimally active dose to pharmacologically active doses was chosen to mitigate the risk of 
CRS based on clinical experience with plamotamab and other CD3-directed antibodies (Hosseini, 
2020; Hutchings, 2021).  
Tafasitamab is an Fc-modified monoclonal antibody that binds to CD19 antigen expressed on the 
surface of pre-B and mature B lymphocytes and on several B-cell malignancies, including DLBCL. 
Upon binding to CD19, tafasitamab-cxix mediates B-cell lysis through apoptosis and immune 
effector mechanisms, including antibody-dependent cellular cytotoxicity and antibody-dependent 
cellular phagocytosis. In a Phase 1 clinical trial (Woyach, 2014), tafasitamab given at 12 mg/kg 
every 4 days reduced peripheral blood B cell counts by 97% after 8 days of treatment in patients 


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with relapsed or refractory DLBCL. Given that tafasitamab may promote B cell depletion, which 
could mitigate CRS with the addition of plamotamab + lenalidomide to the regimen, an 8-day, 
2-dose run-in of tafasitamab at 12 mg/kg is included before C1D1. Other than the 2-dose 
tafasitamab monotherapy run-in, tafasitamab and lenalidomide will be administered according to 
the package inserts (PIs) or Summary of Product Characteristics (SmPCs; Monjuvi® PI, 2021; 
Minjuvi® SmPC, 2021; and Revlimid® PI, 2021; Revlimid® SmPC, 2022). 
Figure 1: 
Log Scale Simulated Median Concentrations and 90% Prediction Intervals 
for Flat Dose and Schedule. 
 
For doses beyond Week 12, the blue area above the line at 0.6 μg/mL illustrates the prediction that 85% of subjects 
maintain Q2W steady state troughs above the 0.6 µg/mL trough chosen to preserve benefit. 
 
2.4.4. 
Benefit/Risk Assessment 
It is anticipated that the addition of plamotamab to the combination of tafasitamab and 
lenalidomide will enhance efficacy, through higher response rates and longer time to progression 
due to the engagement of both CD19 and CD20 antigens with nonoverlapping mechanisms of 
resistance.  
Plamotamab monotherapy demonstrated responses across nearly all dose levels above 80 µg/kg 
maximum dose, see Table 2. Within the NHL Efficacy Population, responses were observed in 
24/55 (43.6%) with 11/55 subjects (20%) subjects achieving a CR. Further, responses were 
observed in 5/9 (55.6%) subjects in the NHL Efficacy Population treated at the RP2D. Tafasitamab 
and lenalidomide established efficacy in R/R DLBCL in a recent Phase 2 study with a response 
rate of 57.5% with 40% achieving a CR. PFS was 11.6 months (Duell, 2021). Regulatory approvals 
have been granted in the US and EU. 


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Although the RP2D of plamotamab monotherapy has been identified, the appropriate dose in 
combination with tafasitamab and lenalidomide has not been established. To assess the safety of 
plamotamab when it is used in combination with tafasitamab and lenalidomide, a safety run-in 
phase is planned in this study. The safety run-in phase will enroll subjects starting at a lower dose 
of plamotamab (see Table 3) prior to enrolling subjects at the RP2D. Safety will be assessed before 
proceeding to the randomized part of the study. 
Other safety measures have been implemented. The step-up dosing regimen used in this study 
reduced CRS events to Grade ≤ 2 in the Phase 1 trial. In addition, the study requires the separation 
of the dosing of tafasitamab, plamotamab, and lenalidomide as well as including dose 
modifications of each product for specific toxicities, along with management guidelines for those 
toxicities.  
These safety measures along with the efficacy observed with both plamotamab and tafasitamab in 
combination with lenalidomide, present a favorable benefit-risk ratio for subjects enrolling in this 
study. 
3. 
TRIAL OBJECTIVES AND PURPOSE 
3.1. 
Primary Objectives 
To determine the safety and efficacy of the combination of plamotamab, tafasitamab, and 
lenalidomide compared to tafasitamab and lenalidomide in adult subjects with R/R DLBCL. 
3.2. 
Secondary Objectives 
The secondary objectives of the study are to compare a combination of plamotamab, tafasitamab, 
and lenalidomide to tafasitamab and lenalidomide as follows: 
1. To compare rates of objective response (ORR = CRR + partial response rate [PRR]) by 
Blinded Independent Review Committee (BIRC) and Investigator per Lugano 2014 criteria 
2. To compare overall survival (OS) 
3. To compare time to treatment failure (TTF)  
4. To assess duration of response (DOR) among subjects achieving an objective response (CR 
+ PR) and among subjects achieving a CR by BIRC 
5. To compare the PFS, as determined by the Investigator 
6. To assess the incidence, timing, and severity of CRS by following CRS-related AEs 
including incidence and grade of AEs and incidence of serious adverse events (SAEs) 
7. To assess the incidence, timing, and severity of neurological AEs and incidence and grade 
of immune effector cell-associated neurotoxicity syndrome 


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8. To assess the dose intensity of tafasitamab and lenalidomide in Part 1 when given in 
combination with plamotamab 
9. To assess the safety profile of a combination of plamotamab, tafasitamab, and lenalidomide 
in Part 2 as determined by the incidence and severity of treatment-emergent adverse events 
(TEAEs), in adult subjects with R/R DLBCL 
3.3. 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
1. To assess the PK of plamotamab and tafasitamab 
2. To assess the potential immunogenicity of plamotamab and tafasitamab 
3. To explore the association of baseline CD19 and CD20 levels, molecularly defined DLBCL 
subtypes, minimal residual disease (MRD) as measured by circulating tumor DNA 
(ctDNA), and immune cell frequency, activation status, and function with clinical 
outcomes 
4. To evaluate biomarkers of CRS (including but not limited to serum cytokine levels) with 
clinical outcomes 
5. To assess potential associations between clinical outcomes and biologically and clinically 
defined subgroups, including but not limited to randomization strata and time since last 
rituximab treatment 
3.4. 
Purpose of Study 
The combination of tafasitamab in combination with lenalidomide has been granted accelerated 
approval in the US for use in patients with R/R DLBCL, NOS. Tafasitamab is an Fc-modified 
monoclonal antibody that binds to CD19 antigen expressed on the surface of pre-B and mature 
B lymphocytes and on several B-cell malignancies, including DLBCL. In combination with 
lenalidomide in a single-arm clinical trial (NCT02399085), tafasitamab had a 57.5% response rate 
in R/R DLBCL with a median DOR of 43.9 months and median PFS of 11.6 months (Duell, 2021). 
Plamotamab is a humanized bsAb that binds both CD3 and the tumor antigen CD20 in order to 
recruit cytotoxic T cells to kill CD20 tumor cells. In an ongoing Phase 1 study 
(Study XmAb13676-01, NCT02924402), plamotamab has produced durable responses in subjects 
with R/R DLBCL. 
It is hypothesized that the engagement of both CD19 and CD20 antigens will enhance efficacy 
outcomes in this population, due to nonoverlapping mechanisms of resistance. Further, this 
combination activates and expands the innate immune system and adaptive effector cells as well 
as modulates the tumor microenvironment. These characteristics support and warrant a study of 
the combination of plamotamab, tafasitamab, and lenalidomide. The trial first determines if the 
combination of the 3 products can be safely administered and to determine the dose for Part 2. The 
second part of this trial is designed to determine the improvement in efficacy, as measured by PFS, 


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of the standard of care for DLBCL, tafasitamab and lenalidomide, with the addition of plamotamab 
to tafasitamab and lenalidomide. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a randomized, multicenter, open-label, Phase 2 study of plamotamab combined with 
tafasitamab plus lenalidomide versus tafasitamab plus lenalidomide in adult subjects with DLBCL 
who have relapsed after or are refractory to at least 1 prior line of therapy, which must have 
included multi-agent chemoimmunotherapy inclusive of an anti-CD20 monoclonal antibody, and 
who are not candidates for ASCT, refuse ASCT, or relapse after ASCT.  
A central pathologist reading will confirm the diagnosis of DLBCL retrospectively after 
enrollment, using archival or recently obtained tissue. Central radiology and clinical reviewers will 
assess objective disease response according to the Lugano 2014 (Cheson, 2014) guidelines. Details 
of the central review will be provided in an imaging charter outlining functions and processes. In 
addition, Investigator-assessed response will be captured in the clinical database, and concordance 
analyses will be performed. All subjects will be treated until progression or withdrawal for other 
reasons and then followed for OS up to 5 years. 
This study will consist of 2 parts which will be performed sequentially, with Part 1 enrolling and 
evaluating subjects for safety and determination of dose and schedule before the start of Part 2. 
4.1.1. 
Part 1: Single-Arm, Safety Run-In 
Part 1 consists of a single-arm evaluation of the safety of the triple combination of plamotamab 
combined with tafasitamab plus lenalidomide in at least 40 subjects in 2 cohorts of a minimum of 
20 subjects per cohort:  
• Cohort 1A treats subjects with the triple combination at plamotamab dose level –1 
(Table 3).  
• Cohort 1B commences enrollment after the Cohort 1A completes enrollment. 
Cohort 1B treats subjects with the triple combination at plamotamab dose level 1 
(Table 3).  
• An initial safety evaluation is conducted after all subjects in Cohorts 1A and 1B either 
receive treatment, at a minimum, through C4D28 or are discontinued prior to C4D28 
due to an AE or progressive disease.  
After the initial safety evaluation of both Cohorts 1A and 1B, the pharmacologically optimal dose 
of plamotamab (dose level -1 or dose level 1) with an acceptable safety profile will be advanced 
to the randomized (Part 2) portion of the study.  


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Table 3:  
Cohort 1A and Cohort 1B Plamotamab Dosing Regimen 
Cohort 
Dose 
Level 
Cycle 1  
Day 1 
(Priming Dose) 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 1 
Day 22 
Cycle 2 
Day 1 
Cycle 2 
Days 1, 8, 15, 
and 22 
Cycle 3 and 
Subsequent 
Q2W Dosing 
1A 
-1 
0.8 mg 
2 mg 
20 mg 
20 mg 
20 mg 
20 mg 
20 mg 
1B 
1 
0.8 mg 
2 mg 
20 mg 
35 mg 
50 mg 
50 mg 
50 mg 
Q2W = every 2 weeks. 
4.1.2. 
Part 2: Open-Label Randomized 
The open-label, randomized portion (Part 2) of the study will begin after an initial safety evaluation 
of at least 40 subjects from Part 1. Prior to the initiation of Part 2, the protocol will be revised with 
the dosing regimen selected from Part 1 and will include adequate justification to support the 
proposed dose/schedule in Part 2. 
During Part 2, subjects are randomized in a 1:1 ratio to the 2 treatment arms, stratified by 
international prognostic index (IPI) risk score at baseline (Sehn, 2007; 3 to 5 versus 0 to 2), 
number of lines of prior therapy (1 versus ≥ 2), and primary refractory (yes versus no). Primary 
refractory enrollment is limited to 36 of 200 subjects. Part 2 will enroll approximately 200 subjects. 
The sample size for Part 2 may be adjusted based on the results from Part 1. An increase in the 
enrollment number beyond 200 will be made by a protocol amendment prior to the initiation of 
the randomized portion. An independent data monitoring committee (IDMC) will review safety 
data during Part 2 with meetings scheduled after 50, 100, and 150 subjects have been randomized. 
The primary analysis for PFS will occur after 89 disease progression and death events. An interim 
analysis for OS will be performed at that time (see Section 11.3).  
4.2. 
Endpoints 
4.2.1. 
Primary Endpoints 
The primary endpoint of the study is 
• For Part 1, safety as measured by incidence of CRS and TEAEs; and 
• For Part 2, PFS, defined as the time from randomization to first documentation of 
progressive disease or death, whichever comes first, as assessed by the BIRC using 
Lugano 2014 criteria. 
4.2.2. 
Secondary Endpoints 
The secondary endpoints of the study are as follows: 
1. Best ORR and CRR, as assessed by Investigator and by the BIRC according to 
Lugano 2014 criteria (Cheson, 2014) 


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2. OS, defined as the time from randomization to death from any cause 
3. TTF, defined as the time from randomization to discontinuation of all study treatment for 
any reason, including disease progression (as assessed by Investigator and by BIRC), 
treatment toxicity, and death, whichever comes first 
4. DOR, defined as the time from first response to progression or death due to any cause, 
whichever comes first, among subjects achieving an objective response (OR) and among 
subjects with CR as assessed by BIRC 
5. PFS, as assessed by Investigator using Lugano 2014 criteria 
6. Incidence, timing, and severity of CRS as assessed by following CRS-related AEs, 
including incidence and grade of AEs and incidence of SAEs, with CRS grading defined 
by the ASTCT Consensus Grading 
7. Incidence, timing, and severity of neurological AEs, and incidence and grade of Immune 
Effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
8. Dose intensity of tafasitamab and lenalidomide as measured by planned and actual dose 
administration in Part 1 
9. Incidence and severity of TEAEs in Part 2, with severity defined by the National Cancer 
Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
4.2.3. 
Exploratory Endpoints 
The exploratory endpoints of the study are as follows: 
1. PK concentrations of plamotamab and tafasitamab 
2. Anti-plamotamab and anti-tafasitamab antibodies 
3. Absolute counts and percentage change from baseline in measurements of B-, T-, and 
natural killer (NK) cell populations 
4. Analyses of exploratory and diagnostic biomarkers (including, but not limited to, cell of 
origin by Hans algorithm [germinal center B-cell (GCB) versus non-GCB], CD10, CD19, 
CD20, MUM1, BCL2, and BCL6 expression); peripheral and intratumoral leukocyte 
frequencies, phenotyping, functional and activation markers at baseline and on treatment; 
gene expression profiling for cell of origin subtyping and exploratory transcriptomic 
analysis, and genomic analysis in tumor including, but not limited to, FcR genotyping and 
MRD ctDNA analysis in blood 
5. Rituximab concentrations at baseline 
6. Biomarkers of CRS; eg, serum cytokine levels 


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7. Randomization strata and baseline characteristics subgroup analyses of ORR, PFS, OS and 
TTF 
4.3. 
Treatment Regimens 
This study consists of 2 parts: 
• Part 1: single-arm, two-cohort, safety run-in 
• Part 2: open-label, randomized, two-arm efficacy and safety 
4.3.1. 
Part 1: Single-Arm, Safety Run-In 
Part 1 is a single-arm, two-cohort, safety run-in intended to establish the safety of the combination 
of plamotamab, tafasitamab, and lenalidomide. 
Treatment consists of the combination of plamotamab, tafasitamab, and lenalidomide administered 
in 28-day cycles, with 2 priming doses of tafasitamab before Cycle 1. Plamotamab and tafasitamab 
can be administered until disease progression, unacceptable toxicity, or discontinuation for any 
other reason, whichever comes first; however, lenalidomide can be given for only up to a total of 
12 cycles. Tafasitamab and plamotamab must not be administered simultaneously. On days when 
both tafasitamab and plamotamab are given, the tafasitamab should be given first followed by 
plamotamab. It is recommended that the infusions are separated by at least 2 hours. 
4.3.2. 
Part 2: Open-Label, Randomized 
Part 2 is an efficacy cohort where subjects are randomized to receive Arm A or Arm B as follows: 
Arm A: 
Treatment consists of the combination of plamotamab, tafasitamab, and lenalidomide administered 
in 28-day cycles, with 2 priming doses of tafasitamab before Cycle 1. Plamotamab and tafasitamab 
can be administered until disease progression, unacceptable toxicity, or discontinuation for any 
other reason, whichever comes first. Lenalidomide can be given for up to a total of 12 cycles.  
Arm B: 
Treatment consists of the combination of tafasitamab and lenalidomide administered in 28-day 
cycles with 2 priming doses of tafasitamab before Cycle 1. Tafasitamab can be administered until 
disease progression, unacceptable toxicity, or discontinuation for any other reason, whichever 
comes first. Lenalidomide can be given for up to a total of 12 cycles.  
Part 1 and Part 2 dose and schedule are presented in the schematic below (Figure 2): 
 


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Figure 2: 
Dosing Schema 
 
Plamotamab 
d1 0.8mg, d8 2mg
 d15 20mg, d22*
Tafasitamab 12 mgkg
Days -8 & -4
Cycle 1
Cycle 2
Cycle 3
Cycle 4-12
Cycle 13+
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
q2wk d1, d15
Tafasitamab 12mg/kg
q2wk d1, d15
Lenalidomide 25mg po
qd d1-d21
Plamotamab 50mg
qwk d1, d8, d15, d22
Plamotamab 50mg
q2wk d1, d15
Plamotamab 50mg
q2wk d1, d15
Plamotamab 50mg
q2wk d1, d15
PART IB Safety Run-in
Day 1
Continue until 
Progression
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Tafasitamab 12mg/kg
Days -8 & -4
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4-12
Cycle 13+
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Plamotamab*
q2wk d1, d15
Plamotamab*
q2wk d1, d15
Plamotamab*
q2wk d1, d15
Arm A
Arm B
PART II Randomized Efficacy
Day 1
Continue until 
Progression
Continue until 
Progression
Tafasitamab 12mg/kg
q2wk d1, d15
Tafasitamab 12mg/kg
q2wk d1, d15
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
q2wk d1, d15
Tafasitamab 12mg/kg
q2wk d1, d15
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Tafasitamab 12mg/kg
Days -8 & -4
Plamotamab*
qwk d1, d8, d15, d22
Plamotamab 
d1 0.8mg, d8 2mg
 d15 20mg, d22 35mg
*Dose determined in Part 1
Tafasitamab 12 mgkg
Days -8 & -4
Cycle 1
Cycle 2
Cycle 3
Cycle 4-12
Cycle 13+
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
q2wk d1, d15
Tafasitamab 12mg/kg
q2wk d1, d15
Lenalidomide 25mg po
qd d1-d21
Plamotamab 20mg
qwk d1, d8, d15, d22
Plamotamab 20mg
q2wk d1, d15
Plamotamab 20mg
q2wk d1, d15
Plamotamab 20mg
q2wk d1, d15
PART IA Safety Run-in
Continue until 
Progression
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Tafasitamab 12mg/kg
qwk d1, d8, d15, d22
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Lenalidomide 25mg po
qd d1-d21
Plamotamab 
d1 0.8mg, d8 2mg
 d15 20mg, d22 20mg


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4.4. 
Number of Subjects 
Part 1 will enroll at least 40 subjects into 2 cohorts with a minimum of 20 subjects per cohort. 
Part 2 will enroll approximately 200 subjects. The sample size for Part 2 may be adjusted based 
on the results from Part 1. Any increase in the enrollment number beyond 200 will be made by a 
protocol amendment prior to the initiation of the randomized portion. Primary refractory 
enrollment will be limited in Part 2 to 36 of 200 subjects.  
Overall, the study is planned to enroll approximately 240 subjects. 
4.5. 
Treatment Assignment 
Treatment assignment for Part 1 and randomization for Part 2 will be performed via a third-party 
randomization and trial supply management (RTSM)/interactive response technology (IRT) 
system.  
4.5.1. 
Part 1: Single-Arm Safety Run-In 
During the Part 1 safety run-in, 40 subjects will be enrolled and treated with plamotamab and 
tafasitamab plus lenalidomide (ie, single-arm, uncontrolled). The subjects will be considered 
enrolled if they have signed the informed consent, are determined to be eligible, and receive the 
Day –8 tafasitamab priming dose. 
4.5.2. 
Part 2: Open-Label Randomized  
During Part 2, a total of 200 subjects will be randomized as follows: with a 1:1 ratio of plamotamab 
and tafasitamab plus lenalidomide versus tafasitamab plus lenalidomide, stratified by IPI risk score 
at baseline (3 – 5 versus 0 – 2); number of lines of prior therapy (1 versus ≥ 2); and primary 
refractory (yes versus no). A maximum of 36 primary refractory subjects may be enrolled. Subjects 
will be randomized only if they have signed the informed consent and are determined to be eligible. 
The initiation of study treatment will occur within 72 hours of randomization. Study treatment will 
begin on Study Day –8 with the tafasitamab priming doses. 
No blinding is specified given the potential for overlapping toxicities. In the presence of 
overlapping toxicities, a blinded study may result in dose modifications or reductions of placebo. 
This may confound the management of toxicities without addressing the source of the toxicity 
through dose modification or reduction schemes. Therefore, to ensure the safety of subjects, the 
study will not be blinded. 
4.5.3. 
Subject Screening and Enrollment Numbers  
Subjects who consent for the study will be assigned a Subject Screening Number, a site 
sequential 8-digit number. The first 3 numbers designate the site number then hyphen, then 5 more 
numbers for the subject number beginning with 9 for screening (ie, 101–90001).  


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Subjects who will be eligible to receive study treatment (Part 1) or be randomized (Part 2) will be 
assigned a Subject Enrollment Number, a study sequential 8-digit number, first 3 numbers for 
the site number, then hyphen, and then 5 more numbers for the subject number (ie, 101–10001).  
4.6. 
Management of Toxicities  
The combination of plamotamab, tafasitamab and lenalidomide has not yet been tested in humans. 
Safety data are available for plamotamab and for the combination of tafasitamab and lenalidomide. 
Important and potentially overlapping toxicities have been identified and are outlined below. 
However, new toxicities of the 3-drug regimen may be identified during this study, and 
investigators should be diligent in the monitoring and management of subjects during treatment. 
Management of known toxicities such as CRS, infusion-related reactions, hematologic toxicities, 
and tumor lysis syndrome are outlined by treatment regimen in the following sections. 
4.6.1. 
Cytokine Release Syndrome 
The ASTCT defines CRS as “a supraphysiologic response following any immune therapy that 
results in the activation or engagement of endogenous or infused T cells and/or other immune 
effector cells. Symptoms can be progressive, must include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end organ dysfunction” (Lee, 2019). 
CRS can present with a variety of symptoms ranging from mild, flu-like symptoms to severe 
life-threatening manifestations of the inflammatory response. Mild symptoms of CRS include 
fever, fatigue, headache, rash, arthralgia, and myalgia. More severe cases are characterized by 
hypotension as well as high fever and can progress to an uncontrolled systemic inflammatory 
response with vasopressor-requiring circulatory shock, vascular leakage, disseminated 
intravascular coagulation, and multi-organ system failure (Shimabukuro-Vornhagen, 2018). CRS 
is more likely to occur after the first dose of plamotamab than subsequent doses, tends to begin 
somewhat later than hypersensitivity reactions, and is more likely to be associated with hepatic 
and neurologic complications. Plamotamab associated CRS Symptoms observed in the Phase 1 
study include: 
• Aphasia or word-finding 
difficulty  
• Arthralgia  
• Confusion/mental status 
changes/delirium 
• Serum creatinine increase 
• Diaphoresis 
• Dizziness 
• Dyspnea 
• Fatigue (asthenia, lethargy, 
malaise) 
• Fever 
• Gait disturbance/dysmetria 
• Headache 
• Hypotension/hypertension 
• Hypoxia 
• Myalgia 
• Nausea/vomiting 
• Rigors/chills 
• Tachycardia 
• Tachypnea 
• Seizures 
• Transaminitis/hyperbilirubine
mia 
• Tremor 
 


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CRS toxicity is defined using the ASTCT CRS Consensus Grading (Lee, 2019). See Table 4 for 
these definitions. 
Table 4: 
American Society for Transplantation and Cellular Therapy Cytokine 
Release Syndrome Consensus Grading 
CRS Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
Temperature  
≥ 38 °C 
 
With 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
 
And/orb 
Hypoxia 
None 
Requiring low-flow 
nasal cannulac or 
blow-by 
Requiring high-flow 
nasal cannula c, 
facemask, 
nonrebreather mask, 
or Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation 
and mechanical 
ventilation) 
BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release 
syndrome; CTCAE = Common Terminology Criteria for Adverse Events. 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0, but they do not influence CRS 
grading.  
a Fever is defined as temperature ≥ 38 °C not attributable to any other cause. In subjects who have CRS then receive 
antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent 
CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a subject with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as Grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/minute. 
Source: Lee, 2019. 
 
4.6.1.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and Lenalidomide) 
Plamotamab is known to cause CRS. CRS has not been observed in clinical trials of tafasitamab 
and lenalidomide. However, lenalidomide, through its potential to activate T cells, may potentiate 
CRS in combination with plamotamab. In addition, to avoid the overlap of CRS caused by 
plamotamab with tafasitamab-induced, infusion-related reactions, plamotamab must always be 
given after tafasitamab if administered on the same day. See Section 4.7 for dose modification of 
lenalidomide and plamotamab in the instance of CRS. 
4.6.1.2. 
Part 2, Arm B (Tafasitamab and Lenalidomide) 
CRS has not been observed in clinical trials of tafasitamab and lenalidomide. If CRS is observed 
with tafasitamab, follow treatment guidelines provided for plamotamab and contact the medical 
monitor as soon as possible. 


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4.6.1.3. 
Cytokine Release Syndrome Versus Allergic/ Hypersensitivity/ Infusion-related 
Reactions 
CRS is mechanistically different from allergic/hypersensitive/Infusion-related reactions (Brennan, 
2010), although some of the manifestations are common to both AEs and both have been reported 
to occur with therapeutic antibodies. It is less clear how cytokine release is triggered, although it 
is likely to be associated with immune cell activation; in this case, CD3-expressing lymphocytes 
may 
be 
the 
prime 
effector 
of 
CRS. 
See 
Section 4.6.2 
for 
management 
of 
allergic/hypersensitive/infusion-related reactions. 
4.6.1.4. 
Management of Cytokine Release Syndrome 
Management of CRS should be per standard investigational site procedures. Alternatively, if there 
are no local standards or if they are incomplete, the approaches discussed below may be used. 
Contact the Xencor Medical Monitor immediately if questions arise concerning the management 
of an infusion reaction/CRS/neurotoxicity.  
Medical Monitor’s contact information:  
 
 
Telephone: 
 
E-mail: 
 
4.6.1.4.1. Use of Tocilizumab for Cytokine Release Syndrome 
Tocilizumab (Acterma®) is a therapeutic antibody that interferes with the binding of interleukin-6 
(IL-6) to the IL-6 receptor. It has been used to decrease the severity and, possibly, the mortality of 
severe CRS (Frey, 2017), and early administration may be useful in improving outcomes. 
Suggested guidelines for its use are in Section 4.6.1.6, in addition: 
• Have sufficient tocilizumab (dose of 8 mg/kg) readily available to the area where 
subjects are receiving their infusions and being observed post-infusion. 
• Repeat dosing of tocilizumab may be necessary if signs and symptoms persist or return 
after initial treatment 
Tocilizumab is the preferred IL-6 antagonist, however, if tocilizumab is unavailable either 
regionally or due to limited supply, follow institutional or local guidelines for the treatment of 
CRS until tocilizumab is available. 
4.6.1.5. 
Fluid Management  
CRS is sometimes associated with myocardial dysfunction, pulmonary edema, or capillary leak 
syndrome (Shimabukuro-Vornhagen, 2018). Although there are little or no data regarding use of 
anti-CD3 antibodies and the need for fluid management, it seems prudent to monitor subjects for 
weight gain and limit intravenous (IV) fluid administration in the acute setting. Following are 
guidelines for managing fluids: 


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• If a subject is noted to have had a ≥ 10% increase in body weight over the previous 
2 weeks in association with new or significantly increased bilateral lower extremity 
edema, delay dosing until this finding is evaluated and, if indicated, treated. 
• For acute hypotension, limit an IV fluid bolus to 500 to 1000 mL of normal saline or 
the equivalent.  
• If there is not an adequate response to fluids, consider treatment with tocilizumab (and 
vasopressors, if necessary) rather than additional fluid boluses. 
4.6.1.6. 
Cytokine Release Syndrome Treatment Guidelines by ASTCT CRS Consensus 
Grade 
The CRS treatment guidelines are listed below by grade: 
Grade 1 
• Symptomatic management is recommended. Administer acetaminophen 650 mg orally 
as an antipyretic or analgesic and/or diphenhydramine 25 to 50 mg intravenously or 
orally for rash, pruritus, or other signs and symptoms of hypersensitivity (allergic) 
reaction if clinically indicated. 
• Measure vital signs every 15 minutes or less, as clinically indicated. 
• Obtain an unscheduled blood sample for cytokine analysis during the event and 
approximately 4 hours later, unless scheduled cytokine monitoring is already in 
progress on the same visit day. 
• Monitor the subject for worsening of condition; if severity of event increases to a higher 
grade, stop the infusion, administer steroids as above, and refer to guidelines below for 
more severe reactions. 
Grade 2 
• Hypotension responsive to fluids not requiring a vasopressor, or mild respiratory 
symptoms treatable with low-flow oxygen, are signs of Grade 2 toxicity. Older subjects 
or those with significant comorbidities may be at a higher risk of decompensation in 
this situation. 
• Discontinue the infusion and consider administration of additional dexamethasone at a 
dose of 10 to 20 mg intravenously; acetaminophen 650 mg orally and/or 
diphenhydramine 25 to 50 mg intravenously or orally may also be given to treat signs 
and symptoms.  
• Once symptoms have resolved, restart the infusion at 50% of the baseline rate. If after 
1 hour, the subject’s symptoms do not return and vital signs are stable, the infusion rate 
may be increased every 30 minutes as tolerated to the baseline rate. 


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• Measure vital signs every 15 minutes or less as clinically indicated. For subjects who 
can tolerate an increase in the infusion rate back to baseline and maintain normal blood 
pressure for 30 minutes after the rate increase then, at the discretion of the Investigator, 
the frequency of vital sign assessment may be reduced to every 30 minutes during the 
infusion. 
• Obtain an unscheduled blood sample for cytokine analysis during the event and 
approximately 4 hours later, unless scheduled cytokine monitoring is already in 
progress on the same visit day. 
• Monitor the subject for worsening of condition; if severity of event increases to a higher 
grade, stop the infusion, administer appropriate treatment, and refer to guidelines below 
for Grades 3 and 4 reactions. 
• Note that older subjects or those with significant comorbidities may be at higher risk 
of decompensation in this situation. When reactions occur in these vulnerable subjects, 
or in the case of rapidly progressing reactions, consider treatment with tocilizumab 
8 mg/kg IV over 1 hour, with or without additional dexamethasone 10 to 20 mg IV (or 
equivalent). 
Grade 3 and 4 
• Stop the infusion and disconnect the infusion tubing from the subject. 
• Administer additional dexamethasone 10 mg intravenously. 
• Immediately give aggressive supportive care. Use pressors, fluids, oxygen, epinephrine 
or bronchodilators, ventilatory support, antipyretics, and analgesics as indicated. 
• Treatment with tocilizumab, 8 mg/kg IV over 1 hour (Hallek, 2018), is encouraged for 
CRS due to the high risk of progression and permanent organ dysfunction. 
• Hospital admission for observations is almost always indicated, usually to an intensive 
care unit, since an initial appearance of improvement may quickly yield to rapid 
decompensation. 
• Subjects with Grade 3 CRS or infusion reaction may be rechallenged once resolved as 
described in Section 4.7 and Table 8. Subjects with recurrent Grade 3 or any Grade 4 
reaction should not receive further plamotamab treatment but will continue to be 
followed on the protocol (ie, followed for long-term survival). 
• Obtain an unscheduled blood sample for cytokine analysis during the event and 
approximately 4 hours later, unless scheduled cytokine monitoring is already in 
progress on the same visit day. 
• Obtain an unscheduled sample for anti-drug antibodies (ADA) testing as close to the 
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following the event, unless scheduled cytokine monitoring is already in progress on the 
same visit day. 
• Notify the Xencor Medical Monitor immediately. 
4.6.1.7. 
Neurotoxicity 
In addition to CRS, another toxicity observed after CAR-T cell therapy and CD3 bispecific 
antibodies is neurotoxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) 
may manifest as delirium, encephalopathy, aphasia, lethargy, difficulty concentrating, agitation, 
tremor, seizures, and, rarely, cerebral edema (Lee, 2019). Neurotoxicity was previously considered 
in aggregate with CRS, but is now treated separately, due to its timing and response to treatment. 
Neurologic symptoms may occur during or after CRS symptoms, but rarely precede CRS 
symptoms. The earliest manifestations of ICANS are tremor, dysgraphia, mild difficulty with 
expressive speech (especially in naming objects), impaired attention, apraxia, and mild lethargy. 
Headache is a nonspecific symptom, frequently occurring during fever or after chemotherapy in 
patients without other neurologic dysfunction. Thus, headache alone is not a useful marker of 
ICANS. Expressive aphasia, on the other hand, appears to be a very specific symptom of ICANS 
(Lee, 2019).  
A consensus grading scheme, which is a slightly modified version of the CARTOX-10 screening 
tool, which incorporates key elements of the mini-mental state examination, the immune effector 
cell-associated encephalopathy (ICE) score, will be used for the grading of ICANS (Table 5). It is 
important to note that the 10-point ICE screening tool is helpful for assessing subjects for 
encephalopathy; however, the grading of ICANS requires assessment of the 10-point ICE score as 
well as evaluation of other neurologic domains, such as level of consciousness, motor symptoms, 
seizures, and signs of elevated intracranial pressure /cerebral edema, which may occur with or 
without encephalopathy. The ASTCT ICANS toxicity grading system is shown in Table 6. This 
grading scale will be used to assess neurotoxicity, rather than the CTCAE version 5.0. 
 
 


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Table 5: 
Immune Effector Cell-Associated Encephalopathy Scoring 
ICE 
Orientation: orientation to year, month, city, hospital: 4 points 
Naming: ability to name 3 objects (eg, point to clock, pen, button): 3 points 
Following commands: ability to follow simple commands (eg, “Show me 2 fingers” or “Close your eyes and 
stick out your tongue”): 1 point 
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”): 1 point 
Attention: ability to count backwards from 100 by 10: 1 point 
ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated. 
Encephalopathy (score). 
Scoring: 10, no impairment; 
7 – 9, Grade 1 ICANS; 
3 – 6, Grade 2 ICANS; 
0 – 2, Grade 3 ICANS; 
0 due to patient unarousable and unable to perform ICE assessment, Grade 4 ICANS (Lee, 2019). 
 
 


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Table 6: 
American Society for Transplantation and Cellular Therapy Immune 
Effector Cell-Associated Neurotoxicity Syndrome Consensus Toxicity 
Grading for Adults 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7– 9 
3 – 6 
0 – 2 
0 (patient is 
unarousable and 
unable to perform 
ICE) 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens to voice 
Awakens only to 
tactile stimulus 
Patient is 
unarousable or 
requires vigorous or 
repetitive tactile 
stimuli to arouse. 
Stupor or coma 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly 
or nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening 
prolonged seizure 
(> 5 min); or 
Repetitive clinical 
or electrical seizures 
without return to 
baseline in between 
Motor findingsc 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
ICP/cerebral edema 
N/A 
N/A 
Focal/local edema 
on neuroimagingd 
Diffuse cerebral 
edema on 
neuroimaging; 
decerebrate or 
decorticate 
posturing; or cranial 
nerve VI palsy; or 
papilledema; or 
Cushing’s triad 
EEG = electroencephalogram; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune 
Effector Cell-Associated Encephalopathy (score); ICP = intracranial pressure; N/A = not applicable; VI = sixth. 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has 
a generalized seizure is classified as grade 3 ICANS. 
a A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient 
with an ICE score of 0 may be classified as Grade 4. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
c Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, 
but they do not influence ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. It may be graded according to CTCAE v5.0 (Lee, 2019). 
 
It has been speculated that high levels of IL-6 may directly mediate neurotoxicity in this situation 
(Lee [A], 2014). A human anti-IL-6 monoclonal antibody, tocilizumab, may reverse this 


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neurotoxicity, but it would not be expected to cross the blood brain barrier, and efficacy in this 
setting has not been confirmed. Therefore, it is suggested that corticosteroids be the primary 
therapy in this situation, and tocilizumab considered only if this proves ineffective. 
Clinical management of neurotoxicity:  
• Monitor subjects closely for signs and symptoms of these events (including the use of 
mental status and neurologic examinations). 
• If neurotoxicity becomes evident, draw an unscheduled blood sample for cytokine 
analysis at that time, and again 4 hours later, unless scheduled cytokine monitoring is 
already in progress on the same visit day.  
• If neurologic toxicity is Grade 4, discontinue plamotamab. 
• For Grade 3 neurologic toxicity, withhold drug until the toxicity has recovered to 
≤ Grade 1 (mild) and has remained at ≤ Grade 1 for at least 3 days before restarting 
therapy. Restart at 75% of the previous dose. Escalate back to full dose at the time of 
the next dose if ≥ Grade 2 toxicity does not recur. If ≥ Grade 2 toxicity reoccurs at 75% 
dose, or if < Grade 2 toxicity takes more than 7 days to resolve, discontinue 
permanently. If Grade 3 neurologic toxicity persists for more than 7 days, permanently 
discontinue plamotamab. 
• For 
severe 
neurologic 
symptoms, 
administer 
additional 
dexamethasone 
10 mg intravenously and repeat every 12 hours if symptoms do not abate rapidly. 
• For recurrent seizures, anticonvulsant therapy may be necessary. 
4.6.2. 
Allergic/Hypersensitivity/Infusion-related Reactions 
Infusion-related reactions have been reported for tafasitamab as well as plamotamab. An allergic 
reaction is often caused by a type 1 hypersensitivity mechanism due to immunoglobulin E 
(IgE)-mediated release of histamines and prostaglandins, although a direct interaction with mast 
cells and basophils can also occur. However, infusion-related reactions, including serious and fatal 
reactions, are not uncommon with monoclonal antibody therapeutics and tend to occur most 
frequently during the first few infusions.  
Signs and symptoms usually develop during or shortly after drug infusion in hypersensitivity 
reactions, are more likely to occur after several doses of the drug and are largely related to 
histamine release. Typical signs and symptoms include rash/urticaria, flushing, pruritus, fever, 
dyspnea, cough, and hypotension, although the following may also occur (Lenz, 2007): 
• Arthralgia  
• Bronchospasm 
• Confusion/mental status 
changes/delirium 
• Dizziness 
• Fatigue (asthenia, lethargy, malaise) 
• Hallucinations 
• Headache 


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• Hypertension 
• Myalgia 
• Nausea/vomiting 
• Rigors/chills 
• Diaphoresis 
• Tachycardia 
 
Allergic/hypersensitivity/infusion-related reactions are managed according to institutional 
practices and guidelines. Allergic/hypersensitivity reactions will be defined according to the NCI-
CTCAE, Version 5.0 (NCI-CTCAE, 2017) definition of allergic reaction. 
4.6.2.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and Lenalidomide) 
Infusion-related reactions have been observed with plamotamab and tafasitamab. To mitigate 
overlapping toxicity with plamotamab, on a given treatment day, tafasitamab must be given first 
with a minimum of 2 hours between the end of the tafasitamab infusion and the start of the 
plamotamab infusion. If a > Grade 1 infusion reaction occurs with tafasitamab, delay the 
plamotamab until the resolution all symptoms of the reaction. Depending on the timing of the 
resolution of all symptoms, it may be necessary to administer the plamotamab the following day. 
4.6.2.2. 
Part 2, Arm B (Tafasitamab and Lenalidomide) 
Infusion-related reactions have been observed with tafasitamab and lenalidomide. Follow toxicity 
management instructions provided in the prescribing information for tafasitamab. Refer to 
Section 4.7 for dosage modifications. 
4.6.3. 
Hematologic Toxicities 
Hematologic toxicities, specifically decreases in absolute neutrophil count (ANC) and platelet 
count, have been observed in clinical trials of tafasitamab and lenalidomide. Decreases in platelets 
and ANC have also been observed with plamotamab (see Table 7). 
Table 7: 
Adverse 
Events 
of 
Neutropenia 
and 
Thrombocytopenia 
with 
Tafasitamab/Lenalidomide and Plamotamab (All Grades) 
 
Tafasitamaba/Lenalidomide 
Plamotamabb 
Neutropenia  
51% 
20.8% 
Thrombocytopenia 
31% 
24.0% 
a Monjuvi® PI, 2021; Minjuvi® SmPC, 2021  
b Plamotamab Investigator’s Brochure, 2021 
 
These decreases may worsen in grade or duration when the products are given in combination. 
Monitor blood counts carefully and follow institutional guidelines for the treatment of neutropenia 
and thrombocytopenia. Treatment may include the use of growth factors and the administration of 
whole blood/blood product transfusions. Management may also include the delay in the 
administration of study drugs until the counts return to at least Grade 2 levels. See Section 4.7 for 
any dose modifications to study drugs. 


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4.6.3.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and Lenalidomide) 
Hematologic toxicities, specifically, decreases in ANC and platelet counts have been observed in 
clinical trials of tafasitamab and lenalidomide. Decreases in platelets and ANCs have also been 
observed with plamotamab. These decreases may worsen in grade or duration when the products 
are given in combination. Monitor blood counts carefully and follow institutional guidelines for 
the treatment of neutropenia and thrombocytopenia, which may include growth factors and whole 
blood/blood product transfusions. Management may also include the delay in the administration 
of study drugs until the counts return to at least Grade 2 levels. See Section 4.7 for any dose 
modifications to study drugs. 
4.6.3.2. 
Part 2, Arm B (Tafasitamab and Lenalidomide) 
Hematologic toxicities have been observed with tafasitamab and lenalidomide. Follow toxicity 
management instructions provided in the prescribing information for tafasitamab. See Section 4.7 
for any dose modifications to study drugs. 
4.6.4. 
Tumor Lysis Syndrome  
Tumor lysis syndrome (TLS) is a rare but serious and life-threatening condition arising from rapid 
release of tumor cellular contents after lysis; resulting metabolic imbalances can lead to acute 
kidney failure and/or other life-threatening conditions. Subjects with high tumor burden, highly 
proliferative disease, and/or certain preexisting conditions such as renal disease are at increased 
risk of TLS. 
4.6.4.1. 
Safety Run-in and Part 2, Arm A (Plamotamab, Tafasitamab and Lenalidomide) 
It is unknown whether treatment with plamotamab, tafasitamab, and lenalidomide can cause TLS 
in R/R DLBCL. The Phase 1 plamotamab monotherapy study in CD20-expressing hematologic 
malignancies had investigator-reported, any-grade TLS in 4 of 96 subjects (4.2%), of which only 
2 of the 80 R/R NHL subjects (2.5%) experienced TLS; importantly, no serious or fatal events of 
TLS have been reported with plamotamab monotherapy in R/R DLBCL (Plamotamab IB 2021). 
Likewise, no events of TLS were reported in the Phase 2 open-label, single-arm, tafasitamab plus 
lenalidomide study in R/R DLBCL (L-MIND) (Duell, 2021). However, fatal instances of TLS 
have been reported with lenalidomide in other indications and combinations (Revlimid® PI, 2021; 
Revlimid® SmPC, 2022). All subjects should be assessed for risk of TLS according to institutional 
practices based on laboratory parameters and tumor bulk prior to initiation of the study 
medications.  
4.6.4.2. 
Prophylaxis, Monitoring, and Treatment of Tumor Lysis Syndrome 
Prophylaxis should be instituted prior to the start of treatment for subjects at high risk for TLS per 
investigator’s assessment. Hospitalization may be considered for subjects considered high risk for 
TLS per investigator and/or creatinine clearance of < 80 mL/min. Allopurinol (or other xanthine 
oxidase inhibitors) should be initiated at least 48 hours prior to C1D1 in subjects considered 
medium to high risk for TLS. Rasburicase is indicated for elevated uric acid levels and monitoring 
of TLS. During study treatment, all subjects require appropriate laboratory testing prior to 
administration of study medications including uric acid, potassium, phosphorus, calcium, and 


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creatinine. Laboratory results should be evaluated in real time. If subjects are not able to consume 
adequate oral fluids, IV fluids should be added.  
If a subject experiences laboratory changes or symptoms suggestive of TLS, treatment with 
plamotamab, tafasitamab and lenalidomide should be interrupted. Investigators should follow 
institutional guidelines for treatment of TLS. Study treatment is held until resolution of TLS. If 
moderate or high risk for TLS remains after resolution, consideration of additional prophylactic 
measures and/or continued dose interruption or reduction of plamotamab, tafasitamab, or 
lenalidomide may be considered. 
4.6.4.3. 
Part 2, Arm B (Tafasitamab and Lenalidomide) 
Follow the guidelines in Section 4.6.4.2 for the prophylaxis, monitoring, and treatment of TLS. 
4.7. 
Dose Modification Guidelines 
Treat subjects experiencing a significant toxicity with standard medical interventions (eg, use of 
filgrastim to treat neutropenia, acetaminophen for fever) as appropriate. For infusion 
reactions/CRS and neurotoxicity management, Investigators may use their standard treatment 
practices, and for additional guidance, see Section 4.6.  
In general, if a > Grade 2 toxicity prevents dosing > 14 days and/or if 2 consecutive doses are 
missed (this applies to weekly and Q2W dosing), the subject may require discontinuation from the 
plamotamab or tafasitamab treatment. Subjects may reinitiate study drug, even after 2 or more 
missed consecutive doses of plamotamab or tafasitamab, if the Investigator determines that the 
benefit outweighs the risk and the toxicity (if applicable) can be controlled by concomitant 
medication or other means. Medical Monitor approval is required for delays of > 14 days and/or 
2 consecutive doses. 
During weekly dosing of plamotamab and/or tafasitamab, if a subject’s dose is held for ≥ 7 days, 
it should be considered missed. During Q2W dosing of plamotamab and/or tafasitamab, if a 
subject’s dose is held for ≥ 14 days, it should be considered missed. If a subject’s dose is given out 
of window or delayed for safety concerns, including AEs, it is not considered a protocol deviation. 
Plamotamab may be resumed after prolonged dose delay for more than one cycle for reasons other 
than toxicity (eg, comorbidity, pseudoprogression, or delayed response). Resuming initial 
treatment course may be allowed on a case-by-case basis if the Investigator and the Sponsor 
consider this in the best interest of the subject. As a safety measure, the dose may be lowered to 
the priming dose for re-titration. Study assessments, including local and/or central labs, are to be 
collected per the Schedule of Assessments. 
For toxicities that could overlap (eg, CRS, infusion reaction, hematologic toxicities), detailed dose 
modifications by grade are presented in Table 8 below: 
 
 


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Table 8: 
Dose Modifications for Select Toxicities 
 Adverse Reaction  
Severity    
Dosage Modification 
Infusion-related 
reactions  
Grade 2 (moderate)  
•  Interrupt infusion of tafasitamab or plamotamab 
immediately and manage signs and symptoms.  
•  Once signs and symptoms resolve or reduce to Grade 1, 
resume infusion at no more than 50% of the rate at 
which the reaction occurred. If the subject does not 
experience further reaction within 1 hour and vital signs 
are stable, the infusion rate may be increased every 
30 minutes as tolerated to the rate at which the reaction 
occurred. 
•  Dosing of other study medications is not modified. 
Grade 3 (severe) 
•  Interrupt infusion of tafasitamab or plamotamab 
immediately and manage signs and symptoms.  
• Once signs and symptoms resolve or reduce to Grade 1, 
resume infusion at no more than 25% of the rate at 
which the reaction occurred. If the subject does not 
experience further reaction within 1 hour and vital signs 
are stable, the infusion rate may be increased every 
30 minutes as tolerated to a maximum of 50% of the rate 
at which the reaction occurred.  
• If the reaction returns after the rechallenge, stop the 
infusion immediately. 
• Dosing of other study medications is not modified. 
Grade 4 (life-
threatening)  
• Stop the infusion immediately and permanently 
discontinue: 
− Tafasitamab if during or immediately following 
tafasitamab infusion. 
− Plamotamab if during or immediately following 
plamotamab infusion. 
Cytokine release 
syndrome  
Grade 2 (moderate)   
• Interrupt plamotamab infusion immediately and manage 
signs and symptoms (see Section 4.6.1.6). 
• Once signs and symptoms resolve or reduce to Grade 1, 
resume plamotamab infusion at no more than 50% of the 
rate at which the reaction occurred. If the subject does 
not experience further reaction within 1 hour and vital 
signs are stable, the infusion rate may be increased every 
30 minutes as tolerated to the rate at which the reaction 
occurred.  
• Tafasitamab and lenalidomide dosing is not modified.  
  
Grade 3 (severe) & 
Grade 4 (life-
threatening)  
• Interrupt plamotamab infusion immediately and 
disconnect infusion tubing from subject. Manage signs 
and symptoms (see Section 4.6.1.6). 
• The next scheduled dose of plamotamab will be given at 
75% of the previous dose, unless the reaction occurred 


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 Adverse Reaction  
Severity    
Dosage Modification 
on the C1D1 dose, in which case 100% of the previous 
dose may be given.  
• For subsequent plamotamab infusions, if:  
− Toxicity does not recur or recurs at a Grade 1 
severity, escalate to full dose of plamotamab at the 
time of the next dose. 
− Toxicity recurs at a Grade 2 severity, maintain 75% 
dosing of plamotamab. 
− Toxicity recurs at ≥ Grade 3 severity at any time or if 
a Grade 2 takes more than 10 days to resolve to 
≤ Grade 1, discontinue plamotamab permanently.  
• Lenalidomide is also modified if a ≥ Grade 3 CRS event 
occurs:  
− During the first 5 doses of plamotamab: Reduce 
current dose of lenalidomide by 10 mg (or to 5 mg if 
currently at 10 mg) for subsequent doses until C4D1, 
when lenalidomide may be increased back to the dose 
prior to CRS. If CRS recurs at ≥ Grade 2 on 
subsequent reduced dose lenalidomide, permanently 
discontinue lenalidomide.  
− After the first 5 doses of plamotamab: Reduce 
lenalidomide by 10 mg (or to 5 mg if currently at 
10 mg) for all subsequent doses. If CRS recurs at 
≥ Grade 2 on subsequent reduced dose lenalidomide, 
permanently discontinue lenalidomide.  
• Tafasitamab dose is not modified.  
Myelosuppression  
Platelet count of less 
than 50,000/μL  
• Withhold plamotamab, tafasitamab, and lenalidomide 
and monitor CBC weekly until platelet count is 
50,000/μL or higher.  
• Resume plamotamab and tafasitamab at the same dose 
and lenalidomide at a reduced dose. Refer to 
lenalidomide prescribing information for dosage 
modifications.   
• If recurrence, repeat drug withholding and lenalidomide 
reduction steps until minimal lenalidomide dose is 
reached per lenalidomide prescribing information.  
• If recurrence at minimal lenalidomide dose, repeat drug 
withholding step (first bullet above) then reduce the next 
scheduled plamotamab dose to 75% of the previous 
dose.  


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 Adverse Reaction  
Severity    
Dosage Modification 
Neutrophil count of 
1,000/μL or less for at 
least 7 days OR  
  
Neutrophil count of 
1,000/μL or less with an 
increase of body 
temperature to 100.4°F 
(38°C) or higher OR  
  
Neutrophil count less 
than 500/μL  
• Withhold plamotamab, tafasitamab, and 
lenalidomide and monitor CBC weekly until neutrophil 
count is 1,000/μL or higher.  
• Resume plamotamab and tafasitamab at the same dose 
and lenalidomide at a reduced dose. Refer to 
lenalidomide prescribing information for dosage 
modifications.  
• If recurrence, repeat drug withholding (first bullet 
above) and lenalidomide reduction steps until minimal 
lenalidomide dose is reached per lenalidomide 
prescribing information.  
• If recurrence at 5 mg lenalidomide, repeat drug 
withholding steps then reduce the next scheduled 
plamotamab dose to 75% of the previous dose.  
Febrile Neutropenia 
Grade 3 (severe) & 
Grade 4 (life-
threatening)  
• Withhold plamotamab, tafasitamab, and 
lenalidomide and monitor CBC until neutrophil count is 
Grade ≤ 1.  
• Once subject is afebrile, off antibiotics and neutrophil 
count is Grade ≤ 1, resume all therapy at the same dose 
and schedule. 
Neurotoxicity  
Grade 3 (severe)  
• Withhold plamotamab and manage signs and symptoms 
(see Section 4.6.1.7) until the toxicity has recovered to 
≤ Grade 1 (mild) and has remained at ≤ Grade 1 for at 
least 3 days before restarting therapy.  
• Reduce next scheduled plamotamab dose to 75% of the 
previous dose. If ≥ Grade 2 toxicity does not recur, 
escalate plamotamab to full dose in subsequent 
administrations.  
• If ≥ Grade 2 toxicity recurs at 75% dose, or if < Grade 2 
toxicity takes more than 7 days to resolve, permanently 
discontinue plamotamab. 
• Tafasitamab and lenalidomide dosing is not modified.  
Grade 4  
(life-threatening)   
• Stop infusion immediately, if still infusing and 
permanently discontinue plamotamab.  
AST, ALT, bilirubin, 
and alkaline 
phosphatase in the 
absence of CRS  
Grade 3 (severe) 
• Withhold plamotamab and manage signs and symptoms 
until the toxicity has recovered to ≤ Grade 1 (mild) or 
baseline.  
• If a  Grade 3 liver toxicity persists > 14 days and/or 
2 consecutive doses are missed and the toxicity cannot 
be attributed to another cause, permanently discontinue 
plamotamab. 
• Tafasitamab and lenalidomide dosing is not modified. 
Grade 4 (life-threatening) • Withhold plamotamab, tafasitamab, and lenalidomide 
and manage signs and symptoms until toxicity returns to 
≤ Grade 1 (mild) or baseline 


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 Adverse Reaction  
Severity    
Dosage Modification 
• If a Grade 4 liver toxicity persists > 3 days, permanently 
discontinue plamotamab, tafasitamab, and lenalidomide 
Renal 
Impairment/failure  
Creatinine clearance 
59-30 mL/min  
• Reduce lenalidomide to 10 mg daily on Days 1-21 of 
each cycle.  
• Tafasitamab and plamotamab dosing is not modified 
Creatinine 
clearance 30 mL/min not 
requiring dialysis  
• Reduce lenalidomide to 15 mg every other day for 
Days 1-21 of each cycle.  
• Tafasitamab and plamotamab dosing is not modified 
 
Creatinine 
Clearance below 
30 mL/min requiring 
dialysis  
• Reduce lenalidomide to 5 mg once daily for Days 1-21 
of each cycle. On dialysis days, administer the dose 
following dialysis. 
• Tafasitamab and plamotamab dosing is not modified 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; C#D#, eg C1D1 = Cycle # Day #; CBC = 
complete blood count; CRS = cytokine release syndrome. 
 
For other Grade ≥ 3 AEs, other dose modifications will be considered on a case-by-case basis, 
after discussion between the Sponsor and Investigator. 
4.8. 
Criteria for Study Modifications 
Part 1 consists of a 40-subject, two-cohort, single-arm evaluation of the safety of the triple 
combination. The Sponsor may adjust the dose and/or schedule for Cohort 2 based on the initial 
safety evaluation of Cohort 1A and 1B. The Sponsor will assess the data from both cohorts to 
determine the dose and/or schedule before beginning the randomized portion of the study. 
4.9. 
Independent Committees 
4.9.1. 
Independent Data Monitoring Committee 
The IDMC will periodically monitor the randomized portion of the study for safety considerations. 
The IDMC will consist of independent reviewers who are not directly involved in the conduct of 
the study and will advise the Sponsor of any trends or safety issues which may impact the study 
and/or the study subjects. The IDMC will operate according to a charter, which the committee will 
review and ratify before enrollment commences. The IDMC, at a minimum, will as follows: 
• Consist of at least 2 oncologists + 1 statistician, all of whom are independent from the 
study personnel 
− Evaluate accumulating safety data during Part 2 for all enrolled and treated subjects 
after 50, 100, and 150 subjects have been randomized. 


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4.9.2. 
Blinded Independent Review Committee 
A BIRC will conduct a blinded review of combined positron emission tomography with 
computerized tomography (PET/CT) scans or CT scans performed during evaluation of efficacy 
during the study. An imaging laboratory will conduct the review to document response (CR, PR, 
stable disease [SD], or progressive disease [PD]) to therapy for all subjects with at least 1 
post-baseline disease assessment. The central reviewers will be independent of the study 
investigators and blinded to study arm assignment. Each efficacy evaluation for every subject will 
be reviewed by 2 independent radiology reviewers and a clinical reviewer, with any discordance 
between the radiology reviewers adjudicated by a third radiologist. The committee will operate 
according to a charter which will be prepared prior to any efficacy analysis. 
4.9.3. 
Independent Confirmation of Histological Diagnosis 
A central pathologist will review tissue (archival or fresh) provided at baseline to retrospectively 
confirm the diagnosis and cell of origin. The pathologist will not be a participating investigator in 
the study and will operate according to a charter. 
5. 
STUDY ASSESSMENTS 
Table 9 defines the timing of study events and assessments, and Table 10 defines the sampling 
days for plamotamab ADA, cytokines, PK, ECGs, and rituximab levels. Table 11 defines the 
sampling days for tafasitamab ADA and PK. For additional details, refer to the protocol text and 
study manuals. 
 


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Table 9: 
Schedule of Assessments  
Pretreatment, Cycle 1, and Cycle 2 
Evaluation or Procedure 
Pretreatment 
Cycle 1 
Cycle 2 
Day 
-35 to -9 
-8 
-4 
-1 
1 
2 
3 
4 
8 
± 1 
9 
15 
± 1 
16 
22 
± 1 
23 
1 
± 1 
2 
8 
± 1 
15 
± 1 
22 
± 1 
26 ±3 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient status a 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Registration (Part 1)/Randomization 
(Part 2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plamotamab administration b, c 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Tafasitamab administration d 
 
X 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Lenalidomide administration e 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
Medical History f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination f 
X 
X 
 
X 
X 
 
X 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
Xg 
Xg 
X 
Neurologic exam, including ASTCT 
ICANS Consensus Grading h 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Vital signs c, i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
Xg 
Xg 
 
ECOG PS 
X 
X 
 
X 
Xg 
 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
Xg 
Xg 
 
CBC w/ differential  j 
X 
X 
 
X 
X 
X 
X 
X 
Xg 
X 
Xg 
X 
Xg 
X 
Xg 
 
Xg 
Xg 
Xg 
 
Chemistry panel j 
X 
X 
 
X 
X 
X 
X 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
Xg 
Xg 
 
Coagulation panel 
X 
 
 
X 
 
X 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
 
 
 
 
Fibrinogen 
 
 
 
X 
 
X 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
 
 
 
 
Urinalysis with microscopy k 
X 
X 
 
X 
 
X 
 
 
Xg 
 
Xg 
 
Xg 
X 
Xg 
 
 
 
 
 
HBsAb, HCV, HIV l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, Hepatitis B DNA m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Urine or serum β–hCG (females of 
childbearing potential) or serum FSH 
(postmenopausal) n 
X 
X 
 
X 
 
 
 
 
Xg 
 
Xg 
 
Xg 
 
Xg 
 
 
 
 
 


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Pretreatment, Cycle 1, and Cycle 2 
Evaluation or Procedure 
Pretreatment 
Cycle 1 
Cycle 2 
Day 
-35 to -9 
-8 
-4 
-1 
1 
2 
3 
4 
8 
± 1 
9 
15 
± 1 
16 
22 
± 1 
23 
1 
± 1 
2 
8 
± 1 
15 
± 1 
22 
± 1 
26 ±3 
LEN Counseling/Dosing Diary 
Collection 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Rituximab levels 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Peripheral blood for TBNK, leukocyte 
flow cytometry o 
X 
X 
 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Peripheral blood for RNA analysis o 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
SARS-CoV-2 nucleic acid or antigen 
test p 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment q, r 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Archival Tissue s 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies t 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
ctDNA Sample u 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Monitor/record adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Phone/email/mail contact for 
progression/survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG (supine) 
X 
 
 
See Table 10 
Cytokines 
See Table 10 
PK Sampling 
See Table 10 
ADA sampling 
See Table 10 


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Cycles 3 + and Post-Treatment 
Evaluation or Procedure 
Cycle 3 
Cycle 4 
Cycle 5 and 
subsequent 
odd cycles 
Cycle 6 and subsequent 
even cycles 
Post treatment 
Day 
1 ± 1 
8 
± 1 
15 
± 1 
22 
± 1 
1 ± 1 
15 
± 1 
26 ± 
3 
1 ± 1 
15 ± 1 
1 
± 1 
15 ± 1 
26 ± 3 
EOT 
30 d 
± 3 
post-
EOT 
90 d ± 10 
post-EOT 
Follow-up 
Q2 mos. 
± 2 weeks 
Informed consent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of inclusion/exclusion 
criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inpatient status a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
(Part 1)/Randomization (Part 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plamotamab administration b, c 
X 
 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Tafasitamab administration d 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Lenalidomide administration e 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
Medical History f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination f 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
X 
Xg 
Xg 
Xg 
Xg 
X 
X 
X 
 
 
Neurologic exam, including 
ASTCT ICANS Consensus 
Grading h 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
Vital signs c, i 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
Height 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
 
Xg 
Xg 
Xg 
Xg 
 
X 
 
 
 
ECOG PS 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
 
Xg 
Xg 
Xg 
Xg 
 
X 
 
 
 
CBC w/ differential 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
 
Xg 
Xg 
Xg 
Xg 
 
X 
 
 
 
Chemistry panel 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
 
Xg 
Xg 
Xg 
Xg 
 
X 
 
 
 
Coagulation panel 
Xg 
 
Xg 
 
Xg 
 
 
Xg 
 
Xg 
 
 
X 
 
 
 
Fibrinogen 
Xg 
 
Xg 
 
Xg 
 
 
Xg 
 
Xg 
 
 
X 
 
 
 
Urinalysis with microscopy k 
Xg 
 
Xg 
 
Xg 
 
 
Xg 
 
Xg 
 
 
X 
 
 
 
HBsAb, HCV, HIV l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, Hepatitis B DNA m 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 


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Cycles 3 + and Post-Treatment 
Evaluation or Procedure 
Cycle 3 
Cycle 4 
Cycle 5 and 
subsequent 
odd cycles 
Cycle 6 and subsequent 
even cycles 
Post treatment 
Day 
1 ± 1 
8 
± 1 
15 
± 1 
22 
± 1 
1 ± 1 
15 
± 1 
26 ± 
3 
1 ± 1 
15 ± 1 
1 
± 1 
15 ± 1 
26 ± 3 
EOT 
30 d 
± 3 
post-
EOT 
90 d ± 10 
post-EOT 
Follow-up 
Q2 mos. 
± 2 weeks 
Urine or serum β–hCG (females 
of childbearing potential) or 
serum FSH (postmenopausal) n 
Xg 
 
 
 
Xg 
 
 
Xg 
 
Xg 
 
 
 
 
X 
 
Lenalidomide 
Counseling/Dosing Diary 
Collection 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Xv 
Rituximab levels 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Peripheral blood for TBNK, 
leukocyte flow cytometry o 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Peripheral blood for RNA 
analysis o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 nucleic acid or 
antigen test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment q,r 
 
 
 
 
 
 
X 
 
 
 
 
X 
Xw 
 
Xw 
 
Archival Tissue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Biopsies t 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ctDNA Sample  
 
 
 
 
 
 
 
Xu 
 
Xu 
 
 
X 
 
 
 
Monitor/record adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xx 
Xx 
 
Record concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Phone/email/mail contact for 
progression/survival 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG (supine) 
See Table 10 
 
 
 
 
Cytokines 
See Table 10 
PK Sampling 
See Table 10 
ADA sampling 
See Table 10 
ADA = anti-drug antibodies; ASCTC = American Society for Transplantation and Cellular Therapy; β–hCG = beta human chorionic gonadotropin; CBC = complete blood count; 
C#D# = Cycle # Day #, eg, C1D1 = Cycle 1 Day 1; CRS = cytokine release syndrome; CT = computerized tomography; ctDNA = circulating tumor DNA; d = day; DICOM = Digital 
Imaging and Communications in Medicine; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EDC = electronic data 
capture; EOI = end of infusion; EOT = end of treatment; FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = 


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hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICANS = immune effector cell-associated neurotoxicity syndrome; IV = intravenous; 
LEN = lenalidomide; mo = month; PE = physical examination; PET = positron emission tomography; PHI = protected health information; PK = pharmacokinetics; PS = performance 
score; Q# = every # (eg, Q2 mo = every 2 months); SAE = serious adverse event ; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 of the genus betacoronavirus; 
TBNK = T-, B-, and NK cell.  
a Subjects are required to be admitted as inpatient for 72 hours after the first dose of plamotamab and for a minimum of 24 hours after any dose increase of plamotamab.  
b  Plamotamab will be administered as an IV infusion 
.  
c For subjects who tolerate 4 consecutive infusions of plamotamab at a stable dose and schedule without CRS or an infusion reaction during the infusion or post-infusion observation 
period, the post-infusion observation period and vital signs assessment may be reduced from 5 hours to 2 hours. 
d Tafasitamab is administered as a 2 hour IV infusion. On days when both plamotamab and tafasitamab are given, the tafasitamab should be administered before plamotamab with 
at least 2 hours between the infusions. 
e Lenalidomide is administered orally once daily in the evening on Days 1 to 21 of each 28-day cycle, up to 12 cycles. 
f Complete medical history and PE is required at screening. For all the other time points an abbreviated, symptom-directed PE is to be performed. 
g May be performed the day prior to the plamotamab infusion. Results should be available and reviewed before starting plamotamab infusion. 
h ASTCT ICANS Consensus Grading for Adults, Table 5 and Table 6, must be completed at least 1 hour post-infusion, but no more than 12 hours post-infusion, on the day of 
plamotamab infusion. On days when no study drug infusion occurs, the assessments should be completed at approximately the same time each day (approximately 24 hours 
post-infusion, 48 hours post-infusion, 72 hours post-infusion, etc.). Beginning with Cycle 4, the ASTCT ICANS Consensus Grading assessments are only required on Day 1 of 
subsequent cycles. ICANS Grading should also be performed if clinically indicated. 
i Supine or sitting blood pressure and heart rate, body temperature, respiratory rate, and blood oxygen saturation by continuous pulse oximetry. On days of infusions, vital signs 
coinciding with the plamotamab dosing should be taken predose; 15, 30, and 60 minutes after start of infusion (± 5 minutes); at EOI (± 5 minutes); 15 (± 5 minutes); 30 (± 5 minutes); 
and 60 (±10 minutes) minutes after EOI; and then hourly for 4 hours (± 15 minutes). Vital signs for the tafasitamab dosing should be taken predose and 30 minutes after EOI 
(± 5 minutes ). All vital signs during infusion should be taken with subject in the same position. The pulse oximetry for blood oxygen saturation level needs to be captured with 
each vital sign collection; however, pulse oximetry monitoring must be maintained continuously, as practical, throughout the entire admission period for each administration of 
plamotamab, regardless of inpatient or outpatient status. For more information of management of oxygen saturation of 90% or lower, see Section 4.6.1.4. 
j If performed on dosing days, the assessment should be performed prior to administration of any study drug. 
k Urinalysis is required; the microscopy is only required if clinically indicated. 
l May be performed up to 8 weeks prior to screening. 
m HBsAg and Hepatitis B DNA repeat testing should be performed only if HBcAb serology is positive and HBsAb serology is negative at screening. Testing for visit Days 1 at 
Cycle 2 and subsequent cycles should be done 1 to 3 days prior to the Day 1 visit so that results are available prior to the Day 1 dose for the subsequent cycles. 
n FSH needs only to be performed at screening for suspected postmenopausal women. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. 
o Draw prior to study drug administration. In addition, unscheduled samples, if available, may be sent to the designated central laboratory per the laboratory manual for flow and 
biomarker analysis. The frequency of biomarker collections may be reduced during the study based on emerging data. 
p SARS-CoV-2 nucleic acid or antigen test, performed locally, is to be completed and resulted within 7 days prior to Day –8. 
q PET/CT and bone marrow biopsy/aspirate (for subjects with known bone marrow involvement). All studies for the baseline assessment should be performed within 21 days prior 
to Day -8. After Cycle 12, perform disease assessments every 3 cycles (or Q12 weeks) up to Cycle 36 and every 4 cycles (Q16 weeks) up to Cycle 60. Any unscheduled disease 
assessment performed in suspicion of progressive disease must be recorded in the eCRF. 
r PHI-redacted tumor assessments including, but not limited to assessment reports and/or digital imaging files (DICOM) for scans/imaging, blood, and bone marrow biopsy pathology 
reports are to be provided to support response assessments. 
s Archival tissue from excisional biopsies of lymph node to be sent to the designated central laboratory as an archival block (preferred) or up to 43, if possible, unstained slides. 
Archival tissue must predate study treatment. If archival tissue is not available or is insufficient, the screening fresh tumor biopsy becomes mandatory to satisfy the inclusion 
criterion. 
t Fresh tumor biopsy will be collected at screening up to 21 days prior to Day –8. The on treatment fresh tumor biopsy performed after the fourth dose between the C1D22 and C2D1 
visit. Fresh tumor biopsy is strongly encouraged but is optional and requires separate consent. The baseline sample becomes mandatory for study participation if archival tissue is 
not available to satisfy the inclusion criterion. 
u The Screening (baseline) sample will come from the submitted archival or fresh tumor biopsy sample to identify malignant clones.  Samples of whole blood and plasma will be 
collected through C2D1; only whole blood will be collected at C2D26, C6D1, C9D1, C12D1 and EOT for the detection and quantification of ID clonotype(s) that were identified 
from the baseline sample. 


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v Male subjects will be followed for 6 months, and female subjects 8 months following the last dose of study drug to confirm contraceptive use. 
w Subjects who complete a tumor assessment within the prior 14 days do not have to repeat the EOT tumor assessment. If a subject was removed from study for disease progression 
and this response data for that applicable visit is adequately documented in EDC, the post-treatment (EOT and 90 days post EOT) tumor assessments do not need to be repeated. 
x Treatment-related SAEs should be followed up until resolution. 
 


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Table 10: 
Sampling for Plamotamab Anti-Drug Antibodies, Cytokines, PK, and ECGs, and Rituximab Levels  
Plamotamab PK, cytokines, and ADA, as well as ECGs, are performed for subjects in Part 1 and subjects randomized to Arm A 
in Part 2. All times are relative to the plamotamab infusion. On days when tafasitamab and plamotamab are administered, draw 
predose samples and perform ECG before the start of the tafasitamab infusion.  
Study Day 
Pretreatment 
Cycle 1 
Cycle 2 
Cycle 3  
Cycle 4+ 
Post-treatment 
-1 
1  
8  
15  
22  
1 
15 
1 
15 
1 
EOT 
30d ±3 
post 
EOT 
Predose 
Rituximab level 
pPK, 
Cyto, 
pADA 
ECGa 
pPK, 
Cyto, 
pPK, 
Cyto 
pPK, 
Cyto, 
pPK 
Cyto, 
pADA 
ECG 
Ritux-
imab 
level 
Cyto 
pPK 
Cyto, 
pADA 
ECG 
 
Cyto, 
pPKb 
pADAb 
ECGb 
Ritux-
imab 
level h 
 
 
During the Infusion 
 
pPKc 
ECGc 
 
pPKd 
ECGd 
 
 
 
 
 
 
 
 
At the end of the infusion  
(+/- 10 min)  
 
pPK 
ECG 
ECG 
 
ECG 
pPK 
ECG 
ECG 
pPK 
ECG 
 
pPKb 
ECG 
 
 
7 hr post infusion 
(+/- 30 min) 
 
Cyto 
Cyto 
Cyto 
Cyto 
Cyto 
Cytog 
Cytog 
Cytog 
 
 
 
24 hr post infusion 
(+/-2 hr) 
 
Cyto 
pPKe
Cyto 
Cyto 
Cyto 
Cyto 
Cyto 
Cyto 
Cyto 
 
 
 
48 hr post infusion 
(Day 3) 
 
pPKf 
 
 
 
 
 
 
 
 
 
 
Post-treatment; not timed 
 
 
 
 
 
 
 
 
 
 
pPK 
pADA 
pPK 
pADA 
Cyto = cytokine assays; d = day; ECG = electrocardiogram; EOT = end of treatment;  pADA = plamotamab anti-drug antibodies; pPK=plamotamab pharmacokinetics.  
a ECG in triplicate: obtain three ECGs each separated by 2 minutes on Day 1 only; other ECGs are single studies. 
b In all even numbered cycles only 
c 1 hour (±10 minutes) after the start of Day 1 plamotamab infusion 
d 1.5 hours (±10 minutes) after the start of third plamotamab infusion 
e 24 hours (±2 hours) after the start of the second plamotamab infusion 
f 48 hours (±4 hours) after the start of the 1st plamotamab infusion 
g Cytokine assessment is optional at these timepoints 
h Required only at Cycle 4 Day 1 
Note: Predose pPK and ECG: can obtain up to 2 hours prior to the start of the infusion and can be -5 minutes before or +15 minutes after the end of infusion. 
In addition to timepoints from Table 10, cytokines should also be drawn if there is clinical suspicion of CRS at any time and repeated 4 hours later.  
In the event of a subject overdose, an unscheduled PK sample should be collected and sent to the designated central lab, if requested by the Medical Monitor.  
Note: Rituximab level, PK, ADA, and cytokine samples are to be sent to the designated laboratory, per the laboratory manual, for analysis. All samples should be drawn within the 
time windows of the designated time and should be labeled with the exact, actual time of sampling. 


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Table 11: 
Sampling for Tafasitamab Anti-Drug Antibodies and Pharmacokinetics  
Tafasitamab anti-drug antibodies and pharmacokinetics performed in all subjects. All times are relative to the tafasitamab 
infusion. 
Study Day 
Pretreatment 
Cycle 1 
Cycle 2 
Cycle 3  
Cycle 4+ 
Post-treatment 
-8 
2 
9 
15  
16 
23 
1 
15 
1 
15 
1 
EOT 
30d ±3 
post 
EOT 
Pre-dose 
tPK, tADA 
 
 
tPK 
 
 
tPK 
tADA 
tPK 
tPK 
tADA 
tPK 
tPKa 
tADAa 
 
 
30 min (± 15 min) after 
end of infusion 
tPK 
 
 
tPK 
 
 
tPK 
tPK 
tPK 
tPK 
 
 
 
Post-treatment; not 
timed 
 
 
 
 
 
 
 
 
 
 
 
tPK 
tADA 
tPK 
tADA 
tPK=tafasitamab pharmacokinetics; tADA = tafasitamab anti-drug antibodies; d = day; ; EOT = end of treatment 
For pre-dose tPK and tADA, samples can be obtained up to 2 hours prior to the start of the infusion. 
a In all even-numbered cycles only. 
Note: PK, and ADA samples are to be sent to the designated laboratories, per the laboratory manual, for analysis. All samples should be drawn within the time windows of the 
designated time and should be labeled with the exact, actual time of sampling. 


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6. 
SELECTION AND WITHDRAWAL OF SUBJECTS  
6.1. 
Subject Inclusion Criteria  
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
• Adult (age ≥ 18 years) 
• Able to provide written informed consent 
• Histologically confirmed diagnosis of DLBCL, NOS, including DLBCL arising from 
low-grade lymphoma (ie, an indolent pathology such as follicular lymphoma, or 
marginal zone lymphoma transforming into DLBCL) 
• Subjects must have CD20+ and CD19+ lymphoma based on flow cytometric or 
immunohistochemical evaluation of their most recent biopsy 
• At a minimum, archival paraffin embedded tumor tissue (preferred) or unstained slides 
must be available for retrospective cell of origin determination by a central independent 
pathologist. Subjects will be consented and may undergo an optional (recommended) 
biopsy to obtain fresh tumor tissue if a peripheral disease site can easily and safely be 
accessed. A fresh tumor tissue sample will satisfy this criterion for those subjects who 
do not have adequate archival tumor tissue; in this case, the fresh tumor biopsy becomes 
mandatory for participation. 
• Subjects must have at least 1 of the following: 
− Relapsed disease after standard therapeutic options, as defined below: 
 Documented PD, according to the Lugano 2014 criteria (Cheson, 2014) after 
the most recently administered anti-lymphoma regimen  
− Primary refractory DLBCL, defined as follows: 
 Documented persistent disease (less than a complete remission [PR, SD, or 
PD], according to the Lugano 2014 criteria [Cheson, 2014]) at the 
completion of first-line therapy, or 
 Progressive disease (according to the Lugano 2014 criteria) within 3 months 
of completion of first-line therapy 
• Subjects must have received at least 1 prior systemic line(s) of therapy, one of which 
must have included multi-agent chemoimmunotherapy that includes an anti‑CD20 
monoclonal antibody. DLBCL arising from low-grade lymphoma must have relapsed or 
refractory disease after at least 2 prior lines of chemoimmunotherapy (at least one of 
which must have been directed at the DLBCL arising from low grade lymphoma). 
• At least 1 bidimensionally measurable disease site. The lesion must have a greatest 
transverse diameter of ≥ 1.5 cm and greatest perpendicular diameter of ≥ 1.0 cm at 


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baseline. The lesion must have a positive finding on PET scan (for definition, see 
Cheson, 2014). 
• Subjects who are ineligible for or refuse hematopoietic stem cell transplantation 
(HSCT). Subjects may be considered ineligible for HSCT for any of the following 
reasons (Documentation of the reason for a subject’s ineligibility must be provided in 
the subject’s source data and electronic case report form [eCRF]):  
− Age 
− Performance status 
− Comorbidities 
− Stem cell mobilization failure 
− Failure of prior transplant 
− Insufficient response to salvage chemotherapy 
− Subject refusal 
− Logistical reasons 
− Other potential reasons not listed above will be considered on a case-by-case basis 
• If eligible for CAR-T therapy, subjects must consent to bypassing the approved 
treatment with demonstrated clinical benefit 
• An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (see 
Appendix A) 
• Completed vaccination for the SARS-CoV-2 virus prior to study entry is recommended 
Laboratory Values 
• Subjects must meet the following laboratory criteria at screening: 
− ANC ≥ 1.5 × 109/L (for subject with bone marrow involvement ANC ≥ 0.5 × 109/L) 
− Platelet count ≥ 90 × 109/L (for subjects with bone marrow involvement platelet 
count ≥ 50 × 109/L) 
− Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN), unless secondary to 
Gilbert’s syndrome or documented liver involvement by lymphoma. Subjects with 
Gilbert’s syndrome or documented liver involvement by lymphoma may be included 
if their total bilirubin is ≤ 5 × ULN  


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− ALT, AST, and alkaline phosphatase ≤ 3 × ULN, or < 5 × ULN in cases of 
documented liver involvement 
− Serum creatinine clearance must be ≥ 60 mL/minute calculated using a standard 
Cockcroft and Gault formula or Modification of Diet in Renal Disease (MDRD; 
Levey, 1999) 
• Willingness to avoid pregnancy or fathering children based on the criteria below. 
− Male subjects with reproductive potential must agree to take appropriate precautions 
to avoid fathering children (with at least 99% certainty) from screening through 180 
days (6 months) after the last dose of study treatment, even if they have undergone 
a successful vasectomy, and must refrain from donating sperm during this period. 
Permitted methods that are at least 99% effective in preventing pregnancy (see 
Section 6.4) should be communicated to the subjects and their understanding 
confirmed. 
− Women of childbearing potential subjects: 
 Must commit either to abstain continuously from heterosexual sexual 
intercourse or agree to take appropriate precautions to avoid pregnancy (by 
using 2 different methods of birth control with at least 99% certainty) starting 
at least 4 weeks before taking the study treatment, while taking the study 
treatment, during breaks (dose interruptions), and for at least 8 months after 
stopping the study treatment. Permitted methods that are at least 99% 
effective in preventing pregnancy (see Section 6.4) should be communicated 
to the subjects and their understanding confirmed. 
 Must have a negative serum pregnancy test at screening (within 10 to 14 days 
of Day –8) and before the first dose of lenalidomide on Day 1 (within 
24 hours of initiating treatment with lenalidomide). 
 Agree to ongoing pregnancy testing during the course of the study: weekly 
during the first month of study drug treatment, then monthly thereafter for 
women with regular menstrual cycles or every 2 weeks for women with 
irregular menstrual cycles (even if true abstinence is the chosen method of 
birth control) up to and including the end-of-treatment (EOT) visit. 
 Must refrain from breastfeeding and donating oocytes during the course of 
study and for 8 months after the last dose of study treatment. 
Note: The subjects should be informed about the option of donation and cryopreservation of germ 
cells before the study if applicable. 
• In the opinion of the Investigator, the subjects must: 
− Be able and willing to receive adequate prophylaxis and/or therapy for 
thromboembolic events  
− Be able to understand, give written informed consent, and comply with all 
study-related procedures, medication use, and evaluations  


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− Not have a history of noncompliance in relation to medical regimens or be 
considered potentially unreliable and/or uncooperative 
− Be able to understand the reason for complying with the special conditions of the 
protocol and supplemental Summary of Pregnancy Prevention Strategies and give 
written acknowledgement of this in the informed consent form (ICF) 
6.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study: 
Exclusionary Diagnosis 
• High-grade B-cell lymphoma, including those with MYC and BCL2 and/or BCL6 
rearrangements (double-hit or triple-hit lymphoma) and high-grade B-cell lymphoma 
NOS, according to WHO 2016 criteria 
• Any other histological type of lymphoma, including primary mediastinal (thymic) large 
B-cell (PMBL) or Burkitt lymphoma 
• A prior diagnosis of CLL (Richter’s Transformation)  
• Primary central nervous system (CNS) lymphoma 
• A history of secondary CNS involvement by DLBCL are ineligible, unless treated into 
remission 
Exclusionary Previous and Current Treatment 
• Subjects who have previously received treatment with an anti-CD20 × anti-CD3 bsAb 
• Subjects who have been previously treated with tafasitamab 
• Anti-CD20 therapy (eg, rituximab) within 21 days prior to Day –8, in order to minimize 
competition with plamotamab binding to CD20 on DLBCL target cells 
• Subjects who have, within 14 days prior to Day –8: 
− Chemotherapy, radiotherapy, or other lymphoma-specific therapy not including 
anti-CD20 therapy. Note: palliative local radiotherapy is permitted; however, these 
lesions may not serve as target lesions.  
− Small molecule or investigational anticancer agents within 6 elimination half-lives 
prior to Day –8  
− Undergone major surgery not related to lymphoma complications or suffered from 
significant traumatic injury 


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− Received live vaccines (see Section 7.2 for details) within 30 days of Day –8 
− Required systemic anti-infective therapy for active, intercurrent infections  
• Subjects who have had the following prior therapies or treatments: 
− Have, in the opinion of the Investigator, not recovered sufficiently from the adverse 
effects of prior therapy(ies) 
− Were previously treated with CD19-targeted therapy, including CAR-T, unless 
current biopsy (after last therapy) is CD19+  
− Have known intolerance to CD20 monoclonal antibody therapy 
− Have a history of hypersensitivity to compounds of similar biological or chemical 
composition to tafasitamab, IMiDs, and/or the excipients contained in the study drug 
formulations 
− Have undergone ASCT ≤ 1 month prior to signing the informed consent form. 
Subjects who have a more distant history of ASCT must exhibit full hematologic 
recovery before enrollment into the study.  
− Have undergone previous allogenic stem cell transplantation 
− Have 
a 
history 
of 
deep 
venous 
thrombosis/embolism, 
threatening 
thromboembolism, or known thrombophilia, or are at high risk for a 
thromboembolic event in the opinion of the Investigator, and who are not 
willing/able to take venous thromboembolic event prophylaxis during the entire 
treatment period 
− Concurrently use other anticancer or experimental treatments 
Exclusionary Subject’s Medical History 
• Prior history of malignancies other than DLBCL, unless the subject has been free of the 
disease for ≥ 3 years prior to screening. Exceptions to the ≥ 3-year time limit include a 
history of the following: 
− Basal cell carcinoma of the skin 
− Squamous cell carcinoma of the skin 
− Carcinoma in situ of the cervix 
− Carcinoma in situ of the breast 
− Carcinoma in situ of the bladder 


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− Tumor/Node/Metastasis stage of T1a or T1b prostate cancer 
• Subjects with the following medical history: 
− Known active hepatitis infection: 
 Positive test for hepatitis B surface antigen (HBsAg) or hepatitis B core 
antibody (HBcAb; a subject whose HBsAg or HBcAb is positive may be 
enrolled if a hepatitis B virus [HBV] DNA test is negative and either the 
subject is treated with potent antiviral therapy or is re-tested for HBV DNA 
every month) 
 Positive test for hepatitis C virus (HCV) antibodies (a subject whose HCV 
antibody test is positive may be enrolled if quantitative HCV polymerase 
chain reaction test is negative) 
− Known seropositivity for or history of active viral infection with human 
immunodeficiency virus (HIV) 
− Positive SARS-CoV-2 nucleic acid or antigen test 
− History or evidence of clinically significant cardiovascular, CNS, and/or other 
systemic disease that would in the Investigator’s opinion preclude participation in 
the study or compromise the subject’s ability to give informed consent 
− History of solid organ transplantation 
− History or evidence of rare hereditary problems of galactose intolerance, Lapp 
lactase deficiency, or glucose-galactose malabsorption 
− Gastrointestinal abnormalities that would interfere with the ability to take or absorb 
oral medication 
6.3. 
Subject Withdrawal Criteria 
6.3.1. 
Criteria for Removal from Study Treatment 
A subject may withdraw from the study treatment at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for any of the following reasons:  
• Disease progression 
• Occurrence of an unacceptable AE 
• Investigator decision 
• Subject non-compliance with study drug 
• Death 


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• Administrative reasons 
• Other  
Subjects must be withdrawn from treatment if the beta human chorionic gonadotropin (β-HCG) 
pregnancy test is consistent with pregnancy. Before permanent study treatment discontinuation, the 
treatment may be interrupted to confirm the positive pregnancy test. Pregnancy should be reported 
as described in Section 10.4. Subjects with a confirmed positive pregnancy test will continue in the 
follow-up phase of the study. 
6.3.2. 
 Criteria for Removal from Study 
The subject is considered to be off study for any of the following reasons: 
• Screen failure 
• Completed study follow-up period of 5 years 
• Subject requests to be withdrawn from study and any follow-up 
• Death 
Whenever possible, the Sponsor must be notified within 24 hours if a subject is withdrawn from 
treatment and/or study. The reason(s) for a subject’s discontinuation from the treatment and study 
are to be reported to the Sponsor and recorded in the source documents and the subject’s eCRF. For 
subjects who withdraw their consent from the study, this must be clearly documented in their 
subject source documents with confirmation that no further follow-up and data may be collected.  
The EOT and end-of-study (EOS) termination pages in the eCRF must be completed for all subjects 
who discontinue permanently.  
For subjects who discontinue study treatment, all assessments described for the EOT visit should 
be performed at the scheduled visit dates (if at all possible). Subjects who complete a tumor 
assessment within 14 days of EOT do not have to repeat the EOT tumor assessment. Complete the 
EOS eCRF and any follow-up forms at the time of screen failure, death, or withdrawal of consent.  
If it is possible, perform all assessments as close to the scheduled dates as is practicable. 
Post-treatment evaluations should attempt to be completed no later than approximately 4 weeks 
after the final dose administration and prior to initiation of a new treatment for the malignancy. 
Subjects who are withdrawn for any reason may not re-enter this study. The Study Sponsor, Xencor, 
reserves the right to terminate this clinical study at any time and for any reason. 
6.4. 
Avoidance of Pregnancy 
Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental 
monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is 
used during pregnancy, it may cause birth defects or embryo-fetal death. Pregnancy must be 


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excluded before start of treatment. Prevent pregnancy during treatment by the use of 
2 reliable methods of contraception (USPI, Section 5.1). For the most recent information on 
lenalidomide, see the prescribing information in Revlimid® PI, 2021; Revlimid® SmPC, 2022. 
For the most recent information on tafasitamab , refer to the US PI (Monjuvi® PI, 2021) or the 
European Medicines Agency SmPc (Minjuvi® SmPC, 2021).  
Subjects receiving tafasitamab and/or lenalidomide should refer to their respective medication 
guides for more information on avoidance of pregnancy.  
Female subjects and male subjects with female partners of childbearing potential must agree to use 
2 highly effective methods of birth control during, and after, the last dose of study drug. Women 
are considered to be of childbearing potential unless there is a documented reason (ie, 
postmenopausal by history with no menses for 1 year and confirmed by follicle-stimulating 
hormone [FSH; using local reference ranges], OR history of hysterectomy, OR history of bilateral 
tubal ligation, OR history of bilateral oophorectomy (CTFG, 2020). 
Male subjects will be followed for 6 months, and female subjects 8 months following the last dose 
of study drug to confirm contraceptive use. If a pregnancy occurs during this timeframe, it will be 
reported per guidelines in Section 10.4. A woman is considered of childbearing potential, ie fertile, 
following menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical cause. 
A high FSH level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is 
considered fertile after puberty unless permanently sterile by vasectomy or bilateral orchiectomy 
(CTFG, 2020). 
Women of childbearing potential must have a negative serum or urine pregnancy test during 
screening, prior to starting study therapy at Day –8 and again at Cycle 1 Day 1. In addition, a 
negative pregnancy test is required at Day 1 of each subsequent cycle prior to study drug infusion, 
and women of childbearing potential must use a combination of one highly effective contraception 
and one effective contraception method during the study and for 8 months following last dose of 
plamotamab, tafasitamab, or lenalidomide (whichever is administered last).  
Highly effective contraception includes the following: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: oral, intravaginal and transdermal  
• Contraception methods that are considered to have low user dependency include the 
following: 
− Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable and implantable 


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− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system (IUS)  
− Bilateral tubal occlusion  
− Vasectomized partner 
• Sexual abstinence 
− Sexual abstinence is considered a highly effective contraception method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject. The Investigator is responsible for evaluating the reliability 
of the subject’s ability to maintain sexual abstinence throughout the duration of the 
clinical trial. 
Effective contraception includes the following: 
• Male condom 
• Diaphragm 
• Cervical cap 
Periodic abstinence (calendar, ovulation, symptom-thermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. Progesterone-only “mini pills,” IUD 
progesterone T, female condoms, and cervical shield are also not acceptable. 
The male subjects must agree to use condoms. 
7. 
TREATMENT OF SUBJECTS 
7.1. 
Dosing Schedule and Premedications 
7.1.1. 
Plamotamab Dosing Schedule and Premedications 
Subjects in Part 1 and those randomized to Arm A in Part 2 will be administered plamotamab IV 
 In Cycle 1, plamotamab 
will be administered once every 7 days (± 1 day) for 4 doses; beginning with Cycle 2, plamotamab 
will be administered every 2 weeks. 
Subjects in Cohort 1A and Cohort 1B receive plamotamab according to the doses and schedule in 
Table 12. 


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Table 12: 
Cohorts 1A and 1B Plamotamab Dosing Regimen  
Cohort 
Dose 
Level 
Cycle 1  
Day 1 
(Priming Dose) 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 1 
Day 22 
Cycle 2 
 Day 1 
Cycle 2 
Days 1, 8, 15, 
and 22 
Cycle 3 and 
Subsequent 
Q2W Dosing 
1A 
-1 
0.8 mg 
2 mg 
20 mg 
20 mg 
20 mg 
20 mg 
20 mg 
1B 
1 
0.8 mg 
2 mg 
20 mg 
35 mg 
50 mg 
50 mg 
50 mg 
Q2W = every 2 weeks. 
 
The dose and schedule of plamotamab for Part 2 will be determined in Part 1. 
Adjustments may be made to the infusion rate to increase the length of infusion time based on the 
Investigator’s judgement of safety. Due to pump accuracy variations, infusions ending within 
5 minutes prior to the required 
 period will not be considered a deviation.  
Administer plamotamab at least 2 hours after tafasitamab on days when both products are given. 
All subjects in Part 1 and randomized to Arm A in Part 2 will be premedicated for plamotamab 
doses as indicated in Table 13. 
Table 13: 
Premedications for Plamotamab 
 
Cycle 1 
Subsequent Cycles 
Dexamethasone 
(if plamotamab alone is 
administered) 
20 mg IV approximately 1 hour 
prior 
Optional 
Diphenhydramine 
25 mg PO or IV approximately 30 
to 60 minutes prior 
Required 
Acetaminophen 
650 mg PO approximately 30 to 
60 minutes prior 
Required 
IV = intravenous; PO = by mouth. 
 
Subjects who have received 4 consecutive infusions at a stable dose and schedule without CRS or 
infusion reactions may have their premedications modified at the discretion of the Investigator.  
In the event of the discontinuation of plamotamab, in the absence of disease progression, and if the 
subject is still receiving benefit from the study treatment, subjects may continue with other study 
treatment(s). 
7.1.2. 
Tafasitamab Dosing Scheme and Premedications 
All subjects will receive tafasitamab. Priming doses will be administered on Days –8 and –4 of a 
1-week run-in period. During the first 3 cycles of the study, tafasitamab will be infused on Day 1, 
Day 8, Day 15, and Day 22 of each cycle. Thereafter, tafasitamab will be administered on a 
biweekly (every 14 days) basis, with infusions on Days 1 and 15 of each 28-day cycle until disease 
progression, unacceptable toxicity, or discontinuation for any other reason, whichever comes first 


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(Table 14). The first infusion of tafasitamab is given at a rate of 70 mL/h for the first 30 minutes; 
then, the rate is increased so that the infusion is administered within 1.5 to 2.5 hours. All subsequent 
infusions should be infused 1.5 to 2 hours. Administer prior to plamotamab on days when both 
products are given. 
Table 14: 
Tafasitamab Dosing Scheme 
Day –8 and –4 
(Priming Dose) 
Cycle 1 
Days 1, 8, 15, 22 
Cycle 2 
Days 1, 8, 15, 22 
Cycle 3 
Days 1, 8, 15, 22 
Cycle 4 
and Subsequent 
Q2W Dosing 
12 mg/kg 
12 mg/kg 
12 mg/kg 
12 mg/kg 
12 mg/kg 
Q2W = every 2 weeks.  
 
Tafasitamab should be administered according to the package insert (Monjuvi® PI, 2021) and by a 
healthcare professional with immediate access to emergency equipment and appropriate medical 
support to manage infusion-related reactions.  
All subjects will be premedicated for tafasitamab doses as indicated in Table 15. 
Table 15: 
Premedications for Tafasitamab 
 
Day -8 and 
Day -4 
Cycle 1 Day 1 
Cycle 1 Days 8, 
15, and 22 
Subsequent Cycles 
Dexamethasone  
(on days when both 
tafasitamab and plamotamab 
are administered) 
Not applicable 
20 mg IV 
approximately 
30 to 60 minutes 
prior to the start 
of tafasitamab 
20 mg IV 
approximately 30 
to 60 minutes 
prior to the start 
of tafasitamab 
Required prior to the 
start of tafasitamab if 
infusion-related 
reaction observed 
 
Optional if no 
reaction 
Prednisone or equivalent 
(if tafasitamab alone is 
administered) 
100 mg IV 30 – 
60 minute prior 
to the start of the 
infusion 
- 
100 mg IV 30 – 
60 minute prior to 
the start of the 
infusion 
Required if 
infusion-related 
reaction observed 
 
Optional if no 
reaction 
Diphenhydramine 
50 – 100 mg PO 
or IV 
approximately 
30 – 60 minutes 
prior 
50 – 100 mg PO 
or IV 
approximately 
30 – 60 minutes 
prior 
Required if 
infusion-related 
reaction observed 
 
Optional if no 
reaction 
Required if 
infusion-related 
reaction observed 
 
Optional if no 
reaction 
Acetaminophen 
650 – 1000 mg 
PO 
approximately 
30 – 60 minutes 
prior 
650 – 1000 mg 
PO 
approximately 
30 – 60 minutes 
prior 
Required if 
infusion-related 
reaction observed 
 
Optional if no 
reaction 
Required if 
infusion-related 
reaction observed 
 
Optional if no 
reaction 
IV = intravenous; PO = by mouth. 
 


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On study days when both tafasitamab and plamotamab are administered, administer a single dose 
of dexamethasone in Cycle 1 prior to the start of the tafasitamab infusion. If plamotamab is held 
and tafasitamab alone is administered, premedication with prednisone or equivalent is required with 
the first 3 doses only and subsequently required if infusion-related reaction is observed. 
For subjects not experiencing infusion-related reactions during the first 3 infusions, premedication 
is optional for subsequent infusions. If a subject experiences an infusion-related reaction, administer 
premedications before each subsequent infusion. 
In the event of the discontinuation of tafasitamab, in the absence of disease progression, and if the 
subject is still receiving benefit from the study treatment, subjects may continue with the other study 
treatment(s). 
7.1.3. 
Lenalidomide Dosing Scheme  
All subjects will receive lenalidomide and self-administer a starting dose of 25 mg oral 
lenalidomide daily on Days 1 to 21 of each cycle. No more than 21 doses of lenalidomide will be 
dispensed per cycle. Investigators will follow the package insert or SmPC (Revlimid® PI, 2021; 
Revlimid® SmPC, 2022) for recommended medications for venous thromboembolic event 
prophylaxis and dosing modifications. It is recommended that subjects take lenalidomide in the 
evening about the same time each day, with or without food. Advise subjects to swallow 
lenalidomide capsules whole with water and not to open, break, or chew them. Treatment with 
lenalidomide may be modified in a deescalating fashion or discontinued based upon clinical and 
laboratory findings. Detailed dose modification guidelines to manage hematologic and/or other 
toxicities are provided in the relevant sections of the protocol.  
In the event of the discontinuation of lenalidomide, in the absence of disease progression, and if the 
subject is still receiving benefit from the study treatment, subjects may continue with the other study 
treatment(s). 
7.2. 
Concomitant Medications 
All medications (including over-the-counter-medications and herbals) and blood products that are 
administered 21 days prior to start of treatment (Day –8) and throughout subject’s participation in 
the study until the 90-day post-treatment follow-up visit must be recorded in the source document 
and on the eCRF, including date, time, and dose of administration. Concomitant medications for 
other medical conditions are permitted as clinically indicated, subject to specific requirements 
outlined below. 
Subjects may not concurrently receive: 
• Other experimental therapeutics for their malignancy 
• Live viral vaccine within 30 days of Day –8, during treatment, within 60 days of the last 
dose of plamotamab, or within 90 days of the last dose of tafasitamab 
Subjects may receive the following concurrent therapy: 


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• Antiemetics, 
antidiarrheals, 
anticholinergics, 
antispasmodics, 
antipyretics, 
antihistamines, analgesics, antibiotics, and other medications intended to treat 
symptoms  
• Prophylactic filgrastim may NOT be administered after the first dose but may be 
administered during subsequent dosing in subjects who experience Grade 3 or 4 
neutropenia as per the American Society of Clinical Oncology guidelines (Robinson, 
2018). If a subject develops neutropenia after the first dose, they may be treated with 
filgrastim after the second or subsequent dose. 
• Subjects who experience CRS should receive aggressive intervention and supportive 
measures. These may include, but are not limited to, acetaminophen, antihistamines, 
corticosteroids, IV fluids, bronchodilators, epinephrine, vasopressors, oxygen, and 
tocilizumab (see Section 4.6 for guidance on management). 
• Transfusions such as red blood cells (RBCs) and platelets are permitted if medically 
indicated. These should be leukocyte-filtered and irradiated to prevent development of 
transfusion-associated, graft-versus-host disease. All attempts should be made to avoid 
blood product transfusions on the same day as study drug administration.  
• Subjects who experience indigestion, nausea, and/or vomiting may be treated with 
histamine receptor, type 2 antagonists, or proton pump inhibitors  
• Subjects may take vitamins and/or supplements provided they are documented on the 
medication eCRF  
• Subjects may have received hepatitis B reactivation prophylaxis with entecavir, 
tenofovir, or lamivudine 
7.3. 
Treatment Compliance 
The Sponsor or its designee will monitor the study according to ICH GCP guidelines. All 
intravenous investigational therapy will be prepared and administered at the study site, and 
complete records of administration doses, times, durations, and supportive therapies will be kept. 
Lenalidomide for oral use will be provided via a specialty pharmacy in the US or as clinical trial 
material/investigational medicinal product. An accurate accounting of the dispensing and return of 
lenalidomide for each study subject will be maintained in source documents or pharmacy drug 
accountability logs on an ongoing basis by a member of the study site staff. Additionally, if any 
IMP is lost or damaged or if the study subject misses a dose, this information should be documented 
in the study subject’s EDC and source documents. Subjects will be asked to complete a diary of 
lenalidomide administration to document compliance with therapy. 
7.4. 
Treatment Assignment, Randomization, and Blinding 
Prior to administration of any study therapy, each subject must have completed all screening 
activities, and the Medical Monitor or designee must review the screening data and provide 
approval for the subject to start treatment in Part 1 or be randomized into Part 2. All subjects that 


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sign an informed consent form (ICF), including screen failures, will be entered into the electronic 
data capture (EDC) system. 
In Part 1, subjects will be considered enrolled if they have signed the ICF, if the Medical Monitor 
or designee has confirmed the eligibility of the subject for entry, and if they have received the Day –
8 tafasitamab priming dose. Treatment assignment and Study Subject Number assignment will be 
done by a Randomization and Trial Supply Management (RTSM/IRT) system.  
In Part 2, subjects that have signed the ICF and have eligibility confirmed by the Medical Monitor 
or designee may be randomized. The initiation of study treatment will occur within 72 hours of 
randomization. Randomized subjects will start with tafasitamab priming doses on Day –8 and –4. 
Subjects will be randomized at a 1:1 ratio to the 2 treatment arms, stratified by IPI risk score at 
baseline (3 to 5 versus 0 to 2), number of lines of prior therapy (1 versus ≥ 2), and primary refractory 
(yes versus no). A maximum of 36 primary refractory subjects may be enrolled. No blinding is 
specified due to the potential of CRS with plamotamab and infusion-related reactions with 
tafasitamab. Randomization is performed by a designated member of the Investigator’s staff once 
the Sponsor has reviewed the eligibility. Treatment assignment and Study Subject Number will be 
assigned by an RTSM/IRT system. Instructions for registering subjects for treatment and 
performing randomization will be provided in a separate user’s manual. 
7.5. 
Pretreatment Evaluations  
Only those subjects who meet all inclusion but no exclusion criteria specified in Section 6 may be 
enrolled into this study. Prior to the initiation of any on-study testing, including screening testing, 
the subject must have signed the ICF and received a Subject Screening Number (see Section 7.4) 
from the EDC system. The pretreatment period lasts for up to 28 days and includes screening 
evaluations (up to 28 days before the first dose of study drug) and baseline assessments.  
See Table 9 for the Schedule of Assessments and Table 10 (plamotamab) for ADAs, cytokines, PK, 
ECGs, and rituximab levels, and see Table 11 (tafasitamab) for the sampling days for ADA and PK 
levels. 
7.5.1. 
Screening Evaluations (Up to Day –35) 
In Part 1, screening assessments are to be performed during the 28-day window prior to the priming 
dose of tafasitamab. In Part 2, screening assessments are to be performed within 28 days of 
randomization.  
• Obtain signed informed consent (may be done up to Day –35) 
• Review inclusion and exclusion criteria 
• Medical history and physical exam (PE) 
• Neurologic examination will be assessed using the ASTCT ICANS Consensus Grading 
for Adults (see Section 4.6.1.7) 


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• Any cytogenetic information available on the tumor from time of original diagnosis and 
at transformation (if applicable) should be recorded, including cytogenetics, fluorescent 
in situ hybridization (FISH) analysis, and sequencing data 
• Vital signs (supine or sitting position, including heart rate, blood pressure, temperature, 
respiratory rate, and blood oxygen saturation by pulse oximetry) 
• Height, weight 
• ECOG performance status (see Appendix A, Performance Status Scale) 
• Electrocardiogram (ECG), standard 12-lead, supine position 
• Complete blood count (CBC): RBC, hemoglobin, hematocrit, mean corpuscular volume 
(MCV), RBC distribution width (RDW), white blood cell (WBC) with differential 
(neutrophils, 
lymphocytes, 
monocytes, 
eosinophils, 
basophils, 
myelocytes, 
promyelocytes; include percent and absolute, if reported) and platelet count 
• Chemistry panel (sodium, chloride, potassium, bicarbonate, blood urea nitrogen, 
creatinine, glucose, uric acid, calcium, phosphorous, total bilirubin, ALT, AST, total 
protein, albumin, alkaline phosphatase, LDH, as well as serum gamma-glutamyl 
transferase [GGT], amylase, lipase, ferritin (screening only), and C-reactive protein 
(screening only) 
• Coagulation panel (prothrombin time [PT]/international normalized ratio [INR] and 
activated partial thromboplastin time [APTT]) 
• Urinalysis with microscopy (pH, specific gravity, ketones, leukocyte esterase, bilirubin, 
blood, and protein; microscopy may include RBCs, WBCs, hyaline casts, RBC casts, 
WBC casts, granular casts, waxy casts [include microscopy findings in EDC only if 
reported]) 
• Hepatitis B (HBsAg, HBcAb, and HBsAb) and C (HCV), and HIV screening. These 
tests may have been performed within the previous 8 weeks.  
• If HBcAb or HBsAg is positive, perform hepatitis B DNA testing. If subject is negative, 
subject may be enrolled if hepatitis B reactivation prophylaxis is initiated with entecavir, 
tenofovir, or lamivudine  
• SARS-CoV-2 nucleic acid or antigen test (to be completed within 7 days prior to Day –
8) 
• Urine or serum β-hCG pregnancy test for women of childbearing potential performed at 
screening (within 10 to 14 days of Day –8) and at Day –8 or an FSH test for 
postmenopausal women. An FSH test only needs to be performed once during screening 
to confirm that the subject is not capable of becoming pregnant.  


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• Lenalidomide Counseling is performed during screening prior to Day –8. Please see the 
supplemental Summary of Pregnancy Prevention Strategies, provided under separate 
cover, for details.  
• The following are to be sent to the central laboratory per the laboratory manual: 
− Peripheral blood for T-, B-, and NK cells (TBNK); leukocyte flow cytometry to 
assess frequencies of circulating leukocytes; and for leukocyte phenotyping, 
function, and activation markers 
− Peripheral blood for ctDNA analysis to assess MRD (see Section 8.2.1)  
− Archival blocks (preferred) or unstained slides for cell of origin determination by a 
central pathologist (see Section 8.2.2.1)  
− Biopsy of disease site. Subjects will be consented and may undergo an optional 
(recommended) biopsy to obtain fresh tumor tissue (for those subjects with 
accessible superficial lymphadenopathy that can easily and safely be accessed) (see 
Section 8.2.2.1 and Section 8.2.2.2). 
• Tumor assessments will be performed by the Investigator using PET/CT or CT scans 
and bone marrow if bone marrow involvement is suspected or known. The same 
evaluations (ie, imaging, blood, bone marrow) performed at baseline will be performed 
at each subsequent disease assessment. All tumor assessments should be performed 
within 21 days prior to the first dose of Study Drug (Day –8). Tumor assessments must 
be read locally, and scans and other relevant information must be submitted to the central 
imaging designee for review by the BIRC. Redacted tumor assessments including, but 
not limited to, assessment reports and/or actual data (Digital Imaging and 
Communications in Medicine [DICOM] files) for scans, blood analysis, and bone 
marrow biopsy pathology reports may be requested by the Sponsor. If requested by the 
BIRC, additional information may be required, including the interpretation, differential, 
and addenda when available (flow cytometry, cytogenetics, FISH, and/or molecular 
testing.) 
• Record AEs and concomitant medications 
• During Part 1 and 2, registering a subject for approval by Sponsor and during Part 2, 
randomization on Day –10/–9 via third party RTSM/ IRT system by a designated 
member of the Investigator’s staff once all eligibility criteria have been verified 
7.5.2. 
Day –8, Day –4, and Day –1 
• Abbreviated PE (Day –8 and Day –1 only) 
• Neurologic examination will be assessed using the ASTCT ICANS Consensus Grading 
for Adults (Day –1 only, see Section 4.6.1.7)  


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• Vital signs (supine or sitting position, including heart rate, blood pressure, temperature, 
respiratory rate, and blood oxygen saturation by continuous pulse oximetry) 
• Weight (Day –8 and Day –1) 
• ECOG performance status (see Appendix A)  
• CBC with differential (percent and absolute) and platelet count (see Section 7.5.1) 
(Day –8 and Day –1 only) 
• Chemistry panel (see Section 7.5.1) (Day –8 and Day –1 only) 
• Fibrinogen (Day –1 only) 
• Coagulation panel (PT/ INR and APTT) (Day –1 only) 
• Urinalysis (see Section 7.5.1) (Day –8 and Day –1 only) 
• Urine or serum β-hCG pregnancy test for women of childbearing potential (Day –8 and 
Day -1 only) 
• The following to be sent to the central laboratory per the laboratory manual: 
− Serum sample for rituximab level (Day –1 only) 
− Serum samples for tafasitamab PK and ADA (Day –8 only)  
− Peripheral blood for TBNK, leukocyte flow cytometry (Day –8 only) 
− Peripheral blood for RNA analysis (Day –8 only, prior to tafasitamab dose) 
• Administration of tafasitamab on Day –8 and Day –4 
• Record concomitant medications and AEs 
7.6. 
Treatment Evaluations 
7.6.1. 
Treatment Cycles 
The schedule of required procedures and clinical site study days for each cycle is detailed in Table 9, 
Table 10, and Table 11. The day prior to C1D1 is Day -1. Subjects in Part 1 and subjects randomized 
into Arm A of Part 2 will be admitted to an inpatient facility and monitored for a minimum of 
72 hours following dosing for the first dose of plamotamab and for 24 hours following any 
subsequent dose escalation.  
After discontinuation of treatment, subjects will be followed for PFS and OS every 2 months by 
telephone, email, or mail contact by the site up to 5 years or until death. 


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Study days for required procedures are specified in the Schedule of Assessments (Table 9). The 
procedures include the following: 
Clinical Assessments: Clinical assessments include the following:  
• Abbreviated (study-related) medical history 
• PE, including weight and tumor assessment (examination of skin, head, eyes, ears, neck, 
and throat [HEENT], bidimensional measurement of cervical, supraclavicular, axillary, 
and inguinal lymph nodes, spleen size [below costal margin], heart, chest, lungs, 
abdomen, extremities, neurologic, and back).  
• Neurologic examination will be assessed using the ASTCT ICANS Consensus Grading 
for Adults (see Section 4.6.1.7)  
• Vital signs (supine or sitting position, including blood pressure, heart rate, respirations, 
temperature, and blood oxygen saturation by continuous pulse oximetry) 
− For tafasitamab infusion, vital signs and clinical assessment for AEs are monitored 
during and after the end of the infusion. Timepoints include the following: predose 
and 30 (± 5) minutes after end of infusion (EOI). 
− For plamotamab infusion, vital signs and clinical assessment for AEs are monitored 
for a minimum of 5 hours after the end of the infusion.  Timepoints include: predose; 
approximately 15, 30, and 60 minutes after start of plamotamab infusion 
(± 5 minutes); at end of infusion (± 5 minutes); approximately 15 (± 5) minutes; 
30 (± 5) minutes; 60 (± 10) minutes after EOI; and then hourly for 4 additional hours 
(all windows ± 15 minutes). The pulse oximetry for blood oxygen saturation level 
needs to be recorded with each vital sign collection; however, pulse oximetry 
monitoring must be maintained continuously, as practical, throughout the entire 
admission period for each administration of plamotamab, regardless of inpatient or 
outpatient status. For subjects who tolerate 4 consecutive infusions of plamotamab 
at a stable dose and schedule without CRS or an infusion reaction during the infusion 
or post-infusion observation period, the post-infusion observation period and vital 
signs assessment may be reduced from 5 hours to 2 hours.  
• ECOG performance status (see Appendix A, Performance Status Scale). 
• Supine ECG, standard 12-lead (see the Schedule of Assessments [Table 9] for timing of 
collections, and as clinically indicated). Triplicate ECG at C1D1 only, prior to the 
Plamotamab infusion. All ECG tracings will be submitted electronically to the Sponsor 
either by file transfer or scanning the original tracing. Additional details will be provided 
in a separate manual. 
• Lenalidomide Counseling is performed on Day 1 of each cycle. Please see the 
supplemental Summary of Pregnancy Prevention Strategies, provided under separate 
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• Record concomitant medications  
• Record AEs (CTCAE and CRS revised grading system) 
• Tumor assessments will be performed as outlined in Section 9 after Cycle 2, then at the 
end of even-numbered cycles up to Cycle 12, then every 3 cycles up to Cycle 36, and 
then every 4 cycles up to Cycle 60, and at EOT. 
Laboratory Assessments: Safety laboratory assessments, including CBC with differential, 
chemistry panel, fibrinogen, coagulation panel, urinalysis, and pregnancy tests, may be completed 
up to 24 hours prior to the visit day. Excepted is the pregnancy test prior to the first dose of 
lenalidomide, which should be completed on Cycle 1 Day 1, within 24 hours of initiating treatment. 
Safety laboratory values, except for differential counts, fibrinogen, coagulation panel, and 
urinalysis, should be reviewed before starting study drug infusion. 
• CBC with differential (absolute and percent), platelet count, and blast count, if reported 
(see Section 7.5.1) 
• Chemistry panel (see Section 7.5.1) 
• Fibrinogen 
• If HBcAb serology is positive, HBsAg and hepatitis B DNA testing should be 
performed, with results available prior to dosing, on Day 1 of Cycles 2 and later, and at 
EOT (unless HBsAb is also present). 
• Coagulation panel (prothrombin time PT/INR and APTT) 
• Urinalysis (see Section 7.5.1) 
• Urine or serum β-hCG pregnancy test for women of childbearing potential should occur 
weekly during the first 4 weeks of lenalidomide, then on Day 1 of each subsequent 
cycles for dosing of plamotamab, tafasitamab, or lenalidomide. If menstrual cycles are 
irregular, the pregnancy testing should occur every 2 weeks during each subsequent 
cycle. 
• The following are to be sent to the central laboratory per the laboratory manual: 
− Serum samples for plamotamab and tafasitamab ADA, cytokines, and plamotamab 
and tafasitamab PK (see Table 10 and Table 11 for collection schedule). All samples 
should be drawn within the window indicated on Table 9 and of the designated time 
and should be labeled with the exact, actual time of sampling.  
− Peripheral blood for TBNK, leukocyte flow cytometry 
− Peripheral blood for RNA analysis  


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− Peripheral blood for ctDNA analysis  
− Tumor biopsies (for those subjects who provided consent) collected once at 
follow-up (See Section 8.2.2 and Table 9) 
7.6.2. 
End of Treatment Visit 
Subjects will have their EOT visit at the end of the last cycle of treatment. If a subject terminates 
before the end of a cycle, the EOT assessments (as indicated in Table 9) will be performed as early 
as possible after study drug discontinuation. Subjects who complete a tumor assessment within 
14 days of EOT do not have to repeat the EOT tumor assessment. 
7.6.3. 
Ninety (90) Days After the Last Dose of Study Medication 
Subjects will have a visit 90 days after the last dose of any study medication (± 10 days). Efforts 
should be made to have subjects complete the 90-day post last treatment visit for safety evaluation. 
The visit is not necessary if the subject enrolls into another trial, if the subject begins treatment for 
the malignancy under study, or if hospice or palliative care is initiated before this visit; if possible, 
this visit should be scheduled earlier. Assessments are as indicated in Table 9.  
7.6.4. 
Long-Term Follow-Up Period 
All subjects will be followed for progression and OS approximately every 2 months (± 2 weeks) 
after the 90-day follow-up visit (see Section 7.6.3) visit. This includes subjects who discontinue 
treatment due to progression or toxicity, as well as those who discontinue before progression to 
pursue a new anti-lymphoma/salvage therapy (chemotherapy, SCT, radiotherapy, etc.). Subjects 
who discontinue due to toxicity and without progression will continue to have efficacy assessments 
performed until progression or the initiation of new therapy. Subjects will be contacted by 
telephone, email, or mail contact by the site until death or 5 years from randomization. The 
following data will be collected at each follow-up contact: 
• Survival status date and cause of death (if applicable) 
• Transplantation date and other transplant related outcomes (if applicable) 
• Date of progression 
• subsequent treatments and efficacy outcomes of those treatments 
• date of last confirmation of survival (last know date alive) 
It is anticipated that the information will be available from the treating Investigator, oncologist, 
primary care physician, local medical records, or the subject. The Investigator may search public 
sources for status information. Completion of the long-term follow-up period is required for any 
randomized subject, even if the subject did not receive the intervention. The duration of follow-up 
on this trial may be modified based on observed subject outcomes, ie, lengthened if significant 
numbers of durable responses are seen or shortened if few subjects require long follow-up. 


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7.7. 
Study Drug 
7.7.1. 
Plamotamab (XmAb13676) 
Plamotamab (XmAb13676) is a humanized bsAb that binds both CD3 and the tumor antigen CD20 
in order to recruit cytotoxic T cells to kill CD20 positive tumor cells. IV Solution Stabilizer (IVSS) 
is a concentrated form of the plamotamab (XmAb13676) buffer that also minimizes protein binding 
to the administration equipment when plamotamab is administered at lower concentrations. 
 
 
 
 Dilution 
instructions for any alternate fill volumes required during the study will be provided in the 
pharmacy manual. 
 
 
  
7.7.2. 
Tafasitamab-cxix (Tafasitamab) 
Tafasitamab-cxix (herein referred to as tafasitamab) for injection is supplied as a 200 mg vial 
containing a sterile, preservative-free, white to slightly yellowish lyophilized powder in a 
single-dose vial for IV use after reconstitution. After reconstitution with 5 mL of Sterile Water for 
Injection, USP, the resulting concentration is 40 mg/mL with a pH of 6.0. Each single-dose vial 
contains 200 mg tafasitamab, citric acid monohydrate (3.7 mg), polysorbate 20 (1 mg), sodium 
citrate dihydrate (31.6 mg) and trehalose dihydrate (378.3 mg). 
7.7.3. 
Lenalidomide 
Lenalidomide may be provided by the Investigator or as clinical trial material/investigational 
medicinal product (Revlimid or regionally approved generic lenalidomide). 
7.8. 
Study Drug Storage 
7.8.1. 
Plamotamab 
Vials containing plamotamab and IVSS must be stored under refrigeration at 
 in an 
appropriately secured area accessible only to the pharmacist, the Investigator, or a duly designated 
person. Since plamotamab does not contain preservatives, opened vials of plamotamab must be 
used within 24 hours.  
7.8.2. 
Tafasitamab 
Vials containing tafasitamab are to be stored according to package insert or SmPC (Monjuvi® PI, 
2021; Minjuvi® SmPC, 2021). 


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7.8.3. 
Lenalidomide 
Lenalidomide is to be stored according to the package label for Revlimid or generic lenalidomide 
(Revlimid® PI, 2021; Revlimid® SmPC, 2022). 
7.9. 
Study Drug Preparation 
7.9.1. 
Plamotamab 
Note that plamotamab has pharmacodynamic effects in vivo at very low concentrations and 
therefore each product vial must be highly diluted before administration.  
Plamotamab solution is prepared under aseptic conditions. Prior to administration, plamotamab will 
be diluted to the required final concentration in one or more infusion bags containing 
 
. Prior to dilution, the vial 
containing parenteral drug product should be inspected visually. If particulate matter and/or 
discoloration are noted, drug should not be administered, and the Sponsor should be notified. After 
dilution, the bag containing plamotamab (XmAb13676) should be gently inverted 2 to 3 times to 
mix the solution. THE BAG MUST NOT BE SHAKEN. See the Study Pharmacy Manual for 
additional details. 
7.9.2. 
Tafasitamab 
Tafasitamab is prepared according to the package insert or SmPC (Monjuvi® PI, 2021; Minjuvi® 
SmPC, 2021). 
7.9.3. 
Lenalidomide 
Lenalidomide is provided as orally administered capsules, which the study center will dispense to 
the subject. 
7.10. 
Study Drug Administration 
7.10.1. 
Plamotamab  
Plamotamab has previously been given to humans in a Phase 1 clinical study (XmAb13676-01). In 
the XmAb13676-01 study, CRS was frequently observed, especially with the Cycle 1 Day 1 dose 
(Section 2.4). Either a Principal Investigator or Sub-Investigator (MD) must be readily available 
during and for a minimum of 24 hours after administration of a plamotamab dose. 
All subjects will be premedicated in Cycle 1 with dexamethasone 20 mg IV approximately 30 to 
60 minutes prior to the start of the tafasitamab infusion. During Cycle 1, if tafasitamab infusion is 
held for any reason, dexamethasone will be given 1 hour prior to the start of the plamotamab 
administration. After Cycle 1, premedication with dexamethasone is not required and is permitted 
at the Investigator’s discretion. (Cetirizine or other antihistamine may be used in place of 
diphenhydramine). 


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Plamotamab administration should begin as soon as possible after the dosing solution is prepared. 
If there is a delay in administration, it may be stored at 
 
.  
Plamotamab SHOULD NOT BE ADMINISTERED AS AN IV PUSH OR BOLUS.  
Study drug will be administered as an open-label solution at a 
 
 using a dedicated infusion set. Precautions for CRS or infusion 
reactions/anaphylaxis should be observed during plamotamab administration. Due to the possibility 
that CRS or allergic/infusion reactions may occur, emergency resuscitation equipment (a “crash 
cart”) and medications including steroids and tocilizumab should be present in the immediate area 
where subjects are receiving their infusions. Additional supportive measures should be available 
and may include, but are not limited to, acetaminophen, antihistamines, corticosteroids, IV fluids, 
bronchodilators, epinephrine, vasopressors, and oxygen.  
Management of CRS and other infusion-related reactions will be per standard investigational site 
procedures, or alternatively, as outlined in this protocol. Please refer to Section 4.6 for management 
of infusion reactions/CRS and neurotoxicity, if needed. 
Vital signs will be measured and recorded as described in Section 7.6.1. 
7.10.2. 
Tafasitamab 
Tafasitamab will be administered according to the package insert or SmPC (Monjuvi® PI, 2021; 
(Minjuvi® SmPC, 2021). 
7.10.3. 
Lenalidomide 
Lenalidomide will be dispensed to the subject to take orally in the evening according to the package 
insert or SmPC (Revlimid® PI, 2021; Revlimid® SmPC, 2022). The subject will be given a diary to 
record the date and time of each administration of lenalidomide and to provide accountability of 
the product. 
If a subject misses a dose of lenalidomide and it is within 12 hours of their normal dosing time, the 
subject should be instructed to make up the missed dose, and to then take their next dose according 
to their regular schedule.  
7.11. 
Study Drug Accountability, Handling, and Disposal 
Detailed instructions and procedures for study drug dispensing are included in the Pharmacy 
Manual. 
Accurate accounting of all study medication must be maintained. The Investigator agrees to keep 
an inventory of study drugs using local investigational pharmacy drug accountability logs. Drug 
disposition records must be kept in compliance with applicable guidelines and regulations. 
Upon completion or termination of the study, any used vials, partially used vials, unused study 
medication, unused diluted drug dosing solutions, or unused IVSS should be destroyed in 


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Any unused lenalidomide must be returned to the study center for accountability and destruction 
according to local regulations or institutional policy. 
Subjects will be required to keep a diary of the administration of lenalidomide. Dosing instructions 
will be provided to the subject. Compliance with study intervention will be assessed at the 
beginning of each cycle. Compliance will be assessed by counting returned capsules, in conjunction 
with subject diary information and subject questioning and counseling during the site visits and 
documented in the source documents and eCRF. Deviation(s) from the prescribed dosage regimen 
should be recorded in the eCRF. 
A record of the number of lenalidomide capsules dispensed to and taken by each subject must be 
maintained and reconciled with study medication and compliance records. Lenalidomide start and 
stop dates, including dates due to delays and/or dose reductions, will also be recorded in the eCRF. 
8. 
PHARMACOKINETIC, PHARMACODYNAMIC, AND 
BIOMARKER ASSESSMENTS 
8.1. 
Serum Assessments for Pharmacokinetic Analyses, Anti-Drug 
Antibodies, Cytokines, and Rituximab Levels 
Venous blood samples for serum analyses of plamotamab and tafasitamab PK, plamotamab and 
tafasitamab ADA, cytokines, and rituximab levels will be obtained as per the schedule listed in 
Table 10 and Table 11. Remaining samples will be stored for additional testing of biomarkers 
associated with pharmacodynamic activity, clinical response, or resistance to the study drugs. This 
testing may occur at ICON Laboratory Services, Inc. or at another Sponsor designee as detailed in 
the Laboratory Manual. 
8.2. 
Pharmacodynamics and Biomarker Assessments 
8.2.1. 
Peripheral Blood Assessments 
Blood specimens will be collected to explore pharmacodynamic effects of plamotamab, 
tafasitamab, and lenalidomide on leukocyte frequencies and markers of T-cell and/or leukocyte 
function, including, but not limited to, checkpoint molecules, markers of proliferation and T-cell 
activation, and markers of T-cell exhaustion. The frequencies of circulating T cells, B cells and NK 
cells will also be monitored. Additional blood samples will be drawn into PAXgene RNA tubes and 
stored for potential explorative studies of leukocyte function and pharmacodynamic effects by RNA 
sequencing and transcriptomic gene and pathway analysis. Baseline and pharmacodynamic markers 
in the periphery will be evaluated for correlation with incidence of CRS and AEs along with clinical 
response and resistance. Assessment of CRS in the 24 hours following each dose will include 
monitoring serum cytokines and flow cytometric evaluation of the change in the quantity and 
activation state of T cells in the peripheral blood.  
A blood sample will be collected at screening and on treatment for measurement of ctDNA. By 
tracking levels of and mutations in ctDNA by DNA sequencing methods on treatment, ctDNA as a 


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measure of MRD will be explored as a marker of clinical response. Blood samples may also be 
used to evaluate germline DNA variation across the genome in order to interpret tumor-specific 
DNA mutations. 
Detailed instructions for processing and shipping peripheral blood samples are provided in the 
Laboratory Manual. For the sampling schedule, see Table 9 (Schedule of Assessments). 
Unscheduled samples may be collected and sent to the designated central laboratory at the 
discretion of the Investigator. Remaining peripheral blood mononuclear cells, plasma samples, and 
serum samples will be stored at the designated central laboratory and may be used for assessment 
of additional future exploratory biomarkers associated with pharmacodynamic activity, clinical 
response, or resistance to the study drugs. 
8.2.2. 
Tumor Biopsies 
8.2.2.1. 
Archival Tissue 
Archival blocks (preferred) or unstained slides will be requested from lymph node biopsies to 
confirm DLBCL diagnosis, determine cell of origin status, and to perform genomic mutation 
analysis. Cell of origin assays (COO), germinal center B-cell (GCB), or activated B cell type (ABC) 
origin will be determined using transcriptional analysis, Nanostring LymphC2x, or other gene 
expression methods. Immunohistochemistry analysis will be performed using relevant markers in 
the Hans algorithm (Yoon, 2017).  
Archival tissues of diagnostic tumor mass or lymph node must be confirmed to be available at the 
time of study entry and will be collected and sent to the designated central laboratory within 8 weeks 
of first dose of study medication or randomization. For the sampling schedule, see Table 9 
(Schedule of Assessments). If archival tissue is not available, a fresh tumor biopsy at baseline will 
be requested (Section 8.2.2.2). 
8.2.2.2. 
Baseline and On-Treatment Tumor Biopsies 
Baseline Biopsies: Fresh tumor biopsies (excisional or core needle biopsies) are encouraged as 
they allow an unbiased analysis of tumor status in contrast to archival biopsies which may not 
reflect impact of therapies prior to study start. Therefore, pretreatment baseline biopsies will be 
requested if the subject provides consent and presents with accessible involved lymph nodes, for 
instance, superficial lymphadenopathy, enabling low-risk procedures to be performed to obtain 
tissue. Excisional or core needle biopsies are acceptable while fine needle aspiration is not 
acceptable. 
On-treatment Biopsies: On-treatment biopsies are requested in subjects with accessible 
lymphadenopathy. On-treatment biopsies are to be obtained in the fourth week of treatment (after 
the C1D22 dose, but prior to the C2D1 dose). In responding subjects, an additional biopsy is 
recommended upon progression to ascertain the molecular and cellular basis of progression, and to 
specifically rule out loss of CD19 or CD20 expression as a mechanism of acquired resistance.  
Tumor tissue from archival, pretreatment, on-treatment and progression biopsies will be processed 
to enable analysis, including, but not limited to, (1) DNA sequencing to identify acquired genetic 


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variants in tumor cells; (2) RNA analysis of tumor and the tumor microenvironment; (3) 
immunostaining of the tumor for CD19 and CD20 expression, and of the inflammatory cells, 
including T cells, in the microenvironment.  
Baseline and on-treatment biopsies will be collected and sent to the central laboratory designated 
in the Laboratory Manual. For the sampling schedule, see Table 9 (Schedule of Assessments). 
Following the study specified tumor biopsy analysis, remaining archival and fresh biopsy samples 
will be stored at the designated central laboratory for assessment of additional future exploratory 
biomarkers associated with pharmacodynamic activity, clinical response, or resistance to the study 
drugs. 
9. 
ASSESSMENT OF EFFICACY 
9.1. 
Efficacy Assessments 
 


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Table 16: 
Assessment of Response 
Response 
Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
Lymph nodes and 
extralymphatic sites 
Complete metabolic response  
Score 1, 2, or 3a with or without a residual mass on 
5PSb 
Complete radiologic response (all of the following) 
Target nodes/nodal masses must regress to <  1.5 cm in LDi  
No extralymphatic sites of disease 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
 
Bone marrow 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC negative 
Partial 
Lymph nodes and 
extralymphatic sites 
Partial metabolic response 
Score 4 or 5b with reduced uptake compared with 
baseline and residual mass(es) of any size 
Partial remission (all of the following) 
> 50% decrease in SPD of up to 6 target measurable nodes and 
extranodal sites 
When a lesion is too small to measure on CT, assign 5 mm × 5 
mm as the default value 
When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm, but smaller than normal, use 
actual measurement for calculation 
Non-measured lesion 
Not applicable 
Absent/normal, regressed, but no increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by > 50% in length beyond normal 
New lesions 
None 
None 
Bone marrow 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the 
context of a nodal response, consideration should 
be given to further evaluation with MRI or biopsy 
or an interval scan 
Not applicable 


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Table 16: 
Assessment of Response (Continued) 
Response 
Site 
PET-CT–Based Response 
CT-Based Response 
Stable or No 
response 
Target nodes/nodal 
masses, extranodal 
lesions 
No metabolic response 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of 
treatment 
Stable disease 
< 50% decrease from baseline in SPD of up to 6 dominant, 
measurable nodes and extranodal sites; no criteria for 
progressive disease are met 
Non-measured lesion 
Not applicable 
No increase consistent with progression  
Organ enlargement 
Not applicable 
No increase consistent with progression 
New lesions 
None 
None 
Bone marrow 
No change from baseline 
Not applicable 
Progressive 
Individual target 
nodes/nodal masses 
 
Extranodal lesions 
Progressive metabolic disease 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or 
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment assessment 
Progressive disease requires at least 1 of the following PPD 
progression: 
An individual node/lesion must be abnormal with: LDi > 1.5 cm 
and 
Increase by > 50% from PPD nadir and  
An increase in LDi or SDi from nadir 
0.5 cm for lesions ≤ 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length must increase 
by > 50% of the extent of its prior increase beyond baseline 
(eg, a 15-cm spleen must increase to > 16 cm). If no prior 
splenomegaly, must increase by at least 2 cm from baseline 
New or recurrent splenomegaly 
Non-measured lesions 
None 
New or clear progression of preexisting non-measured 
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Response 
Site 
PET-CT–Based Response 
CT-Based Response 
New lesions 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be 
considered 
Regrowth of previously resolved lesions 
A new node > 1.5 cm in any axis  
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in 
any axis, its presence must be unequivocal and must be 
attributable to lymphoma Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
5PS = 5-point scale; CT = computed tomography; FDG = fluorodeoxyglucose; IHC = immunohistochemistry; LDi = longest transverse diameter of a lesion; MRI 
= magnetic resonance imaging; PET = positron emission tomography; PPD = cross product of the LDi and perpendicular diameter; SDi = shortest axis 
perpendicular to the LDi = SPD, sum of the product of the perpendicular diameters for multiple lesions. 
 
Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. 
Nodes should preferably be from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions 
include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on palpation. Recently biopsied lesions should 
not be used as a measured dominant lesion.   
Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered not measured. These sites include 
any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. 
 
a In Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response 
but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors). 
b PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake moderately > liver; 5, uptake markedly higher 
than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 


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The Investigator and the BIRC will assess response to study drug at each efficacy timepoint. The 
following endpoints will be reported: 
Progression-free Survival: defined as the time from randomization to the first documentation of 
progressive disease or death, whichever comes first. The Investigator and the BIRC will determine 
the progressive disease event in all randomized subjects. 
Duration of Response: defined as the time from the first response (CR or PR) to progression or 
death due to any cause among subjects achieving a CR or PR and among CR subjects. DOR will 
be derived using disease progression as determined by the BIRC in subjects who have a response 
(CR or PR). 
Overall Survival: defined as the time from randomization to death from any cause. All randomized 
subjects will be followed for up to 5 years for survival. 
Time to Treatment Failure: defined as the time from randomization to discontinuation of all study 
treatment for any reason, including disease progression, treatment toxicity, and death. The time to 
treatment failure will be using disease progression as determined by the Investigator and by the 
BIRC. 
10. 
ASSESSMENT OF SAFETY 
10.1. 
Safety Parameters 
Safety assessments will include the following: 
• AEs/SAEs 
• Vital signs 
• PE findings 
• Clinical laboratory safety assessments  
− Note: Information on cytokines associated with CRS will also be collected as 
additional safety information but will not be assessed in real time.  
• ECG parameters 
• Performance status (ECOG) changes 
10.1.1. 
Treatment/Reporting of Overdose or Medication Errors 
In the event of an overdose, the Investigator should do the following: 
• Contact the Medical Monitor immediately 


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• Closely monitor the subject for any AE/SAE and laboratory abnormalities  
• Obtain a plasma PK sample if requested by the Medical Monitor (determined on a 
case-by-case basis) 
• Document the quantity and duration of the excess dose or error 
The Investigator, in consultation with the Medical Monitor, will decide dose interruptions or 
modifications based on clinical evaluation of the subject. 
All overdose cases should be reported as SAEs. 
10.2. 
Adverse Events and Serious Adverse Events 
10.2.1. 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a study subject. The AE does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug. Adverse events may include the onset 
of new illness and the exacerbation of preexisting conditions. 
Adverse events are classified as “serious” and “non-serious” for regulatory reporting purposes. 
10.2.2. 
Definition of Serious Adverse Events 
A Serious Adverse Event (SAE) is an AE occurring during study after the subject has signed the 
ICF that fulfills one or more of the following: 
• Results in death 
• Is life-threatening; this means that the subject was at immediate risk of death at the time 
of the event. It does not mean that the event hypothetically might have caused death if 
it were more severe. 
• Requires inpatient hospitalization or prolongation in existing hospitalization 
− Note: Hospitalization is defined as more than 24 hours as an inpatient, or 
prolongation of planned hospitalization by >24 hours due to an AE. 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect 
• Is an important medical event. Important medical events are events that may not be 
immediately life-threatening but are clearly of major clinical significance in the opinion 
of the Investigator. They may jeopardize the subject and may require intervention to 


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prevent one of the other serious outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or 
in a physician’s office, blood dyscrasias or seizures that do not result in subject 
hospitalization, and the development of drug dependency or drug abuse.  
A distinction should be drawn between serious and severe (Grade 3) AEs. Severity (see 
Section 10.2.3.1) is a measure of intensity, whereas seriousness is defined by the criteria above. For 
example, a mild degree of gastrointestinal bleeding requiring hospitalization for monitoring 
purposes would be considered an SAE but is not necessarily a severe (Grade 3) SAE. Similarly, an 
AE that is severe (Grade 3) is not necessarily an SAE. For example, alopecia may be assessed as 
severe (Grade 3) but would not be considered an SAE. 
The following should not be reported as an AE/SAE: 
• Signs/symptoms and conditions related to disease progression of the primary condition 
under the investigation (eg, tumor-related pain, metastasis, new lesions, etc.), 
hospitalization, and death due to disease progression unless related to study drug. 
• Hospitalizations for planned surgical/medical elective procedures or planned 
admissions for study drug administration. 
Suspected Unexpected Serious Adverse Reaction (SUSAR):  
During the study, the Sponsor may determine that certain safety reports are required to comply with 
regulations. The Investigator may receive notification of a Suspected Unexpected Serious Adverse 
Reaction (SUSAR). These reports must be submitted to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) per local requirements as soon as possible, and 
documentation of this submission should be available to the Sponsor or ICON. 
10.2.3. 
Adverse Event Monitoring, Recording, Reporting, Follow-up, and Assessments 
AE monitoring will begin upon the signing of the ICF. Concomitant illnesses, which existed prior 
to entry into the clinical study, will not be considered AEs unless they worsen during the treatment 
period. Preexisting conditions will be recorded as part of the subject’s medical history. A 
preexisting condition should be recorded as an AE if the frequency, intensity, or character of the 
condition worsens during the study period. 
All AEs experienced by a subject, irrespective of the suspected causality, will be monitored until 
the event has resolved or stabilized, until any abnormal laboratory values have returned to baseline 
or stabilized at a level acceptable to the Investigator and Sponsor medical representative, until there 
is a satisfactory explanation for the changes observed, or until the subject is lost to follow-up. 
AEs may be volunteered spontaneously by the study subject, discovered by the study staff during 
physical examinations, or by asking an open, nonleading question such as “How have you been 
feeling since you were last asked by us?” or “Have you had any new or changed health problems 
since you were last here?” 


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All AE terms (also called reported term or verbatim) should be recorded individually. Only a 
diagnosis, if known, should be recorded as an AE term rather than each individual symptom. If a 
diagnosis is not available or unclear, all symptoms should be reported. 
The recording of AEs will be done in the following manner:   
Non-serious AEs will be recorded in the EDC database after signing the ICF through 90 days after 
the last dose of any study treatment. For screen failed subjects, the recording of non-serious AEs, 
after the ICF was signed, is not needed. 
Serious AEs or SAEs will be recorded in the EDC AE page (eCRF) and the completed SAE report 
form will be emailed to ICON PVSS. The Investigator is responsible, within 24 hours of 
becoming aware of the SAE, to complete all required details on the initial SAE report form and to 
email to 
  
If new information becomes available or details are changed, the submitted SAE form should be 
retained at the site as is, and a new (blank) follow up SAE report form for the same case should be 
completed, marked as “follow-up,” and emailed to 
 The changes reported 
in the follow-up SAE report form should be also made in EDC. 
Table 17 defines the windows for capturing serious and non-serious AEs.  
Table 17: Investigational Site Recording/Reporting of Adverse Events 
Type of 
Adverse 
Event 
Start of Reporting 
Window 
End of Reporting Window 
Non-serious 
AE 
Signing of ICF  
 
Note: If the subject has 
failed screening, non-
serious AEs should not 
be recorded. 
For non-serious AEs: Any of the following would be considered as 
the end of reporting:  
• 90 days after the last dose  
• initiation of another anticancer therapy  
• withdrawal of consent by subject 
SAE 
Signing of ICF 
• 90 days after the last dose  
• initiation of another anticancer therapy 
• withdrawal of consent by subject 
 
SAEs related to study drug should be followed up until the 
resolution, if possible. 
AE = adverse event; ICF = informed consent form; SAE = serious adverse event. 
 
ICON PVSS may request clarification of omitted or discrepant information from the initial 
notification or follow-up SAE report as needed. ICON PVSS and/or the Sponsor may also request 
additional information regarding the SAE in order to obtain the full clinical picture. The Investigator 


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or an authorized delegate is responsible for providing the requested information in a Data 
Clarification Form (DCF) to ICON PVSS/Sponsor. 
Initial reports of SAEs must be followed up as soon as possible with detailed information; this may 
include clear photocopies of other documents as necessary (eg, hospital records, consultant reports, 
autopsy reports, etc.) with the study subject’s personal identifiers redacted. All relevant information 
obtained by the Investigator through review of these documents will be recorded and forwarded to 
ICON PVSS within 24 hours of receipt of the information.  
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
E-mail: 
  
Fax number: 
 
Emergency contact number: 
 (within US) 
 (toll number and outside of US) 
1. E-mail your SAE report form to the e-mail address above. 
2. Provide the name of the Principal Investigator, your name, the telephone number where you 
can be reached and the protocol number and title. 
3. Immediately forward the SAE report form and any supporting documentation to ICON PVSS; 
this must be done within 24 hours of becoming aware of the event. 
The Investigator is responsible for reporting adverse drug reactions (ADRs) related to the other 
study treatments to the Sponsor. The Sponsor will report the ADRs to the respective Marketing 
Authorization Holders, as applicable. 
Investigators should perform the following assessments of AEs (both for non-serious and serious): 
10.2.3.1. AE Severity/Intensity Grading 
The Investigator will assess all AEs for severity, also known as intensity or grades, utilizing the 
NCI-CTCAE grading scale v5.0 (NCI-CTCAE, 2017). That version will be used for grading AEs, 
except, as follows: 
a. For CRS and infusion reactions for which the ASTCT CRS Consensus Grading 
(Table 4; Lee, 2019) will be employed  
b. For immune effector cell-associated neurotoxicity syndrome, the ASTCT ICANS 
Consensus Grading for Adults (Table 5, Lee, 2019) will be employed.  
Note: some grades are not available for certain AEs (eg, Headache can only be Grade 1, 2, or 3; 
and Sepsis can only be Grade 3, 4, or 5). 
AEs not contained within CTCAE Version 5.0 will be rated on a 5-point scale as described below 
(Table 18). 


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Table 18: 
Severity Grading Scale 
Grade 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADLb 
Grade 4 
Life-threatening consequences: urgent intervention indicated.  
Grade 5 
Death related to AE. 
ADL = activities of daily living. 
a Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden  
Note: A semi-colon indicates “or” within the description of the grade. 
Any change in severity of the AE over a number of days will be captured by recording a new AE, 
with the amended severity grade and the date (and time, if known) of the change.  
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the event should be noted for that day. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined by the criteria under Section 10.2. An AE of severe intensity may 
not be considered serious. 
10.2.3.2. Causality 
The Investigator will assess the causality/relationship between the study treatment and the AE. 
The Investigator determines if there is a “reasonable possibility” that the study treatment caused the 
event (causality would be considered as related). Reasonable possibility is defined as evidence to 
suggest a causal relationship between the study treatment and AE. One of the following categories 
should be selected based on good medical and scientific judgment, considering the definitions in 
Table 19 and all contributing factors.  


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Table 19: 
Causality Assessment Categories 
For the purposes of regulatory reporting, if the Investigator chooses one of the following categories, the AE will be 
identified as “related by the Investigator.” 
Related 
A clinical event, including laboratory test abnormality that occurs in a plausible time 
relationship to treatment administration, and which concurrent disease or other drugs or 
chemicals cannot explain. Biological plausibility or causality mechanism should be 
considered when assessing events as related. 
The response to withdrawal of the treatment (dechallenge a) should be clinically 
plausible. The event must be definitive pharmacologically or phenomenologically, using 
a satisfactory rechallenge b procedure if necessary.  
Probably Related 
A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the treatment, unlikely to be attributed to concurrent disease or other 
drugs or chemicals, and which follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge b information is not required to fulfill this definition.  
Possibly Related 
A clinical event, including laboratory test abnormality, with a reasonable time sequence 
to administration of the treatment, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on treatment withdrawal may be lacking 
or unclear.  
If the Investigator chooses one of the following below, the AE will be identified as “not related by the 
Investigator.” 
Unlikely Related 
A clinical event, including laboratory test abnormality, with a temporal relationship to 
treatment administration that makes a causal relationship improbable, and in which other 
drugs, chemicals, or underlying disease provide plausible explanations. 
Not Related 
A clinical event, including laboratory test abnormality, with little or no temporal 
relationship with treatment administration. May have negative dechallenge and 
rechallenge information. Typically explained by extraneous factors (eg, concomitant 
disease, environmental factors, or other drugs or chemicals). 
a Dechallenge is when a drug suspected of causing an AE is discontinued. If the symptoms of the AE disappear 
partially or completely, within a reasonable time from drug discontinuation, this is termed a positive dechallenge. 
If the symptoms continue despite withdrawal of the drug, this is termed a negative dechallenge. Note that there 
are exceptions when an AE does not disappear upon discontinuation of the drug, yet drug-relatedness clearly 
exists (for example, as in bone marrow suppression, fixed drug eruptions, or tardive dyskinesia). 
b Rechallenge is when a drug suspected of causing an AE in a specific subject in the past is readministered to that 
subject. If the AE recurs upon exposure, this is termed a positive rechallenge. If the AE does not recur, this is 
termed a negative rechallenge. 
10.2.3.3. Action Taken 
Action taken with the study drug will be defined as one of the following: 
• Dose not changed 
• Dose reduced 
• Drug interrupted 
• Drug withdrawn 
• Not applicable 


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10.2.3.4. Outcome 
Outcome will be defined as one of the following: 
• Not recovered or not resolved 
• Recovered or resolved 
• Recovered or resolved with sequelae 
• Recovering or resolving 
• Fatal 
• Unknown 
10.3. 
Evaluation of Subjects Who Experience an Adverse Event during the 
Study 
Subjects who experience an AE during the study will be evaluated to determine the outcome of the 
event. The clinical course of the event will be followed, according to the accepted standards of 
medical practice, until one of the following conditions is met:  
1. Resolution 
2. The event has stabilized 
3. The subject withdrew consent or was lost to follow-up 
For all AEs, the date and time of onset and resolution must be captured, if known. This is especially 
important for CRS, CRS-like events, neurotoxicity, or any infusion reactions. Onset and resolution 
times must be captured for these events. Failure to record these data will result in a deviation. All 
SAEs that are continuing at the completion of the study must be followed to determine outcome, as 
defined previously, to adequately evaluate the subject’s safety.  
In addition, any procedures performed and medications given to treat the AE(s) (details to include 
medication name, start date and time, stop date and time, dose, route, frequency, and reason for 
administration) should be recorded. 
10.4. 
Pregnancy and Breastfeeding 
10.4.1. 
Reporting of Pregnancy 
The teratogenic potential of plamotamab is unknown. During the study, and for 6 months (male 
subjects) and 8 months (female subjects) after the last dose of plamotamab, lenalidomide, and/or 
tafasitamab, all women of childbearing potential or any partner of a male subject must be instructed 
to contact the Investigator immediately if pregnancy is suspected. Pregnancy in a subject or partner 
of a male subject who is receiving treatment should be reported following procedures for an SAE 


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(although it will not be labeled as an SAE). The pregnancy event will be recorded on the pregnancy 
report form. Elective abortions without complications should not be reported as AEs. 
If pregnancy is suspected in a subject prior to study treatment administration, the study treatment 
must be withheld until the β-hCG test result is available. If pregnancy is confirmed, the subject 
must not receive study treatment and must be withdrawn from the study. If pregnancy is suspected 
while the subject is receiving study treatment, the study treatment must be immediately withheld 
until the result of a β-hCG test result is available. If pregnancy is confirmed, the subject will be 
permanently discontinued from the study in an appropriate manner.  
The Investigator must immediately notify the Sponsor of any pregnancy that occurs in subjects 
during study treatment exposure and for at least 8 months after drug administration for female 
subjects and 6 months for sexual partners of male subjects. Protocol-required procedures for study 
discontinuation must be performed unless contraindicated by pregnancy (eg, X-ray studies). Other 
appropriate follow-up procedures should be considered, if indicated. The outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) must be followed up and documented to the Sponsor even if the subject was 
discontinued from the study. The follow-up period will be deemed to have ended when the health 
status of the child has been determined on its birth. 
All outcomes of pregnancy must be reported by the Investigator to the Sponsor and ICON PLC on 
the pregnancy outcome report form within 30 days after he/she has gained knowledge of the normal 
delivery or elective abortion and approximately 30 calendar days postpartum. 
Any SAE that occurs during pregnancy must be recorded on the SAE report form (eg, maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital 
anomaly, birth defect) and reported within 24 hours of awareness in accordance with the procedure 
for reporting SAEs. All reports of congenital abnormalities/birth defects are SAEs. Spontaneous 
miscarriages should also be reported and handled as SAEs. Infants should be monitored for a 
minimum of 8 weeks after birth.  
10.4.2. 
Breastfeeding 
It is unknown whether plamotamab is secreted in human milk. Since it is known that antibodies can 
be secreted in human milk, a risk to the newborns/infants cannot be excluded. A decision should be 
made whether to discontinue breastfeeding or to discontinue plamotamab, taking into account the 
benefit of breastfeeding for the child and the benefit of plamotamab therapy for the woman. 
10.4.3. 
Embryo-Fetal Toxicity from Lenalidomide WARNINGS AND PRECAUTIONS 
Section 
Lenalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. 
Thalidomide is a known human teratogen that causes life-threatening human birth defects or 
embryo-fetal death (see Revlimid® PI, 2021, “Use in Specific Populations” [8.1]). An embryo-fetal 
development study in monkeys indicates that lenalidomide produced malformations in the offspring 
of female monkeys who received the drug during pregnancy, similar to birth defects observed in 
humans following exposure to thalidomide during pregnancy.  


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Women of Childbearing Potential: 
Women of reproductive potential must avoid pregnancy for at least 4 weeks before beginning 
lenalidomide therapy, during therapy, during dose interruptions and for at least 4 weeks after 
completing therapy. Females must commit either to abstain continuously from heterosexual sexual 
intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating 
treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks 
following discontinuation of lenalidomide therapy. Two negative pregnancy tests must be obtained 
prior to initiating therapy. The first test should be performed within 10 days and the second test 
within 24 hours prior to prescribing lenalidomide therapy. Thereafter, tests should occur weekly 
during the first month, then monthly thereafter in females with regular menstrual cycles, or every 
2 weeks in females with irregular menstrual cycles.  
Males: 
Lenalidomide is present in the semen of subjects receiving the drug. Therefore, males must always 
use a latex or synthetic condom during any sexual contact with females of reproductive potential 
while taking lenalidomide and for up to 4 weeks after discontinuing lenalidomide, even if they have 
undergone a successful vasectomy. Male subjects taking lenalidomide must not donate sperm.  
Blood Donation:  
Subjects must not donate blood during treatment with lenalidomide and for 4 weeks following 
discontinuation of the drug because the blood might be given to a pregnant female subject whose 
fetus must not be exposed to lenalidomide.  
Pregnancy Exposure Registry:  
There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to 
lenalidomide during pregnancy as well as female partners of male subjects who are exposed to 
lenalidomide. This registry is also used to understand the root cause for the pregnancy. Report any 
suspected fetal exposure to lenalidomide to the Sponsor.  
Risk Summary:  
Based on the mechanism of action (see Revlimid® PI, 2021, “Clinical Pharmacology” [12.1]) and 
findings from animal studies (see Data]), lenalidomide can cause embryo-fetal harm when 
administered to a pregnant female and is contraindicated during pregnancy (see Revlimid® PI, 2021 
for Boxed Warning, “Contraindications” [4.1], and “Use in Specific Populations” [8.0]). 
Lenalidomide is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high 
frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia 
(short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including 
anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities 
(anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and 
genital malformations have also been documented and mortality at or shortly after birth has been 
reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey 
offspring. Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant 
rats [see Data]. If this drug is used during pregnancy, or if the subject becomes pregnant while 


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taking this drug, the subject should be apprised of the potential risk to a fetus. If pregnancy does 
occur during treatment, immediately discontinue the drug. Under these conditions, refer subject to 
an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and 
counseling. Report any suspected fetal exposure to lenalidomide to the Sponsor. The estimated 
background risk of major birth defects and miscarriage for the indicated population is unknown. 
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The 
estimated background risk in the US general population of major birth defects is 2% to 4% and of 
miscarriage is 15% to 20% of clinically recognized pregnancies.  
Please also refer to lenalidomide prescribing information for pregnancy prevention and other 
reproductive, issue-related questions (Revlimid® PI, 2021).  
11. 
STATISTICS 
11.1. 
General 
Before database lock, a statistical analysis plan (SAP) will be issued as a separate document, 
providing detailed methods for the analyses outlined below. Any deviations from the planned 
analyses will be described and justified in the final clinical study report. 
For descriptive summaries, continuous variables will be summarized with N (ie, sample size), mean, 
standard deviation, median, 25th percentile (Q1), 75th percentile (Q3), minimum (min), and 
maximum (max), and discrete variables will be summarized with frequencies and percentages. 
Summary results will be displayed by treatment group. 
11.2. 
Primary Objective Estimand 
The primary objective of this study is to determine the safety and efficacy of the combination of 
plamotamab, tafasitamab, and lenalidomide compared to tafasitamab and lenalidomide in adult 
subjects with relapsed or refractory diffuse large B-cell lymphoma using Lugano 2014 criteria 
(Cheson, 2014). The attributes for the estimand for the primary objective are outlined in Table 20. 


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Table 20: 
Primary Objective Estimand 
Primary Estimand 
Population 
Variable 
Summary Measure 
Treatment  
Potential 
Intercurrent 
Events 
Intent-to-treat:  
all randomized 
subjects in Part 2 
Blinded 
Independent Review 
Committee 
assessment of PFS, 
defined as the time 
from randomization 
to first 
documentation of 
progressive disease 
or death, whichever 
comes first. 
Hazard ratio based 
on Cox regression 
model stratified by 
IPI risk score at 
baseline, number of 
lines of prior 
therapy, and 
primary refractory. 
KM estimates for 
median, Q1 and Q3. 
Stratified log-rank 
test for treatment 
effect. 
Plamotamab, 
tafasitamab, and 
lenalidomide versus 
tafasitamab, and 
lenalidomide 
Discontinuation of 
treatment(s), 
start of a new  
anti-cancer therapy, 
including transplant 
and missing two or 
more tumor 
assessments. 
Treatment policy 
estimand will apply 
for intercurrent 
events. 
IPI = international prognostic index; PFS = progression-free survival. 
11.3. 
Sample Size and Power 
11.3.1. 
Progression-Free Survival 
PFS as assessed by the BIRC is the primary endpoint for Part 2 of this study. For determination of 
the sample size, it is assumed that triple combination treatment could improve the median PFS from 
12 months (under treatment with tafasitamab + lenalidomide (Duell, 2021) to 23.5 months under 
the triple combination treatment (plamotamab + tafasitamab + lenalidomide), corresponding to a 
hazard ratio (HR) of 0.51 with all randomized subjects (it is estimated that 90% of subjects will be 
central pathologically confirmed as DLBCL). 
The log rank test has 90% power with the sample size of 200 (93 events) to preserve the type-I error 
of 0.025 (one-sided). A loss to follow-up rate of 1.5%/month was assumed for sample size 
calculations.  
Subjects will be randomized 1:1, stratified by IPI risk score at baseline (3 to 5 versus 0 to 2), 
number of lines of prior therapy (1 versus ≥ 2), and primary refractory (yes versus no). A maximum 
of 36 primary refractory subjects may be enrolled into the sample size of 200.  
Enrollment of 200 subjects is estimated to require 27 months with minimum follow-up time of 
6 months. The primary efficacy analysis will occur when 93 PFS events per independent review 
have been observed. Efficacy boundaries and estimated timing for the analysis is displayed in 
Table 21.  
 
 


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Table 21: 
Efficacy Boundaries and Properties for Progression-Free Survival Analyses 
Analysis 
Value 
Efficacy  
Final 
Z 
1.9600  
N: 200 
p (1-sided) 
0.0250  
Events: 93 
HR at bound 
0.6659  
Month: 33 
P(Cross) if HR = 1 
0.0250  
 
P(Cross) if HR = 0.51 
0.9000  
p (1-sided) is the nominal α for testing. 
HR at bound is the approximate HR required to reach an efficacy bound 
P(Cross if HR = 1) is the probability of crossing a bound  under the null hypothesis 
P(Cross if HR = 0.5) is the probability of crossing a bound  under the alternative hypothesis 
HR = hazard ratio. 
An interim analysis for OS at the time of final PFS analysis will be implemented using the group 
sequential design in addition to the final OS analysis. Table 22 provides the timing of PFS and OS 
analysis.  
Table 22: 
Summary of Interim and Final Analyses Strategy 
Analyses 
Key Endpoints 
Timing 
Estimated Time after 
First Subject 
Randomized 
Primary 
Purpose of 
Analysis 
PFS Final OS IA1 
PFS 
ORR 
OS 
TTF 
93 PFS event and 
approx. 50 OS 
events (65% of 
expected total 
OS events) have 
been observed 
Approx. 33 months 
• Final analyses 
for PFS, ORR, 
and TTF 
• Interim OS 
analyses 
Final OS Analysis 
OS 
When approx. 76 
OS events have 
been observed 
Approx. 51 months 
• Final OS 
analyses 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TTF = time to treatment 
failure. 
 
11.3.2. 
Overall Survival 
Overall survival will be assessed in the randomized population (Part 2). The one-sided α level for 
testing OS is at 0.025. It is assumed that the median OS for the Part 2 Arm B is 34 months and that 
Part 2 Arm A will have 40% improvement from Arm B (ie, median OS = 56.6 months, HR = 0.60). 
In addition, assuming completion of enrollment in 27 months, a minimum follow-up time of 
24 months, and an OS censoring rate (dropout rate) of approximately 1% per month, the study will 
result a statistical significance with 60% of power. Once 65% of the information (death events) is 


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available, an interim analysis for OS is planned. Superiority analyses will be performed during the 
interim and final analyses. Table 23 provides more details.  
Table 23: 
Efficacy Boundaries and Properties for Overall Survival Analyses 
Analysis 
Value 
Efficacy 
IA 1: 65%* 
Z 
2.5469 
N: 200 
p (1-sided) 
0.0054 
Events: 50 
HR at bound 
0.4833 
Month: 33.8 
P(Cross) if HR=1 
0.0054 
 
P(Cross) if HR=0.6 
0.2263 
Final 
Z 
1.9896 
N: 200 
p (1-sided) 
0.0233 
Events: 76 
HR at bound 
0.6326 
Month: 51 
P(Cross) if HR = 1 
0.0250 
 
P(Cross) if HR = 0.6 
0.6000 
*Expected percentage of events with respect to the number of events expected at the final analysis. 
p (1-sided) is the nominal α for testing. 
HR at bound is the approximate HR required to reach an efficacy bound. 
P(Cross if HR = 1) is the probability of crossing a bound under the null hypothesis 
P(Cross if HR = 0.6) is the probability of crossing a bound under the alternative hypothesis 
HR = hazard ratio; IA = interim analysis  
Efficacy bounds derived using a Lan-DeMets O’brien-Fleming approximation spending function. 
 
11.3.3. 
Objective Response Rate 
The one-sided α level for testing ORR is at 0.025. It is assumed the ORR for Part 2 Arm B is 60% 
and ORR for Part 2 Arm A is 78%. 100 subjects per arm will provide 80% power for statistical 
significance at 0.025. 
11.3.4. 
Statistical Testing Sequence 
The following secondary endpoints will be tested sequentially in the following order, if the test for 
the primary endpoint is positive: 
1. ORR by BIRC per Lugano 2014 criteria (Cheson, 2014) 
2. OS 
3. TTF 
Other secondary efficacy endpoints will be assessed, including: 


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• PFS, as assessed by Investigator 
• ORR by Investigator 
• DOR among subjects achieving an objective response 
• DOR among subjects achieving a CR 
11.4. 
Independent Data Monitoring Committee 
A separate charter will describe the membership and operation of the IDMC. In Part 2, accumulating 
safety data will be reviewed by the IDMC periodically, as detailed in Section 4.9.  
11.5. 
Analysis Sets 
The following populations will be used for analysis as defined below: 
• Enrolled Analysis Set: All subjects who signs the informed consent form, is determined 
to be eligible, and receives the Day –8 tafasitamab dose 
• Safety Run-in Analysis Set: All subjects who are enrolled in Part 1 of the study and 
receive at least 1 dose each of plamotamab, tafasitamab, and lenalidomide 
• Randomized (Intent-to-Treat) Analysis Set: All subjects who are randomized into 
Part 2 of the study 
• Randomized Safety Analysis Set: All subjects who are randomized into Part 2 of the 
study and receive at least 1 dose of plamotamab, tafasitamab, or lenalidomide 
• Pharmacodynamic Analysis Set (s): All subjects who are enrolled in the study, receive 
at least 1 dose of study therapy, and have at least 1 set of pre- and post-infusion 
pharmacodynamic data available for analysis — defined independently for Parts 1 and 
2. 
• PK Analysis Set (s): All subjects who are enrolled in the study, receive at least 1 dose 
of study therapy, and have at least 1 set of pre- and post-infusion PK data available for 
analysis — defined independently for Part 1, Arm A, and Arm B. 
• Plamotamab Treated Analysis Set: All subjects treated with any amount of 
plamotamab in Part 1 or Part 2.  
11.6. 
Key Subgroups 
Key subgroups include: 
• IPI risk score at baseline (3 to 5 versus 0 to 2) 


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• Primary refractory (yes versus no) 
• Number of lines of prior therapy (1 versus ≥ 2) 
11.7. 
Subject Characteristics and Disposition 
The SAP will define analysis parameters for the study and takes precedence over this protocol 
section. 
Demographic and baseline characteristics will be summarized, as will disease-related 
characteristics (including any available genetic data), prior anti-cancer therapies, and relevant 
supportive care therapies. 
A summary of subject disposition will include the following, by Part and by Arm: 
• Number of subjects enrolled 
• Number of subjects who received each study treatment 
• Number of subjects who terminated treatment earlier and reason for early 
discontinuation of treatment 
• Number of subjects who complete the study follow-up period 
• Number of subjects who terminated study earlier and reasons for early study 
terminations 
11.8. 
Safety Analysis 
Safety Analysis will be performed with Safety Analysis Set. Safety variables will include 
AEs/SAEs, vital signs, PE findings, ECGs, laboratory values, medical history, and concomitant 
medications, which will be summarized by Part and by Arm. 
The extent of exposure to plamotamab and tafasitamab will be summarized based on the number of 
infusions administered and the number of treatment cycles completed, as well as the total dose 
received. Lenalidomide exposure will be summarized similarly, based on number of doses taken.  
Additional summaries of drug exposure will be provided based on the PK parameters described in 
Section 11.10.  
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). The verbatim term recorded by the Investigator will be mapped to System Organ Class 
(SOC) and Preferred Term using MedDRA.  
TEAEs are defined as events with onset dates on or after the start of study treatment or events that 
are present before the first infusion of study treatment and subsequently worsen in severity.  
AE-related endpoints include:  


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• Treatment-emergent AEs 
• Treatment-emergent SAEs 
• Adverse reactions 
• Serious adverse reactions 
• Treatment-emergent AEs by severity, as defined by NCI-CTCAE Version 5.0 
• Treatment-emergent AEs resulting in the permanent discontinuation of plamotamab 
All AE-related endpoints will be summarized by SOC and preferred term. At each level of 
summation, subjects will be counted once, under the greatest severity and strongest study-drug 
relationship.  
The hematology, chemistry, and other laboratory values and change from baseline values will be 
summarized descriptively for each scheduled assessment time point and grouped by dosing cohort. 
The baseline value for each laboratory value is defined as the last assessment performed on or prior 
to the date of first dose of study treatment. The frequencies of Grade 3 and 4 hematologic AEs 
(including neutropenia, thrombocytopenia, and anemia) will be reported. The toxicity grades for 
laboratory tests will be based on NCI-CTCAE Version 5.0 (NCI-CTCAE, 2017) criteria. The use 
of blood transfusions (platelets, RBCs) and/or growth factor support will be reported. Similar 
analyses will be done for chemistry tests (including liver and renal function tests). Subject listings 
of all laboratory data collected during the study will be presented. Laboratory values outside normal 
limits will be identified in the subject listings and will include flags for high and low values. 
Vital sign results (blood pressure, heart rate, respirations, temperature, and blood oxygen saturation 
by continuous pulse oximetry) will be summarized descriptively for each scheduled time point. The 
baseline value for each vital sign measurement is defined as the last assessment performed most 
recently prior to the first dose of study treatment, and any change from these baseline values will 
be reviewed. The change of vital signs values from preinfusion will be summarized for each 
postinfusion point. Preinfusion assessments are defined as last vital assessment prior to the same 
infusion. Subject listings of all vital data collected during the study will be presented. 
ECGs values and change from baseline values will be summarized descriptively for each scheduled 
time point. Subject listings of all ECG data collected during the study will be presented. 
Additional analysis will be performed for AEs of CRS. These will include analyses of time to onset, 
duration, severity, and associations with laboratory cytokine measurements and missed or delayed 
doses (ie, CRS may be associated with longer intervals between doses). Graphical summaries will 
illustrate the timing relative to dosing, the severity of CRS events and cytokine levels.  
11.9. 
Efficacy Analysis 
The Randomized (intent-to-treat) Analysis Set defined in Section 11.5 will be used for primary and 
secondary efficacy analyses, unless otherwise noted. Sensitivity analyses will be provided based on 


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pathologically confirmed DLBCL. Strata might be combined for the analysis if randomization 
resulted in sparse stratum. The decision to combine strata will be made prior to the database lock. 
The primary analysis will be based on PFS as assessed by the BIRC, defined as the time from 
randomization to first documentation of progressive disease or death, whichever comes first. 
Subjects who discontinue the study without progression as assessed by BIRC will be censored 
according to rules specified in the SAP. Kaplan-Meier methodology will be used to summarize the 
distribution of PFS, presenting median survival together with its 95% confidence intervals and PFS 
curves for each treatment arm. The primary inferential comparison between treatment groups will 
use the log-rank test stratified by the randomization stratification factors listing in Section 11.6. The 
HR for triple combination treatment versus control and its 95% confidence intervals (CI) will be 
estimated using a Cox proportional hazards model stratified by the same randomization 
stratification factors. For the secondary endpoint of PFS as assessed by the Investigator, analyses 
will be similar to the primary analysis. In addition, the SAP will detail a tipping-point sensitivity 
analysis of potential impacts of informative censoring among subjects who discontinue the study 
early without progression as assessed by BIRC (ie, not including on-study subjects administratively 
censored at the time of the analysis). 
Analyses of response will be based on the rate of objective response (ORR = CRR + PRR) by BIRC 
per Lugano 2014 criteria (Cheson, 2014). By-arm comparisons will be made with a stratified 
Cochran-Mantel-Haenszel test using randomization stratification factors. In addition, response rates 
and Barnard’s exact confidence intervals will be reported both overall and for the categorical Key 
Subgroups in Section 11.6. The number and percentage of subjects achieving a best overall 
response of CR (confirmed and unconfirmed), PR (confirmed and unconfirmed), stable disease, 
progressive disease, not evaluable, and other disease-specific response criteria will be presented. 
In addition to BIRC response assessments, Investigator-assessed responses will be reported 
similarly, and concordance analyses will be detailed in the SAP. 
The duration of objective response will be calculated from the time of initial response (PR or better) 
to the first documentation of relapse (recurrence after CR), progression, or death. The duration of 
complete response will be calculated from the time of initial response (CR) to the first 
documentation of relapse (recurrence after CR), progression, or death among subjects achieving a 
CR. 
Time to event analysis of OS, measured relative to randomization, will be performed based on the 
Kaplan-Meier method. Median survival time and its 95% confidence interval, as well as the 25th 
and 75th quartiles with their 95% confidence intervals, will be summarized. Subjects who are alive 
at end of the study will be censored at last known contact date. By-arm comparisons will utilize the 
same methods as for PFS. 
The potential antitumor effects of plamotamab may be evaluated in subgroups of subjects, including 
the Key Subgroups defined in Section 11.6. The specifications for these and other similar analyses 
will be described in the SAP, which supersedes any protocol specifications. 


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11.10. 
Pharmacokinetic Analysis 
Serum concentrations of plamotamab and tafasitamab will be listed, summarized in tabular form 
by dosing visit (including, mean, median, range, and 25th and 75th percentiles). Details of additional 
analyses will be provided in a PK analysis plan.  
11.11. 
Immunogenicity Assays 
The incidence and titer of anti-plamotamab antibodies and anti-tafasitamab antibodies will be 
reported by sample collection time point and treatment arm, as applicable. 
12. 
STUDY ADMINISTRATIVE STRUCTURE 
12.1. 
Study Monitoring 
The Sponsor or its designee will monitor the study according to GCP guidelines. The Principal 
Investigator and study center will permit the Sponsor, its representatives, FDA, and other regulatory 
agencies outside the United States (OUS) direct access to all original source data and documents 
for study monitoring audits and inspections. All requested information must be entered into the 
eCRF in the EDC database. The completed eCRF must be promptly reviewed and electronically 
signed and dated by the Investigator.  
During the study, a Xencor monitor and/or designee will have regular contact with the 
investigational site for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each subject 
(eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Xencor/ICON 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to ICON and those SAEs that met criteria for reporting have been 
forwarded to the IRB/IEC 
The monitor will be available between visits if the Investigator(s) or other staff needs information 
or advice. 


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The Principal Investigator may be subjected to a field audit by the Sponsor, ICON, FDA, and/or 
other regulatory (OUS) inspectors in order to validate the participation of subjects in the study and 
to verify the data reported in the clinical database. The Sponsor should be notified immediately of 
any audits scheduled by any regulatory authorities. Copies of audit reports from regulatory 
authorities should be promptly forwarded to the Sponsor.  
The Sponsor and Principal Investigator uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, all data collected and analyzed by the Sponsor 
will be identified only by an identification number. 
ICON will provide the study sites access to the EDC database that will be used to collect the 
required subject eCRF data for this trial. The eCRF must be supported by the corresponding 
information in the source document. 
12.2. 
Deviation from Protocol 
No deviations from this protocol will be permitted except in a medical emergency. In the case of a 
medical emergency, the Sponsor’s Medical Monitor is notified as soon as possible. Any protocol 
deviations must be reported to the Ethics Committee or IRB as required by local regulations. The 
Sponsor or designee will record and compile all protocol deviations.  
12.3. 
Institutional Review Board/Independent Ethics Committee  
The Principal Investigator will submit the protocol, protocol amendments, ICF, Investigator’s 
Brochure, and any subject recruitment materials to the IRB/IEC for approval. 
It is required that a valid IRB/IEC approves, in writing, the conduct of this clinical study together 
with the Investigator’s ICF prior to study initiation. Until written approval by the IRB/IEC has been 
received by the Sponsor, no subject may undergo any procedures solely for the purpose of 
determining eligibility for this study. 
The Principal Investigator must provide study progress reports to the IRB/IEC at least annually for 
all IND studies or more frequently if required by applicable guidelines, regulations, or institutional 
procedures. 
The Principal Investigator must promptly notify the IRB/IEC of any SAEs occurring at the site, as 
well as any IND safety reports/Expedited Safety Reports, regardless of the reporting site location, 
if applicable, per local regulations. The Sponsor reserves the right to amend the protocol during the 
course of the study. It is the Principal Investigator’s responsibility to obtain IRB/IEC approval of 
any protocol amendments and to implement them in a timely manner. Protocol amendments in the 
form of an administrative letter signed by the Principal Investigator should be submitted to the 
IRB/IEC for review. All protocol amendments must have IRB/IEC review and approval prior to 
implementation.  
If a protocol amendment substantially alters the study design or increases the potential risk to 
subjects, the ICF must be revised and submitted to the IRB/IEC for review and approval. The 


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revised ICF must be used to obtain consent from subjects currently enrolled in the study if they are 
affected by the amendment and for all subsequent subjects prior to enrollment. 
Documentation of IRB/IEC approval of the protocol, ICF, and other applicable study documents 
must be provided to the Sponsor or its agent, ICON, before commencement of this study. Copies 
of all study-related correspondence between the Principal Investigator and IRB/IEC must be 
maintained in the site regulatory binder. 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCPs and all applicable regulatory requirements, the Sponsor or its 
representatives may conduct a quality assurance audit. See Section 12.1 for more details regarding 
the audit process. 
14. 
ETHICS 
14.1. 
Ethics Review 
 Please see Section 12.3 for the Principal Investigator’s responsibilities regarding IRB/IEC review. 
14.2. 
Ethical Conduct of the Study 
The study will be conducted in compliance with 
• the protocol, 
• ethical principles of the Declaration of Helsinki (Version 2013) and its amendments, 
• the principles of the GCP provided in the Guideline, E6(R2) Integrated Addendum to 
ICH E6(R1): Guideline for Good Clinical Practice  
• all applicable national laws and regulations including but not limited to country-specific 
GCP. 
14.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 


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The Principal Investigator is responsible for ensuring that subjects sign and date an appropriately 
approved ICF prior to enrolling in the study. This must be obtained before conducting any study 
procedures. 
A copy of the signed ICF must be provided to the subject, another copy kept with the study records, 
and the original kept with the subject’s medical records. In addition, the medical record will include 
documentation of the informed consent process.  
The ICF will also indicate that subjects will be informed of important findings of the study by the 
Principal Investigator and/or staff when data are available and at study completion. 
A sample of any ICF to be used in this study that has been approved by the IRB/IEC must be 
forwarded to the Sponsor or its agent, ICON. 
15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Subject Confidentiality 
Adequate records must be maintained for the study, including but not limited to subject medical 
records, eCRFs, laboratory reports, worksheets, nursing notes, signed ICFs, product forms, SAE 
forms, and information regarding subject discontinuation and reasons for discontinuation. The 
confidentiality of each record with subject identification is to be guaranteed by the clinical 
Investigator.  
15.2. 
Inspection of Records 
The Sponsor or its designee will monitor the study according to GCP guidelines. The Principal 
Investigator and study center will permit the Sponsor, its representatives, FDA, and other regulatory 
agencies direct access to all original source data and documents for study monitoring audits and 
inspections. All requested information must be entered into the eCRF in the EDC database. The 
completed eCRF must be promptly reviewed and electronically signed and dated by the Principal 
Investigator.  
The Principal Investigator may be subjected to a field audit by the Sponsor, ICON, and/or other 
regulatory (OUS) inspectors in order to validate the participation of subjects in the study and to 
verify the data reported in the clinical database. The Sponsor should be notified immediately of any 
audits scheduled by any regulatory authorities. Copies of audit reports from regulatory authorities 
should be promptly forwarded to the Sponsor.  
The Sponsor and Principal Investigator uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, all data collected and analyzed by the Sponsor 
will be identified only by an identification number. 
ICON will provide the study sites access to the EDC database that will be used to collect the 
required subject eCRF data for this trial. The eCRF must be supported by the corresponding 
information in the source document. 


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15.3. 
Retention of Records 
The Principal Investigator shall retain study drug disposition records, copies of CRFs (or electronic 
files), and all source documentation (such as original ECG tracings, laboratory reports, inpatient, 
or office subject records) for the maximum period required by the country and Institution in which 
the study will be conducted or for the period specified by the Sponsor, whichever is longer. The 
Principal Investigator must contact the Sponsor prior to destroying any records associated with the 
study. If the Principal Investigator withdraws from the study (due to relocation, retirement, etc.) the 
records shall be transferred to a mutually agreed upon designee, such as another Principal 
Investigator or the IRB/IEC. Notice of such transfer will be provided in writing to the Sponsor. 
16. 
PUBLICATION POLICY 
By signing the clinical study protocol, the Investigator agrees with the use of results of the clinical 
study for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. If necessary, the competent authorities will be notified 
of the Investigator’s name, address, qualifications, and extent of involvement. 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without receiving approval 
from the Sponsor in advance. Authorship criteria for all publications of Xencor-sponsored clinical 
trials are based on the International Committee of Medical Journal Editors (ICMJE) guideline, 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (ICMJ, 2019). Authorship credit can be granted only to those who make 
substantial contributions to the publication.  
At a minimum, study results will be publisltrials.gov on all primary and secondary outcomes, no 
later than 1 year after completion of the study (including completion of the study if it has been 
terminated early). 
This protocol and other study documents contain trade secrets and commercial information that is 
privileged and confidential. Such information is not to be disclosed unless required by laws or 
regulations. The Principal Investigator agrees to use this information only in conducting this study 
and is not allowed to use it for other purposes without written consent from the Sponsor. Results 
obtained from this study are the property of the Sponsor. 
 


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17. 
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Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
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[CTFG] Clinical Trial Facilitation Group: Recommendations related to contraception and 
pregnancy testing in clinical trials, version 1.1: 21 Sept 2020. 
Coiffier B and Sarkozy C. Diffuse large B-cell lymphoma: R-CHOP failure-what to do? [abstract]. 
Hematology Am Soc Hematol Educ Program. 2016;(1):366–78. 
Duell J, Maddocks KJ, González-Barca E, et al. Long-term outcomes from the Phase II L-MIND 
study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse 
large B-cell lymphoma. Haematologica. 2021;106(9):2417-26. 
Frey N. Cytokine release syndrome: who is at risk and how to treat. Best Pract Res Clin Haematol. 
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coexisting conditions. N Engl J Med. 2014;370(12):1101–10. 
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Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a novel, bivalent CD20-targeting 
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SAP_001.pdf: 
Xencor, Inc. 
XmAb13676-03 
Statistical Analysis Plan  
CONFIDENTIAL 
1 
STATISTICAL ANALYSIS PLAN 
DATE 
19 DECEMBER 2023 
VERSION 
1.1 
PROTOCOL TITLE: 
 A Phase 2 Randomized, Open-Label, Multicenter Study to Evaluate the Efficacy and 
Safety of XmAb®13676 (Plamotamab) Combined with Tafasitamab Plus Lenalidomide 
Versus Tafasitamab Plus Lenalidomide in Subjects with Relapsed or Refractory Diffuse 
Large B-Cell Lymphoma 
NCT: NCT05328102


 
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SIGNATURE PAGE 
 
This document has been authored by: 
 
 
 
 
This document has been reviewed and approved by: 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................5 
2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) ..........................................................6 
2.1. 
Primary Objectives .......................................................................................................6 
2.2. 
Secondary Objectives ...................................................................................................6 
2.3. 
Exploratory Objectives .................................................................................................6 
2.4. 
Endpoints ......................................................................................................................7 
2.4.1. 
Primary Endpoints ........................................................................................................7 
2.4.2. 
Secondary Endpoints ....................................................................................................7 
2.4.3. 
Exploratory Endpoints ..................................................................................................8 
3. 
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS .......................................9 
3.1. 
Study Design .................................................................................................................9 
3.1.1. 
Part 1: Single-Arm, Safety Run-In ...............................................................................9 
3.1.2. 
Part 2: Open-Label Randomized ................................................................................10 
3.2. 
Schedule of Assessments ............................................................................................10 
4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................11 
4.1. 
Changes in Planned Analyses from the Protocol ........................................................11 
4.2. 
Derived and Transformed Data ..................................................................................11 
4.2.1. 
Study Day ...................................................................................................................11 
4.2.2. 
Missing Data ...............................................................................................................11 
4.2.2.1. 
Partial/Missing Dates ..................................................................................................11 
5. 
STATISTICAL CONSIDERATIONS .......................................................................12 
5.1. 
Determination of Sample Size ....................................................................................12 
5.2. 
Interim and Final Analyses .........................................................................................12 
6. 
ANALYSIS SETS ......................................................................................................14 
7. 
STUDY ANALYSES .................................................................................................15 
8. 
REFERENCES ...........................................................................................................16 
9. 
IMPUTATION OF PARTIAL AND MISSING DATES ..........................................17 


 
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List of Abbreviations 
AE 
adverse event 
BMI 
body mass index 
Cmax  
maximum observed serum concentration 
Cmin[trough]  
trough concentration 
CR 
complete response 
CRS 
cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ICH 
International Conference on Harmonisation 
IV 
intravenous 
MCC 
Merkel cell carcinoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
US National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD1 
programmed cell death 1 
PDL1 
programmed cell death ligand 1 
PFS 
progression-free survival 
PK/PD 
Pharmacokinetics/Pharmacodynamics 
PR 
partial response 
RD 
recommended dose 
RECIST 
Response Evaluation Criteria In Solid Tumors  
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SRC 
Safety Review Committee 
TEAE 
treatment-emergent AE 


 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the methods to be used for analysis and reporting of 
clinical data collected throughout the study. It is intended to supplement the study protocol 
(Version 2.0, 08 March 2022), which contains details regarding the design and conduct of the 
study. This plan should be read in conjunction with the study protocol and the electronic case 
report forms (eCRFs).  
The study has been terminated early by the sponsor. Only 3 subjects have been enrolled in the 
study. No efficacy or pharmacokinetic-pharmacodynamic (PK-PD) analyses will be performed. 
Due to the small sample size, only demographics, baseline characteristics, safety, and efficacy 
listings will be generated. 
 


 
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2. 
STUDY OBJECTIVE(S) AND ENDPOINT(S) 
2.1. 
Primary Objectives 
To determine the safety and efficacy of the combination of plamotamab, tafasitamab, and 
lenalidomide compared to tafasitamab and lenalidomide in adult subjects with R/R DLBCL. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are to compare a combination of plamotamab, tafasitamab, 
and lenalidomide to tafasitamab and lenalidomide as follows: 
1. To compare rates of objective response (ORR = CRR + partial response rate [PRR]) by 
Blinded Independent Review Committee (BIRC) and Investigator per Lugano 2014 criteria 
2. To compare overall survival (OS) 
3. To compare time to treatment failure (TTF)  
4. To assess duration of response (DOR) among subjects achieving an objective response (CR 
+ PR) and among subjects achieving a CR by BIRC 
5. To compare the PFS, as determined by the Investigator 
6. To assess the incidence, timing, and severity of CRS by following CRS-related AEs 
including incidence and grade of AEs and incidence of serious adverse events (SAEs) 
7. To assess the incidence, timing, and severity of neurological AEs and incidence and grade 
of immune effector cell-associated neurotoxicity syndrome 
8. To assess the dose intensity of tafasitamab and lenalidomide in Part 1 when given in 
combination with plamotamab 
9. To assess the safety profile of a combination of plamotamab, tafasitamab, and lenalidomide 
in Part 2 as determined by the incidence and severity of treatment-emergent adverse events 
(TEAEs), in adult subjects with R/R DLBCL 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
1. To assess the PK of plamotamab and tafasitamab 
2. To assess the potential immunogenicity of plamotamab and tafasitamab 


 
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3. To explore the association of baseline CD19 and CD20 levels, molecularly defined DLBCL 
subtypes, minimal residual disease (MRD) as measured by circulating tumor DNA 
(ctDNA), and immune cell frequency, activation status, and function with clinical 
outcomes 
4. To evaluate biomarkers of CRS (including but not limited to serum cytokine levels) with 
clinical outcomes 
5. To assess potential associations between clinical outcomes and biologically and clinically 
defined subgroups, including but not limited to randomization strata and time since last 
rituximab treatment 
2.4. 
Endpoints 
2.4.1. 
Primary Endpoints 
The primary endpoint of the study is 
• For Part 1, safety as measured by incidence of CRS and TEAEs; and 
• For Part 2, PFS, defined as the time from randomization to first documentation of 
progressive disease or death, whichever comes first, as assessed by the BIRC using 
Lugano 2014 criteria. 
2.4.2. 
Secondary Endpoints 
The secondary endpoints of the study are as follows: 
1. Best ORR and CRR, as assessed by Investigator and by the BIRC according to 
Lugano 2014 criteria 
2. OS, defined as the time from randomization to death from any cause 
3. TTF, defined as the time from randomization to discontinuation of all study treatment for 
any reason, including disease progression (as assessed by Investigator and by BIRC), 
treatment toxicity, and death, whichever comes first 
4. DOR, defined as the time from first response to progression or death due to any cause, 
whichever comes first, among subjects achieving an objective response (OR) and among 
subjects with CR as assessed by BIRC 
5. PFS, as assessed by Investigator using Lugano 2014 criteria 


 
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6. Incidence, timing, and severity of CRS as assessed by following CRS-related AEs, 
including incidence and grade of AEs and incidence of SAEs, with CRS grading defined 
by the ASTCT Consensus Grading 
7. Incidence, timing, and severity of neurological AEs, and incidence and grade of Immune 
Effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
8. Dose intensity of tafasitamab and lenalidomide as measured by planned and actual dose 
administration in Part 1 
9. Incidence and severity of TEAEs in Part 2, with severity defined by the National Cancer 
Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
2.4.3. 
Exploratory Endpoints 
The exploratory endpoints of the study are as follows: 
1. PK concentrations of plamotamab and tafasitamab 
2. Anti-plamotamab and anti-tafasitamab antibodies 
3. Absolute counts and percentage change from baseline in measurements of B-, T-, and 
natural killer (NK) cell populations 
4. Analyses of exploratory and diagnostic biomarkers (including, but not limited to, cell of 
origin by Hans algorithm [germinal center B-cell (GCB) versus non-GCB], CD10, CD19, 
CD20, MUM1, BCL2, and BCL6 expression); peripheral and intratumoral leukocyte 
frequencies, phenotyping, functional and activation markers at baseline and on treatment; 
gene expression profiling for cell of origin subtyping and exploratory transcriptomic 
analysis, and genomic analysis in tumor including, but not limited to, FcR genotyping and 
MRD ctDNA analysis in blood 
5. Rituximab concentrations at baseline 
6. Biomarkers of CRS; eg, serum cytokine levels 
7. Randomization strata and baseline characteristics subgroup analyses of ORR, PFS, OS and 
TTF 


 
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3. 
STUDY DESIGN AND SCHEDULE OF ASSESSMENTS 
3.1. 
Study Design 
This is a randomized, multicenter, open-label, Phase 2 study of plamotamab combined with 
tafasitamab plus lenalidomide versus tafasitamab plus lenalidomide in adult subjects with DLBCL 
who have relapsed after or are refractory to at least 1 prior line of therapy, which must have 
included multi-agent chemoimmunotherapy inclusive of an anti-CD20 monoclonal antibody, and 
who are not candidates for ASCT, refuse ASCT, or relapse after ASCT.  
A central pathologist reading will confirm the diagnosis of DLBCL retrospectively after 
enrollment, using archival or recently obtained tissue. Central radiology and clinical reviewers will 
assess objective disease response according to the Lugano 2014 guidelines. Details of the central 
review will be provided in an imaging charter outlining functions and processes. In addition, 
Investigator-assessed response will be captured in the clinical database, and concordance analyses 
will be performed. All subjects will be treated until progression or withdrawal for other reasons 
and then followed for OS up to 5 years. 
This study will consist of 2 parts which will be performed sequentially, with Part 1 enrolling and 
evaluating subjects for safety and determination of dose and schedule before the start of Part 2. 
3.1.1. 
Part 1: Single-Arm, Safety Run-In 
Part 1 consists of a single-arm evaluation of the safety of the triple combination of plamotamab 
combined with tafasitamab plus lenalidomide in at least 40 subjects in 2 cohorts of a minimum of 
20 subjects per cohort:  
• Cohort 1A treats subjects with the triple combination at plamotamab dose level –1  
• Cohort 1B commences enrollment after the Cohort 1A completes enrollment. 
Cohort 1B treats subjects with the triple combination at plamotamab dose level 1  
• An initial safety evaluation is conducted after all subjects in Cohorts 1A and 1B either 
receive treatment, at a minimum, through C4D28 or are discontinued prior to C4D28 
due to an AE or progressive disease  
After the initial safety evaluation of both Cohorts 1A and 1B, the pharmacologically optimal dose 
of plamotamab (dose level -1 or dose level 1) with an acceptable safety profile will be advanced 
to the randomized (Part 2) portion of the study.  




 
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4. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
All data analysis output will be generated using SAS version 9.4 or later.  
4.1. 
Changes in Planned Analyses from the Protocol  
The study has been terminated early by the sponsor. Only 3 subjects have been enrolled in the 
study. No efficacy or PK-PD analyses will be performed. Due to the small sample size, only 
listings for demographics, baseline characteristics, safety, and efficacy assessments will be 
generated. 
4.2. 
Derived and Transformed Data 
4.2.1. 
Study Day 
If the date of assessment occurs on or after the first dose date, then study day will be calculated 
as (date of assessment – date of first dose) + 1. If the date of assessment occurs prior to the first 
dose date, then study day will be calculated as (date of assessment – date of first dose). There is 
no study day 0. 
4.2.2. 
Missing Data 
Unless otherwise specified, missing data will be treated as missing, ie, no special handling/ 
missing data imputation will be performed.  
4.2.2.1. 
Partial/Missing Dates 
For partial dates, the algorithms for imputation will vary depending upon the parameter; missing 
or incomplete medications start and stop dates will be imputed to determine whether the 
medications are taken concomitantly. Eg, missing adverse event (AE) start dates will be imputed 
to determine whether the adverse events are treatment emergent. In listings, all dates will be 
listed as recorded. The details of imputation rules can be found in Appendix 1. 


 
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5. 
STATISTICAL CONSIDERATIONS 
5.1. 
Determination of Sample Size 
PFS as assessed by the BIRC is the primary endpoint for Part 2 of this study. For determination of 
the sample size, it is assumed that triple combination treatment could improve the median PFS 
from 12 months (under treatment with tafasitamab + lenalidomide to 23.5 months under the triple 
combination treatment (plamotamab + tafasitamab + lenalidomide), corresponding to a hazard 
ratio (HR) of 0.51 with all randomized subjects (it is estimated that 90% of subjects will be central 
pathologically confirmed as DLBCL). 
The log rank test has 90% power with the sample size of 200 (93 events) to preserve the type-I 
error of 0.025 (one-sided). A loss to follow-up rate of 1.5%/month was assumed for sample size 
calculations.  
Subjects will be randomized 1:1, stratified by IPI risk score at baseline (3 to 5 versus 0 to 2), 
number of lines of prior therapy (1 versus ≥ 2), and primary refractory (yes versus no). A maximum 
of 36 primary refractory subjects may be enrolled into the sample size of 200.  
Enrollment of 200 subjects is estimated to require 27 months with minimum follow-up time of 
6 months. The primary efficacy analysis will occur when 93 PFS events per independent review 
have been observed. 
5.2. 
Interim and Final Analyses 
An interim analysis for OS at the time of final PFS analysis will be implemented using the group 
sequential design in addition to the final OS analysis. Table 2 provides the timing of PFS and OS 
analysis.  


 
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Table 1: 
Summary of Interim and Final Analyses Strategy 
Analyses 
Key Endpoints 
Timing 
Estimated Time after 
First Subject 
Randomized 
Primary 
Purpose of 
Analysis 
PFS Final  
OS IA 
PFS 
ORR 
OS 
TTF 
93 PFS event 
and approx. 50 
OS events (65% 
of expected total 
OS events) have 
been observed 
Approx. 33 months 
• Final analyses 
for PFS, ORR, 
and TTF 
• Interim OS 
analyses 
Final OS Analysis OS 
When approx. 76 
OS events have 
been observed 
Approx. 51 months 
• Final OS 
analyses 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TTF = time to treatment 
failure.  
 


 
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6. 
ANALYSIS SETS 
The following populations will be used for analysis as defined below: 
• Enrolled Analysis Set: All subjects who signs the informed consent form, is 
determined to be eligible, and receives the Day –8 tafasitamab dose 
• Safety Run-in Analysis Set: All subjects who are enrolled in Part 1 of the study and 
receive at least 1 dose each of plamotamab, tafasitamab, and lenalidomide 
• Randomized (Intent-to-Treat) Analysis Set: All subjects who are randomized into 
Part 2 of the study 
• Randomized Safety Analysis Set: All subjects who are randomized into Part 2 of the 
study and receive at least 1 dose of plamotamab, tafasitamab, or lenalidomide 
• Pharmacodynamic Analysis Set(s): All subjects who are enrolled in the study, receive 
at least 1 dose of study therapy, and have at least 1 set of pre- and post-infusion 
pharmacodynamic data available for analysis — defined independently for Parts 1 and 
2. 
• PK Analysis Set(s): All subjects who are enrolled in the study, receive at least 1 dose 
of study therapy, and have at least 1 set of pre- and post-infusion PK data available for 
analysis — defined independently for Part 1, Arm A, and Arm B. 
• Plamotamab Treated Analysis Set: All subjects treated with any amount of 
plamotamab in Part 1 or Part 2. 


 
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7. 
STUDY ANALYSES 
The study has been terminated early by the sponsor. Only 3 subjects have been enrolled in the 
study. No efficacy or pharmacokinetic-pharmacodynamic (PK-PD) analyses will be performed. 
Due to the small sample size, only demographics, baseline characteristics, safety, and efficacy 
listings will be generated. 


 
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8. 
REFERENCES 
1. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol. 2014;32(27):3059–68. 
2. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline. Statistical 
principles for clinical trials (E9); 1998 Feb 5. 
3. International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline. Structure and 
content of clinical study reports (E3); 1995 Nov 30. 
4. National Cancer Institute. Common terminology criteria for adverse events v5.0. NCI, 
NIH, DHHS; 2017 November 27. 
5. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6):649-55. 
 


 
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9. IMPUTATION OF PARTIAL AND MISSING DATES 
Adverse Event  
All AE start dates must be entered on the eCRF as complete dates. In the rare case that all or part of an 
AE start date is missing, but an AE end date is present and after the first dose date, then the AE start date 
will be imputed as follows for the purpose of determining treatment emergent flag only: 
Year of onset 
Month of 
onset 
Day of onset 
Onset date to be imputed as 
Missing 
Missing 
Missing 
Set date to first dose date 
year = year of first dose 
Missing 
Missing/Non-
missing 
Set month and day to those of first 
dose 
year ≠ year of first dose 
Missing 
Missing/Non-
missing 
Set month and day to January 1 
year = year of first dose 
Non-missing 
Missing 
Set day to the day of first dose  
year ≠ year of first dose 
Non-missing 
Missing 
Set day to first day of onset month 
If AE resolution date is present and prior to first dose date, then there is no need to impute incomplete AE 
start date, as the AE is not treatment emergent, and the event should be in the medical history.  
Concomitant Medications 
• 
If year and month are present and day is missing, then set day to first day of the month for 
start date and set day to last day of the month for end date. 
• 
If year and day are present and month is missing, then set month to January for start date and 
set month to December for end date. 
• 
If year is present and month and day are missing, then set month and day to January 1st for 
start date and set month and day to December 31st for end date. 
• 
Completely missing dates will not be imputed. 
• 
If start date is completely missing and end date is on or after the first dose, then the 
medication will be classified as concomitant; if the end date is missing, then the medication 
will be classified as ongoing. Medications for which the start and end dates are completely 
missing will be classified as concomitant.