Conditions: Locally Advanced Lung Non-Squamous Non-Small Cell Carcinoma Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Stage III Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8 Stage IIIB Lung Cancer AJCC v8 Stage IIIC Lung Cancer AJCC v8 Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This phase II trial studies the effect of bintrafusp alfa with pemetrexed and platinum-based chemotherapy (carboplatin or cisplatin) in treating patients with EGFR mutant non-small cell lung cancer that have spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic) and cannot be removed by surgery, and remains despite treatment with tyrosine kinase inhibitors (Resistant). Immunotherapy with bintrafusp alfa, a bifunctional fusion protein composed of the monoclonal antibody anti-PD-L1 and TGF-beta, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carboplatin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving bintrafusp alfa with pemetrexed and platinum-based chemotherapy may help to control the disease.

Detailed description:

Arms:
arm 1: Patients receive bintrafusp alfa IV over 1 hour on day 1 and pemetrexed IV over 10 minutes on day 1. Patients also receive carboplatin IV over 15 minutes or cisplatin IV over 6-8 hours at the physician's discretion on day 1 of cycles 1-4. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Bintrafusp Alfa intervention 2: Pemetrexed intervention 3: Carboplatin intervention 4: Cisplatin
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV

Protocol document:
Prot_SAP_000.pdf: 
i 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2020-1266 
Protocol Title 
A SINGLE-ARM PHASE 2 STUDY TO INVESTIGATE 
BINTRAFUSP ALFA WITH PLATINUM-PEMETREXED FOR TKI-
RESISTANT EGFR-MUTANT NSCLC 
Protocol Phase 
II 
Protocol Version 
5.0 
Version Date 
09/10/2021 
Protocol PI 
Xiunig Le, MD 
Department 
Thoracic Head and Neck Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
155291 
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A SINGLE-ARM PHASE 2 STUDY TO INVESTIGATE BINTRAFUSP ALFA WITH 
PLATINUM-PEMETREXED FOR TKI-RESISTANT EGFR-MUTANT NSCLC 
 
Study Center: 
 
 
 
 
MD Anderson Cancer Center 
 
 
Principal Investigator (PI): 
Xiuning Le, MD PhD 
 
Thoracic Head and Neck Medical Oncology Department 
 
MD Anderson Cancer Center  
 
1515 Holcombe Blvd, Houston 77030 TX, USA 
 
713-792-6980 
 
713-792-1220 
 
Xle1@mdanderson.org 
 
 
Collaborators: 
 
 
Thoracic Head and Neck Medical Oncology Department 
 
MD Anderson Cancer Center 
 
 
Statistician  
 
 
 
Department of Biostatistics 
 
MD Anderson Cancer Center  
 
 
 
 
Department of Biostatistics 
 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
 
 
Original / version 1.0 / Nov 10 2020 
Revision/version 2.0 / Mar 29 2021 
Revision/version 3.0 / Jun 01 2021 
Revision/version 4.0/ Aug 10 2021 
Revision/version 5.0/ Sept 10 2021 
 
 
 
 
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SCHEMA 
 
 
 
 
Key eligibility:  
Metastatic EGFR-mutation non-squamous NSCLC 
Resistant to EGFR TKI 
Naïve to platinum-pemetrexed and anti-PD1/L1 therapy 
 
Sample size:  
40 
 
Primary Endpoints:  
Best objective response rate (ORR) within 6 months 
Landmark progression free survival (PFS) at 18 weeks 
 
Secondary Endpoints: 
Safety and tolerability 
PFS, disease control rate (DCR), duration of response (DoR), overall survival (OS) 
 
 
 
 
 
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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
BACKGROUND AND RATIONALE ................................................................................5 
1.1 
Landscape of resistance mechanisms to osimertinib in EGFR-mutant Non-
Small Cell Lung Cancer ...........................................................................................5 
1.2 
TGF-beta and immune therapy in EGFR-mutant NSCLC ......................................5 
1.3 
Bintrafusp alfa and preliminary data in NSCLC......................................................6 
1.4 
Rationale for study design and objectives ...............................................................6 
2. 
OBJECTIVES and Endpoints ..............................................................................................7 
2.1 
Primary Objective and Primary Endpoints ..............................................................7 
2.2 
Secondary Objectives and Secondary Endpoints .....................................................7 
2.3 
Exploratory Objectives ............................................................................................7 
3. 
PARTICIPANT SELECTION .............................................................................................8 
3.1 
Inclusion Criteria .....................................................................................................8 
3.2 
Exclusion Criteria ..................................................................................................10 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4. 
ETHICAL CONSIDERATIONS .......................................................................................11 
4.1 
Institutional Review Board (IRB) ..........................................................................11 
4.2 
Informed Consent...................................................................................................12 
5. 
STUDY DESIGN...............................................................................................................12 
5.1 
Study Design ..........................................................................................................12 
5.2 
Subject Screening...................................................................................................13 
5.3 
Treatments and Visits ............................................................................................13 
5.4 
Discontinuation, Withdrawal and Termination of the Study .................................13 
5.5 
Duration of Follow Up ...........................................................................................14 
6. 
CALENDAR ......................................................................................................................14 
6.1 
Screening Period (up to 4 weeks) ..........................................................................17 
6.2 
Treatment Period ....................................................................................................18 
6.3 
Follow-up Period ...................................................................................................18 
7. 
STUDY DRUGS ................................................................................................................20 
7.1 
Carboplatin .............................................................................................................20 
7.2 
Pemetrexed .............................................................................................................21 
7.3 
Bintrafusp alfa (M7824) ........................................................................................22 
8. 
DOSING MODIFICATIONS ............................................................................................26 
8.1 
Toxicity management and dose modification for bintrafusp alfa ..........................26 
8.2 
Toxicity management and dose modifications for carboplatin/pemetrexed ..........32 
9. 
ADVERSE EVENTS AND REPORTING ........................................................................32 
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9.1 
Definitions..............................................................................................................32 
9.2 
Documenting and Reporting of Adverse Events and Serious Adverse 
Events by Investigators ..........................................................................................35 
10. 
CORRELATIVE STUDIES ..............................................................................................38 
10.1 
Tissue and Blood Repository .................................................................................38 
10.2 
Tissue .....................................................................................................................38 
10.3 
ctDNA ....................................................................................................................38 
10.4 
Plasma for Cytokine and Immune-modulator Analysis .........................................39 
11. 
MEASUREMENT OF EFFECT........................................................................................40 
11.1 
Antitumor Effect ....................................................................................................40 
11.2 
Safety .....................................................................................................................46 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................46 
12.1 
Data Reporting .......................................................................................................46 
12.2 
Data Safety Monitoring.......................................... Error! Bookmark not defined. 
13. 
STATISTICAL CONSIDERATIONS...............................................................................47 
13.1 
Study Design ..........................................................................................................47 
13.2 
Sample Size Justification .......................................................................................47 
13.3 
Definition of Analysis Sets ....................................................................................49 
13.4 
Analysis Plan .........................................................................................................49 
14. 
PUBLICATION PLAN .....................................................................................................49 
REFERENCES ..............................................................................................................................51 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................53 
 
 
 
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1. BACKGROUND AND RATIONALE  
 
1.1 
Landscape of resistance mechanisms to osimertinib in EGFR-mutant Non-Small 
Cell Lung Cancer  
 
In the last decade, metastatic EGFR-mutant lung cancers were mostly treated with sequential 
EGFR tyrosine kinase inhibitors (TKI)1-3. Since the FDA approval in April 2018, osimertinib, a 
third generation EGFR TKI, has become the first line treatment for all newly diagnosed patients 
with metastatic EGFR-mutant non-small cell lung cancer (NSCLC)3. Our group and others 
examined the resistance mechanisms to osimertinib aiming to identify second line treatment 
strategies after osimertinib progression4-6. In our MD Anderson and Moffitt Cancer Center 
combine cohort of 118 patients treated with osimertinib, 42 had molecular profiling at progression. 
T790M was preserved in 21 (50%) patients and lost in 21 (50%). Tertiary mutations in EGFR is a 
common resistance mechanism in T790M-preserved cases, but not for T790M-loss cases. MET 
amplification is a most common alteration (14%) that induced resistance in both T790M-preserved 
and -loss cases5. Furthermore, preclinical studies confirmed that acquired MET amplification 
renders resistance to EGFR TKI, which can be reversed by addition of c-met inhibitors5,7. In this 
cohort, we also found that resistance to osimertinib in T790M-loss cases were mostly mediated by 
either non-genetic or non-targetable mechanisms, calling for non-TKI strategies as second line 
treatment for patients who progressed on osimertinib. Given the effectiveness of osimertinib at 
suppressing T790M positive subclones, it is conceivable that resistance to osimertinib in the first-
line setting will be similar to the pattern of T790M-loss cases, where MET amplification and 
epithelial to mesenchymal transition to be the predominant resistance mechanisms.  
 
1.2 
TGF-beta and immune therapy in EGFR-mutant NSCLC 
 
Although immune checkpoint blockade (ICB) has been successfully utilized in treating patients 
with metastatic NSCLC, the benefit of ICB for patients with advanced EGFR-mutant NSCLC has 
been limited. Gainor et al reported an objective response rate (ORR) of 3.7% to anti-PD1 
monotherapy in EGFR/ALK driven lung cancers8. Lee et al showed the anti-PD1/PDL1 therapy 
was inferior to cytotoxic chemotherapy as the second line treatment for this population of patients9. 
Therefore, EGFR-mutant lung cancers were generally reviewed as immune “cold” tumors. 
Interestingly, recent data from IMpower150 trial subgroup analysis indicated that combination of 
VEGF inhibition (bevacizumab) with anti-PD-L1 (Atezolumab) and chemotherapy (carboplatin 
and paclitaxel) produced prolonged response in patients with EGFR/ALK driven NSCLC10. The 
clinical benefit of PFS was only seen when VEGF inhibition was used in combination with ICB, 
suggesting an immune modulating effect in the tumor microenvironment and enhances response 
to anti-PD-1 blockade. These results ignited great excitement as this was the first and only clinical 
trial showing that EGFR-mutant lung cancer has the potential to be turned to “hot” tumors.    
 
We performed analysis to understand the difference in tumor immune microenvironment (TME) 
between EGFR-mutant and wildtype (WT) lung cancers. In a retrospective cohort of 94 cases, we 
compared 14 cases with EGFR mutations to the 80 wildtype tumors11. We confirmed that PD-L1 
levels were lower in the EGFR-mutant cancers, as were the Granzyme B levels. TGF-β pathway 
was found to be elevated in the EGFR-mutant group. Furthermore, in cell lines that are resistant 
to osimertinib, TGF-β signaling is further elevated.  The transforming growth factor beta (TGF-β) 
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signaling family comprises of more than 30 factors and displays diverse spatial and temporal 
expression patterns during development and oncogenesis12. TGF-β has established roles in 
mediating epithelial-mesenchymal transition (EMT)13, which was observed in osimertinib-
resistant NSCLC. EMT has been suggested as a mechanism of resistance to therapy by our group 
and others14.  It was known that elevated TGF-β signal also has a profound impact on tumor 
immune microenvironment. It acts as a major enforcer of immune tolerance by inhibiting the 
development and functions of nearly all major components of the innate and adaptive immune 
cells function12. Given the important roles of TGF-β in promoting tumor invasion/metastasis, 
EMT, fibrosis, and immune tolerance, there has been a growing effort in targeting TGF-β for 
treating cancers.  
 
1.3 
Bintrafusp alfa and preliminary data in NSCLC.  
 
Bintrafusp alfa (M7824) is a first-in-class bifunctional fusion protein composed of the extracellular 
domain of the human transforming growth factor β receptor II (TGF-βRII or TGF-β “trap”) fused 
via a flexible linker to the C-terminus of each heavy chain of an IgG1 antibody blocking 
programmed death ligand 1 (anti–PD-L1), designed to target 2 of the key mechanisms of 
immunosuppression in the tumor microenvironment15. This agent is designed to target two major 
mechanisms of immunosuppression in the tumor microenvironment, through its anti-PDL1 and 
TGF-β “trap” activities. In phase I studies, M7824 was showed to be safe and tolerable. The RP2D 
was determined to be 1200mg IV infusion every two weeks. In a recently reported phase 1 study 
of M7824 in HPV-associated diseases (HNSCC, cervical and anal cancers), 9/16 (56%) patients 
had response including a durable CR16. The expansion cohort of the phase 1 study (NCT02517398) 
includes 80 patients with advanced NSCLC who had prior platinum doublet therapy but have not 
received previous immunotherapy. A total of 80 patients were randomized to receive bintrafusp 
alfa 500 or 1200 mg (n = 40 each). Median follow-up was 51.9 weeks (IQR, 19.6-74.0). The ORR 
in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 25.0% (10 of 40) for 
the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), respectively. At the 1200 
mg dose, patients with PD-L1-positive and PD-L1-high (≥80% expression on tumor cells) had 
ORRs of 36.0% (10 of 27) and 85.7% (six of seven), respectively17. With the initial observation 
of efficacy, ongoing study (NCT03840915) is testing the safety and efficacy of M7824 in 
combination with platinum-doublet in NSCLC. The preliminary results indicate that M7824 
administered intra-venously at 2400mg every three weeks in combination with carbo/cisplatin plus 
pemetrexd (cohort A) is safe and feasible. For this trial (NCT03840915), a safety monitoring 
committee (SMC) meeting occurred on January 11th, 2021 to review the safety data from all 
patients enrolled in the study (N=70), including 40 patients treated with cisplatin/carboplatin and 
pemetrexed + bintrafusp alfa. After the presentation and review of data, the SMC has agreed that 
the emerging safety profile is in line with the overall benefit/risk that was anticipated based on the 
clinical experience to date and have recommended to continue the study without modifications. 
 
1.4 
Rationale for study design and objectives 
 
Here we hypothesize that Bintrafusp alfa modulate tumor immune microenvironment and work 
synergistically with chemotherapy therapy to induce response in EGFR-mutant NSCLC. With the 
established safety and efficacy data, we proposed to perform a phase 2 study to understand the 
benefit of bintrafusp alfa with chemotherapy in TKI-resistant EGFR-mutant NSCLC. In this trial, 
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patients who progressed on prior EGFR TKI therapy will receive platinum-pemetrexed 
chemotherapy in combination with bintrafusp alfa.   
 
The primary objective of this study is to evaluate the efficacy of Bintrafusp alfa-chemotherapy 
combination. The primary endpoints are the objective response rate at 6 weeks and landmark PFS 
at 18 weeks. These are appropriate primary efficacy endpoints in this NSCLC population and may 
be associated with an improvement in OS, delay to time of initiation of subsequent therapies, 
symptom control, and quality of life. We expect the addition of bintrafusp alfa to chemotherapy 
render benefit in prolonging disease control. Best objective response rate within 6 months will be 
evaluated as a co-primary endpoint along with the PFS at 18 weeks. Secondary efficacy endpoints 
are those that are appropriate to this patient population and include, Disease Control Rate (DCR) 
[DCR: Complete response (CR) + Partial Response (PR) + Stable disease (SD)] and Duration of 
Response (DoR) and Overall Survival (OS). Safety and tolerability of bintrafusp alfa with 
platinum-pemetrexed will also be assessed as a secondary endpoint.  
 
A collection of exploratory biomarker studies will be performed. Tumor samples and ctDNA will 
be collected at baseline and at the time of progression to evaluate potential mechanisms of 
resistance. Additional plasma will be collected to understand cytokine and immune 
microenvironment following therapies. Optional biopsy at progression will be obtained to 
understand bintrafusp alfa’s immune modulation effect to the tumor immune microenvironment.   
 
Overall, the totality of primary, secondary and exploratory endpoints in this study will allow a 
robust characterization of overall benefit and risk of bintrafusp alfa in combination with platinum-
pemetrexed for patients with TKI-resistant advanced EGFR-mutant non-small cell lung cancer 
(NSCLC)  
 
 
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary Objective and Primary Endpoints  
 
The primary objective of this study is to evaluate treatment efficacy of bintrafusp alfa with 
platinum-pemetrexed in TKI-resistant EGFR-mutant NSCLC. Two co-primary endpoints are the 
best objective response rate (ORR) within 6 months since initiation of treatment and the landmark 
progression free survival (PFS) at 18 weeks since initiation of treatment. 
 
2.2 
Secondary Objectives and Secondary Endpoints 
 
• The secondary objective is to assess safety and tolerability of bintrafusp alfa platinum-
pemetrexed combination and to study other clinical efficacy parameters.  The secondary 
endpoints are the type and grade of toxicities, time to resolve toxicities, the best response rate, 
duration of response, disease control rate, progression-free survival, and overall survival. 
 
2.3 
Exploratory Objectives 
 
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• To explore the association of baseline genomic profiles (from tumor, germline DNA, and 
ctDNA) with clinical benefit in patients treated with bintrafusp alfa platinum-pemetrexed 
combination.  
 
• To explore resistance mechanisms to bintrafusp alfa platinum-pemetrexed combination. At 
C3D1 and at the time of progression, patients will undergo ctDNA genomic tests and an 
optional biopsy to explore resistance mechanisms to bintrafusp alfa platinum-pemetrexed 
combination. 
 
 
• To determine the immunomodulatory effects of bintrafusp alfa platinum-pemetrexed 
combination. We have shown TGF-beta elevation is associated with TKI resistance. We will 
investigate if bintrafusp alfa treatment will suppress TGF-beta and favorably modulate the 
tumor immune microenvironment (TME). Plasma will be collected before treatment, after 
treatment, as well as at the time of disease progression. Plasma TGF-beta level and cytokine 
profiling will be performed to identify potential correlative markers for response and 
resistance. At the time of progression, patients will undergo an optional biopsy. The purpose 
of this additional tissue acquisition is for molecular analysis and comparison with the initial 
specimen, to determine if there are changes in molecular alterations or pathways that shed light 
on TME modulation.  
 
 
3. PARTICIPANT SELECTION 
 
For entry in this study, all eligibility criteria MUST be met.  
3.1 
Inclusion Criteria  
 
1. Age equal or greater than 18 years old and willing to give their signed consent 
 
2. Histologically or cytologically confirmed non-squamous, non-small cell lung cancer  
 
3. Locally advanced or metastatic disease, not amenable to curative surgery or radiotherapy.  
 
4. Patients must have one of the following: 
− 
NSCLC which harbours EGFR Exon 19 deletion.  
− 
NSCLC which harbours EGFR L858R mutation.  
− 
NSCLC which harbours EGFR G719X, S768X, L861X mutation, and other activating 
uncommon mutations in exon 18-21. 
− 
NSCLC which harbours EGFR exon20 insertion 
− 
NSCLC which harbours EGFR T790M mutation 
EGFR deletion/mutation must be documented by a Clinical Laboratory Improvement 
Amendments (CLIA) certified test 
 
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix A) 
 
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6. At least one target lesion, not previously irradiated and not chosen for biopsy during the 
study screening period, that can be accurately measured at baseline at equal or greater than 
10mm in the longest dimension by RECIST 1.1. 
 
7. Patients must have received at least one line of EGFR tyrosine kinase inhibitor (TKI) 
treatment, if an FDA-approved treatment exist for the EGFR mutation. Patients whose tumor 
harboring EGFR T790M mutation must have received prior osimertinib (or another EGFR 
TKI with demonstrated activity against T790M mutation). Patients who received more than 
one EGFR TKIs are eligible. Up to two lines of TKIs are allowed.  
 
8. Patients must have adequate hematologic, coagulation, hepatic, and renal function. All 
laboratory tests must be obtained less than 4 weeks from study entry. This includes: 
A. ANC >/= 1,500/mm3 
B. platelet count >/=100,000/mm3 
C. HgB ≥ 9 g/dL 
D. Creatinine ≤ 1.5x ULN 
E. INR ≤ 1.5 and partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x upper limits of 
normal [ULN]. Patients receiving warfarin must be switched to low molecular weight 
heparin and have achieved stable coagulation profile prior to first dose of protocol 
therapy. 
F. Total Serum Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert Syndrome, a total 
bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN) 
G. SGOT, SGPT ≤ 3 X ULN if no liver metastasis present 
H. SGOT, SGPT ≤ 5 X ULN if liver metastasis present 
 
9. Patients with history of HIV: stable on ART for at least 4 weeks, no documented evidence of 
multi-drug resistance, viral load of < 400 copies/ml and CD4+ T-cells ≤ 350 cells/µL.  
 
10. Patients with history of HBV/HCV: participant on a stable dose of antiviral therapy, HBV 
viral load below the limit of quantification. HCV viral load below the limit of quantification. 
 
11. Females of childbearing potential must not be breast feeding and must have a negative serum 
or urine pregnancy test within 7 days of starting of treatment. The patient must agree to use 
adequate contraception for a minimum of two weeks prior to receiving study medication until 
65 days after discontinuation of the study medication. Acceptable methods of contraception 
include total and true sexual abstinence, hormonal contraceptives that are not prone to drug-
drug interactions (IUS Levonorgestrel Intra Uterine System (Mirena), Medroxyprogesterone 
injections (Depo-Provera)), copper-banded intra-uterine devices, and vasectomized 
partner.  All hormonal methods of contraception should be used in combination with the use 
of a condom by their sexual male partner. Females of childbearing potential are defined as 
those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or 
complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an 
alternative medical cause). Women will be considered post-menopausal if they have been 
amenorrheic for the past 12 months without an alternative medical cause.  The following age-
specific requirements must also apply:  Women < 50 years old:  they would be considered post-
menopausal if they have been amenorrheic for the past 12 months or more following cessation 
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of exogenous hormonal treatments.  The levels of Luteinizing Hormone (LH) and Follicle-
Stimulating Hormone (FSH) must also be in the post-menopausal range (as per the institution). 
Women ≥ 50 years old:  they would be consider post-menopausal if they have been 
amenorrheic for the past 12 months or more following cessation of all exogenous hormonal 
treatments, or have had radiation-induced oophorectomy with the last menses > 1 year ago, or 
have had chemotherapy-induced menopause with >1 year interval since last menses, or have 
had surgical sterilization by either bilateral oophorectomy or hysterectomy. 
 
12. Non-sterilized males who are sexually active with a female partner of childbearing potential 
must use adequate contraception for the duration of the study and 125 days after the last dose 
of study medication. Adequate contraception methods include: birth control pills (e.g. 
combined oral contraceptive pill), barrier protection, and abstinence. Patients should not father 
a child for 125 days after completion of the study medication. Patients should refrain from 
donating sperm from the start of dosing until 125 days after discontinuing the study medication.  
If male patients wish to father children they should be advised to arrange for freezing of sperm 
samples prior to the start of the study medication. 
 
3.2 
Exclusion Criteria  
 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Previous treatments with cytotoxic chemotherapy or checkpoint immunotherapy or 
combination of chemo-immunotherapy for metastatic disease. If the patient had prior 
chemotherapy as neoadjuvant or adjuvant therapy, the completion of treatment must be greater 
than 6 months until the beginning of the treatment on trial.  
 
2. Previous treatment with any anti-TGF-beta medications.  
 
3. Spinal cord compression or brain metastases unless asymptomatic or stable for at least 2 weeks 
prior to start of study treatment.   
 
4. Persisting Grade > 1 CTCAE 5.0 toxicity (except alopecia and vitiligo) related to prior therapy; 
however, sensory neuropathy Grade ≤ 2 is acceptable 
 
5. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, 
inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic 
corticosteroids at doses ≤  8 mg/day of dexamethasone or equivalent; c. Steroids as 
premedication for hypersensitivity reactions (e.g., CT scan premedication).” 
 
6. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory 
agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not 
requiring immunosuppressive treatment are eligible. 
 
7. Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD 
or non-infectious pneumonitis requiring high-dose glucocorticoids.  
 
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8. No previous malignant disease within the last 3 years except for a. superficial/non-invasive 
bladder cancer, or basal or squamous cell carcinoma in situ treated with curative intent; b. 
endoscopically resected GI cancers limited to the mucosal layer without recurrence in > 1 year. 
 
9. No prior organ transplantation including allogenic stem-cell transplantation, except transplants 
that do not require immunosuppression.  
 
10. Active infection requiring systemic therapy. 
 
11. Live vaccination that has received or will receive within 30 days prior to the first administration 
of study intervention. Seasonal flu vaccines that do not contain a live virus are permitted. 
COVID-19 vaccines are permitted.  
 
12. Known severe hypersensitivity [Grade ≥ 3 NCI CTCAE 5.0]) to investigational product or any 
component in its formulations, any history of anaphylaxis, or recent, within 5 months, history 
of uncontrollable asthma. 
 
13. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke 
(< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), 
unstable angina, congestive heart failure (≥ New York Heart Association Classification 
Class II), or serious cardiac arrhythmia requiring medication. 
 
14. History of bleeding diathesis or recent major bleeding events (i.e. Grade ≥ 2 bleeding events 
in the month prior treatment) 
 
15. Males and females of reproductive potential who are not using and effective method of birth 
control and females who are pregnant or breastfeeding or have a positive (urine or serum) 
pregnancy test prior to study entry. Females who are pregnant or breast-feeding.  
 
16. Judgment by the investigator that the patient should not participate in the study if the patient 
is unlikely to comply with study procedures, restrictions and requirement. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
 
 
4. ETHICAL CONSIDERATIONS 
 
 
4.1 
Institutional Review Board (IRB) 
 
Before study initiation, the investigator must have written and dated approval from the IRB for the 
protocol, consent form, subject recruitment materials (e.g., advertisements), and any other written 
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information to be provided to the subjects. The investigator should also provide the IRB with a 
copy of the Investigator Brochure or product labeling information to be provided to subjects and 
any updates. 
 
The instigator should provide the IRB with reports, updates and other information (e.g., expedited 
safety reports, amendments, and administrative letters) according to regulatory requirements or 
institutional procedures. 
 
4.2 
Informed Consent  
 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given by subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues regarding 
clinical studies in which the subject volunteers to participate. The approved informed consent form 
will adhere to the ethical principles that have their origin in the Declaration of Helsinki. 
 
Investigators must: 
 
1) Obtain the IRB written approval of the written informed consent form and any other 
information to be provided to the subjects, prior to the beginning of the study, and after any 
revisions are completed for new information. 
2) Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
3) Allow time necessary for subject or subject’s legally acceptable representative to inquire about 
the details of the study. 
4) Obtain an informed consent signed and personally dated by each subject or the subject’s legally 
acceptable representative and by the person who conducted the informed consent discussion. 
All participants will be registered in the Clinical Oncology Research System (CORe) 
 
 
 
 
 
 
5. STUDY DESIGN 
 
5.1 
Study Design 
 
This is a single-arm open-label phase 2 study that will enroll EGFR-TKI resistant advanced or 
metastatic EGFR-mutant NSCLC patients who are chemotherapy and immunotherapy naïve. All 
subjects will receive bintrafusp alfa with platinum-pemetrexed chemotherapy. If no progression, 
bintrafusp alfa and pemetrexed maintenance therapy is allowed.  
 
 
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Figure 1.  Study schema 
 
 
 
5.2 
Subject Screening  
 
Subjects will be screened and eligible subjects will be offered treatment. Investigator(s) should 
keep a subject screening log of subjects considered for the study. The screening log will be kept 
electroinically in the department clinical trial shared drive for the study monitor to review.  
 
The Investigator(s) will:  
 
• Obtain signed informed consent from the potential subject, or their guardian or legal 
representative before any study specific procedures are performed.   
• Determine subject eligibility.  
• Re-screening is allowed.  
•  
5.3 
Treatments and Visits 
 
Please see Section 6 for calendar (Table 1). 
 
 
5.4 
Discontinuation, Withdrawal and Termination of the Study 
 
5.4.1 Discontinuation:  
 
Subjects may be discontinued from study treatment in the following situations:  
1. Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment   
2. Adverse events that are prolonged unresolved.   
3. Pregnancy   
  
4.   Severe non-compliance with the study protocol as judged by the investigator   
  
5.   Subject incorrectly initiated on study treatment   
  
6.   Objective disease progression or subject is no longer receiving clinical benefit   
7.   Lost to follow up.  
 
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5.4.2 Withdrawal: 
  
Subjects may withdraw from study treatment in the following situations:  
1. Eligibility criteria not fulfilled   
2. Death   
3. Withdrawal of consent.  If a subject wish to withdraw their consent to both treatment 
and study assessments, they should be asked if they are willing to continue with 
survival follow-up (which can be conducted by telephone). If a subject wish to 
withdraw their consent to further participation in the study entirely, including survival 
follow-up, this should be clearly documented in the subject notes and in the clinical 
study database.  
 
5.4.3 Termination:  
 
The study may be terminated if, in the judgment of principal investigator and review committee, 
trial subjects are placed at undue risk because of clinically significant findings that:  
1. Meet individual stopping criteria or are otherwise considered significant   
2. Are assessed as causally related to investigational product   
3. Are not considered to be consistent with continuation of the study.  
 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the electronic database. All reasons for 
discontinuation of treatment must be documented.   
 
5.5 
Duration of Follow Up 
 
Participants will be followed every 4 months after removal from protocol therapy for one year or 
until death, whichever occurs first.  Participants removed from protocol therapy for prolonged 
unresolved adverse event(s) will be followed until resolution or stabilization of the adverse event, 
and every 4 months after removal from protocol therapy for one year or until death, whichever 
occurs first. 
 
6. CALENDAR 
 
Each cycle is defined as 21 days.  
 
Baseline evaluations, including EGFR mutation status, are to be confirmed prior to start of protocol 
therapy.  Scans must be done <4 weeks prior to the start of therapy.  In the event that the 
participant’s condition is deteriorating, laboratory evaluations should be repeated within 5 days 
prior to initiation of the next cycle of therapy. 
 
Office visits are required once at screening, and day one of each cycle. During the office visit, 
laboratory tests as well as physical exam will be performed to identify adverse effects. CT or PET 
scans will be performed every two cycles (within 7 days) for evaluation of disease status. 
Laboratory tests need to be performed within 7 days during each cycle before giving next dose of 
treatment.  
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Study assessments and agents should be administered within + 7 days of the protocol-specified 
date, unless otherwise noted. 
 
Table 1. Study calendar 
 
 
Screen
ing 
4wks 
C1 
D1 
+/- 7 
days 
C2 
D1 
+/- 7 
days 
C3 
D1 
+/- 7 
days 
C4 
D1 
+/- 7 
days 
C5 
D1 
+/- 7 
days 
C6 
D1 
+/- 7 
days 
C7 
D1 
+/- 7 
days 
C8 
D1 
+/- 7 
days 
C9 
D1 
+/- 7 
days 
C10 
D1 
and 
more 
Discontinua-
tion Visitc 
Bintrafusp alfaA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CarboplatinB 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
PemetrexedC 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Confirmation of EGFR status 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
Xb 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistry g,h 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with diff g,h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor measurements  
Xd 
 
 
X 
 
X 
 
X 
 
X 
 
X i 
Tissue collection  
Xe 
 
 
 
 
 
 
 
 
 
 
X (optional) 
ctDNA collection 
Xf 
 
 
X 
 
 
 
 
 
 
 
X  
Plasma collection 
Xf 
 
 
X 
 
 
 
 
 
 
 
X  
A: 
Bintrafusp alfa 2400mg iv on day 1 of every 21-day cycle  
B: 
Carboplatin (AUC 4-5) every three weeks on day 1 of the 21-day cycle for up to 4 cycles. Cisplatin is allowed if the treating physician 
deems appropriate.  
C.     Pemetrexed (400-500mg/m2) every three weeks on day 1 of the 21-day cycle. Folic acid and vitamin B12 will be given according to the 
standard practice.  
 
a: 
Alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, SGOT 
[AST], SGPT [ALT], sodium. 
b: 
Urine or blood pregnancy test (women of childbearing potential). This is only required at screening. 
c: 
Off-study evaluation. Note: follow up visits or other contact are required in order to identify SAEs during the 30 days following the end 
of study treatment. Survival follow up via telephone is every 4 months for 1 year or until death. 
d:      Tumor measurement by PET or CT using RECIST 1.1. Tumor measurements are taken before C3D1, and every two cycles in subsequent 
cycles. Brain MRI is performed at investigator’s discretion.  
e:       Optional biopsy at the time of disease progression.   
f:       ctDNA and plasma collections are required at baseline, C3 and at the off study evaluation.  
g;      Labs might be repeated within 5 days prior to the next cycle for patients with deteriorating conditions.  
h:      Lab tests need to be performed within 7 days during each cycle prior to the next dose. 
i:       Subjects who discontinue study medication for reasons other than objective disease progression will continue RECIST 1.1 assessments 
for objective progression. 
 
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6.1 
Screening Period (up to 4 weeks) 
 
At screening, consenting subjects are assessed to ensure that they meet eligibility criteria. Subjects 
who do not meet these criteria must not be enrolled into the study. Demographic data and other 
characteristics will be recorded and will include date of birth or age, gender, smoking history, race 
and/or ethnicity according to local regulations.  
 
Informed consent will be obtained.  
 
The following information and items will be collected at screening. 
 
6.1.1 Archival tumor sample (if available):  
 
All subjects will be asked to provide consent to supply a sample of their archival tumor blocks if 
a sample taken at the time of diagnosis is available. Any archival biopsy samples taken following 
previous lines of therapy will also be requested, if available. In each case the previous subject 
treatment must be clearly indicated for each sample provided. Tumor samples will preferably be 
in the form of a formalin fixed paraffin embedded block (sample derived from the diagnostic tumor 
or a metastatic site). If this is not possible, 10-20 slides of freshly prepared unstained 5micron 
sections from the archival tumor block may be provided.  
 
6.1.2 Blood for ctDNA and plasma biomarkers:  
All subjects are required to provide two baseline blood samples, one for ctDNA and the other for 
plasma biomarkers. 
6.1.3 Performance Status 
 
The performance status of all patients will be graded according to the ECOG PS scale. 
 
6.1.4 Clinical Laboratory Tests 
 
Clinical laboratory tests will be performed to assess eligibility for enrolment and will be repeated 
according to study calendar included in this section. Laboratory tests can be repeated more 
frequently, if clinically indicated. 
 
6.1.5 Symptoms and Toxicity Assessment 
The symptoms and adverse events of all patients will be graded at scheduled intervals according 
to the NCI CTCAE, v5.0. Patients will be monitored continuously throughout the study for the 
occurrence of adverse events. Planned medical interventions will not be considered an adverse 
event.  
6.1.6 Radiology Assessments 
CT chest (with/without abdomen/pelvis), PET-CT, and CT brain / MRI brain will be obtained 
according to Study Calendar included in Table 1.  Response and progression will be evaluated in 
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the study using the international criteria proposed by the RECIST committee, and will be 
performed by the radiology collaborator(s) on trial in a blind fashion. 
6.1.7 Pregnancy test  
 
Pregnancy test (blood or urine tests are acceptable based on the site’s standard clinical practice) 
for women of childbearing potential only.  
 
6.2 
Treatment Period  
 
6.2.1 Bintrafusp alfa  
 
A cycle of treatment is defined as 21 days. On day one of each 21-day cycle, bintrafusp alfa at 
2400mg is administered via intra-venous infusion. Safety tests (vitals, weight, laboratory tests) and 
clinical visits are required every cycle.  
 
6.2.2 Carboplatin  
 
A cycle of treatment is defined as 21 days. On day one of cycles 1-4, carboplatin (AUC4-5) is 
administered via intra-venous infusion. Safety tests (vitals, weight, laboratory tests) and clinical 
visits are required every cycle.  
 
Cisplatin is allowed if the treating physician deems appropriate.  
 
6.2.3 Pemetrexed  
 
A cycle of treatment is defined as 21 days. On day one of each 21-day cycle, pemetrexed is 
administered via intra-venous infusion. Safety tests (vitals, weight, laboratory tests) and clinical 
visits are required every cycle.  
 
If pemetrexed is permanently interrupted due to toxicities, bintrafusp alfa continuation is 
allowed. Similarly, if bintrafusp alfa is permanently interrupted, pemetrexed continuation is 
allowed.  
 
If a subject continues to receive treatment with bintrafusp alfa and/or pemetrexed beyond RECIST 
1.1 defined progression they must continue to follow the treatment visit schedule and assessments 
excluding study specific RECIST 1.1 assessments.  
 
6.3 
Follow-up Period  
 
6.3.1 Discontinuation visit  
 
A discontinuation visit will be performed at the time when treatment is permanently stopped. This 
is an office visit. Other than clinically indicated laboratory tests, ctDNA and plasma biomarker 
samples will be collected. Optional biopsy will be discussed.  
 
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6.3.2 Progression follow-up  
 
Subjects who discontinue study medication for reasons other than objective disease progression 
will continue RECIST 1.1 assessments for objective progression.  
 
6.3.3 Survival follow-up  
 
Assessments for survival should be made every 4 months following objective disease progression 
for one year or until death, whichever occurs first. Survival information may be obtained via 
telephone contact with the subject, the subject’s family or caretaker or by contact with the subject’s 
current physician.  
 
 
 
 
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7. STUDY DRUGS 
 
7.1 
Carboplatin 
 
7.1.1 Introduction 
 
Carboplatin is a platinum compound alkylating agent which covalently binds to DNA; interferes 
with the function of DNA by producing interstrand DNA cross-links. Carboplatin is apparently 
not cell-cycle specific. It is commonly used (off-label) for non-small cell lung cancers, including 
EGFR-mutant NSCLC.  
 
7.1.2 Dose selection 
 
Doses for adults are commonly calculated by the target AUC using the Calvert formula, 
where Total dose (mg) = Target AUC x (GFR + 25). If estimating GFR instead of a measured 
GFR, the FDA recommends that clinicians consider capping estimated GFR at a maximum of 
125 mL/minute to avoid potential toxicity. Antiemetics may be recommended to prevent nausea 
and vomiting; carboplatin is associated with a moderate to high emetic potential (dose/AUC 
dependent). For Non-small cell lung cancer (off-label use), target AUC 5 every 3 weeks (in 
combination with pemetrexed) was widely accepted and utilized18.  
 
7.1.3 Adverse events 
 
Percentages reported with single-agent therapy. 
>10%: 
Central nervous system: Pain (23%) 
Endocrine & metabolic: Hyponatremia (29% to 47%), hypomagnesemia (29% to 43%), 
hypocalcemia (22% to 31%), hypokalemia (20% to 28%) 
Gastrointestinal: Vomiting (65% to 81%), abdominal pain (17%), nausea (without vomiting: 
10% to 15%) 
Hematologic & oncologic: Bone marrow depression (dose related and dose limiting; nadir at 
~21 days with single-agent therapy), anemia (71% to 90%; grades 3/4: 21%), leukopenia 
(85%; grades 3/4: 15% to 26%), neutropenia (67%; grades 3/4: 16% to 21%), 
thrombocytopenia (62%; grades 3/4: 25% to 35%) 
Hepatic: Increased serum alkaline phosphatase (24% to 37%), increased serum AST (15% to 
19%) 
Hypersensitivity: Hypersensitivity (2% to 16%) 
Neuromuscular & skeletal: Weakness (11%) 
Renal: Decreased creatinine clearance (27%), increased blood urea nitrogen (14% to 22%) 
1% to 10%: 
Central nervous system: Peripheral neuropathy (4% to 6%), neurotoxicity (5%) 
Dermatologic: Alopecia (2% to 3%) 
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Gastrointestinal: Constipation (6%), diarrhea (6%), dysgeusia (1%), mucositis (≤1%), 
stomatitis (≤1%) 
Hematologic & oncologic: Bleeding complications (5%), hemorrhage (5%) 
Hepatic: Increased serum bilirubin (5%) 
Infection: Infection (5%) 
Ophthalmic: Visual disturbance (1%) 
Otic: Ototoxicity (1%) 
Renal: Increased serum creatinine (6% to 10%) 
 
<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Anaphylaxis, 
anorexia, bronchospasm, cardiac failure, cerebrovascular accident, dehydration, embolism, 
erythema, febrile neutropenia, hemolytic anemia (acute), hemolytic-uremic syndrome, 
hypertension, hypotension, injection site reaction (pain, redness, swelling), limb ischemia 
(acute), malaise, metastases, pruritus, skin rash, tissue necrosis (associated with 
extravasation), urticaria, vision loss. 
 
7.1.4 Drug ordering and accountability 
 
Carboplatin will be prescribed as the standard of care (SoC). The investigator is responsible for 
obtaining the drug when prior-authorization is needed  
 
7.2 
Pemetrexed 
 
7.2.1 Introduction 
 
Pemetrexed is an antifolate; it disrupts folate-dependent metabolic processes essential for cell 
replication. Pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), 
glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide 
ribonucleotide formyltransferase (AICARFT), the enzymes involved in folate metabolism and 
DNA synthesis, resulting in inhibition of purine and thymidine nucleotide and protein synthesis. 
 
7.2.2 Dose selection 
 
For the initial treatment of advanced or metastatic NSCLC: 500 mg/m2 on day 1 of each 21-day 
cycle (in combination with platinum) for 4 cycles or until disease progression or unacceptable 
toxicity.  
 
If there is no progression after completion of 4 cycles of carboplatin-pemetrexed, maintenance 
treatment at 500 mg/m2 on day 1 of each 21-day cycle is allowed, until disease progression or 
unacceptable toxicity.  
Due to the mechanism of action, vitamin supplements during the pemetrexed treatment is 
required: (1) folic acid 400 to 1,000 mcg orally once daily (starting prior or at the same time with 
treatment initiation; continue daily during treatment and for 21 days after last pemetrexed dose) 
and (2) vitamin B12 1,000 mcg intra-muscular injection prior or at the same time with treatment 
initiation and then every 3 cycles.  
 
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7.2.3 Adverse events 
 
>10%: 
Central nervous system: Fatigue (18% to 34%) 
Dermatologic: Desquamation (≤14%), skin rash (≤14%) 
Gastrointestinal: Nausea (12% to 31%), anorexia (19% to 22%), vomiting (6% to 16%), 
stomatitis (≤15%), diarrhea (5% to 13%) 
Hematologic & oncologic: Anemia (15% to 19%; grades 3/4: 3% to 5%), neutropenia (6% 
to 11%; grades 3/4: 3% to 5%) 
Respiratory: Pharyngitis (≤15%) 
 
1% to 10%: 
Cardiovascular: Edema (5%) 
Central nervous system: Neuropathy (sensory: 9%; motor: ≤5%) 
Dermatologic: Pruritus (7%), alopecia (6%), erythema multiforme (≤5%) 
Gastrointestinal: Constipation (6%), abdominal pain (1% to <5%) 
Hematologic & oncologic: Thrombocytopenia (8%; grades 3/4: 2%), febrile neutropenia 
(<5%) 
Hepatic: Increased serum alanine aminotransferase (8% to 10%), increased serum aspartate 
aminotransferase (7% to 8%) 
Hypersensitivity: Hypersensitivity reaction (<5%) 
Infection: Infection (1% to <5%), sepsis (1%) 
Ophthalmic: Conjunctivitis (≤5%), increased lacrimation (1% to <5%) 
Miscellaneous: Fever (8%) 
 
<1%, postmarketing, and/or case reports: Bullous rash, cardiac arrhythmia, colitis, depression, 
esophagitis, gastrointestinal obstruction, hemolytic anemia, interstitial pneumonitis, pain, 
pancreatitis, pulmonary embolism, radiation recall phenomenon, renal failure syndrome, 
Stevens-Johnson syndrome, supraventricular cardiac arrhythmia, syncope, toxic epidermal 
necrolysis, ventricular tachycardia 
 
7.2.4 Drug ordering and accountability 
 
Pemetrexed will be prescribed as the standard of care (SoC). The investigator is responsible for 
obtaining the drug when prior-authorization is needed 
 
7.3 
Bintrafusp alfa (M7824) 
 
7.3.1 Introduction 
  
Bintrafusp alfa (MSB0011359C, M7824) is a first-in-class bifunctional fusion protein composed 
of the extracellular domain of the human transforming growth factor β receptor II (TGF-βRII or 
TGF-β “trap”) fused via a flexible linker to the C-terminus of each heavy chain of an IgG1 
antibody blocking programmed death ligand 1 (anti–PD-L1), designed to target 2 of the key 
mechanisms of immunosuppression in the tumor microenvironment. Bintrafusp alfa is the 
proposed international nonproprietary name for M7824. 
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Bintrafusp alfa is designed to target tumors via colocalized, simultaneous blocking of two 
nonredundant immunosuppressive pathways—the TGF-β and PD-L1 pathways, which might 
potentially result in improved clinical benefit.  
 
Bintrafusp alfa was shown to have full biological activity in vitro including the ability to block 
PD-L1and neutralize TGFβ simultaneously. In experiments investigating the combination of 
bintrafusp alfa with standard of care therapies in mouse tumor models, bintrafusp alfa separately 
enhanced the antitumor effects of standard of care therapies including targeted therapies (in 
combination with receptor tyrosine kinase inhibitor pazopanib or anti-VEGF antibody), immuno-
oncology therapies (anti-CTLA4), of radiation therapy, and in combination with chemotherapy 
such as 5-fluorouracil and oxaliplatin (FOLFOX), gemcitabine, cisplatin, and doxorubicin.  
 
7.3.2 Dose selection 
 
For all toxicity studies, a no observed adverse effect level (NOAEL) of 140 mg/kg (maximum 
feasible dose) was established. The only notable clinical effect observed in all studies was a 
decrease in red blood cell (RBC) counts and related parameters (hemoglobin [Hgb] and 
hematocrit) from all treated groups; evaluation of peripheral blood smears did not demonstrate 
evidence of an immune-mediated hemolytic process. 
 
Bintrafusp alfa is being developed as an immuno-oncology agent for treatment in a number of 
tumor types, including non-small cell lung cancer (NSCLC). The results from 2 Phase I studies 
(global study EMR200647-001 and MS200647-0008 in Asia) are summarized in the IB. Both 
studies have a dose escalation phase (following a standard “3 + 3” design) followed by a parallel-
group expansion phase in selected solid tumor indications. Maximum tolerated dose (MTD) was 
not reached in either study at doses tested up to 30 mg/kg q2w. Each study had 1 dose-limiting 
toxicity (DLT) in 1 participant at the 20 mg/kg dose level. With no DLTs at other dose levels up 
to 30 mg/kg, M7824 at 30 mg/kg is considered tolerable. 
 
The dose for the expansion cohorts of both studies has been selected as 1200 mg/infusion (flat 
dose) iv once every 2 weeks for all cohorts except second-line (2L) NSCLC cohort and the 2L 
HCC dose ascending cohorts. The flat dose approach and selection of the recommended Phase II 
dose (RP2D; 1200 mg q2w or 2400 mg q3w when administered concomitantly with 
chemotherapies using q3w regimens) for bintrafusp alfa is supported by population 
pharmacokinetics (popPK) and exposure-response modeling and simulation. 
 
7.3.3 Adverse events 
 
The safety summary for this Investigator’s Brochure includes data (as of 24 August 2018) from a 
total of 689 participants, including: 
 
Data from 36 participants enrolled in the dose escalation part of EMR200647-001; 
 
Data from 23 participants enrolled in the dose escalation part of MS200647-0008 (14 
participants) and in the ascending-dose 2L HCC expansion cohort (9 participants); 
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Pooled data from a total of 630 participants enrolled in the dose expansion cohorts of 
EMR200647-001 and MS200647-0008, including 584 participants who received flat dose of 
M7824 at 1200 mg q2w, 40 participants with 2L NSCLC who received flat dose of M7824 at 
500 mg q2w and 6 participants with 2L HCC who received M7824 at 3 mg/kg q2w. 
 
Of the 630 participants enrolled in the expansion cohorts of EMR200647-001 and 
MS200647-0008, 615 (97.6%) participants experienced TEAE, treatment-related Grade ≥ 3 
TEAEs occurred in 142 (22.5%) participants, treatment-related SAEs were reported in 93 
(14.8%) participants, and 50 (7.9%) participants had treatment discontinuations due to 
treatment-related TEAEs. Death due to treatment-related TEAEs, as assessed by the Investigator, 
occurred in 7 participants (1.1%) from 8 to 182 days following the last dose of M7824. The 
emerging safety profile of M7824 from EMR200647-001 and MS200647-0008 including 689 
patients across tumor types investigated is manageable and consistent with other therapies 
targeting either PD-(L)1 or TGFβ pathways. 
 
Treatment-emergent AEs of special interest (AESI) for bintrafusp alfa are: infusion-related 
reactions (IRRs), immune-related adverse events (irAEs), skin lesions possibly due to TGFβ 
inhibition and treatment-related anemia. Since 23 July 2017, IRRs (including hypersensitivity), 
irAEs /autoimmune disorders, and skin lesions with hyperkeratosis, keratoacanthoma, cutaneous 
squamous cell carcinoma possibly due to TGFβ inhibition are considered to be important 
identified risks with bintrafusp alfa. Anemia, alterations in wound healing or repair of tissue 
damage and embryofetal toxicity remain important potential risks. In addition, mucosal bleeding 
events are a potential risk for bintrafusp alfa. Respective risk mitigation measures have been 
implemented in the protocols. 
 
7.3.4 Clinical efficacy 
 
Bintrafusp alfa has shown preliminary efficacy in NSCLC. The expansion cohort of the phase 1 
study (NCT02517398) includes 80 patients with advanced NSCLC who had prior platinum doublet 
therapy but have not received previous immunotherapy. A total of 80 patients were randomized to 
receive bintrafusp alfa 500 or 1200 mg (n = 40 each). Median follow-up was 51.9 weeks (IQR, 
19.6-74.0). The ORR in all patients was 21.3% (17 of 80). The ORR was 17.5% (seven of 40) and 
25.0% (10 of 40) for the 500 mg dose and the 1200 mg dose (recommended phase 2 dose), 
respectively. At the 1200 mg dose, patients with PD-L1-positive and PD-L1-high (≥80% 
expression on tumor cells) had ORRs of 36.0% (10 of 27) and 85.7% (six of seven), 
respectively17. With the initial observation of efficacy, ongoing study (NCT03840915) is testing 
the safety and efficacy of M7824 in combination with platinum-doublet in NSCLC. 
 
7.3.5 Drug ordering and accountability 
 
EMD serono will supply bintrafusp alfa for this trial. 
The investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity). 
 
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1) If concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product. 
 
2) If the study drug(s) are to be destroyed on site, it is the investigator’s responsibility to ensure 
that arrangements have been made for disposal, and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and institutional procedures. 
 
7.3.6 Storage and dispensing 
 
The investigator should ensure that the study drug is stored in accordance with the environmental 
conditions (temperature, light, and humidity) as per product information and the Investigator 
Brochure and per local regulations. It is the responsibility of the investigator to ensure that 
investigational product is only dispensed to study subjects. The investigational product must be 
dispensed only from official study sites by authorized personnel according to local regulations. 
 
The relevant Drug Product (DP) presentation is a liquid formulation in Type I glass vials, closed 
with a rubber septum and sealed with an aluminum crimp seal closure. The investigational product, 
Bintrafusp alfa is available as a sterile, clear, colorless and non-pyrogenic solution for intravenous 
infusion. 
 
Each single-use vial contains 600 mg of Bintrafusp alfa, formulated as 10 mg/mL of active, 6% 
(w/v) Trehalose, 40 mM NaCl, 5 mM Methionine, 0.05% (w/v) Tween 20, 10 mM L-Histidine at 
pH 5.5. This product requires further dilution prior to IV infusion.  
 
EMD Serono will package and distribute the IMP to sites via their distribution vendor - Fisher 
Clinical Services.  The IMP will be shipped in transport cool containers (2oC to 8oC) that are 
monitored with temperature control devices. 
 
Bintrafusp alfa drug product must be stored in the original packaging (protected from light) at 
refrigerated conditions (2- 8°C, 36-46°F) until use, with a temperature log maintained daily. The 
storage condition is based on data from ongoing long-term stability studies with Bintrafusp alfa.  
  
Bintrafusp alfa drug product stored at room temperature (15-25°C, 59-77°F) or higher 
temperatures for extended periods of time might be subject to degradation. 
  
Bintrafusp alfa drug product must not be frozen. 
 
7.3.7 Destruction  
 
Sponsor/Investigator drug destruction is allowed provided the following minimal standards are 
met: 
• 
On-site disposal practices must not expose humans to risks from the drug. 
• 
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
• 
Written procedures for on-site disposal are available and followed.  
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• 
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented. 
 
 
 
 
8. DOSING MODIFICATIONS 
 
8.1 
Toxicity management and dose modification for bintrafusp alfa 
 
a. Treatment modification for symptoms of infusion-related reactions (Table 2) 
b. Management of immune-mediated adverse reactions (Table 3) 
c. Management of potential TGF-β mediated skin adverse events (Table 4A) 
d. Other potential risks (Table 4B – 4D)  
i. Management of treatment-related anemia 
ii. Management of mucosal bleeding and tumor related bleedings 
iii. Guidance on wound healing alterations 
 
Table 2. Treatment Modification of bintrafusp alfa for Symptoms of Infusion-Related Reactions 
including Immediate Hypersensitivity 
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NCI-CTCAE Grade  
Treatment Modification for bintrafusp alfa 
Grade 1 - mild 
• Mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated 
• Increase monitoring of vital signs as medically 
indicated. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, IV fluids); 
prophylactic medications indicated for  24 h. 
 
• Stop the infusion of the study intervention 
caused IRR 
• Increase monitoring of vital signs as 
medically indicated as participants are 
deemed medically stable by the attending 
Investigator. 
• If symptoms resolve quickly or decrease to 
Grade 1, resume infusion at 50% of 
original rate with close monitoring of any 
worsening signs and symptoms, otherwise 
dosing held until resolution of symptoms 
with mandated premedication for the next 
visit schedule. 
• If symptoms worsen to Grade 3 or 4, 
follow treatment modification guidelines 
accordingly. 
Grade 3 or Grade 4 – severe or 
life-threatening 
o Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae. 
o Grade 4: Life-threatening 
consequences; urgent intervention 
indicated. 
• Stop bintrafusp alfa infusion immediately 
and disconnect infusion tubing from the 
participant with additional appropriate 
medical measures. 
• Monitor closely until deemed medically 
stable by the attending investigator. 
• Hospitalization may be indicated. 
 
 
IRR=infusion-related reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common 
Terminology Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs.  
Once the bintrafusp alfa 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, bintrafusp alfa 
discontinuation is mandated.  
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For all types and grades of infusion reactions, details about drug physical constitution, method of 
preparation, and infusion must be recorded. 
Additional recommendation: critical instructions include the requirement that treatment must be 
permanently discontinued for the following Grade 4 irAE toxicities: rash/inflammatory dermatitis, 
nephritis, autoimmune hemolytic anemia, hemolytic uremic syndrome, aplastic anemia, immune 
thrombocytopenia, acquired TTP, and in certain circumstances, lymphopenia. 
 
Management of immune-mediated adverse reactions (Table 3) 
 
Recommended guidance and management for specific irAEs as provided in the current NCCN 
guideline available at http://www.nccn.org. 
 
According to American Society of Clinical Oncology Clinical Practice Guideline (Brahmer 
2018), 
treatment of irAEs is mainly dependent upon severity as defined by NCI-CTCAE v5.0. In 
general, management by NCI-CTCAE v5.0 grading is listed below: 
 
• Grade 1: study intervention should be continued with close monitoring, with the 
exception of some neurologic, hematologic, and cardiac toxicities. 
• Grade 2: study intervention may be suspended for some 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 intervention 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 intervention is recommended, 
with the exception of endocrinopathies that have been controlled by hormone 
replacement. 
 
Permanent treatment discontinuation is required in case of immune-related Grade 4 
rash/inflammatory dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic uremic 
syndrome, aplastic anemia, immune thrombocytopenia, and acquired thrombotic 
thrombocytopenic purpura, colitis and hepatitis. Permanent discontinuation is also required for 
Grade ≥ 3 pneumonitis and Grade ≥ 3 nervous system irAEs. 
 
For Grade 4 immune-related lymphopenia, permanent treatment discontinuation will be required, 
if lymphopenia is considered immune-related in nature, no clear alternative explanation exists for 
the event, and it does not resolve within 14 days. Permanent treatment discontinuation is not 
required when the AE is manifested by a single laboratory value out of normal range without any 
clinical correlates. In this case, treatment should be held until the etiology is determined. If the 
event is not considered immune-related and resolves to Grade ≤ 1, restarting treatment may be 
considered. 
 
 
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Table 4A Management of TGF-β mediated Skin Adverse Events 
Skin assessment must be performed at baseline and at least every 6 weeks during treatment 
and at the end of treatment or 28 (±5 days) days post-treatment safety follow-up (if not 
performed in the previous 6 weeks). 
• Hyperkeratosis 
• Keratoacanthoma 
• Cutaneous squamous cell carcinoma (cSCC) 
• Basal cell carcinoma 
• Actinic keratosis 
Management 
• Baseline skin assessment with detailed medical history 
• Discontinuation or termination not required in most cases. Continuation of treatment 
should be evaluated by the Investigator. 
• Emollients may be used 
• Develop diagnostic and treatment plan in collaboration with Investigator and 
dermatologist 
• Treatment follow-up will depend on number and localization of lesions. 
o Single lesion: full excision may be recommended 
o Multiple lesion or location not suitable for full excision: Mohrs surgery, 
cryotherapy or other standard treatment options depending on pathology. 
Topical retinoids may be used after discussion with Investigator. 
• Close clinical follow-up for re-evaluation, resolution and potential recurrence should be 
implemented 
• In general, treatment of TGF-β mediated skin lesions should be based on local 
guidelines/standard of care. 
Additional consideration: Keratoacanthoma lesions may resolve spontaneously without 
surgical intervention within weeks after discontinuing bintrafusp alfa. 
Consult with Medical Monitor as needed for management of TGF-β mediated skin lesions. 
 
 
OTHER POTENTIAL RISKS 
Table 4B  
Management of Treatment-Related Anemia 
• Hematology assessment must be performed at baseline, prior to each bintrafusp alfa 
dose, at the end of treatment visit and at 28 (±5 days) days post-treatment safety follow-
up. 
• Participants must enter the study with Hgb values at least 9g/dl 
• All relevant hematological testing for treatment-related anemias should be done prior to 
a blood transfusion, if clinically feasible 
Diagnostic Work-up 
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• Baseline Anemia Evaluation 
o CBC with emphasis on red cell indices 
• If indicated and at clinical discretion, the following should be considered: 
o Iron studies 
o Serum Folate and Vit B12 values 
o Coagulation factors 
o Fecal occult blood 
o Urinalysis 
o Hormone panel: TSH, Erythropoietin 
o Peripheral blood smear 
Further recommendation 
 
• Suspected Hemolysis 
o bilirubin, LDH, Coombs test, haptoglobin 
• Suspected bleeding 
• :  
o Consider imaging/interventional radiology consultation as indicated 
o Consider imaging and/or endoscopy as clinically indicated 
• Suspected aplastic anemia: 
o Hematology consultation 
o Consider bone marrow aspiration/morphologic evaluation 
 
Additional consideration: Treatment-related Anemia is an important identified risk for 
bintrafusp alfa. 
In general, blood transfusions and erythroid growth factors are permitted as clinically 
indicated. 
Abbreviation: CBC: complete blood count, TSH: thyroid stimulating hormone, LDH: lactate 
dehydrogenase 
 
Table 4C     Management of Mucosal/Non-tumor and Tumor Bleeding 
Mucosal Bleeding 
• Events of mild to moderate severity are a potential risk for bintrafusp alfa. 
• In general, these reactions resolve without discontinuation of treatment. 
• Events may include, but are not limited to the following: 
o Epistaxis 
o Hemoptysis  
o Gingival bleeding 
o Hematuria 
Non-tumor Bleeding 
Grading 
Management 
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Grade 2 
• If resolves to Grade ≤ 1 by the day 
before the next infusion, study 
intervention may be continued 
• If not resolved to Grade ≤ 1 by the day 
before the next infusion, but is 
manageable and /or not clinically 
relevant, consult Medical Monitor to 
assess if clinically reasonable to 
administer the following infusion. 
Grade 3 
 
• Permanently discontinue treatment 
unless an alternative explanation can be 
identified (such as concomitant use of 
antithrombotic agents, traumatic events, 
etc.)  
• In case of alternative explanations, hold 
study treatment until the event recovers 
to Grade ≤ 1 
Grade 4 
• Treatment must be permanently 
discontinued if no alternative 
explanation is identified. 
Tumor Bleeding 
Grade ≥ 2 
• Study treatment must be held till the 
event recovers to Grade ≤ 1 
• Permanently discontinue treatment if the 
Investigator considers the participant to 
be at risk for additional severe bleeding. 
 
 
Table 4D 
Guideline on Alterations in Wound Healing or Repair of Tissue Damage 
• Alterations of wound healing and tissue damage repair are considered an important 
risk for bintrafusp alfa 
• Management should be discussed with Medical Monitor for participants requiring 
surgery on study. 
• It is recommended to hold study intervention for approximately 4 weeks post major 
surgery for observation. 
• Post-operative wound healing should be closely monitored 
 
 
 
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8.2 
Toxicity management and dose modifications for carboplatin/pemetrexed 
 
 
The toxicity management for SoC carboplatin and pemetrexed will be by the investigator’s 
discretion. Dose adjustment following drug inserts is recommended.  
 
See carboplatin FDA insert  
 
See pemetrexed FDA insert  
 
 
 
 
9. ADVERSE EVENTS AND REPORTING 
 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. 
9.1 
Definitions  
 
9.1.1 Adverse event 
 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product 
and which does not necessarily have a causal relationship with this treatment.  An AE can therefore 
be any unfavorable and unintended sign (including a clinically significant abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of an investigational 
study drug, whether or not considered related to the study drug. The term AE is used to include 
both serious and non-serious adverse events. 
 
For the purposes of this clinical study, AEs include events which are either new or represent 
detectable exacerbations of pre-existing conditions. 
 
The term “disease progression” should not be reported as an adverse event term.  As an example, 
"worsening of underlying disease" or the clinical diagnosis that is associated with disease 
progression should be reported. 
 
Adverse events may include, but are not limited to: 
− 
Subjective or objective symptoms provided by the patient and/or observed by the 
Investigator or study staff including laboratory abnormalities of clinical significance. 
− 
Any AEs experienced by the patient through the completion of final study procedures. 
− 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with the underlying disease that 
were not present before the AE reporting period  
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− 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as biopsies). 
 
The following are NOT considered AEs: 
− 
Pre-existing condition:  A pre-existing condition (documented on the medical history CRF) 
is not considered an AE unless the severity, frequency, or character of the event worsens 
during the study period. 
− 
Pre-planned or elective hospitalization:  A hospitalization planned before signing the 
informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the 
hospitalization or meets any other SAE criteria, the event will be considered an SAE.  
Surgeries or interventions that were under consideration, but not performed before 
enrollment in the study, will not be considered serious if they are performed after 
enrollment in the study for a condition that has not changed from its baseline level.  Elective 
hospitalizations for social reasons, solely for the administration of chemotherapy, or due 
to long travel distances are also not SAEs. 
− 
Diagnostic Testing and Procedures:  Testing and procedures should not to be reported as 
AEs or SAEs, but rather the cause for the test or procedure should be reported. 
− 
Asymptomatic Treatment Related Lymphocytosis: This event should also not be 
considered an AE.  Patients with treatment-related lymphocytosis should remain on study 
treatment and continue with all study-related procedures. 
− 
Any adverse event clearly attributable to disease progression 
 
9.1.2 Severity criteria (Grade 1-5) 
 
Definitions found in the Common Terminology Criteria for Adverse Events version 5 (CTCAE 
v5) will be used for grading the severity (intensity) of AEs.  The CTCAE v5 displays Grades 1 
through 5 with unique clinical descriptions of severity for each referenced AE.  Should a patient 
experience any AE not listed in the CTCAE v5, the following grading system should be used to 
assess severity: 
 
− 
Grade 1 (Mild AE) – experiences which are usually transient, requiring no special 
treatment, and not interfering with the patient’s daily activities 
− 
Grade 2 (Moderate AE) – experiences which introduce some level of inconvenience or 
concern to the patient, and which may interfere with daily activities, but are usually 
ameliorated by simple therapeutic measures 
− 
Grade 3 (Severe AE) – experiences which are unacceptable or intolerable, significantly 
interrupt the patient’s usual daily activity, and require systemic drug therapy or other 
treatment 
− 
Grade 4 (Life-threatening or disabling AE) – experiences which cause the patient to be in 
imminent danger of death 
− 
Grade 5 (Death related to AE) – experiences which result in patient death 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events, assigning the attribution and assessing the severity of the 
AE, the causal relationship between any events and the clinical study procedure, activities or 
device.  Additionally, the Investigator is responsible for providing appropriate treatment for the 
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event and for adequately following the event until resolution for all adverse events for subjects 
enrolled. 
 
 
AEs will be recorded as per the guidelines for phase II on the table below: 
 
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 
 
 
 
9.1.3 Causality (Attribution) 
 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by the 
investigator(s) and communicated to the sponsor and EMD Serono in accordance with the agreed 
process 
   
Not Related: Another cause of the AE is more plausible; a temporal sequence cannot be 
established with the onset of the AE and administration of the investigational product; or, a causal 
relationship is considered biologically implausible. 
 
Unlikely: The current knowledge or information about the AE indicates that a relationship to the 
investigational product is unlikely. 
 
Possibly Related: There is a clinically plausible time sequence between onset of the AE and 
administration of the investigational product, but the AE could also be attributed to concurrent or 
underlying disease, or the use of other drugs or procedures.  Possibly related should be used when 
the investigational product is one of several biologically plausible AE causes.  These AEs will be 
reported as related if the investigator believes it is more likely than not that the investigational 
product caused the AE. 
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Related: The AE is clearly related to use of the investigational product. 
8.1.5 Unexpected adverse events  
An “unexpected” AE is an AE that is not listed in the Investigator's Brochure/package insert or is 
not listed at the specificity or severity that has been observed. For example, hepatic necrosis would 
be “unexpected” (by virtue of greater severity) if the Investigator's Brochure referred only to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be “unexpected” (by virtue of greater specificity) if the Investigator's 
Brochure/package insert listed only cerebral vascular accidents. "Unexpected" also refers to AEs 
that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the study drug under investigation. 
 
9.2 
Documenting and Reporting of Adverse Events and Serious Adverse Events by 
Investigators 
 
9.2.1 Serious Adverse Events (SAE) Reporting requirements for MD Anderson Sponsor Single 
Site IND protocols.  
 
• 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 event 
• 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. 
• 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 on Reporting Adverse Events for Drugs and Devices”. 
• Serious adverse events will be captured from the time of the first protocol-specific 
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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. 
• All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND Office 
within 5 working days of knowledge of the event regardless of the attribution. 
• Death or life-threatening events that are unexpected, possibly, probably or definitely 
related to drug must be reported (initial or follow up) to the IND Office within 24 hours 
of knowledge 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. 
• The electronic SAE application (eSAE) will be utilized for safety reporting to the IND 
Office and MD Anderson IRB.  
• All events reported to the supporting company must also be reported to the IND Office 
  
• Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor 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 will also be forwarded to EMD Serono as required within the applicable contract excuted 
between EMD Serono and Sponsor-investigator. The SAE will be reported to EMD Serono by 
fax: +49-6151-72 6914 and email: ICSR_CT_GPS@merckgroup.com.  
 
 
 
9.2.2 Assessment of adverse events  
 
Investigators will assess the occurrence of adverse events and serious adverse events at all subject 
evaluation time points during the study. All adverse events and serious adverse events whether 
volunteered by the subject, discovered by study personnel during questioning, detected through 
physical examination, clinically significant laboratory test, or other means, will be recorded.  Each 
recorded adverse event or serious adverse event will be described by its duration (i.e., start and 
end dates), severity, regulatory seriousness criteria (if applicable), suspected relationship to the 
investigational product, and any actions taken. 
 
9.2.3 Adverse Event Reporting Period 
 
All AEs whether serious or non-serious, will be captured from the time signed and dated ICF is 
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obtained until 30 days following the last dose of treatment or until the initiation of alternative 
anticancer therapy.  
 
Progressive disease should NOT be reported as an event term, but instead symptoms/clinical signs 
of disease progression may be reported.  
 
All Grade 3 – 5 adverse events, regardless of seriousness, severity, or presumed relationship to 
study drug, must be recorded using medical terminology in the source document. All records will 
need to capture the details of the duration and the severity of each episode, the action taken with 
respect to the study drug, investigator’s evaluation of its relationship to the study drug, and the 
event outcome. Whenever possible, diagnoses should be given when signs and symptoms are due 
to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should 
be reported as "upper respiratory infection").  
All deaths should be reported with the primary cause of death as the AE term, as death is typically 
the outcome of the event, not the event itself. 
 
9.2.4 Other events requiring reporting 
 
Overdose 
 
An overdose is defined as a subject receiving a dose of bintrafusp alfa in excess of that specified 
in this protocol. If the overdose results in an AE, the AE must also be recorded as an AE. Overdose 
does not automatically make an AE serious, but if the consequences of the overdose are serious, 
for example death or hospitalization, the event is serious and must be recorded and reported as an 
SAE. The investigator will use clinical judgment to treat any overdose. 
 
Pregnancy 
 
Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy. 
However, should a pregnancy occur in a female study subject, consent to provide follow-up 
information regarding the outcome of the pregnancy and the health of the infant until 30 days old 
will be requested. 
A female subject must immediately inform the Investigator if she becomes pregnant from the time 
of consent to 65 days after the last dose of bintrafusp alfa. A male subject must immediately inform 
the Investigator if his partner becomes pregnant from the time of consent to 125 days after the last 
dose of study drug. Any female subjects receiving study drug(s) who become pregnant must 
immediately discontinue study drug. The Investigator should counsel the subject, discussing any 
risks of continuing the pregnancy and any possible effects on the fetus.   
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be 
documented. Any pregnancy occurring in a subject or subject’s partner from the time of consent 
to 30 days after the last dose of bintrafusp alfa (up to 65 days for a female and 125 days for a male) 
must be reported. Any occurrence of pregnancy must be reported per SAE reporting timelines. All 
pregnancies will be followed for outcome, which is defined as elective termination of the 
pregnancy, miscarriage, or delivery of the fetus. Pregnancies with an outcome of live birth, the 
newborn infant will be followed until 30 days old by completing will need to be reported per SAE 
reporting timelines. Any congenital anomaly/birth defect noted in the infant must be reported as a 
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serious adverse event. 
 
Pregnancy will be submitted to the IND Office via eSAE application as “Other Important Medical 
Event”. 
 
Paternal Exposure 
Pregnancy of the subject’s partners is not considered to be an adverse event. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should if possible be followed up and documented. 
To capture information about a pregnancy from the partner of a male subject, the male subject’s 
partner consent must be obtained to collect information related to the pregnancy and outcome. A 
consent form specific to this situation must be used. The outcome of any conception occurring 
from the date of the first dose until 6 months after dosing ends should be followed up and 
documented. 
 
Other Malignancies 
All new malignant tumors including solid tumors, skin malignancies and hematologic 
malignancies will be reported for the duration of study treatment and during any protocol-specified 
follow-up periods including post-progression follow-up for overall survival. 
 
 
 
 
10. CORRELATIVE STUDIES 
 
10.1 
Tissue and Blood Repository 
As part of the study, a tissue and blood sample repository will be created. The objective of this 
tissue sample repository will be to provide material for the correlative studies proposed to evaluate 
the endpoints proposed, and for future evaluations of other relevant biomarkers that may be 
associated with clinical outcomes. A written informed consent will be obtained from patients 
enrolled in this study so that these samples may be analyzed in the future for biomarkers not 
described in this protocol.   
 
10.2 
Tissue 
 
Archived tissue for diagnosis will be requested. Next-generation sequencing (NGS) will be applied 
to the archived tissue to detect co-mutations.  
 
If biopsy is performed at the time of disease progression, tissue will be requested. NGS will be 
applied to the archived tissue to detect resistance mechanisms. 
 
No mandatory biopsy at the time of progression.  
 
10.3 
ctDNA 
 
Plasma ctDNA will be collected at screening or C1D1 (pre-treatment), C3D1 (On-treatment), and 
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at the time of disease progression (post-treatment). NGS profiling will be performed to identify 
potential mechanisms of resistance and to aid selection of next line of treatment.  
 
20ml of blood will be collected at each time point.  
 
10.4 
Plasma for Cytokine and Immune-modulator Analysis 
 
Plasma will be collected at screening or C1D1 (pre-treatment), C3D1 (on-treatment), and at the 
time of disease progression (post-treatment). Plasma cytokine profiling and immune-profiling will 
be performed to identify potential correlative markers for response and resistance.  
 
20ml of blood will be collected at each time point.  
 
 
 
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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect  
 
For the purposes of this study, participants should be re-evaluated for response every two cycles 
(6 weeks).   
 
Objective response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1)19.  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Participants who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by chest 
x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-
measurable. 
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Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.  
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
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Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable.  
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
(a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
(b)  No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD Fwill be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
(c)  FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET-
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CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of 
the PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it 
is not routinely or serially performed.   
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later data and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure from 
CT, MRI may be used instead of CT in selected instances.  
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response.   
 
Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
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that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one 
or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something other 
than tumor (for example, some ‘new’ bone lesions may be simply healing or flare of 
pre-existing lesions). However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a 
new lesion is equivocal (because of small size etc.), follow-up evaluation will clarify if 
it truly represents new disease and if PD is confirmed, progression should be declared 
using the date of the initial scan on which the lesion was discovered. 
 
11.1.4.4 
Evaluation of Objective Response and Best Overall Response 
 
Objective response will be assessed by RECIST 1.1. The best overall response is the 
best 
response recorded from 
the start 
of the treatment 
until 
disease 
progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response 
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assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
Table 8. Definition of Response for Participants with Measurable Disease  
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
*     In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last disease 
evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events reported 
are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
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Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
starting of treatment to the earlier of progression or death due to any cause. Participants 
alive without disease progression are censored at date of last disease evaluation. 
 
Overall Survival: Overall Survival (OS) is defined as the time from treatment to death due 
to any cause, or censored at date last known alive. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from treatment to 
progression, or censored at date of last disease evaluation for those without progression 
reported. 
 
11.2 
Safety 
 
Safety and tolerability will be assessed in terms of AEs, deaths, laboratory data, vital signs (pulse 
and BP) and ECG/ECHO. These will be collected for all subjects.  
 
11.2.1 Adverse events  
 
AEs will be listed individually by subject. Any AE occurring before the trial treatment initiated 
will be included in the data listings but will not be included in the summary tables of AEs.  
 
Any AE occurring within 90 days of discontinuation of investigational product will be included in 
the AE summaries. Any events in this period that occur after a subject has received further therapy 
for cancer (following discontinuation of M7824) will be flagged in the data listings.  
 
 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Adverse events 
and reporting. 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
A customized web-based data capture system, Data Management Initiative (DMI), will be 
used at the study center. The CORe system will be used to register subjects. Concomitant 
medications will be captured in the subject's medical record only. 
 
12.1.2 Responsibility for Data Submission 
 
Participant institutions are responsible for submitting data and/or data forms to the study 
center on the study quarterly.   
 
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12.1.3 Patient Data Confidentiality  
 
All laboratory and clinical data gathered in this protocol will be stored in a password 
protected database. All patient information will be handled using synonymous identifiers. 
Linkage to patient identity is only possible after accessing a pass-word protected database. 
Access to the database is only available to individuals directly involved in the study. 
Information gathered for this study will not be reused or disclosed to any other person or 
entity, or for other research. Once the research has been completed, identifiers will be 
retained for as long as is required by law and by institutional regulations, and at that point 
will be destroyed.  
 
 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
This is an open-label, single arm phase II clinical trial to assess the efficacy of bintrafusp alfa 
with platinum-pemetrexed in patients with metastatic NSCLC who have progressed on prior 
EGFR TKI. The treatment consists of 4 cycles (every 21 days) of platinum + pemetrexed + 
bintrafusp alfa, followed by pemetrexed+ bintrafusp alfa maintenance at 2400mg every 3 weeks 
for patients who have not progressed on C5D1.  
13.2 
Sample Size Justification 
 
The primary endpoints of the study are: the best objective response rate within 6 months and 
progression-free survival at 18 weeks, after initiation of treatment. 
 
The study will be considered positive if at least one the primary endpoints were met.  
 
The ORR under the null hypothesis is assumed to be 30%.  After treatment start, we expect that 
the best ORR increases to 50% within 6 months.  The median PFS for EGFR-mutant NSCLC 
patients who receive chemotherapy is around 4.2-4.4 months. Therefore, 18-week PFS rate is 
estimated to be 50%. We expect an increase in 18-week PFS rate to 70%.   
We simultaneously monitor two co-primary efficacy endpoints using the Bayesian optimal phase 
2 (BOP2) design (Zhou, Lee and Yuan, 2017). Specifically, let 𝑛 denote the interim sample size 
and 𝑁 denote the maximum sample size. Let 𝑌1 (ORR) and 𝑌2 (18-week PFS) denote the two 
binary co-primary endpoints, with 𝑌1 = 1 and 𝑌2 = 1 indicating that patients experienced 
favorable treatment responses in the two respective endpoints. We assume that the joint 
distribution of (𝑌1, 𝑌2) follows a multinomial distribution with 4 elementary outcomes: (𝑌1, 𝑌2) = 
(1, 1), (1, 0), (0, 1) and (0, 0). Let 𝐩= (𝑃11, 𝑃10, 𝑃01, 𝑃00) denote the probabilities of observing 
the four outcomes, and let 𝑝1 = 𝑃𝑟(𝑌1 = 1), 𝑝2 = 𝑃𝑟(𝑌2 = 1), and 𝑝3 = 𝑃𝑟(𝑌1 = 1, 𝑌2 = 1). 
The treatment is deemed as unacceptable if 𝑝1 ≤0.3 and 𝑝2 ≤0.5, i.e., the treatment is not 
promising in both co-primary endpoints. Thus, we will stop enrolling patients and claim the 
treatment is not promising if 
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𝑃𝑟(𝑝1 > 0.3|𝑑𝑎𝑡𝑎) < 𝜆(𝑛
𝑁)𝛼, 
AND 
𝑃𝑟(𝑝2 > 0.5|𝑑𝑎𝑡𝑎) < 𝜆(𝑛
𝑁)
𝛼
, 
where 𝜆=0.95 and 𝛼=0.86 are design parameters optimized to maximize the probability of 
correctly concluding an efficacious treatment as acceptable when 𝑝1 = 0.5, 𝑝2 = 0.7 and 𝑝3 =
0.4, while controlling that the probability of incorrectly claiming an inefficacious treatment, with 
𝑝1 = 0.3, 𝑝2 = 0.5 and 𝑝3 = 0.2, as acceptable is less than 10%. This optimization is performed 
assuming a vague Dirichlet prior 𝐷𝑖𝑟(0.2,0.1,0.3,0.4) for 𝐩. The prior is chosen such that it 
corresponds to a prior effective sample size of 1 patient, and the prior estimates of 𝑝1 and 𝑝2 
match the cutoff values specified above. The above decision rule leads to the following optimal 
stopping boundaries: 
Table 2.1: Optimized stopping boundaries 
# patients treated Stop if # ORR <= AND # PFS <= 
15 
4 
7 
20 
6 
10 
25 
8 
13 
30 
11 
17 
35 
15 
22 
Based on Table 1, we perform the interim analysis when the number of enrolled patients reaches 
15, 20, 25, 30. When the total number of patients reaches the maximum sample size of 35, we 
conclude that the treatment is acceptable if the number of patients with best objective response is 
greater than 15, or the number of progression-free patients by 18 weeks is greater than 22; 
otherwise we conclude that the treatment is unacceptable. The go/no-go criteria in Table 1 are 
non-binding.  To account for a 12.5% inevaluable rate, we will enroll a total of 40 patients.  
Below are the operating characteristics of the design based on 10000 simulations using the BOP2 
web application V1.3.7.0, which is available at http://www.trialdesign.org. 
Table 2.2: Operating characteristics 
Pr(ORR) Pr(PFS) 
Pr(ORR & 
PFS) 
Early stopping 
(%) 
Claim promising 
(%) 
Sample 
size 
0.3 
0.5 
0.20 
73.18 
7.00 
24.9 
0.5 
0.7 
0.40 
2.60 
91.36 
34.7 
0.5 
0.6 
0.35 
7.61 
80.02 
34.1 
0.4 
0.7 
0.32 
6.31 
82.08 
34.3 
0.3 
0.7 
0.25 
9.91 
76.65 
33.8 
0.5 
0.5 
0.30 
12.23 
74.54 
33.5 
 
 
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13.3 
Definition of Analysis Sets 
 
13.3.1 Per protocol analysis set: 
 
The per protocol analysis set will consist of all patients who received at least one dose of bintrafusp 
alfa with platinum-pemetrexed and for whom post dose data are available. This set will be used 
for efficacy and safety analyses. 
 
13.3.2 Safety analysis set:  
 
The safety analysis set will consist of all patients who received at least one dose of bintrafusp alfa 
with platinum-pemetrexed and for whom post dose data are available. Safety data will be 
summarized using the safety analysis set, according to the treatment received. 
 
13.3.3 Evaluable efficacy analysis set: 
 
The evaluable analysis set will consist of patients who received bintrafusp alfa with platinum-
pemetrexed treatment, who had measurable disease, appropriate restaging scans for response 
evaluation and adequate follow-up. This set will be used for all efficacy analyses. 
 
 
13.4 
Analysis Plan 
 
Summary statistics will be provided for continuous variables and frequency tables and percentages 
will be used to summarize categorical variables. The distribution of time-to-event endpoints will 
be estimated using the method of Kaplan and Meier.  Best objective response rate within 6 months 
and progression-free survival rate at 18 weeks will be provided together with 95% confidence 
intervals. Adverse event data will be summarized by type, severity grade, and attribution. Cox 
proportional hazards regression analysis or logistic regression will be used to correlate the time-
to-event endpoints such as PFS or OS and binary endpoints such as objective response with 
medical demographical variables and/or biomarkers or changes in biomarkers.   
 
The Investigator is responsible for completing an efficacy/safety summary report and submitting 
to the IND Office Medical Affairs and Safety Group, for review and approval. 
 
The first analysis will be done after the first 15 evaluable subjects complete 2 cycles of therapy 
and then every 5 evaluable subjects after completing 2 cycles. On every submission, survival 
data of previously reported patients will need to be updated. 
A copy of the summary report should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
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data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
 
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REFERENCES 
 
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Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-
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Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated 
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Oxnard GR, Hu Y, Mileham KF, et al. Assessment of Resistance Mechanisms and 
Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired 
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Le X, Puri S, Negrao MV, et al. Landscape of EGFR -dependent and -independent 
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Gainor JF, Shaw AT, Sequist LV, et al. EGFR Mutations and ALK Rearrangements 
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Lee CK, Man J, Lord S, et al. Checkpoint Inhibitors in Metastatic EGFR-Mutated 
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Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of 
Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378:2288-301. 
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Kadara H, Choi M, Zhang J, et al. Whole-exome sequencing and immune profiling of 
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Nilsson MB, Sun H, Diao L, et al. Stress hormones promote EGFR inhibitor 
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Lan Y, Zhang D, Xu C, et al. Enhanced preclinical antitumor activity of M7824, a 
bifunctional fusion protein simultaneously targeting PD-L1 and TGF-beta. Sci Transl Med 
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Julius Strauss MEG-M, Jason Redman, Ravi Amrit Madan, Elizabeth Lamping, 
Michell Manu, Andrea Burmeister, Jennifer L. Marte, Lisa M. Cordes, Laureen Ojalvo, 
Christoph Helwig, Jeffrey Schlom, James L. Gulley. Safety and activity of M7824, a bifunctional 
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Paz-Ares L, Kim TM, Vicente D, et al. Bintrafusp Alfa, a Bifunctional Fusion Protein 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
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