A Phase II Single Arm Clinical Trial Assessing the Efficacy and Safety of BIntrafusp Alfa (M7824) in Previously Treated Advanced Malignant Pleural MESothelioma (BIMES)
Phase: PHASE2
Conditions: Mesothelioma; Lung
Sponsor: Fundación GECP

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document Dates:  
Protocol Version v.2.2_30Nov2021 
 
 

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A PHASE II SINGLE ARM CLINICAL TRIAL ASSESSING THE 
EFFICACY AND SAFETY OF BINTRAFUSP ALFA (M7824) IN 
PREVIOUSLY TREATED ADVANCED MALIGNANT PLEURAL 
MESOTHELIOMA 
BIMES: BIntrafusp alfa (M7824) for the treatment of MESothelioma 
Study Sponsor: Fundación GECP
EudraCT Number: 2020-004902-67
Sponsor code: GECP 20/09
Version 2.2
GECP 20/09

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Contacts
Trial Chair 
Dr. Ernest Nadal, MD, 
PhD
Oncology Service
ICO-Hospitalet,
Barcelona
Tel. 93 430 20 06
Fax. 93 419 17 68
Email: esnadal@iconcologia.net
Safety and Regulatory 
Affairs
Coordinating office of 
the Fundación GECP
Beatriz García and Ana Querol
Avenida Meridiana 358, 6ª planta
08027 Barcelona
Tel. +34 93 430 20 06
Fax. +34 93 419 17 68
Email: pharmacovigilance.slcg@gecp.org
Coordinating office of the 
Fundación GECP
Monitoring team
Monitor/CRA
Lead CRA
Clinical Operations 
Manager:
Patricio Gabarrón
Avenida Meridiana 358, 6ª planta
08027 Barcelona
Tel. +34 93 430 20 06
Fax. +34 93 419 17 68
Email: pgabarron@gecp.org
Anna Hernández
Avenida Meridiana 358, 6ª planta
08027 Barcelona
Tel. +34 93 430 20 06
Fax. +34 93 419 17 68
Email: ahernandez@gecp.org
Eva Pereira
Avenida Meridiana 358, 6ª planta
08027 Barcelona
Tel. +34 93 430 20 06
Fax. +34 93 419 17 68
Email: epereira@gecp.org
Dr. Ernest Nadal, MD,
PhD
esnadal@iconcologia.net
pharmacovigilance.slcg@gecp.org
Patricio Gabarrón
Avenida Meridiana 
Email: pgabarron@gecp.org
Anna Hernández
Avenida Meridiana 
ahernandez@gecp.org
Email: epereira@gecp.org
Eva Pereira
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Protocol Signature Page
A PHASE II SINGLE ARM CLINICAL TRIAL ASSESSING THE EFFICACY 
AND SAFETY OF BINTRAFUSP ALFA (M7824) IN PREVIOUSLY 
TREATED ADVANCED MALIGNANT PLEURAL MESOTHELIOMA
BIMES: BIntrafusp alfa (M7824) for the treatment of MESothelioma 
Sponsor code: GECP 20/09
Approved by:
Signature
_____________________________
Dr. Ernest Nadal
Trial Chair
Signature
_____________________________
Dr. Mariano Provencio
Fundación GECP President
GECP 20/09
Ernest Nadal
Dr. Mariano Provencio
Fundación GECP President
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Principal Investigator Protocol Signature Page
Study Title: A phase II single arm clinical trial assessing the efficacy and safety of BIntrafusp alfa 
(M7824) in previously treated advanced malignant pleural MESothelioma (BIMES
Sponsor protocol code: GECP 20/09
EudraCT Number: 2020-004902-67
Protocol version: v 2.2, 30th November 2021
As principal investigator of this site, I hereby confirm that:
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with Good Clinical Practice 
guidelines and will apply due diligence to avoid protocol deviations. 
I will provide copies of the protocol and all drug information relating to pre-clinical and prior clinical 
experience furnished to me by the Fundación GECP, to all physicians responsible to me who 
participate in this trial. I will discuss this material with them to assure that they are fully informed 
regarding the drug and the conduct of the trial. 
I agree to keep accurate records on all patient information including patient's informed consent 
statement, drug shipment and return forms, and all other information collected during the trial for 
a minimum period of 25 years according to the Royal Decree 1090/2015 approved in Spain.
Name of Principal Investigator: ___________________________________
_____________________________________
Signature                                                                              Date
GECP 20/09
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TABLE OF CONTENTS 
Section
Page
1.
Protocol summary......................................................................................................7
2.
Trial schedule...........................................................................................................15
3.
Background and rationale........................................................................................18
3.1.
Disease background.............................................................................................18
3.2.
Role of TGF-
..................................................19
3.3.
Blocking TGF-
..........................19
3.4.
Rationale for trial design .....................................................................................22
4.
Objectives and endpoints.........................................................................................24
4.1.
Primary objective and endpoint...........................................................................24
4.2.
Secondary objectives and endpoints....................................................................24
4.3.
Exploratory objectives.........................................................................................24
5.
Trial design, duration and termination.....................................................................25
6.
Patient selection.......................................................................................................26
6.1.
Inclusion criteria..................................................................................................26
6.2.
Exclusion criteria.................................................................................................27
7.
Patient enrollment....................................................................................................29
8.
Trial procedures.......................................................................................................29
8.1.
Overview of treatment sequence .........................................................................29
9.
Investigational Medicinal Product...........................................................................34
9.1.
Packaging and labelling.......................................................................................35
9.2.
Receipt and storage of the IMP ...........................................................................35
9.3.
Unused trial drug supplies...................................................................................35
10.
Trial treatments description .....................................................................................35
10.1.
BINTRAFUSP alfa (M7824)...............................................................................35
11.
Dose modifications criteria......................................................................................36
11.1.
General Notes Regarding Dose Modification .....................................................36
11.2.
BINTRAFUSP (M7824). Toxicity Management ................................................36
12.
Prohibited and permitted concomitant treatments ...................................................43
13.
Adverse events and reporting ..................................................................................45
13.1.
..................................45
13.2.
Definition of Serious Adverse Event (SAE) and Suspected Unexpected Serious 
Adverse Reaction (SUSAR)................................................................................48
13.3.
Adverse events of Special Interest for M7824 (Immediately reportable to the 
Sponsor) ..............................................................................................................50
13.4.
Overdose and secondary malignancies................................................................50
13.5.
SAEs and SUSARs reporting ..............................................................................51
13.6.
Pregnancy ............................................................................................................52
13.7.
Other safety considerations .................................................................................52
14.
Biological material and translational research.........................................................52
15.
Case report forms and documentation .....................................................................54
16.
Statistical considerations .........................................................................................54
17.
Criteria for termination of the trial ..........................................................................55
17.1.
General criteria for termination of the trial .........................................................55
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17.2.
Discontinuation of protocol treatment and from the study for individual patients
.............................................................................................................................55
18.
Ethics aspects, regulatory approval, and Patient Informed Consent .......................56
18.1.
Ethical Review Board/Ethics Committee/Health Authority................................56
18.2.
Informed consent .................................................................................................57
19.
Governance and administrative issues.....................................................................57
19.1.
Study documentation...........................................................................................57
19.2.
Protocol non-compliances/deviations..................................................................58
19.3.
Protocol amendment............................................................................................58
19.4.
Final report ..........................................................................................................58
19.5.
Independent Data Monitoring Committee (IDMC).............................................58
19.6.
Publication...........................................................................................................58
19.7.
Financial disclosure.............................................................................................58
19.8.
Clinical trial insurance.........................................................................................59
19.9.
Quality assurance.................................................................................................59
19.10.
Data protection ....................................................................................................59
19.11.
Study monitoring team ........................................................................................60
19.12.
Record retention ..................................................................................................60
20.
References................................................................................................................61
1.
Supplementary Data: Proposed Radiology Guidelines for Inclusion in Clinical Trial 
Protocols ..................................................................................................................65
1.1.
Definition of measurability..................................................................................65
1.2.
Measurement sites at baseline.............................................................................65
2.
Measurement of disease at subsequent time points:................................................72
3.
Definitions of objective response: ...........................................................................72
Appendices:
1.
Common Terminology criteria for Adverse Events (CTCAE) 
2.
Modified RECIST (mRECIST) criteria version 1.1 for malignant pleural mesothelioma
3.
SAE Form 
4.
Pregnancy Form
5.
Mesothelioma TNM definitions according to the 8th edition
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1.
Protocol summary
A PHASE II SINGLE ARM CLINICAL TRIAL ASSESSING THE EFFICACY 
AND SAFETY OF BINTRAFUSP ALFA (M7824) IN PREVIOUSLY 
TREATED ADVANCED MALIGNANT PLEURAL MESOTHELIOMA
BIMES: BIntrafusp alfa (M7824) for the treatment of MESothelioma 
Sponsor: Fundación GECP
Trial Chair: Dr. Ernest Nadal Alforja (MD, PhD)
Protocol code: GECP 20/09 
Population: advanced malignant pleural mesothelioma patients previously treated with platinum-
based chemotherapy
Design: Open-label, non-randomized, phase II, single arm, multi-center controlled clinical trial 
Study schema:
Dr. Ernest Nadal Alforja (MD, PhD)
GECP 20/09 
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Sample size: 47 patients
Rationale:
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy arising from the 
mesothelial surface of the pleura. In Europe, the incidence is about 20 per million and is almost 
always caused by asbestos exposure, with a usual lag time of 30 years between exposure and 
presentation.1 Histologic subtypes of MPM include epithelioid (about 60%), and non-epithelioid 
(around 40%) including sarcomatoid, biphasic and others. Disease is considered resectable in only 
10-15% of MPM patients.2 The prognosis in unresectable cases remains very poor, with median 
overall survival (OS) of 9 to 12 months.1,3 The disease is invariably fatal, due to anatomical limitations 
preventing the achievement of a complete microscopic surgical resection and tumor relative 
chemo-refractoriness.4
Cytotoxic chemotherapy remains one of the few therapeutic options that has been proven to 
improve survival in advanced MPM in a randomized controlled trial.5 The combination of cisplatin 
and pemetrexed has become standard first-line therapy worldwide for patients who are not suitable 
for aggressive surgery or in whom chemotherapy is recommended as part of a multimodality 
regimen.4 Cisplatin/pemetrexed is associated with a response rate of 30-40% and confers an OS 
advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for 
mesothelioma.3 Carboplatin is often substituted for cisplatin, due to simpler and shorter 
administration and assumption of a more favorable toxicity profile based on experience in other 
diseases. Although carboplatin use is not supported by randomized evidence, and there has been 
no direct comparison between the two platinum agents, phase I and II studies have demonstrated 
similar activity of either carboplatin or cisplatin with pemetrexed, with objective radiological 
response rates between 20% and 30%.6,7 Maintenance with pemetrexed is not considered standard 
of care. The addition of bevacizumab to chemotherapy modestly improved overall survival, but this 
treatment is not available in all countries.8
Dual immune checkpoint inhibition of PD1 and CTLA-4 with nivolumab plus ipilimumab has recently 
demonstrated superiority to platinum plus pemetrexed in the first line setting in the CheckMate-
743 study.9 Dual immune ckeckpoint blockade showed larger OS benefit in patients with non-
epithelioid tumors and those with positive PD-L1 expression.
However, no treatment has yet been shown to improve OS in patients who progressed to prior 
platinum-based chemotherapy, resulting in a high unmet need for effective therapies in previously 
treated patients with MPM. Single agent immunotherapy has demonstrated limited efficacy in the 
relapsed setting in the PROMISE-meso trial, which compared pembrolizumab with gemcitabine or 
vinorelbine. 10
by restoring effective antitumor immunity, blocking metastasis, and inhibiting angiogenesis. 
Inhibition of T
associated with increases in CD8+ T cell antitumor effects. 17
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activated CD4+ T cells and regulatory T (Treg) cells has been shown to inhibit tumor growth and 
protect mice from spontaneous cancer. 18
-associated genes has been linked 
to anti-PD-1 resistance in metastatic melanoma,19 bloc
mechanisms of resistance and sensitize tumor to anti-PD-1/PD-L1 therapies.
Bintrafusp alfa is being developed as an immuno-oncology agent for treatment in a number of tumor 
types, including nonsmall cell lung cancer (NSCLC), biliary tract cancer (BTC), cervical cancer, and 
triple-negative breast cancer (TNBC). Bintrafusp alfa was shown to have full biological activity in vitro 
including the ability to block PD-
Durable clinical activity of 
bintrafusp alfa was observed in a number of tumor types in the 2 Phase I studies (EMR200647-001 
and MS200647-0008).
Prior clinical trials with immune checkpoint inhibitors with anti-PD1 and anti-PD-L1 in previously 
treated MPM showed modest efficacy probably due to the predominantly immune suppressive 
tumor microenvironment, the generally low tumor mutational burden as well as the high aneuploidy 
which is characteristic of this tumor. In the PROMISE-Meso study, pembrolizumab was not superior 
to single chemotherapy in the second line setting in a non-selected population of MPM29. 
We hypothesize that dual targeting of PD-L1 and TGF-
bintrafusp alfa (M7824) may reduce tumor 
aggressiveness in MPM, can reverse the suppressive tumor microenvironment and extend 
progression-free survival (PFS). We propose a single-arm phase II clinical trial to assess the efficacy 
and the safety of M7824 in a cohort of patients with previously treated advanced MPM. We also 
hypothesize that selection of patients based on the TGF-
and stratification of patients based on immune groups will be helpful to identify MPM patients who 
are more likely to benefit from immunotherapy.
Objectives and endpoints:
Primary objective:
To determine the efficacy of M7824 in terms of the Progression Free Survival (PFS) assessed 
by the investigator according to the modified Response Evaluation Criteria in Solid Tumors 
(mRECIST) Version 1.1.
PFS is defined as the time from administration of first dose of bintrafusp alfa until objective 
tumor progression or death.
Secondary objectives:
To determine the ORR of the treatment as measured by investigator-assessed overall 
response rate (ORR) with M7824 according to modified RECIST v1.1.
To determine the PFS assessed by an independent review committee by revised modified 
RECIST criteria v1.1.
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To evaluate secondary measures of clinical efficacy including duration of response, disease 
control rate and the Overall survival (OS).
To evaluate the safety and tolerability of the treatment assessed by adverse events graded 
according CTCAE v5.0
Exploratory Objectives:
To correlate efficacy endpoints (PFS and ORR) with PD-L1 expression. This will be measured 
by PD-L1 immunohistochemistry in the central laboratory.
To correlate efficacy endpoints (PFS and ORR) with activation of TGF-
biopsies obtained at baseline and at tumor progression. This will be measured by SMAD2/3 
and phosphor-SMAD2/3 immunohistochemistry in tumor biopsies obtained at baseline and 
at tumor progression.
To correlate efficacy endpoints (PFS and ORR) with TGF-
along with additional 
cytokines measured in serum obtained prior to initiation of immunotherapy and cytokines
at tumor progression.
To correlate efficacy endpoints (PFS and ORR) with TGF-
along with additional 
cytokines measured in pleural effusion obtained prior to initiation of immunotherapy and at 
tumor progression. To determine the immune cell subpopulations harvested in the pleural 
effusion at baseline and at tumor progression using flux cytometry in a subset of patients 
included in the study.
To determine the predictive value of the immune groups based on the expression of 
cytotoxic T cells and Th2 cells signature measured in the tumor sample at baseline by using 
gene expression panels from NanoString technologies.
Eligibility criteria:
Inclusion criteria:
1.
Male or female subjects aged 
18 years and capable of giving signed informed consent or 
requirement per local legislation.
2.
ECOG performance status of 0-1.
3.
Histologically confirmed malignant pleural mesothelioma (all histological subtypes are 
eligible), unresectable advanced or metastatic.
4.
Patients that progressed or be intolerant to 
regimens of chemotherapy, including 
platinum-based chemotherapy with pemetrexed. Prior bevacizumab treatment given during 
chemotherapy are allowed.
5.
Evaluable disease or measurable disease as assessed according to the modified RECIST v1.1 
criteria.
6.
Availability of tumor tissue for translational research (at least 10 slides); Archival tumor 
tissue at diagnosis can be sent if it was obtained less than 18 months ago. 
7.
Life expectancy of at least 3 months.
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8.
Adequate hematologic and organ function defined by the following laboratory results 
obtained within 14 days prior to enrollment:
Hematologic: Absolute neutrophil count (ANC) 
1.5 
109/L, platelet count 
100 × 109/L, 
and hemoglobin 
9 g/dL 
Hepatic: Total bilirubin level 
the upper limit of normal (UNL) range, AST and ALT levels 
1.5 x ULN and ALP 
2.5 x ULN. For participants with liver involvement in their tumor, AST 
5 x ULN, ALT 
5 x ULN, and bilirubin 
3.0 x ULN.
Renal: Creatinine level 
1.5 x ULN or estimated creatinine clearance 
30 mL/min 
according to the Cockcroft-Gault formula (or local institutional standard method) (may be 
modified to a higher creatinine clearance threshold, e.g. 
50 ml/min or 
60 ml/min as 
appropriate based on the target population or other drugs used in a combination regimen). 
For participants with Creatinine > 1.5 x ULN, glomerular filtration rate (GFR) can also be used.
Coagulation: normal international normalized ratio (INR), PT 
1.5 x ULN and activated 
partial thromboplastin time (aPTT) 
1.5 x ULN.
9.
For patients with HIV infection, it needs to be a stable HIV infection 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. For patients with HBV/HCV infection, it needs to be a controlled HBV/HCV infection on a 
stable dose of antiviral therapy, HBV viral load below the limit of quantification. HCV viral 
load below the limit of quantification.
11. All patients are notified of the investigational nature of this study and signed a written 
informed consent in accordance with institutional and national guidelines, including the 
Declaration of Helsinki prior to any trial-related intervention.
12. For female patients of childbearing potential, agreement (by patient and/or partner) to use 
a highly effective form(s) of contraception that results in a low failure rate (< 1% per year) 
when used consistently and correctly throughout the study and for at least 2 months after 
last bintrafusp alfa treatment administration. 
13. For male patients with female partners of childbearing potential, agreement (by patient 
and/or partner) to use a highly effective form(s) of contraception that results in a low failure 
rate [< 1% per year] when used consistently and correctly.
14. Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drugs. The same rules are valid for male 
patients involved in this clinical study if they have a partner of childbirth potential. Male 
patients must always use a condom. For male patients the duration of contraception after 
the last dose of bintrafusp alfa is 4 months.
15.
-induced amenorrhea) 
or surgically sterile must have a negative serum pregnancy test result within 8 days prior to 
initiation of study drug.
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Exclusion criteria:
1.
Prior immune checkpoint therapy with an anti-PD-1, anti-PD-L1, anti-CD137, or anti-CTLA-4 
antibody.
2.
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.
3.
Previous malignant disease (other than the target malignancy to be investigated in this 
study) within the last 3 years. Participants with a history of cervical carcinoma in situ, 
superficial or noninvasive bladder cancer, localized prostate cancer or basal cell or squamous 
cell carcinoma in situ previously treated with curative intent and endoscopically resected GI 
cancers limited to the mucosal layer without recurrence in > 1 year are NOT excluded. 
4.
Active central nervous system (CNS) metastases and/or carcinomatous meningitis that 
require therapeutic intervention or are causing clinical symptoms. Patients with previously 
treated brain metastases may participate provided they are stable and are not using steroids 
for at least 7 days prior to randomization.
5.
Prior major surgery within 4 weeks prior to the first dose of study intervention.
6.
Unstable or unresolved surgical or chemotherapy-related toxicity that would compromise 
Persisting Grade > 1 NCI CTCAE 5.0 toxicity 
(except alopecia and vitiligo) related to prior therapy; however, sensory neuropathy Grade 
2 is acceptable.
7.
Prior organ transplantation including allogenic stem-cell transplantation, except transplants 
that do not require immunosuppression.
8.
Live vaccines given 30 days prior to first dose of protocol treatment (M7824). Seasonal flu 
vaccines that do not contain a live virus are permitted. Also, COVID-19 vaccines approved by 
the authorities that do not contain live virus are permitted. 
9.
Drug-induced interstitial lung disease (ILD) or participant has had a history of drug-induced 
pneumonitis that has required oral or IV steroids, and/or other diseases, which in the opinion 
consistently participate in study procedures.
10. Active and serious autoimmune disease that might deteriorate upon treatment with 
immunotherapy. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid 
diseases not requiring immunosuppressive treatment are eligible. Replacement therapy (i.e. 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) or topical therapy (e.g., steroids) for psoriasis or eczema is not considered 
a form of systemic treatment.
11. Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, 
or antifungal therapy.
12. Known history of active tuberculosis or any active infection requiring systemic therapy. 
13. Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to enrollment, EXCEPT for the 
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following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); b. Systemic corticosteroids at physiologic doses 
10 mg/day of prednisone or 
equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication).
14. 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.
15. History of bleeding diathesis or recent major bleeding events within 12 months prior to 
enrollment (i.e. Grade 
2 bleeding events in the month prior treatment)
16. History of abdominal or tracheoesophageal fistula, active gastrointestinal ulcer or 
gastrointestinal perforation within 12 months prior to enrollment
17.
to participate in the trial.
18. Substance or alcohol abuse, medical, psychological or social conditions that may interfere with 
19.
Women who are pregnant or in the period of lactation.
Treatment:
Bintrafusp alfa (M7824): 1200mg, over 60 minutes IV infusion
The treatment will start within 1-5 days from enrollment. The treatment will be administered at day 
1 and day 14 (2 weeks ±3days) of 28 days cycle.
Treatment will be administered until unacceptable toxicity, loss of clinical benefit, disease 
progression or completion of 2 years of therapy. If the patient has benefit after 2 years, the trial chair 
and the sponsor must be consulted to evaluate how to continue with the treatment.
If pseudoprogression is suspected, patients can continue with the study therapy until loss of clinical 
benefit as judged by the principal investigator. Prior to continuing with the study therapy, the trial 
chair of the study must be informed.
Statistical considerations: 
This study is designed to show that experimental treatment will achieve a median PFS of 4.5 months 
(expected median for standard scheme is 3 months which is equivalent to consider an improvement 
of 0.66 in terms of hazard ratio), with a statistical power of 90% and a one-sided type I error of 10%. 
On these bases and considering Lachin design, 45 pts are needed (44 or more events for null 
hypothesis and 43 or less events for alternative hypothesis) over a period of 18 months with a 
minimum median follow-up of 12 months to perform an exponential test. Considering a 5 % of drop-
out patients and a hazard of 0.04 for dropouts a total sample size of 47 patients will be needed.  In 
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case of having 43 or less events during follow-up alternative hypothesis will be concluded and 
experimental treatment will be declared as promising.
The expected accrual rate is 2 patients per month for the first 6 months, increasing to 4-5 patients 
per month thereafter. Primary analysis is expected to be available 18 months after the inclusion of 
the first patient. In order to reach the proposed sample size, if a patient initially enrolled in the study 
does not fulfil the inclusion criteria, they will be replaced by a new one subject that fulfil them, this 
replacement will ensure that the sample size will be the one calculated initially. 
Total trial duration: 3.5 years (1.5 years of recruitment, approximately 2 years of treatment and 1
month for the safety follow up)
Translational research: 
Blood samples, tumor biopsy and malignant pleural effusion will be collected prior to initiating 
M7824 and when possible at tumor progression for the correlative studies. 
The main objective is to assess whether the activation of the TGF-
levels of TGF-
baseline blood and in the pleural effusion are correlated with the efficacy of 
M7824 and also to explore the predictive value of the immune group classification identified by our 
group to identify patients who benefit from immunotherapy.
Endpoints for the translational research:
-To correlate PFS and ORR with activation of TGF-
-
SMAD2/3 immunohistochemistry in tumor biopsies obtained at baseline and at tumor progression.
-To correlate efficacy PFS and ORR with TGF-
and cytokines measured by ELISA in serum 
obtained prior to initiation of immunotherapy and cytokines at tumor progression. 
- To correlate efficacy PFS and ORR with TGF-
levels along with additional cytokines in pleural 
effusion , if the patient has pleural effusion. A pleural tap will be performed to measure TGF-
and cytokines measured by ELISA at baseline and at tumor progression.
-To determine the immune cell subpopulations by flux cytometry in the pleural effusion at baseline 
and at tumor progression. These results will be correlated with TGF-
effusion by ELISA and with clinical benefit from M7824.
-To stratify patients according to the immune groups by gene-expression profiling using nanostring 
to cover cytotoxic T cells and Th2 cells signatures and a panel of immune checkpoints (PD1, PD-L1, 
PD-L2, TIM3, B7-H3) and correlate whether immune groups have distinct clinical outcome when 
treated with M7824.
- To correlate efficacy endpoints (PFS and ORR) with PD-L1 expression. This will be measured by PD-
L1 immunohistochemistry in the central laboratory.
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2.
Trial schedule
Baseline
(-28 days before 
enrollment)
Treatment 
Bintrafusp alfa 
(M7824) Cycles16
Progression 
Disease (PD)
End of 
Treatment17
Follow up18
Informed consent1
X
Medical history and 
demographic data
X
X
Reason of EOT
Physical examination:
Skin inspection
X
X
X
Height
X
First follow up
Performance status (ECOG),
X
X
X
Weight, Temperature, 
Blood pressure
Oxigen saturation
X
X
X16
X
X
X
First follow up
Hematology2, 3
X
X2,3
X
First follow up
Biochemistry2, 4
(Including renal and hepatic 
function)
X
X2,4
X
First follow up
Coagulation2, 5
X
X2,5
if clinically indicated
X
First follow up
Thyroid function2, 6
X
X2,6
Every 4 weeks
X
First follow up
HIV / Hepatitis B/C7
X
Pregnancy test8
X
X
Every 4 weeks
X8
First follow up
Urine dipstick9
X
X9
if clinically indicated
X
First follow up
12-lead ECG
X
X
First follow up
Adverse events10
(Toxicity evaluation)
X
baseline symptoms
Continuous
Continuous
X
First follow up10
Concomitant medications11
X
Continuous
Continuous
X
First follow up
Tumor assessments12
X
X
X12
FFPE tumor material13
X
X
Blood samples14
X
X
X
Pleural effusion liquid15
X
X
1 Before any trial specific evaluations or interventions. The patient has to sign the informed consent (IC) of the 
study.
2 Laboratory testing: within 14 days in baseline visit and within 3 days prior to day 1 administration of cycle 1 
(week 1). 
Informed consent1
X
Medical history and 
X
X
demographic data
Reason of EOT
Physical examination:
Skin inspection
X
X
X
Height
X
First follow up
Performance status (ECOG),
X
X
X
Weight, Temperature, 
X
X
X16
Blood pressure
X
X
X
Oxigen saturation
First follow up
X
Hematology2, 3
X
X2,3
First follow up
Biochemistry2, 4
X
X
X2,4
(Including renal and hepatic 
First follow up
function)
X2,5
X
Coagulation2, 5
X
First follow up
if clinically indicated
X2,6
X
Thyroid function2, 6
X
First follow up
Every 4 weeks
HIV / Hepatitis B/C7
X
X8
X
Pregnancy test8
X
First follow up
Every 4 weeks
X9
X
Urine dipstick9
X
First follow up
if clinically indicated
X
12-lead ECG
X
First follow 
Adverse events10
X
X
Continuous
Continuous
First follow up10
(Toxicity evaluation)
baseline symptoms
X
Concomitant medications11
X
Continuous
Continuous
First follow up
Tumor assessments12
X
X
X12
X
FFPE tumor material13
X
Blood samples14
X
X
X
Pleural effusion liquid15
X
X
Before any trial specific evaluations or interventions. The patient has to sign the informed consent (IC) of the 
study.
2 Laboratory testing: within 14 days in baseline visit and within 3 days prior to day 1 administration of cycle 1
(week 1
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Note that in the first 3 months of treatment, hematology and biochemistry must be done within 3 days 
prior to day 1  administration, and within 3 days prior to day 14 administration.
Laboratory testing timelines:
-
Hematology and Biochemistry must be done within 3 days prior to day 1 administration, and within 3 
days prior to day 14 administration (every 2 weeks) for the first 3 months (cycles 1, 2 and 3). From 
cycle 4 onwards hematology and Biochemistry must be done only within 3 days prior to day 1
administration (every 4 weeks) and at first follow up.
-
Coagulation must be done at baseline and during treatment administration if clinically indicated. Also,
it must be done at first follow up
-
Thyroid function must be done within 3 days prior to day 1 of administration, every 4 weeks and at 
first follow up
3Hematology: White Blood Cell (WBC) count, neutrophils, haemoglobin, platelet count
4Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total bilirubin, alkaline phosphatase, creatinine and 
clearance of creatinine calculated by Cockcroft-Gault formula, total protein, albumin, amylase, lipase.
5Coagulation: PT, INR and APTT 
6Thyroid function: thyroid-stimulating hormone (TSH). Total or free T3 and total or free T4 must be analyzed if 
TSH result is out of ULN or LLN.
7 HIV / Hepatitis B/C: The following baseline local laboratory assessments should be done within 28 days prior 
to first dose: Hepatitis B and C testing (HBV sAg, HBV Ab and HCV Ab) and HIV test. In patients with positive 
hepatitis B/C results, HBV DNA/HCV RNA must be performed (Hepatitis B vaccinated patients are excluded).
8 Pregnancy Tests: Only applicable in WOCBP. A serum or urine pregnancy testing is required within 3 days prior 
to study enrollment, then every 4 weeks and within 30 days of last treatment dose, at first follow up (more 
frequently if required by local standard).
9Urine test: A urine dipstick is required within 3 days prior to study enrollment. During treatment it will be done 
only if clinically indicated. Also, it must be done at first follow up.
10 Adverse events must be recorded and followed from the day of the signs the patient Informed consent for 
the study to 30 days from last dose of administration. SAEs and AESIs must be recorded and followed from the 
subject written consent to 30 days from last dose of administration.
11 Concomitant medications must be recorded and followed from 7 days prior to day 1 cycle 1 to 30 days from 
last dose of administration.
12 Tumor assessment:
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) must be done at baseline 
within 28 days before enrollment (+ 10 days). During the treatment, tumor assessments will be 
performed every 8 weeks (+/- 7 days) from day 1-week 1. CT SCAN must be performed until progression 
disease or until last dose of Bintrafusp alfa (M7824) in case of continuing beyond pseudoprogression. 
The CT SCAN schedule will be maintained even if a delay in administration occurs. 
Note that it is not mandatory to perform the tumor assessment in first follow up visit if the end of treatment 
reason is other than progression disease and a tumor assessment has been performed in the previous 8 weeks.
During follow up, tumor assessment will be maintained every 8 weeks (+/- 7 days) in case end of treatment 
reason is other than disease progression. Tumor assessments every 8 weeks must be performed until 
progression disease.
within 3 days 
prior to day 1  administration, and within 3 days prior to day 14 administration.
Laboratory testing timelines:
-
Hematology and Biochemistry must be done within 3 days prior to day 1 administration, and within 3 
days prior to day 14 administration (every 2 weeks) for the first 3 months (cycles 1, 2 and 3). From
cycle 4 onwards hematology and Biochemistry must be done only within 3 days prior to day 1
administration (every 4 weeks) and at first follow up.
-
Coagulation must be done at baseline and during treatment administration if clinically indicated. Also,
it must be done at first follow up
-
Thyroid function must be done within 3 days prior to day 1 of administration, every 4 weeks and at 
first follow up
3Hematology: White Blood Cell (WBC) count, neutrophils, haemoglobin, platelet count
4Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total bilirubin, alkaline phosphatase, creatinine and 
clearance of creatinine calculated by Cockcroft-Gault formula, total protein, albumin, amylase, lipase.
5Coagulation: PT, INR and APTT 
6Thyroid function: thyroid-stimulating hormone (TSH). Total or free T3 and total or free T4 must be analyzed if 
TSH result is out of ULN or LLN.
7 HIV / Hepatitis B/C: The following baseline local laboratory assessments should be done within 28 days prior
to first dose: Hepatitis B and C testing (HBV sAg, HBV Ab and HCV Ab) and HIV test. In patients with positive 
hepatitis B/C results, HBV DNA/HCV RNA must be performed (Hepatitis B vaccinated patients are excluded).
8 Pregnancy Tests: Only applicable in WOCBP. A serum or urine pregnancy testing is required within 3 days prior 
to study enrollment, then every 4 weeks and within 30 days of last treatment dose, at first follow up (more 
frequently if required by local standard).
9Urine test: A urine dipstick is required within 3 days prior to study enrollment. During treatment it will be done 
only if clinically indicated. Also, it must be done at first follow up.
10 Adverse events must be recorded and followed from the day of the signs the patient Informed consent for 
the study to 30 days from last dose of administration. SAEs and AESIs must be recorded and followed from the 
subject written consent to 30 days from last dose of administration.
11 Concomitant medications must be recorded and followed from 7 days prior to day 1 cycle 1 to 30 days from 
last dose of administration.
12 Tumor assessment:
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) must be done at baseline 
within 28 days before enrollment (+ 10 days). During the treatment, tumor assessments will be 
performed every 8 weeks (+/- 7 days) from day 1-week 1. CT SCAN must be performed until progression 
disease or until last dose of Bintrafusp alfa (M7824) in case of continuing beyond pseudoprogression. 
The CT SCAN schedule will be maintained even if a delay in administration occurs. 
Note that it is not mandatory to perform the tumor assessment in first follow up visit if the end of treatment 
reason is other than progression disease and a tumor assessment has been performed in the previous 8 weeks.
During follow up, tumor assessment will be maintained every 8 weeks (+/- 7 days) in case end of treatment
reason is other than disease progression. Tumor assessments every 8 weeks must be performed until
progression disease.
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The other follow ups CT-SCANs after progression will be done as per local standard.
13 Tumor sample (or at least 10 slides) is mandatory at baseline (it might be the archival tissue biopsy obtained 
when diagnosed with mesothelioma) and a rebiopsy at progression disease is strongly recommended.
14Blood samples for correlative studies will be drawn at:
- Baseline or before day 1-week 1 of treatment
- First tumor assessment 
- At disease progression
15Pleural Liquid at baseline and at progression disease are strongly recommended.
16 Cycles will be administered every 2 weeks (±3 days). Day 1 of week 1 treatment will start within 1-5 days 
from enrollment. If pseudoprogression is shown it is allowed to continue with study treatment until 
progression disease will be confirmed. A confirmation from the trial chair/sponsor has to be granted to 
continue treatment.
Blood pressure must be taken always before the drug administration. Blood pressure should be routinely 
measured before every infusion after a resting period of 10 min. If baseline record is performed more than 3 
days before first study dose, they must be repeated on day 1 week 1.
17 End of treatment is defined as the day of discontinuation of the treatment.
18 A safety follow up visit must be done within 30 days (±3 days) after the last dose the treatment or 
immediately before the initiation of any other anticancer therapy. See section 8.1.5 for more details about 
safety follow up visit procedures.
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3.
Background and rationale
3.1.
Disease background
Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy arising from the mesothelial 
surface of the pleura. In Europe, the incidence is about 20 per million and is almost always caused by 
asbestos exposure, with a usual lag time of 30 years between exposure and presentation.1 Histologic 
subtypes of MPM include epithelioid (about 60%), and non-epithelioid (around 40%) including sarcomatoid, 
biphasic and others. Disease is considered resectable in only 10-15% of MPM patients.2 The prognosis in 
unresectable cases remains very poor, with median overall survival (OS) of 9 to 12 months.1,3 The disease 
is invariably fatal, due to anatomical limitations preventing the achievement of a complete microscopic 
surgical resection and tumor relative chemo-refractoriness.4
Cytotoxic chemotherapy remains one of the few therapeutic options that has been proven to improve 
survival in advanced MPM in a randomized controlled trial.5 The combination of cisplatin and pemetrexed 
has become standard first-line therapy worldwide for patients who are not suitable for aggressive surgery 
or in whom chemotherapy is recommended as part of a multimodality regimen.4 Cisplatin/pemetrexed is 
associated with a response rate of 30-40% and confers an OS advantage of 3 months over cisplatin alone, 
and is the only licensed systemic therapy for mesothelioma.3 Carboplatin is often substituted for cisplatin, 
due to simpler and shorter administration and assumption of a more favorable toxicity profile based on 
experience in other diseases. Although carboplatin use is not supported by randomized evidence, and there 
has been no direct comparison between the two platinum agents, phase I and II studies have demonstrated 
similar activity of either carboplatin or cisplatin with pemetrexed, with objective radiological response rates 
between 20% and 30%.6,7 Maintenance with pemetrexed is not considered standard of care. The addition 
of bevacizumab to chemotherapy modestly improved overall survival, but this treatment is not available in 
all countries.8
Dual immune checkpoint inhibition of PD1 and CTLA-4 with nivolumab plus ipilimumab has recently 
demonstrated superiority to platinum plus pemetrexed in the first line setting in the CheckMate-743 study.9 
Dual immune ckeckpoint blockade showed larger OS benefit in patients with non-epithelioid tumors and 
those with positive PD-L1 expression.
However, no treatment has yet been shown to improve OS in patients who progressed to prior platinum-
based chemotherapy, resulting in a high unmet need for effective therapies in previously treated patients 
with MPM. Single agent immunotherapy has demonstrated limited efficacy in the relapsed setting in the 
PROMISE-meso trial, which compared pembrolizumab with gemcitabine or vinorelbine. 10
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3.2.
Role of TGF- in the tumor microenvironment 
The TGF- cytokine is overexpressed in various cancer types with correlation to tumor stage.11,12 Many types 
of cells in the tumor microenvironment produce TGF- , including the tumor cells themselves, immature 
myeloid cells, Treg cells, and stromal fibroblasts; these cells collectively generate a large reservoir of TGF-
in the extracellular matrix including apoptotic neutrophils, myeloid-derived suppressor cells (MDSCs), T cells, 
and tumor cells. 13,14
The tumorigenic effect of TGF-
relies on its effect on the tumor cell and the tumor microenvironment. It 
has been shown that TGF-
supports the self-renewal and prevents differentiation of CD44 high/Id1
high cancer-initiating cells that promote tumor initiation, relapse, and resistance to standard treatments.
Moreover, TGF- can induce cancer-associated fibroblasts and cooperate with vascular endothelial growth 
factor, hypoxia-inducible factor, platelet-derived growth factor, and other growth factors to modulate 
angiogenesis. 15 TGF-
signaling contributes to tumor progression by promoting metastasis, stimulating 
angiogenesis, and suppressing innate and adaptive antitumor immunity.11
Indeed, TGF- is one of the most potent immune suppressive cytokines and negatively regulates both innate 
and adaptive immune responses. As a broadly immunosuppressive factor, TGF- directly downregulates the 
effector function of activated cytotoxic T cells and NK cells and potently induces the differentiation of naïve 
CD4+ T cells to the immunosuppressive Treg phenotype. 12 In addition, TGF-
polarizes macrophages and 
neutrophils to a wound-healing phenotype that is associated with production of immunosuppressive 
cytokines. 16
As a therapeutic strategy, neutralization of TGF-
activity has the potential to control tumor growth by 
restoring effective antitumor immunity, blocking metastasis, and inhibiting angiogenesis. Inhibition of TGF-
by soluble TGF- RII reduced malignant mesothelioma in a manner that was associated with increases in 
CD8+ T cell antitumor effects. 17 The absence of TGF- 1 produced by activated CD4+ T cells and regulatory T 
(Treg) cells has been shown to inhibit tumor growth and protect mice from spontaneous cancer. 18 Thus, 
TGF- appears to be important for tumor immune evasion. Furthermore, because the upregulation of TGF-
signaling-associated genes has been linked to anti-PD-1 resistance in metastatic melanoma,19 blockade of 
TGF- signaling may target mechanisms of resistance and sensitize tumor to anti-PD-1/PD-L1 therapies.
3.3.
Blocking TGF- signaling pathway:  Bintrafusp alfa (M7824)
Bintrafusp alfa (M7824, MSB0011359C) is a first-in-class, bifunctional fusion protein composed of the 
TGF- RII or TGF-
covalently linked via a flexible linker to the C-terminus of each heavy chain of an immunoglobulin G1 (IgG1) 
antibody blocking programmed death ligand 1 (anti-PD-L1). 
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Bintrafusp alfa is designed to simultaneously target 2 pathways that have independent and complementary 
immunosuppressive functions in the tumor microenvironment. PD-L1 signaling plays a key role in the 
immunosuppressive network that dampens T cell activity and TGF- functions as an autocrine or paracrine 
signal within the local tumor microenvironment, where it promotes tumor progression. Preclinical studies 
showed that dual blockade of TGF-
and PD-L1 triggers a strong immune response through the combined 
inhibition of TGF- -mediated epithelial-to-mesenchymal transition, stimulation of the cytotoxic activity of 
natural killer cells and CD8+ lymphocytes, and the suppression of Tregs.
Bintrafusp alfa was shown to have full biological activity in vitro including the ability to block PD-L1 and 
neutralize TGF-
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), immune-oncology therapies (anti-cytotoxic T-
lymphocyte-associated protein 4 [CTLA-4]), of radiation therapy, and in combination with chemotherapy 
such as 5-fluorouracil and oxaliplatin (FOLFOX), gemcitabine, cisplatin, and doxorubicin. Bintrafusp alfa also 
potentiated the abscopal effect of radiation therapy. These findings suggest that bintrafusp alfa can be 
combined with standard of care therapies to improve antitumor responses. For all repeat-dose 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), biliary tract cancer (BTC), cervical cancer, and triple-negative 
breast cancer (TNBC).
A total of 689 participants participated in two phase I clinical trials (EMR200647-001 and MS200647-0008, 
as of 24 August 2018). Maximum tolerated dose (MTD) was not reached in either of the two studies at doses 
tested up to 30 mg/kg every 2 weeks (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, bintrafusp alfa at 30 mg/kg is 
considered tolerable. The emerging safety profile of bintrafusp alfa (from EMR200647-001, MS200647-0008, 
MS200647-0005, MS200647-0024, MS200647-0037, MS200647-0047, and MS200647-0055) across tumor 
types investigated is manageable and consistent with other therapies targeting either PD-L1 or TGF-
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 TGF- 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 TGF- inhibition 
are considered to be important identified risks with bintrafusp alfa. Anemia, alterations in wound healing or 
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repair of tissue damage and embryofetal toxicity remained important potential risks. In addition, mucosal 
bleeding events are a potential risk for bintrafusp alfa. 
Durable clinical activity of bintrafusp alfa was observed in a number of tumor types in the 2 Phase I studies 
(EMR200647-001 and MS200647-0008), specifically: 
In the 2L NSCLC cohort, durable clinical activity of bintrafusp alfa (1200 mg q2w) was observed in 40 
participants regardless of PD-L1 expression status (overall response rate [ORR] by the Independent Endpoint 
Review Committee [IRC] according to RECIST v1.1; 25.0%), with a higher ORR of 37.0% in the PD-L1 positive 
group, and 85.7% in the PD-L1 high subgroup. After close to 2 years of follow-up, bintrafusp alfa continues 
to show manageable safety with encouraging long-term survival (17.1 months), especially in participants 
with positive to high PD-L1 expression (21.7 months for PD-L1 positive, not estimable for the PD-L1 high 
subgroup) with 24-month overall survival (OS) rate at 39.7% (data cutoff 15 October 2019).
In the biliary tract cancer 2L cohort (N = 30), durable responses were observed; the ORR as adjudicated by 
the IRC according to RECIST 1.1 was 20%. The median duration of response was 9.7 months as assessed by 
the Investigator. Clinical activity was observed regardless of PD-L1 expression level and was also 
independent of microsatellite instability-high (MSI-H) status; after close to 2 years of follow-up, bintrafusp 
alfa continues to show manageable safety with encouraging long-term survival (12.7 months), with 24-
month OS rate of 27.7% (data cutoff 24 October 2019). 
In participants with heavily pretreated cervical cancer (N = 25), durable responses were observed. The 
confirmed ORR as assessed by Investigator according to RECIST 1.1 was 24.0%, with duration of response 
ranging from 4.2 to 30.4 months. The median OS was 11.6 months, and the 18-month OS rate was 40%.
In a pooled analysis of participants with heavily pretreated human papillomavirus (HPV)-associated cancers 
including anal, cervical and squamous cell carcinoma of the head and neck (SCCHN; N = 43), the confirmed 
ORR as assessed by Investigator according to RECIST 1.1 was 27.9%. Duration of response ranged from 2 to 
25 months, with ongoing responses at data cutoff (09 January 2019). The median OS was 16.2 months and 
12- and 24-month OS rates were 56.2% and 46.9%, respectively. 
In the TNBC second-line or greater cohort (N = 30), the ORR as assessed by Investigator according to RECIST 
1.1 was 12.1%, the median duration of response was 5.4 months (ranging from 4.7 to 5.5 months) for 
participants with confirmed responses. Median OS was 7.8 months with 12-month OS rate of 33.3%. During 
integrated biomarker analyses of the TNBC cohort, high expression of high-mobility group AT-hook 2 
(HMGA2) was identified as a potential predictive biomarker of clinical response for patients treated with 
bintrafusp alfa. In tumor samples from participants who experienced disease control, HMGA2 expression 
was 32-fold higher than in samples from participants who had progressive disease; the ORR for HMGA2-high 
tumors was 50.0%.
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3.4.
Rationale for trial design
During the last decade, limited advances have been done since the pemetrexed approval in combination 
with cisplatin back in 200420. Not surprisingly, life expectancy of MPM remains suboptimal with a median 
overall survival (OS) of 10-13 months and with 5-year OS of approximately of 5%.21
Immune checkpoint inhibitors in MPM demonstrated modest efficacy, partly due to the lack of predictive 
biomarkers of clinical benefit from immunotherapy and to the immunosuppressive tumor 
microenvironment and low mutational burden. In MPM, TGF-
ng pathway is frequently deregulated 
leading to an epithelial-to-mesenchymal transition (EMT) phenotype that confers more aggressive biological 
behavior and shorter OS22-23. TGF-
-independent cell growth of 
human non transformed mesothelial cells (MeT-5A), while TGFR1 inhibitors can block this effect24. 
Accordingly, asbestos promotes TGF-
-5A)25.
By using publicly available gene-expression data from two large studies in MPM22,26, we observed that TGF-
-
prognosis (Figure 1). These results suggest that deregulation of TGF-
in mesothelioma and confers an aggressive phenotype.
We characterized the immune contexture of MPM using gene-expression data from a large cohort of MPM 
(N=516) to improve patient stratification and enhance a better definition of therapeutic strategies in MPM27-
28. We found that tumors with upregulation of cytotoxic T cells and low T-helper 2 signatures were associated 
with better clinical outcome (Figure 2A). By combining groups derived from those two signatures, we 
identified three distinct immune groups based on the relative abundance of T-helper 2 and cytotoxic T cells 
Figure 1. Kaplan-Meier plots of overall survival according to the expression of TGF-
-
signaling pathway activation score using publicly available transcriptomic data on MPM.
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(Figure 2B). Immune-group 3 (Low TH2
High TC) was enriched for the expression of members of the TNF 
receptor superfamily and checkpoint inhibitors (PD1, TIGIT, LAG3) and are more likely to respond to anti-
PD1 therapy (Figure 2C & 2D).
Figure 2. A) Kaplan-Meier plots of overall survival according to the expression of T-helper 2 and cytotoxic 
cells. B) Heatmap showing differential expression of immune cell signatures classified based on the relative 
abundance of T-helper 2 and cytotoxic T cells. C) Volcano plot showing immune checkpoint (ICP) enrichment 
in immune group 3. D) Gene signatures predicting benefit from ICP inhibitors are upregulated in immune 
group 3. 
Prior clinical trials with immune checkpoint inhibitors with anti-PD1 and anti-PD-L1 in previously treated 
MPM showed modest efficacy probably due to the predominantly immune suppressive tumor 
microenvironment, the generally low tumor mutational burden as well as the high aneuploidy which is 
characteristic of this tumor. In the PROMISE-Meso study, pembrolizumab was not superior to single 
chemotherapy in the second line setting in a non-selected population of MPM29. 
We hypothesize that dual targeting of PD-L1 and TGF-
Bintrafusp alfa (M7824) may reduce tumor 
aggressiveness in MPM, can reverse the suppressive tumor microenvironment and extend progression-free 
survival (PFS). We propose a single-arm phase II clinical trial to assess the efficacy and the safety of M7824 
in a cohort of patients with previously treated advanced MPM. We also hypothesize that selection of 
patients based on the TGF-
of patients based 
on immune groups will be helpful to identify MPM patients who are more likely to benefit from 
immunotherapy.
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4.
Objectives and endpoints
4.1.
Primary objective and endpoint
To determine the efficacy of M7824 in terms of the Progression Free Survival (PFS) assessed by the 
investigator according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) 
Version 1.1. 
PFS is defined as the time from administration of first dose of bintrafusp alfa until objective tumor 
progression or death.
4.2.
Secondary objectives and endpoints
To determine the ORR of the treatment as measured by investigator-assessed overall response rate 
(ORR) with M7824 according to modified RECIST v1.1.
To determine the PFS assessed by an independent review committee by revised modified RECIST 
criteria v1.1.
To evaluate secondary measures of clinical efficacy including duration of response, disease control 
rate and the Overall survival (OS).
To evaluate the safety and tolerability of the treatment assessed by adverse events graded according 
CTCAE v5.0.
4.3.
Exploratory objectives
To correlate efficacy endpoints (PFS and ORR) with PD-L1 expression. This will be measured by PD-
L1 immunohistochemistry in the central laboratory.
To correlate efficacy endpoints (PFS and ORR) with activation of TGF-
obtained at baseline and at tumor progression. This will be measured by SMAD2/3 and phosphor-
SMAD2/3 immunohistochemistry in tumor biopsies obtained at baseline and at tumor progression.
To correlate efficacy endpoints (PFS and ORR) with TGF-
along with additional cytokines 
measured in serum obtained prior to initiation of immunotherapy and cytokines at tumor 
progression.
To correlate efficacy endpoints (PFS and ORR) with TGF-
along with additional cytokines in 
pleural effusion obtained prior to initiation of immunotherapy and at tumor progression. To 
determine the immune cell subpopulations harvested in the pleural effusion at baseline and at 
tumor progression using flux cytometry in a subset of patients included in the study.
To determine the predictive value of the immune groups based on the expression of cytotoxic T cells 
and Th2 cells signature measured in the tumor sample at baseline by using gene expression panels 
from NanoString technologies.
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5.
Trial design, duration and termination
This is an open-label, non-randomized, phase II, single arm, multi-center clinical trial.
Patients enrolled in the study will receive treatment with M7824 that will be administered at day 1 and day 
14 o (2 weeks ±3 days) of 28 days cycle. Cycles will be administered until unacceptable toxicity, loss of clinical 
benefit, disease progression or completion of 2 years of therapy. If the patient has benefit after 2 years, the 
trial chair and the sponsor must be consulted to evaluate how to continue with the treatment.
Patient accrual is expected to be completed within 1.5 years excluding a run-in-period of 4-6 months. 
Treatment and follow-up are expected to extend the study duration to a total of 3.5 years. Patients will carry 
out a safety follow-up 1 month after the end of treatment independently of the cause of end of treatment.
The study will end once safety follow-up has concluded.
The trial will end with the preparation of the final report, scheduled for 4.5 years after the inclusion of the 
first patient approximately.
Study schema:
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6.
Patient selection
Written Informed Consent (IC) must be signed and dated by the patient and the investigator prior to any 
trial-related intervention for trial treatment and/or biomaterial submission to the central laboratory.
Patients should only be selected and consented for enrollment if they fulfil the following criteria:
6.1.
Inclusion criteria  
1.
Male or female subjects aged 
18 years and capable of giving signed informed consent or 
requirement per local legislation.
2.
ECOG performance status of 0-1.
3.
Histologically confirmed malignant pleural mesothelioma (all histological subtypes are eligible), 
unresectable advanced or metastatic.
4.
Patients that progressed or be intolerant to 
regimens of chemotherapy, including platinum-
based chemotherapy with pemetrexed. Prior bevacizumab treatment given during chemotherapy 
are allowed.
5.
Evaluable disease or measurable disease as assessed according to the modified RECIST v1.1 criteria.
6.
Availability of tumor tissue for translational research (at least 10 slides); Archival tumor tissue at 
diagnosis can be sent if it was obtained less than 18 months ago.
7.
Life expectancy of at least 3 months.
8.
Adequate hematologic and organ function defined by the following laboratory results obtained 
within 14 days prior to enrollment:
Hematologic: Absolute neutrophil count (ANC) 
1.5 
109/L, platelet count 
100 × 109/L, and 
hemoglobin 
9 g/dL 
Hepatic: Total bilirubin level 
the upper limit of normal (UNL) range, AST and ALT levels 
1.5 x 
ULN and ALP 
2.5 x ULN. For participants with liver involvement in their tumor, AST 
5 x ULN, 
ALT 
5 x ULN, and bilirubin 
3.0 x ULN.
Renal: Creatinine level 
1.5 x ULN or estimated creatinine clearance 
30 mL/min according to 
the Cockcroft-Gault formula (or local institutional standard method) (may be modified to a higher 
creatinine clearance threshold, e.g. 
50 ml/min or 
60 ml/min as appropriate based on the target 
population or other drugs used in a combination regimen). For participants with Creatinine > 1.5 x 
ULN, glomerular filtration rate (GFR) can also be used.
Coagulation: normal international normalized ratio (INR), PT 
1.5 x ULN and activated partial 
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thromboplastin time (aPTT) 
1.5 x ULN.
9.
For patients with HIV infection, it needs to be a  stable HIV infection 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. For patients with HBV/HCV infection, it needs to be a  controlled HBV/HCV infection on a stable dose 
of antiviral therapy, HBV viral load below the limit of quantification. HCV viral load below the limit 
of quantification.
11. All patients are notified of the investigational nature of this study and signed a written informed 
consent in accordance with institutional and national guidelines, including the Declaration of 
Helsinki prior to any trial-related intervention.
12. For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly 
effective form(s) of contraception that results in a low failure rate (< 1% per year) when used 
consistently and correctly throughout the study and for at least 2 months after last bintrafusp alfa 
treatment administration . 
13. For male patients with female partners of childbearing potential, agreement (by patient and/or 
partner) to use a highly effective form(s) of contraception that results in a low failure rate [< 1% per 
year] when used consistently and correctly.
14. Oral contraception should always be combined with an additional contraceptive method because of 
a potential interaction with the study drugs. The same rules are valid for male patients involved in 
this clinical study if they have a partner of childbirth potential. Male patients must always use a 
condom. For male patients the duration of contraception after the last dose of bintrafusp alfa is 4 
months.
15.
-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 8 days prior to initiation 
of study drug.
6.2.
Exclusion criteria
1.
Prior immune checkpoint therapy with an anti-PD-1, anti-PD-L1, anti-CD137, or anti-CTLA-4 
antibody.
2.
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.
3.
Previous malignant disease (other than the target malignancy to be investigated in this study) within 
the last 3 years. Participants with a history of cervical carcinoma in situ, superficial or noninvasive 
bladder cancer, localized prostate cancer or basal cell or squamous cell carcinoma in situ previously 
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treated with curative intent and endoscopically resected GI cancers limited to the mucosal layer 
without recurrence in > 1 year are NOT excluded. 
4.
Active central nervous system (CNS) metastases and/or carcinomatous meningitis that require 
therapeutic intervention or are causing clinical symptoms. Patients with previously treated brain 
metastases may participate provided they are stable and are not using steroids for at least 7 days 
prior to randomization.
5.
Prior major surgery within 4 weeks prior to the first dose of study intervention.
6.
Unstable or unresolved surgical or chemotherapy-related toxicity that would compromise the 
. Persisting Grade > 1 NCI CTCAE 5.0 toxicity (except 
alopecia and vitiligo) related to prior therapy; however, sensory neuropathy Grade 
2 is 
acceptable.
7.
Prior organ transplantation including allogenic stem-cell transplantation, except transplants that do 
not require immunosuppression.
8.
Live vaccines given 30 days prior to first dose of protocol treatment (M7824). Seasonal flu vaccines 
that do not contain a live virus are permitted. Also, COVID-19 vaccines approved by the authorities 
that do not contain live virus are permitted.
9.
Drug-induced interstitial lung disease (ILD) or participant has had a history of drug-induced 
pneumonitis that has required oral or IV steroids, and/or other diseases, which in the opinion of the 
Investigator might impair the 
participate in study procedures.
10. Active
and serious
autoimmune disease that might deteriorate upon treatment with 
immunotherapy. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases 
not requiring immunosuppressive treatment are eligible. Replacement therapy (i.e. thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) 
or topical therapy (e.g., steroids) for psoriasis or eczema is not considered a form of systemic 
treatment.
11. Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or 
antifungal therapy.
12. Known history of active tuberculosis or any active infection requiring systemic therapy. 
13. Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any other form 
of immunosuppressive therapy within 7 days prior to enrollment, EXCEPT for the following: a. 
intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. 
Systemic corticosteroids at physiologic doses 
10 mg/day of prednisone or equivalent; c. Steroids 
as premedication for hypersensitivity reactions (e.g., CT scan premedication).
14. 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.
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15. History of bleeding diathesis or recent major bleeding events within 12 months prior to enrollment 
(i.e. Grade 
2 bleeding events in the month prior treatment)
16. History of abdominal or tracheoesophageal fistula, active gastrointestinal ulcer or gastrointestinal 
perforation within 12 months prior to enrollment
17.
participate in the trial.
18. Substance or alcohol abuse, medical, psychological or social conditions that may interfere with the 
.
19. Women who are pregnant or in the period of lactation.
7.
Patient enrollment
The patients will be eligible for the study after 
criterion. This trial will use a web-based enrollment system (eCRF-Electronic Case Report Form). Each 
participating centre will access the system directly to enroll the patients. 
Patient eligibility needs to be checked before enrollment of the patient in the Fundación GECP web-based 
system (eCRF). The dates of the patient signature of the Informed Consent of the study and the specific 
informed consent to tumor tissue and blood samples are required to be filled in the eligibility checklist of 
the eCRF.
The treatment should start preferably the date of enrollment or within 1-5 days from the date of enrollment.
8.
Trial procedures
8.1.
Overview of treatment sequence
8.1.1.
Baseline visit: 
The following procedures must be performed 28 days before enrollment:
1.
Sign the informed consent form
2.
Demographic data including age and gender and medical relevant history, including 
comorbidities and allergies, surgeries, cancer history (including prior cancer therapies 
and procedures), reproductive status and smoking history.
3.
To register whether patients experienced weight loss 5% in the previous 3 months or 
since mesothelioma diagnosis.
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4.
Complete physical examination including skin inspection and collection of: Height, 
weight, ECOG performance status, Temperature and blood pressure and oxygen 
saturation.
5.
Laboratory testing must be performed within 14 days before the enrollment and 
includes:
Hematology and
coagulation: White blood cells (WBC)
count,
neutrophils, haemoglobin, platelet count, PT, INR and APTT.
Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total bilirubin, 
alkaline phosphatase, creatinine and clearance of creatinine calculated
by Cockcroft-Gault formula, total protein, albumin, amylase, lipase.
Thyroid function: thyroid-stimulating hormone (TSH). Total or free T3
and total or free T4 must be analyzed if TSH result is out of ULN or LLN.
HIV / Hepatitis B/C test: The following local laboratory assessments 
should be done within 28 days prior to first dose: Hepatitis B and C 
testing (HBVsAg, HBV Ab and HCV Ab) and HIV test. In patients with 
positive hepatitis B/C results, HBV DNA/HCV RNA must be performed
(Hepatitis B vaccinated patients are excluded).
Pregnancy Tests: A serum or urine pregnancy testing is required within 
8 days prior to study enrollment.
Urine test: A urine testing (dipstick is allowed) is required within 3 days
prior to study enrollment.
6.
Electrocardiograms: A 12-lead ECG is required at screening and as clinically indicated. 
ECGs should be obtained on the same machine whenever possible. Lead placement 
should be as consistent as possible. ECG recordings should be performed after the 
patient has been resting in a supine position for at least 10 minutes. For safety 
monitoring purposes, the investigator must review, sign, and date all ECG tracings. Paper 
copies of ECG tracings will be kept as part of the patient's permanent study file at the 
site. Any morphologic waveform changes or other ECG abnormalities must be 
documented on the eCRF.
7.
Baseline symptoms within
will be recorded.
8.
Medications (e.g. prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) from 7 days prior to initiation of study 
treatment (day 1 cycle 1) will be recorded.
9.
Tumor assessment must be done within 28 days before enrollment (+ 10 days):
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Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) to 
determine measurable disease according to modified RECIST v1.1.
10. Correlative studies (exploratory analysis): 
- Blood samples will be drawn before day 1 of week 1 of treatment
- Pleural effusion liquid (when feasible) before day 1 of weeks 1 of treatment
8.1.2.
Patient registration and enrolment 
After baseline visit, the enrollment of the patient will be done in the Fundación GECP web-based system 
(eCRF). The dates of the patient signature of the Informed Consent of the study and the specific informed 
consent to tumor tissue and blood samples are required to be filled in the eligibility checklist of the eCRF.
8.1.3.
Bintrafusp alfa (M7824) treatment
Day 1 of week 1 of treatment will start within 1-5 days from enrollment. Treatment will be administered 
every 2 weeks (±3 days) until progression or other reason to discontinue. If a pseudoprogression is suspected 
patient is allowed to continue treatment until loss of clinical benefit as judged by principal investigator and 
after the permission from the trial chair is granted.
On Day 1 and Day 14 of each cycle (QW2), all eligible patients will receive:
Bintrafusp alfa (M7824): 1200mg, IV infusion over 60 minutes
Current experience revealed that IRRs to bintrafusp alfa occur seldomly and are generally mild to moderate 
in severity. Therefore, administration of a premedication is generally not required. If an Investigator deems 
necessary to administer a premedication to a particular participant, an antihistamine (e.g. 25 to 50 mg 
diphenhydramine) and paracetamol (acetaminophen, 500 to 650 mg intravenously or equivalent oral dose) 
is recommended. Premedication should be administered for subsequent bintrafusp alfa doses based upon 
clinical judgment and presence/severity of prior infusion reactions. This regimen may be modified based on 
local treatment standards and guidelines as appropriate provided it does not include systemic 
corticosteroids.
Management of symptoms should follow the guidelines shown in section 11.2.
The following procedures must be performed on day 1 of every 2/4 weeks (±3 days):
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1.
Every 2 weeks: Physical examination, including skin inspection and collection of: weight, 
ECOG, Temperature, blood pressure and oxygen saturation. 
2.
Every 2 weeks: Blood pressure must be taken always before the drug administration. 
Blood pressure should be routinely measured before every infusion after a resting 
period of 10 min. If baseline record is performed more than 3 days before first study 
dose, they must be repeated on day 1 week 1.
3.
Laboratory testing prior to each dose administration within 3 days prior to day 1 
administration of each 4 weeks (note that for the first 3 months of treatment, 
haematology and biochemistry must be done every 2 weeks). If baseline testing is 
performed more than 3 days before first study dose, they must be repeated on day 1 
week 1:
Hematology and coagulation: WBC count, neutrophils, haemoglobin, 
platelet count, PT, INR and APTT.
Note that coagulation must be done only if clinically indicated.
Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total bilirubin, 
alkaline phosphatase, creatinine and clearance of creatinine calculated 
by Cockcroft-Gault formula, total protein, albumin, amylase, lipase.
Thyroid function: thyroid-stimulating hormone (TSH). Total or free T3 
and total or free T4 must be analyzed if TSH result is out of ULN or LLN.
Pregnancy Tests: A serum or urine pregnancy testing is required every 4 
weeks during treatment.
Urine test: A urine testing (dipstick is allowed) must be done during 
treatment only if clinically indicated.
4.
Adverse events: Changes from baseline symptoms (new or worsened clinically 
significant ones) should be recorded as adverse events on the Adverse Event form of the 
eCRF. For laboratory parameters, only grade 2 events will be reported as an AE. All the 
other events not related to laboratory values will be reported from grade 1.
5.
Concomitant medications: Changes from baseline should be recorded on the eCRF.
6.
Tumor assessment will be done every 8 weeks (± 7 days) from cycle 1 week 1. CT SCAN 
must be performed until progression disease or until last dose of bintrafusp alfa in case 
of continuing beyond pseudoprogression. The CT SCAN schedule will be maintained 
even if a delay in administration occurs.
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) to 
determine measurable disease according to mRECIST v1.1. 
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7.
Correlative studies (exploratory analysis): 
- Blood samples will be drawn at first tumor assessment
8.1.4.
Progression Disease
When the progression disease will be confirmed by mRECIST criteria and/or by principal investigator 
judgement these samples are strongly recommended to be collected:
-
Tumor tissue from a rebiopsy, if clinically feasible and patient accepts this procedure
-
Blood samples
-
Pleural effusion liquid (when feasible)
8.1.5.
End of treatment and first follow up visit
End of treatment is defined as the day of discontinuation of the treatment. The reason for end of treatment 
should be registered in the medical chart.
A safety follow-up visit must be done within 30 days (±3 days) after the last dose of treatment or immediately 
before the initiation of any other anticancer therapy. If the reason for the end of treatment is progression
the following procedures can be performed during the end of treatment visit and should be always 
conducted between the end of treatment and the initiation of the next treatment. The following procedures 
must be performed in the safety follow-up visit (or at the end of treatment when the cause is tumor 
progression):
1.
Physical examination, including skin inspection and collection of weight, ECOG, 
temperature, blood pressure and oxygen saturation. 
2.
Laboratory testing:
Hematology and coagulation: WBC count, neutrophils, hemoglobin, platelet count, 
PT, INR and APTT.
Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total bilirubin, alkaline 
phosphatase, creatinine and clearance of creatinine calculated by Cockcroft-Gault 
formula, total protein, albumin, amylase, lipase.
Thyroid function: thyroid-stimulating hormone (TSH). Total or free T3 and total or 
free T4 must be analyzed if TSH result is out of ULN or LLN. 
Pregnancy Tests: A serum or urine pregnancy testing is required.
Urine test: A urine testing (dipstick is allowed) is required for proteinuria.
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3.
Electrocardiograms: A 12-lead ECG is required at screening and as clinically indicated. 
ECGs should be obtained on the same machine whenever possible. Lead placement 
should be as consistent as possible. ECG recordings should be performed after the patient 
has been resting in a supine position for at least 10 minutes. For safety monitoring 
purposes, the investigator must review, sign, and date all ECG tracings. Paper copies of 
ECG tracings will be kept as part of the patient's permanent study file at the site. Any 
morphologic waveform changes or other ECG abnormalities must be documented on the 
eCRF.
4.
Adverse events: Changes from baseline abnormalities (new or worsened clinically 
significant ones) should be recorded as adverse events on the Adverse Event eCRF until 
this visit. For laboratory parameters, only grade 2 events will be reported as an AE. All 
the other events not related to laboratory values will be reported from grade 1. SAEs and 
AESIs must be recorded and followed from the subject written informed consent
signature to 30 days from last dose of treatment.
5. Concomitant medications: Changes from baseline should be recorded on the eCRF until 
this visit (30 days from last dose of treatment).
6. Tumor assessment: if the end of treatment reason is other than disease progression the 
CT SCAN schedule will be performed every 8 weeks:
a.
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) to 
determine measurable disease according to mRECIST v1.1. 
It is not mandatory to perform the tumor assessment in first follow up visit if the end of 
treatment reason is other than progression disease and a tumor assessment has been
performed in the previous 8 weeks.
After the safety follow up visit, all the patients will be followed by a telephone call every 3 months until the
end of study participation or last patient last visit.
End of study participation of the patients included in the study will be the date of the last study assessment.
9.
Investigational Medicinal Product
Bintrafusp alfa (M7824) is the Investigational Medicinal Products (IMP) used in this trial. Merck will provide 
the IMPs at no cost for this trial.
Complete details of the trial drug logistics, distribution, packaging, labelling, storage and handling as well as 
accountability are described in the BIMES drug supply manual that will be provided in the Pharmacy site file 
to all the participant sites.
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Description of the Investigational Medicinal Products
Bintrafusp alfa (M7824) is a bifunctional fusion protein composed of the extracellular domain of the 
-
-
antibody blocking programmed death-ligand 1 (PD-L1).
9.1.
Packaging and labelling
Merck will provide the IMP Bintrafusp alfa (M7824) at no cost for this study. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements. 
The Bintrafusp alfa (M7824) drug product is provided as a sterile concentrate solution for infusion 10m/ml 
in single-use glass vials.  The vial is designed to allow an extractable volume of 60 mL (600 mg/60 mL). For 
further details on the formulation and handling of Bintrafusp alfa (M7824), see the BIMES drug supply 
manual
of the IMP.
9.2.
Receipt and storage of the IMP
Accurate records of the IMP received at, dispensed from, returned to, and disposed of by the study site 
should be recorded on the Drug Accountability Log. In the event that the IMPs are destroyed a certification 
of destruction form should be generated and retained in the Pharmacy Site File.
The IMPs must be stored in a secure area according to local regulations. The investigator must ensure that 
the IMPs are stored refrigerated at 2-8 C, protected from light and freezing, see the BIMES drug supply 
manual for details.
9.3.
Unused trial drug supplies
If the IMPs are
made for disposal and that procedures for proper disposal have been established according to applicable 
regulations, guidelines, and institutional procedures. Appropriate records of the disposal must be 
maintained. Provide a certificate of destruction to Fundación GECP upon disposal. See the BIMES drug 
supply manual for details.
10.
Trial treatments description
10.1.
BINTRAFUSP alfa (M7824)
Patients will receive 1200 mg of M7824 administered once every 14 days (+/- 3 days) over 60 minutes (+/-
10-20 minutes) intravenous infusion in a monitored setting where there is immediate access to trained 
personnel and adequate equipment/medicine to manage potentially serious reactions.
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Refer to BIMES drug supply manual for detailed instructions on drug preparation, storage, and 
administration.
11.
Dose modifications criteria
Doses cannot be delayed beyond the treatment window. Participants must skip dose if the treatment 
window is missed. Doses can be omitted until a maximum time of 8 weeks, for longer periods of time, the 
Trial Chair must be consulted. Reasons for dose delays, the supportive measures taken, and the outcomes 
will be documented in the patient's chart and recorded on the eCRF.
11.1.
General Notes Regarding Dose Modification
When several toxicities with different grades of severity occur at the same time, the dose modifications 
should be according to the highest grade observed.
The investigator may use discretion in modifying or accelerating the dose modification guidelines depending 
on the severity of toxicity and an assessment of the risk versus benefit for the patient, with the goal of 
maximizing patient compliance and access to supportive care.
11.2.
BINTRAFUSP (M7824). Toxicity Management
Treatment modification guidance for symptoms of infusion-related reactions including immediate 
hypersensitivity:
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NCI-CTCAE Grade 
Treatment Modification
Grade 1 - mild
Mild transient reaction; in general, infusion 
interruption not indicated; intervention not 
indicated
Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.
Hold infusion if deemed necessary by the 
investigator.
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. 
Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.
If symptoms resolve quickly, 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 
scheduled visit.
If not improving, consider administration of 
glucocorticoids and stop the infusion for that 
day.
If the participant has a second IRR Grade 
2 
on the slower infusion rate despite 
premedication, the infusion should be stopped, 
and the investigator may consider withdrawal of 
this participant from the study.
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 the infusion of study intervention 
immediately and disconnect infusion tubing 
from the participant with additional appropriate 
medical measures and closely monitor until 
deemed medically stable by the attending 
Investigator. Hospitalization and/or close 
monitoring is recommended
Administration of glucocorticoids may be 
required
For Grade 3 or 4 IRRs, permanent 
discontinuation of study intervention is 
mandated.
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Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions. 
For all types and grades of infusion reactions, details about drug physical constitution, method of 
preparation, and infusion must be recorded.
Participants should be instructed to report any delayed reaction immediately.
IRR=infusion-related reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common 
Terminology Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs. 
Management of immune-mediated adverse events
Immune-related AEs are specific to immunotherapies and vary by organ system. Immune-related AEs 
are important identified risks for bintrafusp alfa. 
Recommended guidance and management for specific irAEs are provided in the current NCCN
guideline available at http://www.nccn.org.
Requirements in addition to NCCN guidelines:
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, acquired thrombotic 
thrombocytopenic purpura inflammatory arthritis, myositis and polymyalgia-like syndrome.
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.
For Grade 1 immune-related pneumonitis: continue treatment. If clinically indicated, monitor 
participants weekly or more frequently as needed with history, physical examination and pulse 
oximetry. If symptoms appear and/or changes in the physical exam are noted, treat as Grade 
2.
For myositis: in case of management with rituximab, treatment should be discontinued.
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Management of TGF- 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-
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-
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Management of Anemia
Anemia is considered an important identified risk for bintrafusp alfa.
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
Basic Anemia Evaluation
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 Based on Suspected Etiology (in Addition to Basic Anemia Testing)
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: 
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
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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
Mucosal/Non-tumor Bleeding
Grading
Management
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
If Grade 
3 bleeding event is observed, regardless of 
causality with the study intervention, upon resumption of 
study intervention bintrafusp alfa dose should be reduced 
by 50% (600 mg Q2W. Once there is stable resolution 
and no recurrence of bleeding on reduced dose, 
Investigator is encouraged to communicate with sponsor
on potential dose re-escalation after careful benefit-risk 
assessment
Grade 4
Treatment must be permanently discontinued if 
no alternative explanation is identified.
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In case of rapid decrease of hemoglobin (Hgb), such as a decrease greater than 2.0 g/dL across a 2 
weeks period, withhold the subsequent cycles of study intervention until Hgb is stabilized and do a 
thorough assessment of bleeding (for example, upper and lower GI endoscopy, enhancement CT 
etc.); if Grade 1 or greater bleeding is observed or suspected, withhold the bintrafusp alfa until the 
bleeding is resolved/controlled and resume the dose of bintrafusp alfa reduced by 50%. Once Hgb 
decrease is recovered to 
Grade 1 or baseline and stably controlled, the Investigator is 
encouraged to communicate with Medical Monitor to re-escalate the dose. The dose of bintrafusp 
alfa may be re-escalated to full dose once Hgb is stabilized without further need for blood 
transfusion in the subsequent cycles. The timing of re escalation may need a case-by-case 
decision. See Section Table on Management of anemia
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.
Grade 
3
If Grade 
3 bleeding event had been observed, 
regardless of causality with the study intervention, upon 
resumption of the study intervention bintrafusp alfa dose 
should be reduced by 50%. Once there is stable 
resolution and no recurrence of bleeding on reduced 
dose, Investigator is encouraged to communicate with 
the sponsor potential dose re-escalation after careful 
benefit-risk assessment. Treatment should be 
permanently discontinued if the Investigator considers 
the participant to be at risk for additional severe 
bleeding.
In case of rapid decrease of hemoglobin (Hgb), see 
Section Mucosal/Non-Tumor bleeding.
Impaired Wound Healing
Impaired wound healing is considered important potential 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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12.
Prohibited and permitted concomitant treatments
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to protocol-
mandated treatment from 7 days prior to initiation of study drug to the study completion/discontinuation 
visit. All such medications should be reported to the investigator and recorded on the Concomitant 
Medications form in the eCRF. 
Prohibited Concomitant Therapy 
The following medications are prohibited while on study, unless otherwise noted:
Cytoreductive therapy
Radiotherapy delivered for non-palliative indications
Immunotherapy, immunosuppressive drugs (that is, chemotherapy or systemic corticosteroids 
except for short-term treatment of allergic reactions or for the treatment of irAEs), or other 
experimental pharmaceutical products. Short-term administration of systemic steroid (that is, for 
allergic reactions or the management of irAEs is allowed).
Live vaccine administration within 30 days before M7824. Vaccination with live vaccines while on 
study is prohibited. Administration of inactivated vaccines is allowed (for example, inactivated 
influenza vaccines)
The concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety 
profiles, and potential drug-drug interactions are generally unknown. However, their use for patients on 
study is allowed at the discretion of the investigator provided that there are no known interactions with any 
study treatment. As noted above, herbal therapies intended for the treatment of cancer are prohibited.
Permitted Concomitant Therapy
Premedication with antihistamines may be administered for any M7824 infusions before day 1 week 1 and 
week 3. The following therapies should continue while patients are on study:
- Oral contraceptives.
- Hormone-replacement therapy.
- Prophylactic or therapeutic anticoagulation therapy, such as low molecular weight heparin (preferred) 
or warfarin at a stable dose level.
- Inactive influenza vaccinations.
- COVID-19 vaccination with an approved vaccine is allowed for patients included in the study 
- Megestrol administered as an appetite stimulant.
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- Inhaled corticosteroids for chronic obstructive pulmonary disease.
- Mineralocorticoids (e.g., fludrocortisone).
- Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency  (e.g 
oral hidroaltesona 20 mg per day).
- G-CSF is allowed as per local standard.
- Any medications (other than those excluded by the exclusion criteria or the prohibited medicines) 
- Other drugs to be used for prophylaxis, treatment of hypersensitivity reactions, and treatment of fever
or flu-like symptoms
indicated per 
local standards.  Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine or another H2-receptor antagonist 
per standard practice. Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be 
managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and 2-adrenergic 
agonists).
Cautionary Concomitant Therapy
Systemic corticosteroids and TNF-
inhibitors may attenuate potential beneficial immunologic effects of 
treatment with bintrafusp alfa.  Therefore, in situations where systemic corticosteroids or TNF-
inhibitors 
would be routinely administered, alternatives, including antihistamines, should be considered first by the 
treating physician. If the alternatives are not feasible, systemic corticosteroids and TNF-
inhibitors may be 
administered at the discretion of the treating physician except in the case of patients for whom CT scans 
with contrast are contraindicated (i.e., patients with contrast allergy or impaired renal clearance). 
Systemic corticosteroids are recommended, with caution at the discretion of the treating physician, for the 
treatment of specific adverse events when associated with bintrafusp alfa therapy.  Guidelines for the 
management of immune-mediated adverse events are described in Appendix 7.
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13.
Adverse events and reporting
13.1.
Definition of an Adverse Event
reporting
The main criterion for tolerability is the occurrence of toxicities and Adverse Events (AEs). An AE is defined 
as any untoward medical occurrence that occurs from 
study through 30 days after the final administration of the IMP, regardless of whether it is considered related 
or not to the study drug. After informed consent has been obtained, but prior to initiation of study drug, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive procedures such as 
biopsies, discontinuation of medications) should be reported.
An adverse event can therefore be any of the following:
Any unfavorable and unintended sign (including an abnormal laboratory finding) (see NOTE 1 below), 
symptom, or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or severity 
of a known condition), except events that are clearly consistent with the expected pattern of the 
disease progression. These data will be captured as efficacy assessment data only. If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported as an adverse 
event.
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline.
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is associated with 
symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from 
study drug.
Adverse events that are related to a protocol-mandated intervention, including those that occur prior to 
assignment of study treatment (e.g., screening invasive procedures such as biopsies).
Adverse events that occur during or within 24 hours after study drug administration and are judged to be 
related to study drug infusion should be captured as a diagnosis (e.g., "infusion-related reaction" or 
"anaphylactic reaction") on the Adverse Event eCRF. If a patient experiences both a local and systemic 
reaction to the same dose of study drug, each reaction should be recorded separately on the Adverse 
Event eCRF. Associated signs and symptoms should be recorded on the dedicated Infusion-Related 
Reaction eCRF.
A pre-existing medical condition should be recorded as an adverse event only if the frequency, severity, or 
character of the condition worsens during the study
.  
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An AE is defined 
as any untoward medical occurrence that occurs from 
study through 30 days after the final administration of the IMP, regardless of whether it is considered related 
or not to the study drug. After informed consent has been obtained, but prior to initiation of study drug, 
only serious adverse events caused by a protocol-mandated intervention (e.g., invasive procedures such as 
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NOTE 1: Abnormal laboratory and vital signs values:
A laboratory test result must be reported as an adverse event if it is a change from baseline and meets any 
of the following criteria:
Is accompanied by clinical symptoms,
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation),
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a change in 
concomitant therapy,
.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself 
should be recorded on the Adverse Event eCRF, along with a descriptor indicating if the test result is above 
or below the normal range (e.g., "elevated potassium").
A vital sign result must be reported as an adverse event if it is a change from baseline and meets any of the 
following criteria:
Is accompanied by clinical symptoms,
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation),
Results in a medical intervention or a change in concomitant therapy,
Is clin
.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood pressure), 
only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event eCRF.
The finding of an elevated ALT or AST ( 3
baseline value) in combination with either an elevated total 
bilirubin ( 2
ULN) or clinical jaundice in the absence of cholestasis or other causes of hyperbilirubinemia 
is considered to be an indicator of severe liver injury. Therefore, investigators must report as an adverse 
event the occurrence of either of the following:
Treatment-emergent ALT or AST 3
baseline value in combination with total bilirubin 2
ULN (of which 
35% is direct bilirubin),
Treatment-emergent ALT or AST 3
baseline value in combination with clinical jaundice.
This abnormal laboratory values related to the liver function should be recorded on the Adverse Event eCRF 
and reported immediately as a SAE (AESI).
The severity will be classified according to the NCI CTCAE Version 5.0. The CTCAE is available for downloading 
on the internet (see appendix 1).
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The AE severity grade provides a qualitative assessment of the extent or intensity of an AE, as determined 
by the investigator or as reported by the patients.  The severity grade does not reflect the clinical seriousness 
of the event, only the degree or extent of the affliction or occurrence (e.g., severe nausea, mild seizure), and 
does not reflect the relationship to study drug.
Severity grade for other adverse events not covered in the toxicity grading scale:
1 = Grade 1
Mild
2 = Grade 2
Moderate
3 = Grade 3
Severe
4 = Grade 4
Life-threatening
5 = Grade 5
Fatal
However, depending on the SAE term used, there is some AE that do not have all the grades (e.g., the SAE 
term Alopecia only has the Grade 1 and 2).
The causal relationship to study drug is determined by the physician and should be used to assess all AE. 
The casual relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and the AE.
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
About the AEs that must be recorded in the eCRF note that:
Baseline symptoms will be recorded on the eCRF and changes and updates in grade as well as 
resolution of an AE during treatment must be reported,
An AE should be reported for each SAE notified,
AEs should not be reported in a narrative description.
AEs can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation 
of a subject (to prevent reporting bias, subjects should not be questioned regarding the specific occurrence 
of one or more AEs).
Any AE must be reported by an entry in the eCRF within 5 days of awareness, even if they do not meet the 
whole information. The diagnosis of the event should be recorded as AE term. If there is a secondary AE 
separated in time from the initiating event, it should be recorded as an independent event (e.g., if vomiting 
results in severe dehydration, both events should be reported separately).
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13.2.
Definition of Serious Adverse Event (SAE) and Suspected Unexpected Serious 
Adverse Reaction (SUSAR)
A Serious Adverse Event (SAE) is defined in general as any undesirable medical occurrence/adverse drug 
experience that occurs from 
30 days after 
the final administration of the IMP, regardless of whether it is considered related or not to the study drug 
and that, at any dose, results in any of the following:
results in death (fatal)
is life-threatening (defined as an event in which the participant was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it was more severe)
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 2 below)
results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect
is an important medical event. Defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require intervention (e.g., medical, surgical, laboratory 
(see NOTE 3 below)
After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events 
caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, discontinuation of 
medications) should be reported.
Seriousness is based on patient/event outcome or action criteria usually associated with events that pose a 
threat to a patient's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations
NOTE 2: The following hospitalizations are not considered SAEs:
A visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission, except if it is considered as an important medical event or life- threatening
elective surgery which has been planned prior to signing consent
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routine health assessment requiring admission for baseline/trending of health status (e.g., routine 
colonoscopy)
admissions as per protocol for a planned medical/surgical procedure
admission for administration of anticancer therapy in the absence of any other SAEs
admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason)
progression of disease. By convention, clinical events related to the primary cancer being studied or 
to the primary cancer progression are not to be reported as SAEs, even if they meet any of the 
seriousness criteria from the standard SAE definition, unless the event is more severe than expected 
and therefore the investigator considers that their clinical significance deserves reporting.
NOTE 3: Any laboratory abnormalities should be documented as a SAE if:
Intensive treatment in an emergency room or at home for allergic bronchospasm is needed,
Blood dyscrasias or convulsions that do not result in hospitalization,
Any untoward event related, and unexpected, to the protocol procedures, 
The laboratory test result is clinically significant or meets the definition of a SAE,
The laboratory abnormality required the participant to have study drug discontinued or interrupted,
The laboratory abnormality required the subject to receive specific corrective therapy.
A SAE report should be completed for any event where doubt exists regarding its seriousness. Although 
overdose, pregnancy, AESI (e.g., potential drug-induced liver injury (DILI)), important medical event, and 
cancer (secondary malignancy) are not always serious by regulatory definition, these events must be handled 
as SAEs. If applicable, SAEs must be collected that relate to any later protocol-specified procedure (e.g., a 
follow-up skin biopsy).
If the investigator believes that a SAE is not related to study drug but is potentially related to the conditions 
of the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship 
should be specified in the narrative section of the SAE Report Form and an important medical event would 
be the seriousness.
All deaths that occur during the reporting period that are clearly the result of disease progression should not 
be reported as a SAE, but they should be collected as an AE. All deaths where it is not due to disease 
progression and deaths with an unknown cause should always be reported as a SAE. 
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Death should be considered as an outcome and not the event, the AE causing the death must be reported 
as the SAE term. The term "sudden death" should be used only for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without preexisting heart disease, 
within 1 hour after the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours 
after the patient was last seen alive and stable.  If the cause of death is unknown and cannot be ascertained 
at the time of reporting, "Death due to Unknown Cause" should be recorded on the Adverse Event eCRF. If 
the cause of death later becomes available (e.g., after autopsy), the event should be replaced by the 
established cause of death.
If the SAE is considered as related to the study drug by the Principal Investigator, it is a Serious Adverse 
Reaction. The SAR is assessed by the Fundación GECP (SLCG/GECP) to know if it is expected. A SAR that is 
not listed as a known toxicity of the investigational drug in the summary of product characteristics 
(Investigator Brochure or Data Sheet) will be considered as a Suspected Unexpected Serious Adverse 
Reaction (SUSAR). The sponsor will inform to the Principal Investigator that this SAE has been considered as 
a SUSAR. In Spain, Health authority (AEMPS: Agencia Española del Medicamento y Productos Sanitarios) will 
also be informed about all SUSARs via EudraVigilance. Also, the autonomous regions will be informed about 
all SUSARs according to the current Spanish clinical trial regulation.
13.3.
Adverse events of Special Interest for M7824 (Immediately reportable to the 
Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the Fundación GECP 
(SLCG/GECP) immediately) (no more than 24 hours after learning of the event; see Section 13.5 for reporting 
instructions), despite not being serious.  Adverse events of special interest for this study include the 
following:
o
Infusion-related reactions including immediate hypersensitivity
o
Immune-related adverse events grade 3 to 5 
o
Potential TGF- -mediated skin adverse events
o
Treatment-related anemia adverse events
13.4.
Overdose and secondary malignancies
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as a SAE, 
-
Secondary malignancies are not always serious by regulatory definition, these events must be handled as 
SAEs.
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Immune-related adverse events grade 3 to 5 
o
Potential TGF- -mediated skin adverse events
o
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13.5.
SAEs and SUSARs reporting
All SAEs that occur within 30 days of the last administered study medication must be collected. Any SAE must 
be reported by submitting the completed Initial SAE Form in the online eCRF within 24 hours of awareness, 
even if they do not meet any of the seriousness criteria.
In case of the eCRF is unavailability, the submission could be done by sending the SAE form preferably by 
email to pharmacovigilance.slcg@gecp.org or by fax to the Fundación GECP (SLCG/GECP) Pharmacovigilance 
Office: +34 93 419 17 68. An appropriate SAE form (see appendix 3) should be used to report SAEs to 
Fundación GECP (SLCG/GECP). The paper SAE form has to be sent within the timeline period for reporting of 
24 hours of awareness. Once the eCRF system is available again, the SAE has to be completed and 
submitted by the site into the eCRF.
If only limited information is initially available, a follow-up report is required to complete the information as 
soon as possible. (Note: Follow-up SAE reports should include the same SAE term(s) initially reported.) 
The SAE outcome must be reported within 14 days after initial reporting by submitting the Follow up SAE 
Form in the online eCRF. In case the SAE is reported as ongoing after 14 days, a follow-up report has to be 
submitted again with the final outcome.
If an ongoing SAE changes in its grade, relationship to study drug, seriousness, SAE term or if new information
becomes available, a new follow-up SAE report should be sent within 24 hours to the Fundación GECP
(SLCG/GECP) using the same procedure after described. 
Any SUSAR occurred during the trial will be notified under Spanish clinical regulation to the principal 
investigators, to the Health Authority (AEMPS) via Eudravigilance within the timelines specified in the Royal 
Decree 1090/2015 on clinical trials regarding the recording, evaluation and reporting of adverse events. Also, 
the autonomous regions will be informed about all SUSARs according to the current Spanish clinical trial 
regulation.
For any doubt please contact Fundación GECP (SLCG/GECP) pharmacovigilance office by this email: 
pharmacovigilance.slcg@gecp.org or by the telephone: +(34) 93 430 20 06.
Also, Fundación GECP (SLCG/GECP) will ensure that all SAEs, SUSARs, AESIs and pregnancy reports in the 
clinical database (eCRF) are reported to the authorization holder y during the conduct of the study including 
periodic reconciliation.
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13.6.
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study participant is 
pregnant or may have been pregnant at the time of investigational product exposure, within 5 months after 
the last dose of M7824, the investigational product will be permanently discontinued. 
Any pregnancy that occurs in a female partner of a male study participant should also be reported to the 
Fundación GECP (SLCG/GECP). Male patients will be instructed through the Informed Consent Form to 
immediately inform the investigator if his partner becomes pregnant during the chemotherapy treatment 
period or within 6 months after the last dose of chemotherapy. To allow Fundación GECP (SLCG/GECP) or 
designee to collect any pregnancy surveillance information from the female partner, the female partner 
must sign an informed consent form for disclosure of this information. 
In both cases, the investigator must immediately notify to the Fundación GECP (SLCG/GECP)
Pharmacovigilance Office by sending the Pregnancy form (see appendix 4) preferably by email to 
pharmacovigilance.slcg@gecp.org or by fax to the Fundación GECP (SLCG/GECP) Pharmacovigilance Office: 
+34 93 419 17 68.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome 
and, where applicable, offspring information, study discontinuation must be reported following the before 
procedure described during at least 1 year after child-bearing.
  Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) or abortion should 
be reported as a SAE.
13.7.
Other safety considerations
Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-rays, 
and any other potential safety assessments, whether or not these procedures are required by the protocol, 
should also be recorded as a non-serious or serious AE, as appropriate, and reported accordingly. 
14.
Biological material and translational research
Several samples will be collected during the study. All the samples will be stored at:
Fundación de Investigacion Biomédica de Bellvitge (IDIBELL)
Hospital Duran i Reynals
C/ Avda Gran Via 199-203, 08908, Hospitalet, Barcelona
Fundación de Investigacion Biomédica de Bellvitge (IDIBELL)
Hospital Duran i Reynals
C/ Avda Gran Via 199-203, 08908, Hospitalet, Barcelona
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The following samples will be collected:
o
FFPE (formalin-fixed paraffin-embedded) tumor tissue for translational research analysis should be 
sent to the central laboratory at baseline and at progression disease. At least 10 slides are required. 
Tumor block should be shipped at patient inclusion or before if possible.
o
Pleural effusion liquid at baseline and at progression (when possible)
o
Blood samples will be collected at baseline, at first tumor evaluation and at progression (one SST gel 
serum tube of 10 ml)
Please, refer to the BIMES Samples Manual for more information.
FFPE (formalin-fixed paraffin-embedded) tumor tissue for translational research analysis should be 
sent to the central laboratory at baseline and at progression disease. At least 10 slides are required. 
Tumor block should be shipped at patient inclusion or before if possible.
Pleural effusion liquid at baseline and at progression (when possible)
o
Blood samples will be collected at baseline, at first tumor evaluation and at progression (one SST gel 
o
serum tube of 10 ml)
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15.
Case report forms and documentation
eCRFs will only be available on-line at the Remote Data Entry (RDE) facility of Fundación GECP for patient 
enrollment.
Only the patient pre-screening form will be used in a paper form and will be send scanned by email or by fax
(+34 93 419 17 68) to obtain the pre-screening number.
Also, another exception will be a paper SAE form and pregnancy form that will be used only in case of eCRF 
system unavailability.
16.
Statistical considerations
Three populations will be considered for different analyses:
Per protocol population (PP): Per protocol population will consider patients that will receive a minimum 
of 3 cycles of treatment or that have at least the first tumor response evaluation carried out. Patients 
without any radiological evaluation who may die during the first 9 weeks will also be considered PP 
population. Patients without the first tumor response evaluation carried out but with a progression 
disease (also clinical progression) at 8 weeks will also be considered into PP population. 
Intention to treat analysis (ITT): Intention to treat analysis will include all patients that fulfill inclusion 
and exclusion criteria and will be registered into the clinical trial.
Safety population (SFP): Safety population will include all patients that will be exposed to study 
treatment (bintrafusp alfa), whatever will be the quantity received
This study is designed to show that experimental treatment will achieve a median PFS of 4.5 months 
(expected median for standard scheme is 3 months which is equivalent to consider an improvement of 0.66 
in terms of hazard ratio), with a statistical power of 90% and a one-sided type I error of 10%. On these bases 
and considering Lachin design, 45 pts are needed (44 or more events for null hypothesis and 43 or less events 
for alternative hypothesis) over a period of 18 months with a minimum median follow-up of 12 months to 
perform an exponential test. Considering a 5 % of drop-out patients and a hazard of 0.04 for dropouts a total 
sample size of 47 patients will be needed.  In case of having 43 or less events during follow-up alternative 
hypothesis will be concluded and experimental treatment will be declared as promising.
The expected accrual rate is 2 patients per month for the first 6 months, increasing to 4-5 patients per month 
thereafter. Primary analysis is expected to be available 18 months after the inclusion of the first patient. 
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In order to reach the proposed sample size, if a patient initially enrolled in the study does not fulfil the 
inclusion criteria, they will be replaced by a new one subject that fulfil them, this replacement will ensure 
that the sample size will be the one calculated initially. 
Reference: Lachin, John M (2000). Biostatistical Methods: The assessment of Relative Risks. John Wiley & Sons, New 
York, NY.
17.
Criteria for termination of the trial
17.1.
General criteria for termination of the trial
The trial may be discontinued early in parts or completely if the information on the product leads to doubt 
as to the benefit/risk ratio, by decision of Fundación GECP or Trial Steering Committee, or at the suggestion 
of the IDMC.
The trial can be terminated at any time if the authorization and approval to conduct the study is withdrawn 
by ethics committee or regulatory authority decision, insufficient accrual, emerging new data impacting the 
scientific value of the trial or on ethical grounds.
17.2.
Discontinuation of protocol treatment and from the study for individual patients 
Patients may be withdrawn from the protocol treatment and from the study in the following situations:
Occurrence of unacceptable toxicities. Stopping protocol treatment is determined by medical 
judgment of the treating physician.
Disease progression per investigator assessment according to mRECIST v1.1 and loss of clinical 
benefit
Symptomatic deterioration attributed to clinical disease progression
Intercurrent severe illnesses which would in the judgment of the investigator affect assessments 
of the clinical status to a significant degree and require discontinuation of protocol therapy
Request by the patient. Patients have the right to refuse further trial treatment at any time 
during the trial. Such patients will remain in the trial and will be transferred to the follow-up 
phase.
If a patient refuses to have follow-up examinations and tests needed to determine whether the 
treatment is safe and effective
Protocol non-compliance or study termination by sponsor or site closure by the sponsor (poor 
protocol adhere
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Pregnancy
Patient non-compliance, defined as a failure to comply with the protocol requirements as 
determined by the protocol
The decision for discontinuation of protocol treatment and the study of individual patients is taken by the 
treating physician based on his medical evaluation and taking into consideration
situation. Specific reasons for trial discontinuation in which further collection of data is not allowed are: 
withdrawal of consent, patient lost to follow up, death.
All possible measures will be undertaken to maintain the investigation program and to continue the follow-
up even if the treatment was prematurely concluded and/or if the patient did not attend the follow-up visits 
at the participating institution.
The primary reason for the treatment and study discontinuation should be documented on the appropriate 
eCRF.
18.
Ethics aspects, regulatory approval, and Patient Informed Consent
The Investigator will ensure that this study is conducted in full conformance with the principles of the 
the research is conducted, 
whichever affords the greater protection to the individual. The study must fully adhere to the principles 
6 Tripartite Guideline (January 1997) or local Spanish
law if it affords greater protection to the patient. For studies conducted in the EU/EEA countries, the 
Investigator will ensure compliance with the EU Clinical Trial Directive (2001/20/EC).
18.1.
Ethical Review Board/Ethics Committee/Health Authority
All protocols and the patient informed consent forms must have the approval of a properly constituted 
committee or committees responsible for approving clinical trials. The Ethic Committee decision must 
contain approval of the designated investigator, the protocol (identifying protocol title and version number), 
and of the patient informed consent.
The Ethic Committee written, signed approval letter/form must contain approval of the designated 
investigator, the protocol (identifying protocol title and version number), and of the patient informed 
consent. 
Any modifications made to the protocol must be submitted to the appropriate Ethic Committee for 
information or approval in accordance with local procedures and regulatory requirements and to Health 
Authorities if required. 
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities (if required), the 
investigator shall implement the protocol modifications. 
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If applicable, in addition to the approval of the Ethics Committee according to national legislation, the 
protocol, other protocol related documents including patient information and informed consent and other 
documents as required locally must be submitted to and be approved by the health authority.
18.2.
Informed consent 
Informed consent for each patient will be obtained prior to initiating any trial procedures in accordance with 
.  Once signed and dated, a copy of the informed consent 
must be given to each patient and the original copy must be retained in the investigator s site file.  The 
informed consent form must be available in the case of data audits. 
The Declaration of Helsinki
recommends that consent be obtained from each potential patient in 
biomedical research trials after the aims, methods, anticipated benefits, and potential hazards of the trial, 
and discomfort it may entail, are explained to the individual by the physician.  The potential patient should 
also be informed of her/his right to not participate or to withdraw from the trial at any time.  The patient 
should be told that material from her/his tumor and blood and serum samples will be stored and potentially 
used for additional studies not described in this protocol.
If the patient is in a dependent relationship to the physician or gives consent under duress, the informed 
consent should be obtained by an independent physician. It is preferable that the patient who gives the 
consent signs the form but if it is not possible or if the patient is legally incompetent (i.e., a minor, or mentally 
incompetent), informed consent must be obtained from the parent, legal guardian, or legal representative 
in accordance with the law of the country in which the trial is to take place.  
By signing this protocol, the investigator agrees to conduct the trial in accordance with Good Clinical Practice 
and the "Declaration of Helsinki".
The template Patient Information Sheet and Informed Consent has been written according to ICH guidelines 
which state the Informed Consent should adhere to GCP and to the ethical principles that have origin in the 
19.
Governance and administrative issues
19.1.
Study documentation
The investigator must maintain adequate and accurate records to enable the conduct of the study to be fully 
documented, including, but not limited to, the protocol, protocol amendments, Informed Consent Forms, 
and documentation of IRB/EC and governmental approval.
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19.2.
Protocol non-compliances/deviations
The investigator should document and explain any protocol non-compliances/deviations. The investigator 
should promptly report any non-compliances/deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC policies and 
procedures.  The Sponsor will review all protocol non-compliances/deviations and assess whether any 
represent a serious breach of Good Clinical Practice guidelines and require reporting to health authorities.
All protocol non-compliances/deviations will be recorded by the monitoring team.
19.3.
Protocol amendment
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will be submitted to the 
IRB/EC and to regulatory authorities in accordance with local regulatory requirements. Approval must be 
obtained from the IRB/EC and regulatory authorities (as locally required) before implementation of any 
changes, except for changes necessary to eliminate an immediate hazard to patients or changes that involve 
logistical or administrative aspects only (e.g., change in Medical Monitor or contact information).
19.4.
Final report
A final clinical trial report will be written and distributed to the Ethic committees and Health Authorities as 
required by applicable regulatory requirements.
19.5.
Independent Data Monitoring Committee (IDMC)
The trial will be presented periodically for review to the Fundación GECP BICR (blinded independent central 
review). This IDMC will held expedite meeting/s if any safety issue or other concerns come up during the 
study. The management staff of the Fundación GECP, will be in charge of informing the IDMC of any issue 
related with the study.
19.6.
Publication
Authorship on the final manuscript or publications or provisional extracts will be decided in accordance with 
the Fundación GECP publication and authorship guidelines (SOP GECP: Política de publicaciones y autorías).
None of the participants will present data to his center in isolation from the rest of the results of the study 
and will need to seek approval from the sponsor.
19.7.
Financial disclosure
Investigators will provide the sponsor with enough, accurate financial information in accordance with local 
regulations to allow the Sponsor to submit complete and accurate financial certification or disclosure 
statements to the appropriate health authorities.  Investigators are responsible for providing information on 
financial interests during the course of the study and for 1 year after completion of the study.
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19.8.
Clinical trial insurance
Spanish legislation demands cover with a civil responsibility policy for subjects participating in a clinical trial. 
Fundación GECP will contract the appropriate liability insurance for this trial. Patients who suffer injuries due 
to the trial should report them immediately to their physician. 
19.9.
Quality assurance
Fundación GECP conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The Trial Data 
Manager reviews each eCRF as per monitoring plan schedule.
Fundación GECP will conduct periodic triggered visits to the participating sites to ensure proper trial conduct, 
verify compliance with GCP, and perform source data verification.
The Investigator should ensure that source documents are made available to appropriately qualified 
personnel from Fundación GECP, or to ethics committee and health authority inspectors after appropriate 
notification.
At regular intervals during the clinical trial, the center will be contacted, through monitoring visits, letters or 
telephone calls, by a representative of the Monitoring Team to review study progress, investigator and 
patient compliance with clinical trial protocol requirements and any emergent problems. These monitoring 
visits will include but not be limited to review of the following aspects: patient informed consent, patient 
recruitment and follow-up, SAE documentation and reporting, AEs with pre-specified monitoring 
documentation and reporting, AE documentation, dispensing IMP, compliance with protocol, drug 
accountability, concomitant therapy use, quality of data and storage of blood and serum samples.
19.10. Data protection
The samples and data collected will be coded to protect patient confidentiality. Each patient will have a pre-
screening number at the pre-screening phase to identify the biological material and a unique identifier 
assigned by the eCRF of the study once enrolled. Sites are responsible to keep a patient log locally to be able 
to link the pre-screening number and the unique identifier to the record of the patient. 
No identifiable / personal data will be stored in the trial database or the tissue repositories in the central 
laboratories.
Regulatory authorities and pertinent Ethics Committees (IRB/ERB) may have access to patient data on-site. 
Fundación GECP audit or monitoring personnel will also have access to such data on-site.
In Spain to ensure the patient confidentiality of data applies from the 25th of May 2018 the Reglamento (UE) 
2016/679 del Parlamento europeo y del Consejo de 27 de abril de 2016 de Protección de Datos (RGPD) and 
the Organic Law 3/2018, 5th of December, on Personal data protection and digital rights guarantee.
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19.11. Study monitoring team
The Fundación GECP will be responsible for monitoring the trial at Spanish sites.
The clinical monitor is obliged to rigorously follow the study. For this, the clinical monitor will regularly visit 
the study centers and the investigators as well as maintain necessary written and telephone 
communications. 
The clinical monitor will assess the data collected in the acquisition forms and compare them with the 
original data of the clinical history and other original documents in conjunction with the study investigator. 
The contact persons will be:
Patricio Gabarrón
Fundación GECP CRA
Meridiana 358, 6ª planta
08027 Barcelona
Tel. 93 430 20 06
Fax. 93 419 17 68
Email: pgabarron@gecp.org
Anna Hernández
Fundación GECP Lead CRA
Meridiana 358, 6ª planta
08027 Barcelona
Tel. 93 430 20 06
Fax. 93 419 17 68
Email: ahernandez@gecp.org
19.12. Record retention
The center must retain all essential documents according to ICH GCP. This includes copies of the patient trial 
records, which are considered as source data, patient informed consent statement, laboratory printouts, 
drug inventory and destruction logs, and all other information collected during the trial. These documents 
are to be stored until at least 25 years after the termination of the trial. 
In the event of the Principal Investigator retires or changes employment, custody of the records may be 
transferred to another competent person who will accept responsibility for those records. Written notice of 
such transfer must be given to the Fundación GECP and the local Ethics Committee at least 1 month in 
advance.
Patricio Gabarrón
@gecp.org
Email: pgabarron@
Anna Hernández
Email: ahernandez@gecp.org
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20.
References
1.
Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet 2005; 366(9483): 
397-408.
2.
Tsiouris A,Walesby RK. Malignant pleural mesothelioma: current concepts in treatment.
Nat Clin Pract Oncol 2007; 4(6): 344-52.
3.
Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in 
combination with cisplatin versus cisplatin alone in patients with malignant pleural 
mesothelioma. J Clin Oncol 2003; 21(14): 2636-44.
4.
FennellDA,Gaudino G,O'Byrne KJ,MuttiL, vanMeerbeeck J.Advancesin thesystemic 
therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol 2008; 5(3): 136-47.
5.
Nowak AK. Chemotherapy for malignant pleural mesothelioma: a review of current 
management and a look to the future. Ann Cardiothorac Surg 2012; 1(4): 508-15.
6.
Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus 
carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006; 24(9): 1443-8.
7.
Ceresoli GL, Zucali PA, Mencoboni M, et al. Phase II study of pemetrexed and 
carboplatin plus bevacizumab as first-linetherapy inmalignant pleuralmesothelioma.
Br J Cancer 2013; 109(3): 552-8.
8.
Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural 
mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a 
randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Apr 2; 387(10026):
1405-1414.
9.
Baas et al. CheckMate 743 Shows That Dual Immunotherapy, Nivolumab + 
Ipilimumab, Improves Overall Survival for Patients with Previously Untreated 
Mesothelioma. International Association for the Study of Lung Cancer. WCLC Virtual 
Presidential Symposium. 2020 Aug 8.
10. Popat S, Curioni-Fontecedro A, Dafni U, et al. A multicentre randomised phase III trial 
comparing pembrolizumab vs single-agent chemotherapy for advanced pre-treated 
malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-
15) PROMISE-meso trial. Ann Oncol. 2020 Sep 22: S0923-7534(20)42459-7.
11. Lebrun JJ. The Dual Role of TGF-
in Human Cancer: From Tumor Suppression to 
Cancer Metastasis. ISRN Mol Biol. 2012 Dec 24; 2012: 381428.
12. Wrzesinski SH, Wan YY, Flavell RA. Transforming growth factor-beta and the immune 
response: implications for anticancer therapy. Clin Cancer Res. 2007 Sep 15;13 (18 Pt 
1): 5262-70.
13. Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J 
Med. 2014 Jul 24;371(4):380-3.
14. Souza-Fonseca-Guimaraes F, Smyth MJ. Myeloid TGF-
responsiveness promotes 
Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet 2005; 366(9483): 
397-408.
2.
Tsiouris A,Walesby RK. Malignant pleural mesothelioma: current concepts in treatment.
Nat Clin Pract Oncol 2007; 4(6): 344-52.
3.
Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in 
combination with cisplatin versus cisplatin alone in patients with malignant pleural 
mesothelioma. J Clin Oncol 2003; 21(14): 2636-44.
4.
FennellDA,GaudinoG,O'Byrne KJ,MuttiL, vanMeerbeeck J.Advances in thesystemic 
therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol 2008; 5(3): 136-47.
5.
Nowak AK. Chemotherapy for malignant pleural mesothelioma: a review of current 
management and a look to the future. Ann Cardiothorac Surg 2012; 1(4): 508-15.
6.
Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus 
carboplatin in malignant pleural mesothelioma. J Clin Oncol 2006; 24(9): 1443-8.
7.
Ceresoli GL, Zucali PA, Mencoboni M, et al. Phase II study of pemetrexed and 
carboplatin plus bevacizumab as first-linetherapy in malignant pleuralmesothelioma.
Br J Cancer 2013; 109(3): 552-8.
8.
Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly diagnosed pleural 
mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a 
randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Apr 2; 387(10026):
1405-1414.
9.
Baas et al. CheckMate 743 Shows That Dual Immunotherapy, Nivolumab + 
Ipilimumab, Improves Overall Survival for Patients with Previously Untreated 
Mesothelioma. International Association for the Study of Lung Cancer. WCLC Virtual 
Presidential Symposium. 2020 Aug 8.
10. Popat S, Curioni-Fontecedro A, Dafni U, et al. A multicentre randomised phase III trial 
comparing pembrolizumab vs single-agent chemotherapy for advanced pre-treated 
malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-
15) PROMISE-meso trial. Ann Oncol.
A
2020 Sep 22: S0923-7534(20)42459-7.
11. Lebrun JJ. The Dual Role of TGF-
in Human Cancer: From Tumor Suppression to 
Cancer Metastasis ISRN Mol Biol. 2012 Dec 24; 2012: 381428.
12. Wrzesinski SH, Wan YY, Flavell RA. Transforming growth factor-beta and the immune 
response: implications for anticancer therapy. Clin Cancer Res. 2007 Sep 15;13 (18 Pt 
1): 5262-70.
13. Hotchkiss RS, Moldawer LL. Parallels between cancer and infectious disease. N Engl J 
Med. 2014 Jul 24;371(4):380-3.
14. Souza-Fonseca-Guimaraes F, Smyth MJ. Myeloid TGF-
responsiveness promotes 

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metastases. Cancer Discov. 2013 Aug;3(8):846-8.
15. Ciardiello D, Elez E, Tabernero J, Seoane J. Clinical development of therapies targeting 
TGF-
: current knowledge and future perspectives. Ann Oncol 2020 Oct; 31(10): 
1336-1349.
16. Hao NB, Lü MH, Fan YH, et al. Macrophages in tumor microenvironments and the 
progression of tumors. Clin Dev Immunol. 2012; 2012: 948098.
17. Suzuki E, Kapoor V, Cheung HK, et al. Soluble type II transforming growth factor-beta 
receptor inhibits established murine malignant mesothelioma tumor growth by 
augmenting host antitumor immunity. Clin Cancer Res 2004 Sep 1; 10 (17): 5907-18.
18. Donkor MK, Sarkar A, Li MO. TGF-
produced by activated CD4(+) T Cells 
Antagonizes T Cell Surveillance of Tumor Development. Oncoimmunology 2012 Mar 
1; 1(2): 162-171.
19. Hugo W, Zaretsky JM, Sun L, et al. Genomic and Transcriptomic Features of Response 
to Anti-PD-1 Therapy in Metastatic Melanoma. Cell 2016 Mar 24;165(1):35-44.
20. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in 
combination with cisplatin versus cisplatin alone in patients with malignant pleural 
mesothelioma. J Clin Oncol. 2003 Jul 15; 21 (14): 2636-44.
21. Remon J, Nadal E, Dómine M et al. Malignant pleural mesothelioma: Treatment 
patterns and outcomes from the Spanish Lung Cancer Group. Lung Cancer 2020 Sep;
147 :83-90.
22. Hmeljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative Molecular Characterization 
of Malignant Pleural Mesothelioma.  Cancer Discov. 2018 Dec; 8 (12): 1548-1565.
23. De Reyniès A, Jaurand MC, Renier A, et al. Molecular classification of malignant 
pleural mesothelioma: identification of a poor prognosis subgroup linked to the 
epithelial-to-mesenchymal transition. Clin Cancer Res. 2014 Mar 1; 20 (5): 1323-34. 
24. Fujii M, Toyoda T, Nakanishi H, et al. TGF-
synergizes with defects in the Hippo 
pathway to stimulate human malignant mesothelioma growth. J Exp Med. 2012 Mar 
12; 209 (3): 479-94
25. Turini S, Bergandi L, Gazzano E, et al. Epithelial to Mesenchymal Transition in Human 
Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-
as Mediator of 
Malignant Mesothelioma Development or Metastasis via EMT Event. Int J Mol Sci.
2019 Jan 3; 20 (1): 150
26. Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of 
malignant pleural mesothelioma identifies recurrent mutations, gene fusions and 
splicing alterations. Nat Genet. 2016; 48(4): 407-16.
27. Alay A et al. Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma 
Reveals aClinically Relevant Immune-Based Classification WCLC, WCLC Virtual 
Presidential Symposium. 2019. MA12.07. 
15. Ciardiello D, Elez E, Tabernero J, Seoane J. Clinical development of therapies targeting 
: 
TGF-
current knowledge and future perspectives. Ann Oncol 2020 Oct; 31(10): 
1336-1349.
16. Hao NB, Lü MH, Fan YH, et al. Macrophages in tumor microenvironments and the 
progression of tumors. Clin Dev Immunol. 2012; 2012: 948098.
17. Suzuki E, Kapoor V, Cheung HK, et al. Soluble type II transforming growth factor-beta 
receptor inhibits established murine malignant mesothelioma tumor growth by 
augmenting host antitumor immunity. Clin Cancer Res 2004 Sep 1; 10 (17): 5907-18.
18. Donkor MK, Sarkar A, Li MO. TGF-
produced by activated CD4(+) T Cells 
Antagonizes T Cell Surveillance of Tumor Development. Oncoimmunology 2012 Mar 
1; 1(2): 162-171.
19. Hugo W, Zaretsky JM, Sun L, et al. Genomic and Transcriptomic Features of Response 
to Anti-PD-1 Therapy in Metastatic Melanoma. Cell 2016 Mar 24;165(1):35-44.
20. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in 
combination with cisplatin versus cisplatin alone in patients with malignant pleural 
mesothelioma. J Clin Oncol. 2003 Jul 15; 21 (14): 2636-44.
21. Remon J, Nadal E, Dómine M et al. Malignant pleural mesothelioma: Treatment 
patterns and outcomes from the Spanish Lung Cancer Group. Lung Cancer 2020 Sep;
147 :83-90.
22. Hmeljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative Molecular Characterization 
of Malignant Pleural Mesothelioma.  Cancer Discov. 2018 Dec; 8 (12): 1548-1565.
23. De Reyniès A, Jaurand MC, Renier A, et al. Molecular classification of malignant 
pleural mesothelioma: identification of a poor prognosis subgroup linked to the 
epithelial-to-mesenchymal transition. Clin Cancer Res. 2014 Mar 1; 20 (5): 1323-34. 
24. Fujii M, Toyoda T, Nakanishi H, et al. TGF-
synergizes with defects in the Hippo 
pathway to stimulate human malignant mesothelioma growth. J Exp Med. 2012 Mar 
12; 209 (3): 479-94
25. Turini S, Bergandi L, Gazzano E, et al. Epithelial to Mesenchymal Transition in Human 
Mesothelial Cells Exposed to Asbestos Fibers: Role of TGF-
as Mediator of 
Malignant Mesothelioma Development or Metastasis via EMT Event. Int J Mol Sci.
2019 Jan 3; 20 (1): 150
26. Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of 
malignant pleural mesothelioma identifies recurrent mutations, gene fusions and 
splicing alterations. Nat Genet. 2016; 48(4): 407-16.
27. Alay A et al. Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma 
Reveals aClinically Relevant Immune-Based Classification WCLC, WCLC Virtual 
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28. Nadal E, Alay A, Cordero D, et al. Immune-based classification of pleural malignant 
mesothelioma by using integrative transcriptome analysis. Journal for Immuno Therapy 
of Cancer 2019, 7(Suppl 1): P101
29. Popat S, Curioni-Fontecedro, Polydoropoulou V et al. LBA91_PR - A multicenter 
randomized phase III trial comparing pembrolizumab versus standard chemotherapy 
for advanced pre-treated malignant pleural mesothelioma (MPM) results from the 
European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial.  ESMO 2019
Appendices:
1. Common Terminology criteria for Adverse Events (CTCAE)
2. Modified RECIST (mRECIST) criteria version 1.1 for malignant pleural mesothelioma
3. SAE Form 
4. Pregnancy Form
5. Mesothelioma TNM definitions according to the 8th edition
lignant 
mesothelioma by using integrative transcriptome analysis. Journal for Immuno Therapy
of Cancer 2019, 7(Suppl 1): P101
29. Popat S, Curioni-Fontecedro, Polydoropoulou V et al. LBA91_PR - A multicenter 
randomized phase III trial comparing pembrolizumab versus standard chemotherapy 
for advanced pre-treated malignant pleural mesothelioma (MPM) results from the 
European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial.  ESMO 2019
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APPENDIX 1. Common Terminology criteria for Adverse Events (CTCAE)
Version 5.0: November 27, 2017 is available from the internet at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE
_v5_Quick_Reference_8.5x11.pdf
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APPENDIX 2. Modified RECIST (mRECIST) criteria version 1.1 for malignant pleural mesothelioma
1.
Supplementary Data: Proposed Radiology Guidelines for 
Inclusion in Clinical Trial Protocols
Guidelines for measuring pleural mesothelioma as per modified RECIST 1.1 
Measurement of pleural tumor and other sites at baseline:
1.1.
Definition of measurability
o Pleural tumor is measurable if there exists at least one pleural site for which tumor
mm.
o Non-pleural sites of disease can determine measurability, and will have a
o Measurable involved lymph nodes have a short-
baseline.
o Pleural effusion is not considered a measurable lesion.
1.2.
Measurement sites at baseline
o Unidimensional pleural tumor measurements should be determined by constructing a 
line segment perpendicular to a tangent to the curve of the pleura at the outer 
measurementpoint (Figure 1). The outer measurement point is best placed on the 
chest wall or mediastinum, avoiding the anterior pleural reflexion.
o Image sections chosen for measurement should be readily identified at subsequent time
points and ideally related to clear fixed anatomical mediastinal or chest wall landmarks 
(Figure 2).
o Areas of pulmonary atelectasis, pleural effusion, and indistinct tumor boundaries 
should be avoided if possible.
o Where a measurement site is related to the pulmonary fissures, unidimensional
measurements should be made perpendicular to a tangent to the pleura at that point 
(Figure 3).
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o Pleural thickness is recorded at up to two measurement sites, if possible, at each of up 
tothree separate axial sections (levels) of the thoracic CT scan at baseline (Figures 2 
and 4). Axial sections should be at least 1 cm apart. The sum of these (up to) 6 
measurements gives the baseline sum of pleural measurements.
o Each selected measurement must individually satisfy the criterion for minimally
measurable disease.
o In the event of bilateral disease, the pleura is considered a single organ and pleural 
measurement sites may be distributed across both hemithoraces, up to three 
independent CT sections per hemithorax, no more than two measurement sites per 
section, to a total of 6 sites.
o Additional unidimensional non-pleural target lesion measurements meeting the 
definition of measurable disease may be made of involved lymph node sites, chest wall 
masses, or metastatic disease and added to the sum of pleural tumor thickness 
measurements to give a baseline sum of target lesion measurements. Measurements of 
non-pleural disease may be included from a maximum of five lesions total, and a 
maximum of two lesions per organ. Measurements acquired from pleural sites are to be 
considered a contribution from one organ.
o
-
pleural
diaphragm
-
measureable disease as well as measurable but non-measured pleural disease. It is not 
practical to separately identify individual pleural lesions that are contiguous or exceed a 
reasonable number.
o Images of the baseline scan measurement segments should be stored for visual 
reference when measuring subsequent images.
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Figure 1: Unidimensional measurements are determined by constructing a line segment 
perpendicular to a tangent to the curve of the pleura at the outer measurement point. Avoid areas 
of pleural reflexion or unclear disease boundaries (boxes).
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(i)
(ii)
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(iii)
Figure 2: Example of two measurements at each of three anatomically reproducible levels (i, ii, and 
iii).
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Figure 3: Lesions in the pleural fissure should be measured perpendicular to the fissure at that point.
Figure 4: Pleural thickness is recorded at up to two measurement sites at each of up to three 
separate axial sections (levels) of the thoracic CT scan at baseline. Axial sections should be at 
least 1 cm apart.
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(i)
(ii)
-target lesion 
-target lesion descriptor.
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2.
Measurement of disease at subsequent time points:
o Pleural tumor measurements should always be performed at the same site, in 
the same orientation (direction), and with the same image display parameters 
as the baseline measurement, irrespective of changes in lesion morphology 
and shape. If tumor is present at a site but is too thin to measure on a 
magnified window, a default value of 2 mm should be used.
o Lesions that are viewed on the same image slice at baseline but are 
subsequently best viewed on different images slices due to alterations in 
thoracic contraction, respiration, or patient positioning may be measured on 
different slices on subsequent scans.
o Modified RECIST 1.1 recommends that the same observer acquire 
measurements fromall CT scans from a given patient.
o Stored images of the baseline measurement line segments should be 
visuallyreferenced when acquiring measurements from scans at 
subsequent time points.
3.
Definitions of objective response:
Complete response (CR): Disappearance of all pleural and non-pleural disease (including 
pleural thickening considered to represent tumor).
Partial response (PR): Summed measurement decrease by at least 30% from the baseline 
scan summed measurement, which must be confirmed at a subsequent follow-up scan at 
least 4 weeks later (at which time the summed measurement must not exceed 70% of the 
baseline scan summed measurement).
Progressive disease (PD): Summed measurement increase by at least 20% from the nadir 
of the summed measurements from all prior scans (up to and including the baseline scan), 
even if the summed measurement is <70% of the baseline scan summed measurement; 
classification as PD also requires an absolute summed measurement increase of at least 5 
mm over the nadir summed measurement. An unequivocal new non-pleural lesion or an 
unequivocal new focus of pleural thickening that exceeds the minimum measurable size 
(and represents either a pleural tumor mass physically distinct from that associated with 
existing measurement sites or a region of a previously existing pleural tumor mass that 
would now unequivocally qualify as a measurement site) would be considered progressive 
disease#.
Stable disease (SD): A decrease in the summed measurement that does not qualify as PR, or 
an increase in the summed measurement that does not qualify as PD.
Note: Confirmation of objective response on a subsequent occasion at least 4 weeks 
later is required to assign a response of Confirmed PR or Confirmed CR.
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# An unequivocal new non-pleural lesion or an unequivocal new focus of pleural 
thickening that exceeds the minimum measurable size (and represents either a pleural 
tumor mass physically distinct from that associated with existing measurement sites or a 
region of a previously existing pleural tumor mass that would now unequivocally qualify 
as a measurement site) would be considered progressive disease; the assessment of 
was not present previously in an adjacent section.
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APPENDIX 3. SAE Form
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APPENDIX 4. Pregnancy Form
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APPENDIX 5. Mesothelioma TNM definitions according to the 8th edition
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