Phase I/II Study of M7824 Plus Curative Intent Re-Irradiation With Stereotactic Body Radiation Therapy (SBRT) in Patients With Local-Regionally Recurrent Head and Neck Squamous Cell Carcinoma
Phase: PHASE1
Conditions: Recurrent Head and Neck Squamous Cell Carcinoma, Second Primary Squamous Cell Carcinoma of the Head and Neck
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-0608 
Protocol Title 
Phase I/II Study of M7824 plus curative intent re-irradiation 
with Stereotactic Body Radiation Therapy (SBRT) in patients 
with local-regionally recurrent head and neck squamous cell 
carcinoma. 
Protocol Version 
03 
Version Date 
12/19/2019 
Protocol PI 
Renata Ferrarotto, MD 
Department 
THNMO 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
124757 
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Phase I/II Study of M7824 plus curative intent re-irradiation with Stereotactic Body Radiation Therapy 
(SBRT) in patients with local-regionally recurrent head and neck squamous cell carcinoma 
   
 
Principal Investigators:  Renata Ferrarotto, MD 
 
 
 
 
 
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Table of Contents  
 
 
1. 
OBJECTIVES ................................................................................................................................................................. 5 
1.1 
Primary objective of Lead In ......................................................................................................................... 5 
1.2 
Primary objective of Phase 2 ......................................................................................................................... 5 
1.3 
Secondary objectives ........................................................................................................................................ 5 
1.4 
Correlative Studies ............................................................................................................................................ 5 
2. 
BACKGROUND AND RATIONALE ........................................................................................................................ 5 
2.1 
Introduction ......................................................................................................................................................... 6 
2.2 
Reirradiation ....................................................................................................................................................... 7 
2.3 
Stereotactic Radiotherapy .............................................................................................................................. 7 
2.4 
Checkpoint Inhibitors in Head and Neck Cancer ................................................................................... 8 
2.5 
M7824:  Rationale For Combination PD-L1 and TGF- β-inhibition ................................................ 9 
2.6 
M7824 and SBRT ............................................................................................................................................ 10 
2.7 
Functional and patient reported outcome measures ....................................................................... 10 
3. 
PATIENT ELIGIBILITY .......................................................................................................................................... 10 
3.1 
Inclusion Criteria ............................................................................................................................................ 11 
3.2 
Exclusion Criteria ........................................................................................................................................... 12 
4. 
STUDY SCHEMA ...................................................................................................................................................... 12 
5. 
STUDY EVALUATIONS .......................................................................................................................................... 13 
5.1 
Details regarding function and quality of life endpoints ................................................................. 16 
6. 
THERAPY ................................................................................................................................................................... 18 
6.1 
Radiotherapy .................................................................................................................................................... 18 
6.1.1 
Simulation ................................................................................................................................................. 18 
6.1.2 
Contouring and Treatment Planning .............................................................................................. 19 
6.1.3 
Radiation Dose Specifications ........................................................................................................... 19 
6.1.4 
Treatment Verification ........................................................................................................................ 19 
6.1.5 
Normal Tissue Dose Constraints ...................................................................................................... 19 
6.2 
M7824 Systemic Therapy ............................................................................................................................ 20 
6.2.1 
Description of the Investigational Medicinal Product ............................................................. 20 
6.2.2 
Dosage and Administration ............................................................................................................... 21 
6.2.3 
Management of adverse events attributable to M7824 .......................................................... 21 
Infusion-related Reactions Including Immediate Hypersensitivity .................................................... 22 
Management of Immune-related Adverse Events ..................................................................................... 25 
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Potential TGF-β-mediated Skin Adverse Events ........................................................................................ 25 
Anemia ........................................................................................................................................................................ 26 
Alterations in Wound Healing or Repair of Tissue Damage................................................................... 28 
7. 
DEFINITION OF DISEASE PROGRESSION/RECURRENCE ...................................................................... 28 
8. 
CRITERIA FOR SUBJECT WITHDRAWAL ...................................................................................................... 29 
8.1 
Withdrawal from Trial Therapy ................................................................................................................ 29 
8.2 
Withdrawal from Study ................................................................................................................................ 30 
8.3 
Premature Discontinuation of the Trial ................................................................................................. 30 
8.4 
Definition of End of Study ........................................................................................................................... 31 
9. 
CONCOMITANT MEDICATIONS AND PROCEDURES ................................................................................ 31 
9.1 
Permitted Medicines/Prohibited Medicines ........................................................................................ 31 
9.2 
Permitted/Prohibited Procedures ........................................................................................................... 32 
10. 
ASSESSMENT OF SAFETY ................................................................................................................................ 33 
10.1 
General Assessments ................................................................................................................................ 33 
10.2 
Adverse Drug Reactions Requiring Treatment Modification .................................................... 33 
Specific Planned Assessments or Adverse Events of Special Interest ............................................... 34 
11. 
PHARMACOKINETICS........................................................................................................................................ 38 
12. 
ADVERSE EVENTS .............................................................................................................................................. 39 
13. 
STATISTICAL CONSIDERATIONS .................................................................................................................. 43 
13.1 
Study Design and Study Endpoint Summary ................................................................................... 43 
13.2 
Safety Lead-in .............................................................................................................................................. 43 
13.3 
Phase II Primary Endpoint ...................................................................................................................... 44 
13.4 
Secondary Endpoints ................................................................................................................................ 44 
13.5 
Sample Size ................................................................................................................................................... 45 
13.6 
Statistical Analysis ..................................................................................................................................... 45 
14. 
REFERENCES ........................................................................................................................................................ 47 
 
 
 
 
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1. OBJECTIVES 
  
1.1 
Primary objective of Lead In 
• 
To evaluate the safety, tolerability and feasibility of M7824 when administered together with 
             SBRT reirradiation.     
 
1.2 
Primary objective of Phase 2 
• 
To evaluate the progression-free survival (PFS) rate of M7824 plus SBRT reirradiation at 1 year  
 
1.3 
Secondary objectives 
• 
To evaluate the overall response rate by RECIST or RECIST 1:1 
• 
To evaluate the 1- year locoregional control (LRC), locoregional failure-free survival (LFFS), distant 
metastasis (DM) and overall survival (OS) rates  
• 
To evaluate acute and late toxicity using Common Terminology Criteria for Adverse Events 
(CTCAE)-v5.0  
• 
To evaluate fibrosis-related toxicities and functional outcomes  
• 
To evaluate Patient Reported Outcome (PRO) measures of symptoms using MD Anderson 
              Symptom Inventory (MDASI). 
• 
To evaluate volumetric tumor regression rate and MRI kinetic biomarkers after M7824 plus SBRT  
• 
To compare Quality-Adjusted-Life-Years (QALY) between M7824 plus SBRT reirradiation and 
              historic SBRT reirradiation control  
 
1.4 
Exploratory Objectives 
Biomarkers will be accessed in the tumor and blood samples and correlated with clinical outcomes and 
toxicity. Correlative tissue studies include but are not limited to profiling of the tumor immune 
microenvironment by IHC and multiplex immunofluorescence analyses (mIF) including quantitative 
assessment of CD8 T cells and PD-L1 expression levels, immune gene expression signatures by 
NanoString or HTG, target DNA sequencing to access tumor mutational burden, detailed assessments of 
immunocyte populations and functional markers by multicolor flow cytometry, and other biomarkers 
that may emerge to be important related to the use of the proposed agent. Blood will be collected prior 
to cycles 1, 3 and at disease progression (3 time points) for evaluation of ctDNA, circulating immune 
biomarkers of interest including cytokines, and measurements of T-cell activation by flow cytometry. 
Functional outcome measures include but are not limited to validated clinical grading criteria (Head and 
Neck-Lymphedema and Fibrosis, HN-LEF)1,2 and patient-reported measures of head and neck fibrosis 
(Lymphedema Symptom Inventory Distress Scale, L-SIDS)3, as well as radiographic dysphagia grade 
(Dynamic Imaging Grade of Swallowing Toxicity, DIGEST)4, and cervical range of motion 
(CROM).  Correlative imaging studies include functional and anatomic magnetic resonance imaging 
(MRI). 
 
2. BACKGROUND AND RATIONALE  
 
Stereotactic Body Radiation Therapy (SBRT) enables precise and focused delivery of ablative dose 
radiation in a few fractions and is capable of providing durable local-regional control in patients with 
recurrent head and neck squamous cell carcinoma (HNSCC)5,6, after a median follow-up of 16.7 months, 
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the 1-year disease control within the reirradiation field (hereafter referred to as local control) is 84% 
among 67 patients with recurrent HNSCC treated with SBRT reirradiation at MD Anderson. Although the 
local control with SBRT reirradiation is promising, recurrences outside the reirradiation field remains 
problematic, with 1-year regional and distant recurrence rates of 18.2% and 21.2%, respectively. 
Furthermore, while head and neck reirradiation provides high local control rates, it is associated with 
severe, long-term treatment related adverse events such as fibrosis and dysphagia, with rates as high as 
40%7,8. Even with the use of conformal radiotherapy techniques such as intensity modulated radiation 
therapy (IMRT) or proton therapy, the 2- year rates of ≥ grade 3 toxicity approach 30%9,10. 
Transforming growth factor beta (TGFβ) is a cytokine frequently overexpressed by cancers that promotes 
epithelial-to-mesenchymal transition and is immune suppressive in the tumor microenvironment. TGFβ 
suppresses the expression of IFNγ and induces differentiation of immune suppressive Tregs.  Notably, 
co-targeting of TGFβ and immune checkpoints PD-1/L1 or CTLA4 demonstrates greater tumor control 
than either alone in in vivo models of melanoma11. M7824 is a first-in-class bi-functional fusion protein 
composed of a monoclonal antibody (mAb) against programmed death ligand 1 (PD-L1) fused to a TGFβ 
“trap”. M7824 was well tolerated in patients with heavily pretreated solid tumors and promising clinical 
activity was seen particularly in HPV-related cancers. In addition to the therapeutic effects of blocking 
PD-L1, the TGF-β trapping property of M7824 has potential for anti-inflammatory and anti-fibrosis 
activity 12,13.  
In spite of a recent small randomized trial of nivolumab with SBRT versus nivolumab alone in 53 recurrent 
HNSCC patients not showing an improvement in overall response rate, progression-free and overall 
survival over nivolumab alone 14, abscopal response in patients with widely metastatic HNSCC has been 
reported15. Furthermore, trials of radiotherapy and immune checkpoint blockade have demonstrated 
abscopal response in non-irradiated lesions between 10 and 27% of patients with metastatic melanoma 
16,17. Anti-PD1 can also potentiate the radiation effect locally, which is particularly attractive in the 
proposed population with oligo, loco-regional recurrent disease amenable to radio-ablative re-
irradiation, and pre-clinical studies using mouse models demonstrated significantly less radiation-
induced inflammation and fibrosis by the concurrent administration of TGF-β inhibitors 18,19. 
In summary, rationale for evaluating the combination of SBRT and M7824 in patients with recurrent, 
previously irradiated HNSCC include: (1) the increasing evidence for radiotherapy to generate antitumor 
immune response and synergize with PD-L1 inhibitors; (2) the compelling preliminary efficacy and safety 
data of M7824 in patients with refractory solid tumors; (3) the synergy between co-targeting of PD-1/L1 
and TGFβ in the tumor microenvironment; and (4) the anti-fibrotic properties of M7824 due to its anti-
TGF-β component to mitigate reirradiation fibrosis/toxicity. These findings support a strong rationale for 
testing M7824 in combination with SBRT in patients with local-regionally recurrent, previously irradiated 
HNSCC. 
 
2.1 
Introduction 
 
HNSCC account for over 550,000 cases worldwide and 55,000 cases in the U.S. annually, with an 
estimated 12,000 dying each year from the disease 20.   Radiotherapy, alone or in combination with 
chemotherapy, is integral to the treatment of many HNSCC, either in the primary management as part 
of an organ preservation approach or in the adjuvant setting after surgery21.  Despite improvements in 
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HNSCC treatment, local-regional recurrence occurs in 15-50% of patients and is the most common cause 
of death 22-24.  Among survivors, secondary primary HN tumors can occur in up to 40% of patients 25.   
 
Although, salvage surgery is historically the treatment of choice among patients with recurrent or second 
primary HNSCC after radiotherapy, many have unresectable disease, are medically unfit, or refuse 
surgery for various reasons, including loss of organ function26,27.   In these patients, the previous 
standard-of-care was chemotherapy.  Unfortunately, the prognosis with chemotherapy alone is poor, 
with pooled-analyses showing a median survival of 7.4 months compared to 4.6 months with supportive 
care alone, with a marginal improvement to 10 months with the addition of cetuximab to platinum-
based chemotherapy 24,28 26,29.   Furthermore, prior radiation has been reported as an independently 
poor prognostic factor in patients receiving systemic therapy for recurrent HNSCC30. 
 
2.2 
Reirradiation 
 
In select patients who are not surgical candidates, reirradiation is a potentially curative treatment 
option3,4.  However, head and neck reirradiation is a clinical challenge, and carries a significant risk of 
severe morbidity and toxicity to nearby normal tissue5.  Reirradiation with older two-dimensional (2D) 
and three-dimensional (3D) approaches have yielded modest local-regional control (LRC) rates of up to 
50% at 3 years, albeit with serious treatment-related toxicity risks, including 40-60% grade 3 or higher 
toxicity and up to 20% treatment related deaths 6,9 27,31.  An additional challenge with recurrent HNSCC 
is the development of tumor radioresistant clones acquired through prior treatment, which may limit 
the effectiveness of subsequent therapy 26,32.  Proposed retreatment strategies to reduce reirradiation 
toxicity and overcome tumor radioresistance include the use of conformal radiotherapy techniques, 
altered fractionation strategies and/or the addition of systemic radiosensitizers.  More-recently, the 
combination of immunotherapy and radiotherapy has demonstrated synergy33.  
 
2.3 
Stereotactic Radiotherapy  
 
Modern highly conformal radiotherapy techniques, such as intensity modulated radiation therapy 
(IMRT), proton therapy, and SBRT are attractive options for those with recurrent HNSCC.  Retrospective 
and prospective reports have demonstrated improved local disease control and survival compared with 
use of 2D and 3D radiotherapy 34-36.  Our institution recently published the largest series of 207 patients 
reirradiated with IMRT with curative intent.  The 2-year LRC and overall survival (OS) rates were 65% and 
57%, and 5-year rates were 49% and 42%, respectively 9.  The median survival was 25.1 months overall 
and 22.5 months for patients with SCC histology.   The grade 3 or higher treatment related morbidity 
was 32% at 2 years and 48% at 5 years.  Multivariate analysis showed that retreatment volume >50 cc 
(P=0.001) and use of platinum based chemotherapy (P=0.02) were associated with higher late grade 3 
toxicity rates9.   Similarly, our recently published study of 60 patients reirradiated with proton beam 
showed 2 year LRC and OS rates of 73% and 70%, respectively. The 2 year late grade 3 or higher toxicity 
rate was 26% 10.   
 
SBRT enables precise and focused delivery of ablative dose radiation in a limited number of treatments 
(typically 1-5) and has become a standard approach in several disease sites such as lungs, brain and 
prostate 37-41.  Logistical and financial advantages of SBRT over existing conformal radiotherapy 
modalities include fewer number of treatments, shorter treatment duration (typically <2 weeks vs 6-7 
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weeks), fewer clinic visits and/or lost work hours.   Clinical advantages of SBRT include reduced exposure 
of nearby normal tissues to reirradiation dose, use of ablative/high doses to confer additional  
mechanisms of cell kill, superior immune elicitation compared with standard fractionation, and a shorter 
interval to systemic therapy that benefits a population at high risk for metastatic development42.    
 
A growing body of literature demonstrates SBRT for HNSCC reirradiation can provide durable local-
regional control and is well tolerated relative to conventionally fractionated RT 37-41 29-30.   Retrospective 
and prospective studies from the University of Pittsburgh and others demonstrate SBRT is associated 
with late grade 3 toxicity rates between 10% and 30% when delivered with every other day (QOD) 
frequency.  The 2-year local control rates were 35-65% and 1-year OS rates were 30-60%43,44 41,45,46.   Our 
recently reviewed institutional experience of 101 patients with recurrent HNSCC reirradiated with SBRT 
to a median dose of 45 Gy in 5 fractions (delivered QOD) showed a 1-year local control rate of 87%, with 
a median follow-up of 15.9 months (unpublished data).  Patient reported quality of life outcomes showed 
lower symptom burden associated with SBRT47.  No difference in disease control rate or progression free 
survival for recurrent versus second primary tumors in a previously radiated field was noted on our 
institutional data, which is consistent with other published experiences9,48,49. 
 
Although local control with SBRT reirradiation is promising, recurrences outside the reirradiation field 
remains problematic.  Our data demonstrates 1- and 2- year regional recurrence rates of 16% and 24%, 
respectively, and 1- and 2-year distant recurrence rates of 16% and 28%, respectively (manuscript in 
progress).  Furthermore, head and neck reirradiation is associated with severe, long-term treatment 
related adverse events, with rates of severe fibrosis/dysphagia as high as 40%7,8. Even with the use of 
conformal IMRT and proton radiotherapy, 2-year grade 3 or higher toxicity rates approaches 30%9,10. 
 
2.4 
Checkpoint Inhibitors in Head and Neck Cancer 
 
Cancer immunotherapy is based on the premise tumors can be recognized as foreign invaders and 
effectively killed by an activated immune system.  However, it is also recognized that tumor-infiltrating 
lymphocytes (TILs) in proliferating cancers can be rendered ineffective by the tumor microenvironment.  
The pathogenesis and progression of HNSCC may therefore be facilitated by local immunosuppressive 
alterations. Down-regulation of T cell function has been reported in HNSCC. And is thought to be 
mediated by multiple mechanisms.  These include increased expression of the programmed death 
receptor ligand-1 (PD-L1) in tumor cells, suppression of TIL activity by tumor associated fibroblasts, 
production of immune suppression factors such as TGF-β, and co-stimulation of B7-CD28 family 
molecules50 51,52. Recurrent HNSCC can be particularly immunosuppressive, with impaired natural killer 
(NK) activity, reduced antigen-presenting function, impairment of tumor infiltrate lymphocytes (TILs), 
and increased population of suppressive Treg51,53-56. 
 
PD-L1 is one of two specific ligands for the programmed death receptor-1 (PD-1), a transmembrane 
protein and a member of the CD28 family of T-cell co-stimulatory receptor expressed on activated T cells.  
PD-L1 has been shown to down-regulate T-cell activation upon binding to PD-1. PD-L1 expression on 
tumor cells has been correlated with increased tumor aggressiveness, development of distant metastasis 
and decrease survival57.  Several clinical trials of anti-PD-L1 therapy have demonstrated clinical activity 
of immunotherapy in patients with heavily pre-treated, recurrent/metastatic HNSCC.  Several clinical 
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trials (Keynote 12; Keynote 55) have demonstrated an ORR of 11-22% and 1 year OS of 38% (Keynote 
12) with use of single agent anti-PD1 or anti-PD-L1 monoclonal in those with recurrent metastatic 
HNSCC.  Importantly, data from a phase III trial (CheckMate 141) demonstrated that anti-PD-1 improved 
survival of patients with platinum-refractory recurrent or metastatic HNSCC compared to standard of 
care chemotherapy and reduced the risk of death by 30% (HR 0.70, 96% CI 0.51-0.96) compared to single 
agent methotrexate, docetaxel or cetuximab of investigator’s choice12.  The 1-year OS was 36% with anti-
PD-1. 
More recently results of CheckMate-048 published in abstract form demonstrated that anti-PD1 as a 
single agent is non-inferior to chemotherapy with cetuximab in the first line setting and superior to 
chemotherapy with cetuximab in patients with a PD-L1 combined positive score of at least 1%, 
supporting anti-PD1 as a standard of care first line therapy for patients with recurrent/metastatic 
HNSCC58. 
 
TGF-β plays a critical role in regulation of epithelial proliferation and differentiation, and disruption of 
TGF-β signaling is common in HNSCC59. TGF-β overexpression in the tumor microenvironment promotes 
tumor immune evasion and metastasis and is associated with poor prognosis. TBF-β is a critical mediator 
of epithelial-to-mesenchymal transition to promote immune evasion and metastasis of HNSCC. 
Moreover, TGF-β is immunosuppressive in the tumor microenvironment. It decreases activity of 
Anaphase-promoting complex (APC) and NK cells, decreases T cell proliferation, facilitates recruitment 
of Tregs, promotes M2 polarization of TAM and angiogenesis by increasing VEGF production by TAM. 
TGF-β also mediates cell cycle quiescence and resistance to chemotherapy in squamous cell carcinomas60 
. TGF-β is also implicated as a driver of numerous fibrotic diseases through stimulation of collagen 
deposition, including the fibrosis induced by radiotherapy61. As a consequence of its pathophysiological 
roles in cancer and fibrotic syndromes, numerous TGF-β inhibitors have been developed62. 
 
2.5 
M7824:  Rationale For Combination PD-L1 and TGF- β-inhibition  
 
M7824 is a first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused to a TGFβ 
“trap”. M7824 consists of the PD-L1 antibody linked to the extracellular domain of 2 TGFBRII molecules63. 
Synergy between TGFβ inhibition and anti-PD-L1 has been demonstrated in animal models, supporting 
the combination into one molecule11. M7824 blocks the immunosuppressive effects of TGFβ on NK cell 
function63. M7824 has also been shown to reverse EMT, a mechanism of immune evasion, in lung 
cancer64. M7824 also demonstrated synergy with radiotherapy and enhanced the abscopal effect. In 
phase 1 clinical trials, the maximal tolerated dose could not be defined with the highest dose level tested 
being 20mg/kg every 2 week13s. Based upon pharmacokinetic data, a dose of 1200 mgs every 2 weeks 
has been chosen for further development. 
In a phase I 3+3 dose escalation and expansion study of 19 patients, M7824 was well tolerated in patients 
with heavily pretreated solid tumors and promising clinical activity was seen. Responses observed 
include a complete response in a patient with cervical cancer, 2 partial responses in anal and pancreatic 
cancer, and prolonged stable disease in 6 subjects13.  
Based upon a total of 377 patients in expansion cohorts, M7824 administration has been associated with 
infusion-related reactions, immune mediated adverse events and skin lesions with hyperkeratosis, which 
is a known drug class effect of TGF-β inhibitors. The most frequent treatment related adverse events of 
any grade were pruritus (11.4%), rash (13%), diarrhea (9%), asthenia (10.3%), fatigue (7.7%), decreased 
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appetite (5.6%) and anemia (6.1%). Of the 377, 58 subjects (15.4%) experienced at least 1 grade 3 or 
greater adverse event. These included anemia, rash, colitis, diarrhea, vomiting, lipase increase, ALT 
increase, fatigue, acute kidney injury, hypophosphatemia and keratoacanthoma (0.5%). One subject with 
pancreatic cancer had a grade 4 lipase increase and 1 subject died from grade 5 hemolysis, 
thrombocytopenia and dyspnea.   
Additional details regarding the clinical development of M7824 as well as adverse events are provided 
in the attached Investigator’s Brochure.  
 
2.6 
M7824 and SBRT 
 
Recurrences outside the reirradiation field remain problematic. Furthermore, while head and neck 
reirradiation offers the promise of durable disease control, it is associated with severe, long-term 
treatment related fibrosis and dysphagia7,8.  
The combination of targeted SBRT and immune checkpoint inhibition offers the potential to control the 
local recurrence using smaller reirradiation fields while mitigating disease recurrence regionally and 
distantly.   Studies have shown their combination have been improved antitumor activity compared to 
either therapy alone16.  Recent trials of radiotherapy and immune checkpoint blockade demonstrate 
abscopal response in unirradiated lesions in 10-27% of patients with metastatic melanoma17. In addition 
to blocking PD-L1, M7824 TGF-β trapping properties have anti-inflammatory and anti-fibrosis activity12. 
Pre-clinical studies using mouse models demonstrated significantly less radiation-induced inflammation 
and fibrosis when concurrent administered with TGF-β inhibitors18,19.  
Therefore, there is a strong impetus to evaluate the combination of SBRT and M7824 in patients with 
recurrent, previously radiated HNSCC based on the following rationale:  (1) evidence for radiotherapy to 
generate antitumor immune response and synergize with PD-L1 inhibitors; (2) compelling preliminary 
efficacy and safety data of M7824 in patients with refractory solid tumors; and (3) M7824 anti-fibrotic 
properties from its anti-TGF-β component. 
 
2.7 
Functional and patient reported outcome measures 
 
An unanswered question is how specific immune checkpoint blockade and radiotherapy toxicities can 
impact health-related quality of life (HR-QOL) and function.   A few studies have suggested that HR-
QOL scales, together with clinical data, might improve survival prediction 65-67 19,20,21.   While PRO and 
quality of life and symptom burden measures of this population are of great interest, there are few 
prospective studies that assess the impact of SBRT and checkpoint inhibitor blockade.   In this setting, 
an additional purpose of this study is to analyze functional and patient reported outcome measures 
with the combination of M7824 plus SBRT reirradiation for recurrent HNSCC. To minimize survey 
burden and personalize PROs to expected patterns of toxicity, the PRO bundle differs by site of 
recurrence (mucosal, neck, skull base anterior v non-anterior) as detailed in Table 1.  
 
 
3. PATIENT ELIGIBILITY 
 
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3.1 
Inclusion Criteria 
 
Patients with histologically documented local-regional recurrent squamous cell carcinoma of the head 
and neck, or second primary squamous cell carcinoma of the head and neck; 
 
Patients must be willing to undergo research biopsy for tissue collection at baseline and at disease 
progression; 
 
Previous receipt of at least 30 Gy of radiation for HNSCC with overlapping fields; 
 
Not eligible or poor candidate or patient refusal of surgery for recurrence;   
 
Evaluable disease apparent on imaging (MRI or CT); 
 
1 to 3 sites of recurrence (<60 cm3 per site, total volume <100 cm3); 
 
Age ≥ 18 years; 
 
Eastern Cooperative Oncology Group (ECOG) = 0, 1, or 2;  
 
Adequate hematologic function defined as follows: 
WBC ≥ 2000/μL; 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; 
Platelets ≥ 100,000 cells/mm3; 
Hemoglobin ≥ 9.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb 
≥ 9.0 g/dl is acceptable. 
 
Adequate renal function as follows: 
Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min determined by 24-
hour collection or estimated by Cockcroft-Gault formula: 
 
 
CCr male = [(140 – age) x (wt in kg)] 
 
 
 
       [(Serum Cr mg/dl) x (72)] 
 
 
 
CCr female = 0.85 x (CrCl male). 
 
Adequate hepatic function as follows: 
Total bilirubin  ≤ 1.5 x ULN (except patients with Gilbert Syndrome who can have total 
bilirubin < 3.0 mg/dL); 
 
AST or ALT < 3 x the upper limit of normal. 
 
Negative serum pregnancy test for women of childbearing potential and confirmation within 24 hours 
of first dose of study drug. 
 
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3.2 
Exclusion Criteria 
 
Presence of distant metastases; 
 
Less than six-month disease free interval from end of prior radiotherapy to the head and neck; 
 
Prior receipt of anti-PD-1/L1 therapy.  
 
Patients who are pregnant or breast feeding; 
 
Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or 
hematologic disease but not limited to: 
Symptomatic congestive heart failure, unstable angina, or cardiac dysrhythmia not 
controlled by pacer device; myocardial infarction within 3 months of registration. 
 
Active autoimmune disorder or immunosuppression (including HIV, but excluding endocrine 
abnormalities that are controlled with replacement medications); 
 
Active viral hepatitis; 
  
Steroid therapy of greater than prednisone 10 mgs a day or equivalent; 
  
Prior history of invasive non-head and neck cancer within two years, with the exception of screen 
detected prostate cancer treated with observation only, basal cell and squamous cell carcinoma of the 
skin, and micro-invasive resected cervical carcinoma.  
 
4. STUDY SCHEMA 
 
  
 
 
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Fig 1. Study Schema 
 
Abbreviations:  HNSCC = head and neck squamous cell carcinoma; XRT = Radiotherapy;  PROs = Patient 
Reported Outcomes; SBRT = Stereotactic Body Radiation Therapy 
 
 
 
5. STUDY EVALUATIONS 
 
Table 1 summarizes the pretreatment (initial screening, baseline measures prior to enrollment), on 
treatment, post-treatment phases of the trial, and the evaluations that would be required during these 
phases.   
 
TABLE 1: Summary of Study Evaluations 
 
Procedure 
Screenin
g 
On-Treatment 
First Follow-up 
Follow-Up 
 
Day -28 
to D1 
C1-C12, D1,D15 
(+/- 3 days), Q28D 
cycles 
90 days after 
last dose of 
M7824 (+/- 14 
days) 
Q6 mo. Yr. 2-5 
(+/- 28 days) 
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Informed 
consent 
X 
 
 
 
Medical 
history 
X 
 
Physical 
exam 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Dermatolo
gical exam 
X 
Every 3 mo. 
X 
X 
Performan
ce status  
X 
X 
X 
X 
Review of 
prior 
radiation 
fields 
X 
 
CT or MRI 
of neck  
X 
3, 6, 9, 12 mo. 
 
18, 24 mo. 
CT scan of 
chestd  
X 
3, 6, 9, 12 mo. 
 
18, 24 mo. 
BMP, 
creatinine,  
CBC diff, 
Mg, 
hepatic 
function 
X 
X 
 
 
X 
As clinically 
indicated 
Lipase, 
amylase, 
TSH, free 
T4 
X 
X (every other 
cycle) 
 
X 
As clinically 
indicated 
HBsAg, 
HCV Ab 
X 
 
 
As clinically 
indicated 
Preg Test 
for 
childbearin
g women 
X 
Every 3 mo. 
 
As clinically 
indicated 
12 lead 
EKG 
X 
 
 
 
Adverse 
event 
evaluation 
X 
X 
 
 
X 
 
Tumor 
biopsy a 
X 
 
 
 
At progression 
Blood  
(serum)for 
PK b 
 
X 
 
At progression 
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Blood  
(serum)for 
ADA b 
 
X 
 
 
 
At progression 
Blood for 
biomarker 
analyses c 
 
X 
 
At progression 
At progression 
All 
patients 
 
 
 
 
Medical 
Photo 
X 
 
Q6 mo. Yr. 2-5 
 
 
 
 
 
MDASI-HN 
X 
3, 6, 12 mo. 
 
18, 24 mo. 
EQ-5D 
X 
3 mo. 
 
24 mo. 
Radiation 
Swallow 
Pathway (all 
mucosal, all 
neck, non-
anterior SB) 
 
 
 
 
Swallowing 
clinic/Ther
apy  
X 
 
MBS  
X 
3-6 mo. 
 
18-24 mo. 
PSS-HN 
X 
3-6 mo. 
 
18-24 mo. 
CROM + 
HN-LEF 
X 
3-6 mo. 
 
18-24 mo. 
MDADI 
X 
3-6 mo. 
 
18-24 mo 
LSIDS-HN 
 
 
 
 
Mucosal 
primary 
only 
 
 
 
 
Video-
Strobe +/-2 
wks 
X 
3-6 mo. 
 
18-24 mo. 
Anterior 
skull base 
only 
 
 
 
 
ASBQ 
X 
3-6 mo. 
 
18-24 mo 
Footnote: Radiation Swallowing Therapy Pathway includes all patients with mucosal site of 
recurrent disease, all with cervical lymph node recurrence, and non-anterior skull base, MBS + 
MDADI, LSIDS-HN and CROM/HN-LEF occurs at baseline, 3-6 months and 18-24 months after 
end RT; assessment with SLP post-RT videostroboscopy and recommended on same schedule 
for mucosal primaries; SLP therapy visits are at clinician discretion but typically include a 
minimum of pre, during week 1, and end RT during week 2, and 6 weeks evaluation may include 
FEES particularly if laryngeal primary tumors. 
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a. Mandatory tumor biopsies will be collected prior to treatment and at progression, refer to section 
10.2 for details on tumor collection.  
b. Blood samples of approximately 3.5 mL will be drawn prior to and immediately after M7824 infusion 
for doses 1 and 3 (cycle 1 day 1 and cycle 3 day 1), and only prior to infusion for cycle 2 day 1 and 
cycle 6 day 1 OR end of treatment (whatever comes first) for analysis of pharmacokinetics.  Blood 
samples will also be collected prior to infusion of cycle 1 day1 and cycle 6 day 1 or end of treatment 
(whatever comes first) for analysis of ADA. 
c. Blood (2 x 10 cc streck, 2 x 10 cc EDTA plasma and 2 x 10 cc heparin PBMCs) will be collected for 
biomarker analysis prior to infusion on C1D1, C1D15, C2D1, C2D15, C3D1, C6D1, and C12D1, refer 
to section 10.2 for details. 
d. CT abdomen and pelvis and/or MRI brain should be ordered if clinically indicated at the discretion 
of the treating physician. 
 
Vital signs include HR, BP, and temperature; all laboratory assessments at baseline and on treatment 
may occur within 72 hours of drug administration;  windows for disease assessment by imaging and QOL 
endpoints are +/- 7 days. 
For female participants of childbearing potential, a urine or serum β-human chorionic gonadotropin test 
will be performed according to the Schedule of Assessments. Participants who are not WOCBP are 
exempted from pregnancy testing, but the reason must be documented. 
 
 
5.1 
Details regarding function and quality of life endpoints 
 
The PRO-QOL will consist of a battery of previously validated HR-QOL and Symptom Inventory 
questionnaires 60-68.  This includes: M.D. Anderson Dysphagia Inventory (MDADI), M.D. Anderson 
Symptom Inventory-Head and Neck (MDASI-HN), M.D. Anderson Symptom Inventory – Brain Tumor 
(MDASI-BT) for skull base only, Anterior Skull-Base Questionnaire (ASBQ) for skull base only, Brief Fatigue 
Inventory (BFI), EuroQol (EQ5D), Performance Status Scale For Head and Neck Cancer Patients (PSS-HN), 
Work Productivity and Activity Impairment Questionnaire: Specific Health Problem V2.0 (WPAI:SHP). 
These questionnaires will be performed in person by mail or by phone or by secure electronic methods.   
The research coordinator will notify the patient via telephone, email or via electronic notification 1-3 
weeks after the questionnaire is sent to remind the patient and give them the option of performing the 
survey by other means.  During patient follow-up period, HR-PRO will be assessed at the completion of 
reirradiation, and subsequently during follow up visits for all patients up to 24-months post reirradiation 
(Table 2).    
 
Clinician-rated, fibrosis-related measures will be conducted according to the schedule in Table 1. 
Clinician-rated measures are standard, brief procedures incorporated into the supportive care visits of 
patients receiving radiotherapy for HNSCC at MD Anderson Cancer Center. In addition to these 
functional measures, patients may be eligible for dual consent for an imaging study with serial MRI 
(separately funded) to quantify soft tissue parameters that may serve as an objective and quantitative 
imaging marker of fibrosis. PRO and functional outcome schedules are harmonized.  
 
Cervical Range of Motion (CROM): A goniometer will measure CROM (degrees) to assess active cervical 
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spine ROM. Five core CROM measures will be collected, including cervical extension, sagittal plane at 
rest, lateral flexion (left/right), coronal plane at rest, and lateral rotation (left/right). The primary 
CROM measure of interest is cervical extension. Cervical extension measures are highly reliable 
(ICC=.90). Average extension measures in healthy adults aged 60 to 69 range from 57 degrees in males 
(SD: 10.5) to 65 degrees in females (SD: 13.3).  Cervical extension measures decrease by approximately 
5 degrees for each decade of life.68  
 
Lymphedema/Fibrosis Grading: Clinician-grading of lymphedema/fibrosis will be conducted according 
to the published Head and Neck-Lymphedema Fibrosis (HN-LEF)1,2 per physical examination of the 
patient. Clinical grading is a brief assessment that can be completed in <5 minutes.  
 
Modified Barium Swallow (MBS) Studies: The MBS (also known as a videofluoroscopic swallowing 
study) is a dynamic, radiographic study used to measure oropharyngeal swallow physiology, aspiration 
and/or pharyngeal residue.69 Digital videos from SOC MBS will be scored by a trained speech 
pathologist blinded to patient, study, and follow-up interval using methods including the Dynamic 
Imaging Grade for Swallowing Toxicity (DIGEST)70. 
 
M.D. Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) is a patient-reported 
outcome questionnaire designed to measure severity or burden of systemic and head and neck (HN) 
specific symptoms and their interference with or effect on patients’ daily functioning. This 28-item 
multi-symptom inventory includes 13 core items (“systemic symptoms”: pain, fatigue, sleep, etc.), nine  
 
HN-specific items (“local symptoms”: dry mouth, mucus, shortness of breath, taste, etc.), and six 
interference items (activity, work, relations, etc.). The core MDASI items have been validated for use in 
cancer patient populations regardless of the specific diagnosis or type of therapy and thus can be used 
to compare overall burden of disease between different types of cancer71. The HN-specific items were 
validated internally with regard to construct and concurrent validity in HN cancer patients.72,73 MDASI 
includes the following symptom items for possible IO related toxicity: pain, fatigue, skin 
pain/burning/rash, shortness of breath, dry mouth, appetite, and nausea. Internal consistency 
reliability is high in the core, HN-specific, and interference items (Cronbach’s alphas of 0.72-0.92). 
Validated linguistic translations (Chinese, French, German, Greek, Italian, Spanish, and Turkish) of the 
MDASI-HN may be administered to non-English speaking participants.  
 
EuroQOL-5 Dimensions - 5L (EQ5D-5L) is a modified version of the widely used EuroQOL 5 Dimension. 
(Herdman, M. et al. 2011). The 6-item EQ5D-5L questionnaire is used to measure generic quality of life. 
The EQ5D-5L descriptive system measures five levels of severity in each of the existing five dimensions 
that includes mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The 
questionnaire also contains a Visual Analog Scale, by which respondents can report their perceived 
health status with a grade ranging from 0 (the worst possible health status) to 100 (the best possible 
health status). 
 
M.D. Anderson Dysphagia Inventory (MDADI) is a written questionnaire to evaluate dysphagia-specific 
QOL in H&N cancer patients.74 The 20-item MDADI questionnaire quantifies an individual’s global, 
physical, emotional, and functional perceptions of his or her swallowing ability. In an internal validation 
in 100 patients with HNC, concurrent validity was found to be moderate by comparison with the 
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Performance Status Scale for Head and Neck Cancer Patients (Spearman correlation, 0.47-0.61). 
Correlation with the physical functional subscale (Spearman correlation, 0.40) and emotional subscale 
of SF-36 (36-Item Short Form Survey) (Spearman correlation, 0.36) demonstrated convergent and 
divergent validity, respectively, of the MDADI. Test-retest reliability (physical, 0.86; emotional, 0.88; 
functional, 0.88) and internal consistency reliability (overall Cronbach’s alpha, 0.96) were sound.  
 
Lymphedema Symptom Intensity and Distress Survey – Head and Neck (LSIDS-H&N) 3 is a 64-item 
instrument designed to assess lymphedema symptoms in head and neck cancer patients. Survey items 
were selected to address six domains (head and neck-specific functioning, systemic symptoms, 
psychosocial issues, altered sensation symptoms, neck-shoulder musculoskeletal/skin symptoms, and 
miscellaneous symptoms) identified by an expert panel. Preliminary testing of LSIDS-H&N 
demonstrated both feasibility and readability.  
 
Anterior Skull Base Questionnaire (ABSQ) is a validated and widely utilized 35-item questionnaire 
designed as a standardized tool for assessment of quality of life concerns unique to patients with 
anterior skull base tumors (Gil Z, Abergel A, Spektor S et al.  Arch Otol Head Neck Surg. 2003; 
129(12):1303-1309.   The questionnaire consists of 35 questions divided into 6 domains covering the 
areas of performance, physical function, vitality, pain, specific symptoms (e.g.  taste, smell, nasal 
function and visual function) and influence on emotions.  
 
 
6. THERAPY 
 
6.1 
Radiotherapy 
 
6.1.1 Simulation 
 
All patients will undergo CT simulation. Patients will be simulated in the supine position.  Patients must 
be immobilized with a customized Klarity AccuCushion (Klarity Medical Products, Newark, OH), a 
thermoplastic head neck and shoulder mask (Orfit Industries America, Wijnegem, Belgium), and a 
customized bite-block attachment fixated to the thermoplastic mask.  The Klarity AccuCUsion is shaped 
to the veretx and sides (mastoid process and temple) of the head, and along the curvature of trapezius 
and sternocleidomastoid muscles of the neck to shoulders. This creates a custom posterior cup for 
indexing of the thermoplastic mask and minimizes mask-air space. A preheated moldable bite-block 
(Precise Bite, Civico, Coralville, IA) is then conformed to the patient’s upper teeth. The bite-block 
contains two outward attachments that are indexed to the warm thermoplastic mask and secured by 
snapping a small backing plate to the mouth piece from outside the mask. Six IR passive reflection balls 
are placed on the mask before CT scans for ExacTrac use during treatment for in-room alignment and 
motion tracking 75.  
 
For each patient, a simulation CT scan will be acquired with 1 mm slice thickness and coregistered in the 
treatment planning system (Pinnacle, version 9.8, Philips Medical Systems, Andover, MA) with diagnostic 
MRI and/or PET-CT, as well as treatment planning MRI and/or DECT and/or PET-CT images obtained with 
patient immobilized with the CMB. 
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6.1.2 Contouring and Treatment Planning 
 
Each patient will get a CABI/PTC-MRI and either a CABI PET CT or dual energy CT at the treating 
physician’s discretion, which will be fused with the simulation CT to assist with target delineation and 
contouring.  
 
The gross target volume (GTV) and critical structures will be contoured.  Based on our published 
outcomes with the CMB system, a 2–4 mm PTV margin should added to the target volume by the 
attending physician (Wang He, Wang Congjun, Tung S, et al.  J Applied Clin Med Physics 17(3): 1-10. 
2016).  
 
6.1.3 Radiation Dose Specifications 
 
SBRT will be delivered to a total prescription dose of up 40-45 Gy to 5 fractions prescribed to PTV 
delivered every other day for an overall treatment time of two weeks.  SBRT will be performed using 
either 6 MV photon beams on Varian TrueBeam STx system (Varian Medical Systems, Inc., Palo Alto, CA) 
with high definition (2.5 mm) leaflets or on the Accuray CyberKnife M6 (with or without HDI) (Accuray, 
Inc., Sunnyvale, CA).    
 
The prescribed dose should cover at least 95% of the PTV. No more than 2% of PTV receives < 92% of 
the prescribed dose, except in the area adjacent to critical structures including spinal cord and 
brainstem, in which optimal sparing of these structures could not be achieved.  In such instances, no 
more than 5% receives <80% of the prescribed dose may be permitted.  
 
 
6.1.4 Treatment Verification 
ExacTrac and cone beam CT will be used for each SBRT treatment.   
 
6.1.5 Normal Tissue Dose Constraints 
 
The compliance criteria listed in Table 6.16 below will be used to evaluate each case.  The per Protocol 
and Variation Acceptable categories are both considered to be acceptable.   The Per Protocol cases can 
be viewed as ideal plans, and the Variation Acceptable category can include more challenging plans that 
do not fall at or near the ideal results.   Deviation Unacceptable category are plans that do not meet the 
Variation Acceptable limits and are considered suboptimal and additional treatment planning 
optimization is recommended to avoid protocol deviation. 
 
Table 6.1.6 Planning Target Volume and Critical Normal Tissue Constraints and 
Compliance Criteria for SBRT in 5 Fractions 
Structure 
Name 
Dosimeric 
Parameter 
Per 
Protocol 
Dose  
Variation 
Acceptable 
PTV 
D95%* (Gy) 
V40-45 Gy (%) 
40-45 Gy 
≥95 % 
>35-50 Gy 
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Cochlea 
Dmax** (Gy) 
< 18 Gy 
<23 Gy 
Optic 
nerve(s) 
Dmax** (Gy) 
V21 Gy (cc) 
<15 Gy 
<23 Gy 
<0.2 cc 
Optic 
chiasm 
Dmax** (Gy) 
 
< 12 Gy 
<18 Gy 
Brainstem 
Dmax** (Gy) 
V21 Gy (cc) 
<15 Gy 
<23 Gy 
<21 Gy 
Temporal 
lobe 
Dmax** (Gy) 
V25 Gy (cc) 
<20 Gy 
<27 Gy 
<1.0 cc 
Spinal Cord Dmax** (Gy) 
 
<12 Gy 
<15 Gy 
Brachial 
Plexus 
Dmax** (Gy) 
V27 Gy (cc) 
<25 Gy 
<32 Gy 
<3.0 cc 
  
*D95% (Gy) = dose to 95% of volume; **Dmax = maximum dose to 0.03 cc of volume 
 
 
Table 6.1.7 Recommended dose acceptance criteria for other normal tissue (not overlapping PTV), but 
not to be used for plan score 
Structure Name SBRT 
(5 
fractions) 
Recommended 
dose 
acceptance criteria 
Parotid(s) 
As low as possible; Mean dose <15 Gy  
Carotid(s) 
As low as possible; Max dose <30 Gy; <5% hot 
spots in volume overlapping PTV 
Larynx 
As low as possible; Mean dose <10 Gy; Max dose 
<15 Gy  
Mandible 
As low as possible; Mean dose <10 Gy; Max dose 
<30 Gy  
Esophagus 
As low as possible; Mean dose < 10 Gy; Max dose 
< 30 Gy 
Oral Cavity 
As low as possible; Mean dose < 10 Gy; Max dose 
< 20 Gy 
Pharyngeal 
Mucosa 
As low as possible; Mean dose < 10 Gy; Max dose 
< 20 Gy 
 
 
6.2 
M7824 Systemic Therapy  
6.2.1 Description of the Investigational Medicinal Product 
The M7824 Concentrate for Solution for Infusion (liquid formulation) is packaged at a 10 mg/mL 
concentration in USP / Ph Eur type I 50R vials that are filled with drug product solution to allow an 
extractable volume of 60 mL (600 mg/60 mL). The vials are closed with rubber stoppers in serum format 
complying with USP and Ph Eur with an aluminum crimp seal closure. 
 
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6.2.2 Dosage and Administration 
A cycle is defined as 28 days with M7824 administered on days 1 and 15. 
Participants will receive an IV infusion of M7824 at a dose of 1200 mg over 1 hour (-10 minutes/+20 
minutes, ie, over 50 to 80 minutes) on days 1 and 15. 
Modifications of the infusion rate due to infusion-related reactions (IRRs) are described in Section 6.2.3. 
In order to mitigate potential IRRs, premedication with an antihistamine and with acetaminophen 
approximately 30 to 60 minutes prior to each dose of M7824 is mandatory for the first 2 infusions. 
Premedication is optional and at the discretion of the Investigator after the second infusion. If Grade ≥ 
2 infusion reactions are seen during the first 2 infusions, then premedication should not be stopped. 
Steroids as premedication are not permitted. Special precautions for monitoring of participants and 
management of IRRs/hypersensitivity, including modifications of the infusion rate and stopping of study 
drug are described in Section 6.2.3. 
 
6.2.3 Management of adverse events attributable to M7824 
Adverse drug reactions (ADRs) are defined in this study as any AEs related to study treatment assessed 
by the Investigator and/or Supporting company EMD Serono. Serious adverse reactions (SARs) are ADRs 
that are assessed as serious. Questions or concerns with regards to management and/or follow up of 
ADRs should be discussed with the Medical Monitor. 
Immune-related AEs, IRRs, anemia, and potentially TGF-β-mediated skin AEs are managed and followed 
up in their respective sections. Permanent treatment discontinuation may be recommended, so the 
relevant section must be reviewed: 
• 
For suspected irAEs, irAE management and guidance is presented below. General management 
by NCI-CTCAE v5.0 toxicity grading, as per ASCO, is listed below: Grade 1: study treatment should be 
continued with close monitoring, with the exception of some neurologic, hematologic, and cardiac 
toxicities; Grade 2: study treatment may be suspended for most Grade 2 toxicities, with consideration 
of resuming when symptoms revert to Grade 1 or less. Corticosteroids may be administered (initial dose 
of 0.5 to 1 mg/kg/day of prednisone or equivalent); Grade 3: study treatment is generally suspended and 
the high-dose corticosteroid treatment (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 
mg/kg/day) should be initiated. Corticosteroids should be tapered over the course of at least 4 to 6 
weeks. Some refractory cases may require infliximab or other immunosuppressive therapy; Grade 4: in 
general, permanent discontinuation of study treatment is recommended, with the exception of 
endocrinopathies that have been controlled by hormone replacement. 
• 
IRRs and hypersensitivity reactions guidance are presented below.  
• 
Anemia guidance is presented below.  
• 
Guidance and management for potentially TGF-β-mediated skin AEs are discussed below.  
Management of KA and cSCC: Any suspicious skin lesion should be biopsied (excisional biopsy preferred) 
and surgically removed as clinically indicated. No treatment interruption is required. Any questions or 
concerns should be discussed with the Medical Monitor 
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For ADRs related to M7824 that are not covered by the ASCO guideline, follow the guidance below: 
• Grade 2 ≥doesn’t require treatment modification when clinically manageable. 
• Grade 3, M7824 should be permanently discontinued for most of Grade 3 recurrent AEs, except for 
tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or suspected 
tumor and clinically manageable Hgb decrease (< 8.0 g/dL).  
• Grade 4, discontinue permanently, except for single laboratory values out of normal range that do 
not have clinical relevance. 
 
Infusion-related Reactions Including Immediate Hypersensitivity 
 
Infusion reaction may vary in manifestation and timing, and signs and symptoms usually develop 
during or shortly after drug infusion that generally resolve completely within 24 hours of completion of 
infusion. Infusion reactions like cytokine release syndrome may manifest similar signs and symptoms of 
immediate hypersensitivity/allergic reaction.  
 
All study treatments will be administered on an outpatient basis. As a routine precaution, for the first 2 
infusions, all participants enrolled in this study must be observed for 2 hours post end of infusion, in an 
area with resuscitation equipment and emergency agents. At all times during M7824 treatment, 
immediate emergency treatment of an IRR or a severe hypersensitivity reaction according to 
institutional standards must be assured. In order to treat possible hypersensitivity reactions like 
anaphylactic reactions, for instance, dexamethasone 10 mg and epinephrine in a 1:1000 dilution or 
equivalents, should always be available along with equipment for assisted ventilation. If no IRRs are 
observed during the first 2 infusions, the mandated 2 hours post infusion observation time may be 
reduced to 60 minutes. 
Premedication with an antihistamine and with acetaminophen (eg, 25-50 mg diphenhydramine and 500-
650 mg acetaminophen) approximately 30 to 60 minutes prior to each dose of M7824 is mandatory for 
the first 2 infusions, after which premedication is optional and at the discretion of the Investigator. 
Steroids as premedication are not permitted. If Grade ≥ 2 infusion reactions are seen during the first 2 
infusions, premedication should not be stopped. 
An assessment for possible IRR should be triggered based upon the development of specific symptoms 
within 24 hours of an infusion. These possible IRRs are identified based on a list of Medical Dictionary 
for Regulatory Activities (MedDRA) preferred terms (PTs) and criteria on the timely relationship to an 
infusion. IRRs are divided into reactions versus signs and symptoms. 
• An IRR should be considered when onset is on the day of infusion (during or after the infusion) or the 
day after the infusion (irrespective of resolution date) for any infusion related reaction, drug 
hypersensitivity, anaphylactic reaction, hypersensitivity, and/or Type 1 hypersensitivity. 
Signs and symptoms of IRRs and hypersensitivity/allergic reactions should be considered when onset is 
on the day of infusion (during or after the infusion) and resolved completely with the end date within 2 
days after onset. Signs and symptoms may include but not limited to pruritus, rash, and hypoxemia. 
 
 
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Table 2 
Treatment Modification of M7824 for Symptoms of Infusion-related Reactions Including 
Immediate Hypersensitivity 
NCI-CTCAE Grade v5 
Treatment Modification  
Grade 1 – mild 
• Mild 
transient 
reaction; 
infusion 
interruption not indicated; intervention not 
indicated. 
 
• Increased monitoring of vital signs as 
medically indicated as participants are 
deemed medically stable by attending 
Investigator. 
Grade 2* – moderate 
• Therapy or infusion interruption indicated 
but if responds promptly to symptomatic 
treatment (for example, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hours. 
 
• Stop infusion of the drug caused IRR. 
• Increased monitoring of vital signs as 
medically indicated as participants are 
deemed medically stable by attending 
investigator.  
• If symptoms resolve quickly or decreased 
to Grade 1, resume infusion at 50% of 
original rate with close monitoring of any 
worsening otherwise dosing held until 
resolution of symptoms with mandated 
premedication for the next schedule.  
• If worsens to Grade 3 or 4, follow 
treatment modification guidelines 
accordingly. 
Grade 3 or Grade 4 – severe or 
life-threatening 
• Grade 3: Prolonged (e.g., not rapidly 
responsive to symptomatic medication and / 
or brief interruption of infusion); recurrence 
of symptoms following initial improvement; 
hospitalization indicated for clinical sequelae. 
• Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
 
• Stop the infusion caused IRR immediately 
and disconnect infusion tubing from the 
participant with additional appropriate 
medical measures and close monitoring until 
deemed medically stable by attending 
Investigator. Hospitalization may be 
indicated. 
• Restart the medication taking out the drug 
that is the cause of IRRs from the next 
scheduled visit  
IV = intravenous, NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Event, and NSAIDs = nonsteroidal anti-inflammatory drugs.  
Once the M7824 infusion is interrupted or rate reduced to 50% of previous infusion rate, it 
must remain decreased for all subsequent infusions. For Grade 3 or 4 IRRs, M7824 
discontinuation is mandated.  
For all types and grades of infusion reactions, details about drug physical constitution, 
method of preparation, and infusion must be recorded. 
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In the event of a Grade 2* IRR that does not improve or worsens after implementation of the dose 
modifications indicated in  
 
 
Table  (including reducing the infusion rate by 50%), the Investigator may consider treatment with 
corticosteroids and the infusion should be stopped for that day. At the next infusion, the Investigator 
may consider the addition of H2 blocker antihistamines (eg, famotidine or ranitidine), in addition to 
premedication, for select participants. However, prophylactic steroids are NOT permitted. At the next 
dose, if the participant has a second IRR Grade ≥ 2 on the slower infusion rate, with the addition of 
further medication to premedication, the infusion should be stopped and the participant removed from 
treatment. 
Hypersensitivity Reaction 
If a hypersensitivity reaction occurs, the participant must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions according 
to the Working Group of the Resuscitation Council (United Kingdom) and can be found at 
https://www.resus.org.uk/pages/reaction.pdf. Participants should be instructed to report any delayed 
reactions to the Investigator immediately. 
Symptoms may include but are not limited to:  
• Impaired airway 
• 
Decreased oxygen saturation (< 92%) 
• 
Confusion 
• 
Lethargy 
• 
Hypotension 
• 
Pale / clammy skin 
• 
Cyanosis. 
Management of hypersensitivity includes:  
1. Epinephrine injection and IV dexamethasone 
2. Participant should be placed on cardiac, blood pressure, heart rate, and oxygen saturation monitor 
immediately 
3. Alert intensive care unit for possible transfer if required. 
Prophylaxis of flu-like symptoms 
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For prophylaxis of flu-like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), eg, ibuprofen 400 
mg or comparable NSAID dose, may be administered 2 hours before and 8 hours after the start of each 
IV infusion. 
 
Management of Immune-related Adverse Events 
 
The spectrum of irAEs is similar for M7824 as compared to other checkpoint inhibitors, in general. irAEs 
are considered important identified risks for M7824. Effective risk management of these toxicities (irAEs) 
primarily caused due to inhibiting PD-L1 and PD-1 pathways respectively is based on key 
recommendations76. Participant education for on time reporting of symptoms of potential irAEs and 
prompt clinical assessment is critical for effective management and quicker resolution of immune 
mediated toxicities, thus preventing progression into severe forms of toxicity that otherwise may 
become life threatening and difficult to manage or warrant permanent discontinuation from study. 
For treatment management of irAE per NCI-CTCAE v.5 criteria, refer to American Society of Clinical 
Oncology (ASCO) Clinical Practice Guidelines and National Comprehensive Cancer Network irAE 
Management Guidelines. 
The recommendations for irAE management, in accordance with the joint American Society of Clinical 
Oncology Clinical Practice Guidelines77 and National Comprehensive Cancer Network Guidelines. 
Treatment of irAEs is mainly dependent upon severity as defined by NCI-CTCAE v5.0. In general, 
management by NCI-CTCAE v5.0 grading, as per ASCO, is listed below: 
• 
Grade 1: study treatment should be continued with close monitoring, with the exception of some 
neurologic, hematologic, and cardiac toxicities.  
• 
Grade 2: study treatment may be suspended for most Grade 2 toxicities, with consideration of 
resuming when symptoms revert to Grade 1 or less. Corticosteroids may be administered (initial dose of 
0.5 to 1 mg/kg/day of prednisone or equivalent).  
• 
Grade 3: study treatment is generally suspended and the high-dose corticosteroids (prednisone 
1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) treatment should be initiated. 
Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may 
require infliximab or other immunosuppressive therapy.  
• 
Grade 4: in general, permanent discontinuation of study treatment is recommended, with the 
exception of endocrinopathies that have been controlled by hormone replacement. 
For organ/system specific management guidelines, review ASCO guideline tables in the joint American 
Society of Clinical Oncology Clinical Practice Guidelines77 . 
Potential TGF-β-mediated Skin Adverse Events 
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Skin AEs, possibly due to TGF-β inhibition, including hyperkeratosis, keratoacanthomas (KA) and/or 
cutaneous squamous cell carcinomas (cSCC), are important identified risks for M7824 and are described 
in this section. 
Skin assessments are performed at baseline and every 3 months for all participants (per Schedule of 
Assessments in Table 1). 
 
 
 
A detailed medical history of genetic or iatrogenic skin conditions, skin type, geographical location, 
occupational or environmental exposure to radiation or chemicals will be queried. For participants 
experiencing a dermatologic-related AE (hyperkeratosis, KA, or cSCC), initial biopsy with pathology 
report of initial AE is expected. Additional excisional biopsies of suspicious lesions should occur, and 
management discussed with the Medical Monitor, as indicated. Dermatology consultation is 
encouraged for diagnosis, outcome, and follow up.  
 
Anemia 
Preclinical testing of M7824 led to classification of treatment-related anemia is an AESI (refer to 
Investigator Brochure). Notably, there are many reasons for anemia in patients with advanced cancer, 
which is why a thorough investigation of new anemia cases of unspecified etiology is requested.  
For new anemia events assessed as treatment related, items queried may include but are not limited to 
detailed relevant past medical and treatment history, bruising tendency, history of blood transfusions 
and/or dependency, and a request for an updated eCRF including details such as concomitant 
medications, all laboratory data, updated dosing information and recent tumor evaluation scans. 
General guidance for anemia management and evaluation: 
• 
Participants must enter the study with Hgb values at least 9 g/dL; routine blood test parameters 
are required in the Schedule of Assessments. 
• 
All relevant hematologic testing for treatment-related anemias should be done prior to blood 
transfusion, if clinically feasible. 
• 
If a participant experiences significant anemia (e.g., < 8 g/dL), then the amount of blood to be 
drawn may be reduced by not taking blood at selected time points for pharmacodynamic biomarkers. 
The decision to reduce the time points for these biomarkers will be taken by the Investigator in 
consultation with the Medical Monitor. This will be documented. Blood will continue to be taken as 
scheduled for safety analyses, PK, and anti-drug antibodies (ADAs). 
• 
Transfusion should be performed at the discretion of the Investigator, based on clinical 
assessment and considered when participant experiences significant anemia. An attempt should be 
made to initiate work up (as specified below) for cause of anemia prior to transfusion if clinically feasible 
to not confound this work up. In general, blood transfusions and erythroid growth factors are permitted 
for Hgb ≤ 7 g/dL and/or for life-threatening bleeding. 
Guidance for evaluation of suspected treatment-related anemias is provided in 
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Table 3. 
Discuss further management with the Medical Monitor for clinically significant treatment 
related- anemias. 
 
Table 3 
Evaluation Guidance of Suspected Treatment-related Anemia Adverse Events 
Baseline Anemia Evaluation (Prior to Transfusion, if Feasible) 
Hb and CBC with differential (e.g., MCV, RDW, ANC, hematocrit, reticulocytes counts) 
Peripheral blood smear for cell morphological assessment 
Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and serum 
folate, B12 values and other chemistries: 
• 
Coagulation factors (PT, PTT, INR) 
• 
Urinalysis  
• 
Iron panel (TIBC, ferritin, Fe) 
• 
TSH/hormonal panel 
• 
Fecal-occult blood testing 
• 
Erythropoietin. 
Further Recommendation Based on Suspected Etiology (in Addition to Baseline Anemia Testing) 
Unknown etiology, 
suspect possible 
hemolysis 
Coombs test, fibrinogen, haptoglobin, d-dimer 
Consider hematology consultation. 
Consider blood transfusion at clinical discretion. 
Unknown etiology, 
suspect possible 
bleeding 
Consider blood transfusion at clinical discretion. 
Consider surgical/interventional radiology consultation. 
Consider imaging, as clinically indicated (e.g. FAST scan, CT scan, MRI, 
angiography). 
Consider endoscopy (upper/lower).  
Unknown etiology 
despite above work-up 
Hematology consultation. 
Consider bone marrow aspiration/morphologic evaluation. 
ANC = absolute neutrophil count, Hgb = hemoglobin, CBC = complete blood count, INR = 
international normalized ratio, LDH = lactate dehydrogenase, LFT = liver function test, MCV = 
mean corpuscular volume, PT = prothrombin time, PTT = partial thromboplastin time, RDW = red 
cell distribution width, TIBC = total Iron binding capacity, and TSH = thyroid stimulating- hormone. 
Anemia severity reporting will follow the NCI-CTCAE v5 guidelines as below ( 
Table 4). 
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Table 4 Common Terminology Criteria for Adverse Events (CTCAE) Guidelines for Anemia Severity 
CTCAE v.5 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Anemia 
Hgb 
Hgb < LLN-10.0 
g/dL; 
< LLN-6.2 mmol/L; 
< LLN-100 g/L 
Hgb < LLN-10.0-
8g/dL; 
< LLN-6.2-4.9 
mmol/L; 
< LLN-100-80 g/L 
Hgb < LLN-
8.0g/dL; 
< LLN-4.9 
mmol/L; 
< LLN-80 g/L;  
transfusion 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Hgb = hemoglobin and LLN = lower limit of normal. 
Signs and symptoms of anemia may include pallor of the skin and mucous membranes, shortness 
of breath, palpitations of the heart, soft systolic murmurs, lethargy, and fatigability. 
Alterations in Wound Healing or Repair of Tissue Damage 
Alterations of wound healing and tissue damage repair are considered a potential, theoretical risk for 
M7824 given TGF-β role in wound healing. Management should be discussed with the Medical Monitor 
for participants requiring surgery on study. Post-operative wound healing will be closely monitored. 
Management should be discussed with the Supporting company EMD Serono for participants requiring 
surgery on study. 
 
 
7. DEFINITION OF DISEASE PROGRESSION/RECURRENCE 
Contrast-enhanced CT of neck and chest is the first choice of imaging modality. If a participant should 
not receive iodinated contrast medium or due to radiation protection reasons, magnetic resonance 
imaging (MRI) of the same area, using gadolinium enhancement according to local protocol as permitted 
in conjunction with unenhanced CT of the chest from the thoracic inlet to the inferior costophrenic 
recess should be done. The same method should be used per participant throughout the study. 
A brain CT/MRI scan should be performed, if clinically indicated by development of new specific 
symptoms. 
Baseline scans are taken within 28 days prior to treatment. Disease must be evaluable by RECIST or 
RECIST 1:1. All the scans performed at baseline need to be repeated at subsequent visits for tumor 
assessment as per Table 1 (Summary of study evaluations). In general, lesions detected at baseline need 
to be followed using the same imaging methodology and preferably the same imaging equipment at 
subsequent tumor evaluation visits. 
 
Due to the landmark end-point of progression-free survival at 1 year, this study will utilize RECIST or 
RECIST 1:1.  
 
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Biopsy with histopathological confirmation of first progression is required unless contra-indicated by risk 
to the patient.   
 
Disease progression will be categorized as in-field or out-of-field. For the purposes of this trial, the 
following definitions will be utilized: 
 
Local progression is defined as any evidence of disease progression by RECIST or RECIST 1:1 or 
histologically confirmed within the re-irradiation treatment field.  
 
Regional progression is defined as any evidence of disease progression by RECIST or RECIST 1:1 or 
histologically confirmed 2 cm or more outside the re-irradiation field and within the head and neck or 
regional lymph nodes not in reirradiation field.   
 
Distant progression is defined as any evidence of disease involving a distant organ by RECIST or RECIST 
1:1 or histologically confirmed.   
 
Due to the known phenomenon of pseudo-progression associated with SBRT, progression should be 
confirmed with further evaluation which may include ultrasound, FDG-PET. Biopsy for confirmation 
should be considered to verify disease recurrence.  
 
8. CRITERIA FOR SUBJECT WITHDRAWAL 
8.1 
Withdrawal from Trial Therapy 
Participants will be withdrawn from treatment for any of the following reasons: 
1. 
Participants meeting the definition of PD while on treatment based on RECIST or RECIST 1:1 with 
the exception that participant may continue past PD if the ECOG PS has remained stable, and if in the 
opinion of the Investigator, the participant will benefit from continued treatment. 
2. 
In case of premature withdrawal from the study treatment for reasons other than PD, the 
participants will be asked to attend scheduled visits, including tumor assessment and other assessments 
as planned until PD and end of study or death.    
3. 
Significant clinical deterioration (clinical progression), defined as new symptoms that are deemed 
by the Investigator to be clinically significant or significant worsening of existing symptoms. 
4. 
Therapeutic failure requiring urgent additional or alternative anticancer treatment. 
5. 
Occurrence of AEs resulting in the permanent discontinuation of the study treatment being 
desired or considered necessary by the Investigator and/or the participant. 
6. 
Occurrence of pregnancy in the participant. 
7. 
Use of a prohibited concomitant drug, as defined in Section 9.1, where the predefined 
consequence is withdrawal from the study treatment if considered necessary by the Investigator or the 
Supporting company EMD Serono. 
8. 
Noncompliance. 
 
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8.2 
Withdrawal from Study 
1. 
A participant may withdraw from the study at any time, at his/her own request (i.e., withdrawal 
of consent), and without giving a reason. 
2. 
The participant may be withdrawn by the Investigator due to participation in another clinical 
study. 
3. 
The participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons. 
4. 
The Schedule of Assessments specifies the data to be collected at study discontinuation and 
follow up, and any additional evaluations that need to be completed. 
In case of withdrawal from the study: 
1. 
The appropriate electronic case report forms (eCRFs) for the End-of-Treatment visit must be 
completed.  
2. 
The day of withdrawal will correspond to the day of end of treatment and the assessments 
scheduled for the visit should be performed, if possible, with a focus on the most relevant assessments.  
3. 
Participants will be asked to continue safety and survival follow up, which includes the collection 
of data on survival, patient reported outcome (PRO) questionnaires, and subsequent anticancer therapy. 
After completion of the Follow-up period or after the End of Treatment visit, whatever is applicable, the 
appropriate eCRF section for Study Termination must be completed. 
If the participant is enrolled into a new study or any new therapy post-withdrawal from the study, the 
Safety Follow-up visit should be scheduled prior to the start of the new treatment irrespective of the 28-
day safety follow up period. 
 
8.3 
Premature Discontinuation of the Trial 
The whole study may be discontinued prematurely in the event of any of the following: 
• 
New information leading to unfavorable risk-benefit judgment of the study drug, for example, 
due to: 
• 
evidence of inefficacy of the study drug, 
• 
occurrence of significant previously unknown adverse reactions or unexpectedly high intensity or 
incidence of known adverse reactions, or 
• 
other unfavorable safety findings. 
(Note: Evidence of inefficacy may arise from this study or from other studies; unfavorable safety findings 
may arise from clinical or nonclinical examinations, for example, toxicology.) 
• 
Supporting company EMD Serono’s decision that continuation of the study is unjustifiable for 
medical or ethical reasons. 
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• 
Poor enrollment of participants making completion of the study within an acceptable time frame 
unlikely. 
• 
Discontinuation of development of the Supporting company EMD Serono’s study drug. 
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) will be 
informed about the discontinuation of the study in accordance with applicable regulations. 
The whole study may be terminated or suspended upon request of Health Authorities. 
 
8.4 
Definition of End of Study 
If the study is not terminated for a reason given in Sections 8.1, 8.2 or 8.3, the end of the study is defined 
as 1 year after the last participant receives the last dose of M7824. 
 
9. CONCOMITANT MEDICATIONS AND PROCEDURES 
 
9.1 
Permitted Medicines/Prohibited Medicines 
Permitted Medicines 
Any medications (other than those excluded by the clinical study protocol) that are considered necessary 
for the participants’ welfare and will not interfere with the study drug may be given at the Investigator’s 
discretion. 
The Investigator will record all concomitant medications taken by the participant during the study, from 
the date of signature of informed consent, in the appropriate section of the eCRF.  
Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, dose, 
duration, and indication of each drug. 
Blood transfusions and erythroid growth factors are permitted for hemoglobin (Hgb) ≤ 7 g/dL and/or for 
life-threatening- bleeding. 
Prohibited Medicines 
As stated in the exclusion criteria, participants must not have had prior therapy with any antibody or 
drug targeting programmed- death 1 (anti-PD-1) or anti-PD-L1, concurrent systemic anticancer 
treatment, or cytokine therapy (except for erythropoietin), major surgery (excluding prior diagnostic 
biopsy), concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any 
investigational drug within 28 days before the start of study treatment. 
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In addition, the following treatments must not be administered during the study: 
• 
Immunotherapy, immunosuppressive drugs (ie, chemotherapy or systemic corticosteroids 
except for short-term treatment of allergic reactions or for the treatment of immune-related adverse 
events [irAEs]), or other experimental pharmaceutical products. Short-term administration of systemic 
steroid (ie, for allergic reactions or the management of irAEs) is allowed. Steroids with no or minimal 
systemic effect (topical, inhalation) are allowed. Also, hormone replacement with corticosteroids for 
adrenal insufficiency is allowed if the steroids are administered only for the purpose of hormonal 
replacement and at doses ≤ 10 mg or equivalent prednisone per day. 
 
Prophylactic use of corticosteroids for infusion-related reactions is prohibited. However, short courses 
of steroids may be used at the discretion of the treating physician to prevent pain and/or swelling due 
to inflammation associated with SBRT, particularly transient neurogenic pain common in skull-based 
tumors.   
• 
Any vaccine therapies for the prevention of infectious disease (e.g., seasonal flu vaccine, human 
papilloma virus vaccine) except administration of the inactive influenza vaccine. 
• 
If the administration of a nonpermitted concomitant drug becomes necessary during the study, 
the participant will be withdrawn from study treatment (the Supporting company EMD Serono may be 
contacted to discuss whether the study treatment must be discontinued). 
Medications other than those specifically excluded in this study (see above) may be administered for the 
management of symptoms associated with the administration of M7824 as required. These might 
include analgesics, anti-nausea medications, antihistamines, diuretics, anti-anxiety medications, and 
medication for pain management, including narcotic agents. 
Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, dose, 
duration, and indication of each drug. 
 
9.2 
Permitted/Prohibited Procedures 
The following nondrug therapies must not be administered during the study (and within 28 days before 
the start of study treatment) before the verification of PD by the IRC: 
• 
Major surgery (excluding prior diagnostic biopsy) 
• 
Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to 
potentially interfere with major organ function (e.g., hypericin). 
Any diagnostic biopsies collected for clinical reasons during the study should be documented as a 
concomitant procedure including the outcome of available pathological reports. 
 
 
 
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10. ASSESSMENT OF SAFETY 
 
Respective safety measures comprise inclusion/exclusion criteria for participation in clinical studies 
with M7824, guidance for prevention, monitoring, and medical management of potential risks, as well 
as guidance on study treatment interruption or discontinuation. 
 
10.1 
General Assessments 
The safety profile of M7824 will be assessed through the recording, reporting, and analysis of baseline 
medical conditions, AEs, physical examination findings, including vital signs, laboratory tests, ECOG PS, 
and 12-lead electrocardiogram (ECG) recordings.  
The AE reporting period for safety surveillance begins when the participant receives the first dose of the 
investigational agent and continues until last Safety Follow-up visit or before start of any anticancer 
therapy, whatever comes first.  
The safety assessments will be performed according to the Schedule of Assessments in Table 1. 
 
10.2 
Adverse Drug Reactions Requiring Treatment Modification 
Clinical Laboratory Assessments 
It is essential that the Supporting company EMD Serono or designee be provided with a list of laboratory 
normal ranges before shipment of study drug. Any change in laboratory normal ranges during the study 
will additionally be forwarded to the CRO and the Supporting company EMD Serono. 
All routine laboratory analyses will be performed at a laboratory facility local to the study site, and 
relevant results must be available and checked before administration of treatment (details to be 
provided in the Laboratory Manual). 
If a participant has a clinically significant abnormal laboratory test value that is not present at baseline, 
the test should be closely monitored until the test value has returned to the normal range or the 
Investigator has determined that the abnormality is chronic or stable.  
The report of the results must be retained as a part of the participant’s medical record or source 
documents.  
Abnormal laboratory findings and other abnormal investigational findings (eg, on an ECG trace) should 
not be reported as AEs unless they are associated with clinical signs and symptoms, lead to treatment 
discontinuation, or are considered otherwise medically important by the Investigator. If a laboratory 
abnormality fulfills these criteria, the identified medical condition (eg, anemia, increased ALT) must be 
reported as the AE rather than the abnormal value itself. 
See the Schedule of Assessments in Table 1 for further details. 
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Specific Planned Assessments or Adverse Events of Special Interest  
AESIs are serious or non-serious AEs specific to known mechanism of action of the treatment drug that 
are of clinical interest requiring ongoing monitoring and rapid communication for optimal on-time 
management.  
IRRs, including immediate hypersensitivity 
Any signs or symptoms experienced by participants during the infusion or any event occurring during or 
within one day of drug administration should be evaluated as potential IRRs. IRRs are common ADRs 
with monoclonal antibodies (mAbs) timely related to drug administration and have been reported as 
anaphylaxis, anaphylactoid reactions and cytokine release syndrome, among other terms used. IRRs are 
an AESI for M7824, and important identified risks (adverse reactions) for M7824, the precautions and 
management are discussed in Section 0. 
Immune-related adverse events (irAEs) 
Immune-related AEs are defined as off target side effects associated with exposure of an immunogenic 
drug and are consistent with an immune mechanism. In the process of identification of irAEs, any 
possible etiology of neoplastic, infectious, metabolic, toxin, or any other factor should be ruled out. 
Serologic, histologic (biopsy), and/or immunologic results should be obtained to evaluate the differential 
diagnosis and/or support an immune-mediated cause. Immune-related AEs are AESIs for M7824 and 
important identified risks for M7824, the precautions and management are discussed in Section 0. 
Skin adverse events 
Skin AEs are AESIs for M7824, and include 2 potential mechanisms: 
1. 
Skin AEs possibly due to TGF-β inhibition: rash with hyperkeratosis, KA, and SCC. Skin lesions with 
hyperkeratoses, keratoacanthoma, cSCC possibly due to TGF-β inhibition are identified risks for M7824. 
For more information, see Section 0.  
Treatment-related skin lesions with hyperkeratosis, KA, cSCC possibly due to TGF-β inhibition were 
reclassified as important identified risks (adverse reactions) at the end of the safety reporting period of 
July 2017; however, they have been manageable and did not lead to permanent discontinuations in 
Studies EMR200647-001/EMR200647-008. 
2. 
Immune-related skin AEs (irAEs) possibly mediated by PD-L1 inhibition (events in this category 
are also reported under irAEs). For more information, see Section 0.  
Treatment-related anemia adverse events  
Anemia is considered a potential risk based on toxicological findings with M7824 in the cynomolgus 
monkey indicating a decrease in Hgb, red blood cells (RBCs), and hematocrit that was fully reversible or 
showed a substantial trend toward recovery. Treatment-related anemia AEs are AESIs for M7824. A 
consistent clinical risk of treatment-related anemia on M7824 was not observed in Study EMR200647-
001. As summarized in the Investigator Brochure, treatment-related anemia was reported in 6.1% (n=23)  
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of the participants from a number of cohorts. For more information, see Section 0 and refer to the 
Investigator Brochure. 
Alterations in wound healing or repair of tissue damage 
Due to the involvement of TGF-β in repair of skin and other tissue injuries, alterations in wound healing 
or repair of tissue damage is considered a potential risk. No AEs have been reported in Phase I studies. 
For any surgeries conducted post-treatment initiation, surgical wound healing will be closely monitored. 
Embryo fetal toxicities 
Embryo fetal toxicities are a known risk of the PD-1/PD-L1 targeting class. Animal models link the PD-
1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune 
tolerance to fetal tissue (Guleria, 2005; Leber 2010; Wafula, 2009; Zenclussen 2013). Embryofetal and 
reproductive toxicities have also been investigated in animal models for a humanized mAb targeting TGF-
β1. At a dose as high as 30 mg/kg, no maternal reproductive toxicity or embryofetal lethality was 
observed (Hilbish 2016).  
Respective safety measures comprise inclusion/exclusion criteria for participation in clinical studies with 
M7824, guidance for prevention, monitoring, and medical management of potential risks, as well as 
guidance on study treatment interruption or discontinuation. 
Methods of AESI recording and reporting will follow the guideline for AE recording and reporting. Refer 
to the Investigator Brochure for reporting the identified risks. 
 
Embryo fetal toxicity is an important potential risk of M7824. An appropriate contraception warning is 
provided as part of inclusion criteria. Pregnant and breastfeeding women are not allowed in the M7824 
study and adequate contraceptive measures are recommended during the study to minimize or 
eliminate the potential risk to the developing fetus. 
 
Functional and patient reported outcomes include but are not limited to: 
• Validated clinical grading criteria (Head and Neck-Lymphedema and Fibrosis, HN-LEF)  
• Patient-reported measures of head and neck fibrosis (Lymphedema Symptom Inventory 
Distress Scale, L-SIDS)3 
• Radiographic dysphagia grade (Dynamic Imaging Grade of Swallowing Toxicity, DIGEST) 
• Cervical range of motion (CROM).   
 
Biomarker Assessments 
Due to limited understanding of the biological activities induced by M7824 and radiation in cancer 
subjects, biomarker assessment will be conducted to examine if the doses are associated with relevant 
antitumor immune activities. As part of the translational work, this trial will serve to:  
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1. Evaluate PD-L1 expression as a predictor of response 
2. Evaluate the effect on TGFβ concentrations in plasma. 
3. Evaluate potential predictive / prognostic biomarker candidates related to the drug and / or the 
cancer (such immune infiltrating populations, tumor mutational burden, systemic cytokine 
profiles) 
a. Pancancer Immune Profiling Formalin-Fixed Paraffin-Embedded (FFPE) based assay using 
Nanostring or HTG technology. 
 
b. Immune infiltrating populations will be analyzed by immunohistochemistry (IHC), and 
Multiplex IF analyses. 
i. IHC markers will include, but are not limited to, PD-L1 (clone E1L3N, 
405.9A11, 28-8, EPR1161(2), SP142, SP263, 22C3, E1J2J), CD20, CD61, 
LAG3, PD1, CD21, CD66b, OX40, CD3, CD3, CD68,  B7-H3 (CD276), CD4, 
CD33, CD73, B7-H4 (VTCN1), CD5, CD38, CD137, TIM-3, CD8, CD45 LCA, 
FOXP3, VISTA, CD11b CD45 RO, Granzyme B, CD14, CD56, ICOS, CD19, 
CD57 (Leu-7), IDO-1. 
ii. Multiplex IF Analysis. Up to 10 immune markers, various panels of immune 
markers may be utilized. Panel #1, CD3, CD8, CD68, PD-L1, PD-1 pan-
cytokeratin and DAPI; Panel #2, CD20, CD45RO, FOXP3, Granzyme B, CD57, 
pan-cytokeratin and DAPI.  Myeloid panel 5: Arg1, Cd68, CD11B, CD33, CD14, 
CD66B, AE1/AE3/, DAPI. For multiplex IF analysis, we will use the Opal 
chemistry and multispectral microscopy Vectra system (Perkin-Elmer) which 
includes the Nuance software; analysis will be performed using the InForm 
software. From various optimized panels, additional will be selected according 
the results of the gene expression analysis and may include other 
immunotherapy targets (e.g., OX-40, Vista, GITR, TIM-3, LAG-3, NKp46/CD16, 
etc.) and proliferation markers (e.g., Ki67).  
iii. RNAscope.  TGF-β and other additional markers may be analyzed by 
RNA scope.  
c. Immune infiltrating populations and systemic cytokine profiles 
i. Blood collections and biopsies will be collected for immune studies under the 
supervision of the Translational Molecular Pathology Immunoprofiling Lab (TMP-IL) at 
MD Anderson. 
ii. Fresh tissue will be available for flow cytometry for assessment of the proportion of 
MDSC, macrophage, DC and NK cell subsets within the Live CD45+ cells in panel 3. The 
expression of checkpoint ligands will be explored using panel 4. Live cells will be sub-
gated as CD45-negative to exclude immune cells. EPCAM will be used as a marker of 
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tumor cells and CD90 as a fibroblast marker. The expression of CD80, CD86, GITR-L, 
ICOS-L, MIC A/B, B7-H3, B7-H4, CD73, PD-L2, OX40L and other relevant immune cells 
will be assessed. 
iii. In peripheral blood, evaluation by circulating immune populations will include, but 
not be limited to, CD4+, CD8+, NK, Treg, monocytes and neutrophils as outlined by the 
Schedules of Assessments (Tables 1). High order flow cytometry panels will be 
designed. The panels will focus on 1) delineation of major immune cell types (T cells, B 
cells, NK cells, DC), 2) determination of T cell differentiation status and limited 
functionality (IFNγ, TNFα, GB) and 3) defining the expression level of costimulatory and 
coinhibitory molecules on T cells. The proposed studies will be conducted 
retrospectively on cryopreserved PBMCs. 
v. Serum Cytokine Analyses.  Cytokines (IFN-γ, IL-1α, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, 
IL-13, and TNF-α) will be measured in the serum using the Meso Scale Discovery 
Platform (Rockville, MD). This technology allows for the detection of up to 40 analytes 
per well and uses a very low sample volume. This method has a sensitivity up to 1000 
fold higher than traditional ELISA assays with a large linear range of 3-4 logs. The 
instrument performs immunoassays utilizing electrochemiluminescense to detect the 
signal in a 96 well plate format. This technology can be utilized for either single agent 
detection or in multiplex format. A wide menu of validated single or multiplex kits for 
the detection of 1 to 40 analytes are available from the manufacturer and can be 
customized. 
d. Mutational profiling 
i. Genomic profile will be assessed via next generation sequencing in a panel of 409 
genes that sequences known hotspots to a coverage of at least x250 coverage 
depth performed in the Molecular Diagnostic Laboratory (MDL) at MD Anderson. 
The lab is CAP accredited and CLIA certified to perform high complexity molecular 
testing for clinical purposes. 
ii. TGFβ signaling pathway mutations may also be assessed via this panel which will 
include, but not limited to, TGFβR2, ACVR2A, SMAD2 and SMAD4. 
iv. 
iv. Circulating free DNA (cfDNA) will be analyzed in peripheral blood using the Guardant 
Health platform to monitor tumor response and progression. Identified gene mutations 
will be correlated with target DNA sequencing in the tumor sample.  
i.   
b. TCR sequencing 
TCR sequencing analysis may be performed using DNA from tumor tissues as well as PBMC. 
Briefly, 500 ng tumor DNA or 3-6 ug PBMC DNA will be subjected to high throughput TCR 
Vβ CDR3 sequencing on an Illumina HiSeq sequencer with at least 5-fold coverage by 
ImmunoSEQ™ sequencing (Adaptive Biotechnologies, Seattle, WA). TCR diversity and 
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clonality (defined as 1-(entropy)/log2(#) of productive unique sequences, where the 
entropy term takes into account the varying clone frequency) will be calculated using a 
software by Adaptive Technologies. T-cell repertoire diversity and clonality will be 
correlated with clinic-pathological parameters such as response to treatment, survival 
and immune infiltrating profile as well as genomic profiles (total mutation burden, non-
synonymous mutation burden, predicted neoantigen burden, clonal mutation burden and 
clonal predicted neoantigen burden). TCR profile generated from treatment-refractory 
tumors at the time of disease progression will be compared to data from pre-treatment 
tumor samples to explore the TCR repertoire evolution of these tumors under therapeutic 
pressure. The dynamic changes of TCR from PBMC, when longitudinal blood samples are 
available, will be correlated to response to immune checkpoint blockade or 
chemotherapy and survival.  
Details of time points and sampling are provided in the Schedules of Assessments (Table 1). An SOP 
detailing the tissue collection will be available to clinical team.  
All proposed biomarker analyses are exploratory and dependent on the quality and availability of 
sufficient materials. The panel of biomarkers might be adjusted based on results from ongoing research 
related to anti-PD-1 / PD-L1 therapies and / or safety, therefore, each subject will also be asked whether 
any remaining tumor tissue and blood-derived samples can be stored at a central repository (until such 
time as these samples cannot support any further analysis) and can be used for future exploratory 
research on the drug and / or disease-related aspects. A subject’s consent to the use of any remaining 
samples for such future exploratory research shall be optional and shall not affect the subject’s 
participation in the current trial. 
 
11. PHARMACOKINETICS 
Samples for PK and ADA will be collected according to the Schedule of Assessments in Table 1.  
The following PK parameters will be estimated and reported in the PK Analysis Set: 
• 
Ceoi 
• 
Ctrough 
• 
Blood samples of approximately 3.5 mL will be collected for measurement of serum 
concentrations of M7824, as specified in the Schedule of Assessments. Instructions for the collection and 
handling of biological samples will be provided by the Supporting company EMD Serono. The actual date 
and time (24-hour clock time) of each sample will be recorded. 
• 
Samples will be used to evaluate the PK of M7824. Each serum sample will be divided into 2 
aliquots (1 each for PK and a back up). Samples collected for analyses of M7824 serum concentration 
may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study. 
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The PK parameters will be summarized using descriptive statistics. Individual as well as mean 
concentration-time plots will be depicted. Unresolved missing data may be imputed when the analysis 
integrity is affected. The conservative principle will be used for data imputation. 
Table 5 
Pharmacokinetic Parameters 
Symbol 
Definition 
Ceoi 
The concentration observed immediately at the end of infusion 
Ctrough 
The concentration observed immediately before next dosing (corresponding to 
pre-dose or trough concentration for multiple dosing) 
 
PK and ADA samples collected at the same time points may be used interchangeably if the dedicated 
sample has insufficient quantity as the participants will have consented to all collections and tests. 
 
PK sampling: 
Prior to infusion and immediately after infusion: cycle 1, day 1 and cycle 3 day 1 
Prior to infusion cycle 2 day 1 and cycle 6 day 1 OR end of treatment (whatever comes first) and 
follow-up visit.ADA sampling: 
Prior to infusion cycle 1 day1 and cycle 6 day 1 or end of treatment (whatever comes first) and 
follow-up visit. 
 
12. ADVERSE EVENTS 
 
The investigator is required to report to the supporting company EMD Serono or its representative all 
AEs occurring during the clinical study (Title 21 Code of Federal Regulations [CFR] Part 312.64[b] and 
International Conference on Harmonization [ICH] E6 [R2]).  
 
At each study visit, subjects will be evaluated for new Adverse Events (AE) and the status of existing 
AEs. All AEs observed from the date of the first administration of study treatment until the end of the 
follow-up period of the study (study cut-off date) are to be recorded on the AE page of the e-CRF. The 
date of onset and resolution, determination of seriousness, severity, grade, corrective treatment, 
outcome, and relationship to study treatment (M7824, Radiotherapy) will be recorded for all AEs.  
 
All Serious Adverse Events (SAEs) occurring from the date of onset of the study treatment until the end 
of follow-up period of the study (study cut-off date) will be collected. 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for 
adverse event (AE) reporting. The CTCAE version 5.0 is located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An Adverse Event is defined as any untoward medical occurrence in a patient regardless of its causal 
relationship to study treatment. An AE can be any unfavorable and unintended sign (including any 
clinically significant abnormal laboratory test result), symptom, or disease temporally associated with 
the use of the study treatment, whether or not it is considered to be study drug(s) related. Included in 
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this definition are any newly occurring events and any previous condition that has increased in severity 
or frequency since the administration of study therapy. 
 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for subjects 
enrolled. 
 
Serious Adverse Events (SAEs) will be reported within 24 hours of acknowledge by the study team, unless 
it occurs over the weekend or holidays, when it will be notified in the first business day.  They are defined 
as any adverse drug event (experience) occurring at any dose that results in any of the following 
outcomes: death; a life-threatening adverse drug experience; inpatient hospitalization or prolongation 
of existing hospitalization; a persistent or significant disability/incapacity; a congenital anomaly/birth 
defect.  Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the outcomes listed in 
the definition.   
 
Toxicities will be assessed by the treating physician/s according to the CTCv5 criteria.   
Early onset (acute) toxicities occurring prior to 90 days will also be considered late onset (chronic) 
toxicities if they persist for at least one day beyond the 90 days used to define late onset (chronic) 
toxicities. In analyses that examine acute and chronic toxicities separately, those toxicities that began as 
acute but became chronic will be included in both the analysis of acute toxicities and in the analysis of 
chronic toxicities. 
Immune-related AEs should be documented as an ‘Adverse Event of Special Interest (AESI),’ and it is 
recommended to involve the Medical Monitor at first incidence and subsequently as needed for follow 
up. Details of the diagnostic work up will be requested by the study team. Immune-related AEs are 
described in Section 0. 
For reporting irAE severity/toxicity grading, refer to NCI-CTCAE v.5 toxicity grading system. 
Toxicities related to radiation therapy include: Pain, mucositis, constipation, dysphagia, odynophagia, 
hemoptysis, epistasis, trismus, fatigue, weight loss, dysgeusia, nausea,  radiation dermatitis, 
myelosuppression, skin erythema, subcutaneous fibrosis, esophagitis, myelitis, superficial soft tissue 
fibrosis and esophageal stricture. 
Toxicities related to IO therapy are described in detail in the investigator’s brochure.  
Toxicity monitoring:  Both Acute (From radiation start to 90 days after completion of radiation therapy) 
and Late (90 days to 2 years from the completion of radiation therapy) side effects of radiation therapy 
will be documented and graded according to the NCI-CTCAE version 5.0.   
 
 
 
 
 
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Table 6: Adverse Event Recording Guidelines 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
Serious Adverse Event (SAE) Reporting 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in the view 
of the initial reporter, at immediate risk of death from the adverse experience as it occurred. It does not 
include an adverse experience that, had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
• Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Sponsor, IND Office. 
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• All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The University of 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Serious Unanticipated Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a 
written report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.   
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to the 
IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific intervention, until 90 
days after the last dose of drug, unless the participant withdraws consent. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 90 day time period that are related to the 
study treatment must be reported to the IND Office. This may include the development of a secondary 
malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND Office) 
according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
 
SAEs, whether related or not related to study drug, must be reported to EMD Serono within 24 hours. 
SAEs must be recorded on BMS approved form. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours to the EMD Serono (or designee) using 
the same procedure used for transmitting the initial SAE report. 
All SAEs should be followed to resolution or stabilization. 
The principal investigator will ensure that all SAEs in the clinical database are reported to EMD Serono 
and any applicable health authority during the conduct of the study.  
 
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SAEs will be reported on MDACC IRB approved form for prompt reporting (full form): 
“Internal SAE Report Form for Prompt Reporting” Institutional Review Board. 
SAEs will be submitted to both the Office of Protocol Research, Unit 1437 at The University of Texas MD 
Anderson Cancer Center and also sent to MEDWATCH 
All SAEs should simultaneously be faxed or e-mailed to EMD  Serono.  
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
 
Definition of Dose Limiting Toxicity (DLT) 
DLT for the combination of SBRT and M7824 in patients with recurrent HNSCC will be defined as:   
1. Any ≥ grade 3 AE resulting in inability to complete radiotherapy due 
to toxicity related to M7824 or the combination of M7824 and 
SBRT. 
 
Drug destruction  
 
Normal saline solution may be disposed of according to local site procedures. Other items used in the 
dose preparation and administration should be disposed of according to local site procedures. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design and Study Endpoint Summary 
 
This protocol will be performed at M.D. Anderson, with a safety lead-in study to evaluate the safety, 
tolerability and feasibility of SBRT plus M7824 prior to initiation of the phase 2.   The primary outcome 
for this study is the progression free survival (PFS) rate. 
 
This is a phase I/II, open label, single arm study to evaluate M7824 plus SBRT in patients with locoregional 
recurrent HNSCC after prior head and neck therapy that are not good candidates for salvage surgery 
(Figure 1).  Patients must have evaluabledisease by RECIST or RECIST 1:1 and a performance status ECOG 
0-2. Time elapsed from prior radiotherapy must be at least 6 months. 
 
 
 
13.2 
Safety Lead-in 
 
The Dose limiting toxicity (DLT) window for the combination of SBRT and M7824 in patients with 
recurrent HNSCC is from first M7824 administration (D1) until 14 days post SBRT (D28).   
 
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Patients will be administered 12 cycles of M7824 1200 mg intravenously every 2 weeks (Q2W), starting 
2 weeks prior to the first fraction of SBRT until disease progression, intolerability, or consent withdrawal 
for up to 1 year. A cohort of 8 patients will be enrolled in the lead-in phase to assess safety and toxicity.  
More than 2 DLTs in 8 evaluable patients will be considered unacceptable.    
 
With a cohort of 8 patients, the probability of the combination M7824 plus SBRT will be considered too 
toxic with a probability of 0.86 if the DLT rate is 50%. If the DLT rate is 0.20, the probability that the 
therapy will be deemed safe is 80%.  
 
The phase 2 trial will proceed based upon the DLT data from the first 8 patients. Data from all patients 
will be evaluated when available.  
 
This study will be monitored by the MD Anderson IND Office and a protocol-specific monitoring plan will 
be followed.  
 
Bayesian toxicity monitoring will be applied to evaluate the safety profile of the treatment in the first 20 
patients (including both Phase I and Phase II parts of the study).  The first time of the toxicity monitoring 
will be in the cohort of the first 8 patients as described earlier.  The treatment is considered too toxic if 
Probability (DLT rate > 0.3) > 0.6.  Based on the criteria and a prior distribution of the probability of 
toxicity as beta (0.3, 0.7), the patient enrollment will be halted if the numbers of observed DLTs exceed 
the following stopping rules:  
at least 3 in 8, 4 in 9-11, 5 in 12-14, 6 in 15-17, and 7 in 18-20 patients.   
 
If the stopping boundary is crossed, the results will be reported to the principal investigators and the 
study supporting company EMD Serono. The PI and supporting company EMD Serono will review this 
data to determine if the study design will need to be adjusted. By applying this rule, the following table 
shows the operating characteristics of the Bayesian toxicity monitoring rule.  The results were obtained 
from the Bayesian toxicity monitoring program version 2.1.1 at http://ibl.mdanderson.org/BTM/. 
 
Scenario Prob.Of.Tox Prob.Early.Stop Prob.Declare.Tox Avg.N.Patients 
1 
0.1 
0.045 
0.045 
20.444 
2 
0.2 
0.272 
0.279 
17.832 
3 
0.3 
0.611 
0.631 
13.986 
4 
0.4 
0.866 
0.883 
10.754 
5 
0.5 
0.973 
0.979 
8.948 
 
 
13.3 
Phase II Primary Endpoint 
 
The study primary endpoint is progression free survival (PFS) rate at 1 year.   
 
 
13.4 
Secondary Endpoints 
• 
The study secondary endpoints include: Overall response rate by RECIST or RECIST 1:1 
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• 
1- year locoregional control (LRC), locoregional failure free survival (LFFS), distant metastasis 
(DM) and overall survival (OS) rates  
• 
Acute and late toxicity accessed by the Common Terminology Criteria for Adverse Events 
(CTCAE)-5.0  
• 
Fibrosis-related toxicities/functional outcomes  
• 
Patient Reported Outcome (PRO) measures of symptoms using MD Anderson Symptom 
Inventory (MDASI). 
• 
Volumetric tumor regression rate and MRI kinetic biomarkers after M7824 plus SBRT therapy 
• 
Quality-Adjusted-Life-Years (QALY) between M7824 plus SBRT reirradiation and historic SBRT 
reirradiation control  
 
 
13.5 
Sample Size 
 
The statistical considerations for the Phase I/II design are described as follows: 
 
This is a phase I/II, open label, single arm study to evaluate M7824 plus SBRT in patients with locoregional 
recurrent HNSCC after prior head and neck radiotherapy that are not good candidates for salvage surgery 
(Figure 1).  Patients must have evaluable disease by RECIST or RECIST 1:1 and a performance status ECOG 
0-2. Time elapsed from prior radiotherapy must be at least 6 months. 
 
Sample Size 
 
In the phase I portion, 8 patients will be enrolled to access safety and toxicity. The primary endpoint is 
dose-limiting toxicity (DLT) defined as M7824 related ≥ grade 3 adverse event (AE) unresolved to ≤ grade 
1 in ≤ 28 days, or incomplete SBRT. DLT window is from first M7824 dose (D0) until 14 days post SBRT 
(D28). More than 2 DLTs in 8 evaluable patients will be considered unacceptable.    
 
In the phase II portion, the primary endpoint is PFS at 1 year.  Based on the prior studies [unpublished 
data from MD Anderson], we assume that the one-year PFS of the standard treatment is 0.60.  If the 
new treatment improves the one-year PFS to 0.80 or higher, it will be considered a clinically important 
improvement.   A sample size of 21 patients (with 1.5-year additional follow-up after the last patient is 
enrolled) will allow us to observe an improvement in 1-year PFS from 0.60 to 0.80.   This will enable the 
study 80% power to detect the specified difference in PFS.  Power was calculated using a log-rank test 
with a one-sided type 1 error rate of 0.10 (EAST 5.4 and STPLAN version 4.5).   Based on our estimated 
accrual rate of 2 patients per month, we expect enrollment to be completed in 11 months.   The total 
study duration is 29 months.   
 
DMI (Data Management Initiative) database 
 
Clinical data capture called DMI (Data Management Initiative) and CORe will be the electronic database 
used for this study’s electronic case report forms.  
 
13.6 
Statistical Analysis 
 
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Summary statistics including mean, standard deviation, median, and range will be provided for 
continuous variables such as age, BMI, lab measurements, and scores from some HR-PRO measures of 
symptoms, and frequency count and percentage will be provided for categorical variables such as 
gender, response, toxicity type and severity.   
 
To assess the primary endpoint (PFS), we will use the methods of Gooley et al. 44 to estimate the 
cumulative incidence of PFS “events”.  A PFS event is defined as death or disease progression, including 
locoregional recurrence/progression or distant metastases.  Time to PFS event is measured from 
treatment initiation until a recurrence, progression or occurrence or death, whichever occurs first.   
 
Secondary endpoints include local-regional control, locoregional failure-free survival (LFFS), distant 
metastases (DM), DM free survival (DMFS) and overall survival (OS). Local failure is defined as failure 
(recurrence or progression) within the prescribed radiation field, including failure within 2 cm of the 
radiation field.  Local control is defined as absence of local failure.  LFFS is defined as alive and free of 
local recurrence or progression.  Time to an LFFS event is measured from treatment initiation until local 
failure or death from any cause, whichever occurs first.  Similarly, time to a DMFS event is measured 
from treatment initiation until distant metastases or death from any cause, whichever occurs first. 
Finally, OS is measured from treatment initiation until time to death from any cause.   
 
The student t-test or the Wilcoxon rank sum test will be used to compare continuous variables between 
patient groups.  The chi-square test or the Fisher’s exact test will be applied to evaluate the association 
between two categorical variables.  Logistic regression models will be used to evaluate the effects of the 
important patient clinical factors including treatment on PFS.  The distribution of time-to-event 
endpoints will be estimated using the method of Kaplan and Meier.  Comparison of time-to-event 
endpoints by important subgroups will be made using the log-rank test.  Proportional hazards regression 
may be employed for multivariate analysis on time-to-event outcomes.  PROs will be assessed at the 
completion of reirradiation, and subsequently every ±3-months until 24-months post reirradiation.  
Generalized linear models for the repeated measures analysis will be performed to assess the change in 
PROs overtime with important covariates including treatment in the models. 
 
The Investigator is responsible for completing safety summary report, and submitting it to the IND 
Office Medical Affairs and Safety Group, for review and approval.  
 
Lead in phase/phase I: 
Toxicity summary will be submitted  after the first eight evaluable patients’ complete 1 cycle of therapy.   
 
Approval from IND office will be obtained before  advancing to phase 2. 
 
Phase II: 
Toxicity summary will be submitted  after first 3 evaluable patients’ complete 1 cycle of therapy and 
every 3 evaluable patients complete cycle 1 thereafter.  
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under “sponsor 
correspondence”.  
 
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13.7 
Subject Identification and Privacy 
A unique number will be assigned to each subject, immediately after informed consent has been obtained. 
This number will serve as the subject’s identifier in the trial as well as in the clinical trial database. All 
subject data collected in the trial will be stored under the appropriate subject number. Only the 
Investigators will be able to link trial data to an individual subject via an identification list kept at the site. 
For each subject, original medical data will be accessible for the purposes of source data verification by 
the Monitor, audits and regulatory inspections, but patient confidentiality will be strictly maintained. 
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and storing 
subject data. Subjects will be informed accordingly, and will be requested to give their consent on data 
handling procedures in accordance with national regulations. 
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