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Clinical Trial Results:
A phase II trial assessing Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in a pre-operative setting for resectable and untreated head and neck squamous cell carcinoma.

Summary
EudraCT number	2019-004052-11
Trial protocol	FR
Global end of trial date	07 Jan 2022

Results information
Results version number	v1(current)
This version publication date	09 Mar 2025
First version publication date	09 Mar 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

UC-HNG/1909

ISRCTN number

US NCT number

NCT04428047

WHO universal trial number (UTN)

Sponsor organisation name

UNICANCER

Sponsor organisation address

101 rue de Tolbiac, Paris, France,

Public contact

Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr

Scientific contact

Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

09 Aug 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

07 Jan 2022

Global end of trial reached?

Yes

Global end of trial date

07 Jan 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

To evaluate the efficacy of bintrafusp alfa, measured by pathological response (PathR), given in a pre-operative setting.

Protection of trial subjects

This study was conducted in conformity with the Declaration of Helsinki (1964) and subsequent amendments, ICH Good Clinical Practice (GCP) Guidelines (CPMP/ICH/135/95), the European Directive (2001/20/CE) and the applicable French regulatory requirements and laws.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Aug 2020

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 7

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Between 18-MAR-2021 (first inclusion) and 8-OCT-2021 (inclusion suspension), 11 patients were enrolled in the ICING study. However, only 7 patients recruited by 2 cancer centers.

Screening details

Patients were included in the study with histologically or cytologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, previously untreated, with indication of primary surgery. Patients with a diagnosis of HNSCC of occult primary cannot be enrolled.

Period 1 title

Overall periode

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

COHORT A

Arm description

Arm type

Experimental

Investigational medicinal product name

Bintrafusp alfa

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

bintrafusp alfa will be administered by intravenous infusion over 60 minutes at a dose of 1200 mg on Day1 and Day15

Number of subjects in period 1	COHORT A
Started	7
Completed	6
Not completed	1
Adverse event, non-fatal	1

Baseline characteristics

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Reporting group title

COHORT A

Reporting group description

Reporting group values	COHORT A	Total
Number of subjects	7	7
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	5	5
From 65-84 years	2	2
85 years and over	0	0
Age continuous
Units: years
median (full range (min-max))	61 (34 to 74)	-
Gender categorical
Units: Subjects
Female	4	4
Male	3	3
ECOG
Units: Subjects
ECOG 0	6	6
ECOG 1	1	1
The primary site of cancer
Units: Subjects
Oral cavity	5	5
Oropharynx	2	2
Serology for HPV
Units: Subjects
Negative	7	7
Cancer stage T
Units: Subjects
T2	2	2
T3	1	1
T4	4	4
Cancer stage N
Units: Subjects
N0	2	2
N1	1	1
N2	3	3
N3	1	1
Cancer stage M
Units: Subjects
M0	7	7

End points

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Reporting group title

COHORT A

Reporting group description

Primary: Pathological response (PathR)

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End point title

Pathological response (PathR) ^[1]

End point description

Pathological tumor response was evaluated as the percentage of the tumor area showing evidence of anti-tumor activity, such as tumor cell necrosis and/or giant cell/histolytic reaction to keratinous debris. * and/or giant cell/histolytic reaction to keratinous debris

End point type

Primary

End point timeframe

From inclusion to 1 month after surgery

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statiscal analyses for the primary end point. Due to an early trial termination only 7 patients were included, such a low number of patients did not allow to evaluate Bintrafusp alfa efficacy with enough power.

End point values	COHORT A
Number of subjects analysed	7
Units: percent
arithmetic mean (inter-quartile range (Q1-Q3))
Tumor diameter (mm)	33.9 (27.5 to 45)
Number of slides (n)	8.4 (8 to 10)
Sum of tumor necrosis*	183.5 (58.3 to 240)
PathR	17.8 (4.4 to 22.4)

No statistical analyses for this end point

Secondary: Evaluation of the impact of inking the tumor margins during baseline endoscopy to avoid surgical plan changes putatively induced by tumor shrinking under therapy

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End point title

Evaluation of the impact of inking the tumor margins during baseline endoscopy to avoid surgical plan changes putatively induced by tumor shrinking under therapy

End point description

Evaluation of the impact of inking the tumor margins during baseline endoscopy to avoid surgical plan changes putatively induced by tumor shrinking under therapy. Just before the beginning of the surgery, surgeons will answer a question (4-level: Yes, No, Not evaluable, Unknown) to indicate if their surgical plan would have been different in the absence of ink labelling.

End point type

Secondary

End point timeframe

From inclusion to surgery, an average of 21 days

End point values	COHORT A
Number of subjects analysed	7
Units: Cm
arithmetic mean (inter-quartile range (Q1-Q3))
Tumor front to inked zone mean distance	0.83 (0.75 to 1.5)

No statistical analyses for this end point

Post-hoc: Survival

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End point title

Survival

End point description

Number of patients alive at time of statisticals analysis.

End point type

Post-hoc

End point timeframe

At time of statisticals analysis

End point values	COHORT A
Number of subjects analysed	7
Units: Number
Alive	7

No statistical analyses for this end point

Post-hoc: Endoscopy to surgery interval

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End point title

Endoscopy to surgery interval

End point description

The mean time between endoscopy and surgery and the mean time between the first dose of Bintrafusp alfa and surgery

End point type

Post-hoc

End point timeframe

At the end of study.

End point values	COHORT A
Number of subjects analysed	7
Units: Days
arithmetic mean (inter-quartile range (Q1-Q3))
Endoscopy to surgery mean time	27.4 (25 to 28.5)
Bintrafusp alfa first dose to surgery mean time	23.3 (21.5 to 24.5)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From inclusion to 12 weeks after the last administration of the investigational product.

Adverse event reporting additional description

Due to an early trial termination only 7 patients were included, such a low number of patients did not allow to evaluate Bintrafusp alfa efficacy with enough power. Similarly, Bintrafusp alfa safety data gathered from this restricted population over 6 months instead of the 36 months initially envisioned does not provide significant evidence.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

COHORT A

Reporting group description

Serious adverse events	COHORT A
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 7 (28.57%)
number of deaths (all causes)	1
number of deaths resulting from adverse events	0
Injury, poisoning and procedural complications
Postoperative hemorrhage
subjects affected / exposed	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0
Infections and infestations
Sepsis
subjects affected / exposed	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	COHORT A
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 7 (28.57%)
occurrences all number	2
Fatigue
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Hyperthermia
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Mucositis
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Pain
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	2
Investigations
Weight loss
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Injury, poisoning and procedural complications
Infusion reaction
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Tracheostomy complication
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Vascular access complication
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Nervous system disorders
Dysarthria
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 7 (42.86%)
occurrences all number	5
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 7 (28.57%)
occurrences all number	3
Hypersalivation
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Tongue pain
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Xerostomia
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Hyperpigmentation skin
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Intertrigo
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Rash vesicular
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Infections and infestations
Gingivitis
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	2
Pneumonia
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Surgical site infection
subjects affected / exposed	3 / 7 (42.86%)
occurrences all number	4
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1
Hypophosphataemia
subjects affected / exposed	1 / 7 (14.29%)
occurrences all number	1

More information

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Were there any global substantial amendments to the protocol? Yes

09 Dec 2021

Amendment N°1 (Substantial; approved on 09-DEC-2021): - Study enrollment suspension. Amendment N°2 (Substantial; approved on 12-DEC-2022): - Study inclusion period reduced from 24 to 8 months - Study enrollment termination - Protocol modification: - Efficacy assessment: The assessment of disease-free survival (DFS), overall survival (OS), loco- regional disease-free survival (LR-DFS), and distant disease-free survival (D-DFS) rates that was to be conducted at 12, 18, 24 and 36 was solely performed at 6 months post-surgery. -Safety assessment: Toxicity survey were reduced from 36 to 6 months post-surgery.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
07 Jan 2022	The study ICING was suspended early on in response to the preliminary results gathered from two NSCLC randomized trials demonstrating an equivalence or slight inferiority but not superiority of Bintrafusp Alfa compared to anti-PD1/PDL1-based therapy. As a security measure, UNICANCER resorted to suspend all inclusion. At the time of suspension, seven patients had already been enrolled and given the investigational product. Due to this early termination all analyses were restricted to the data collected from those seven patients and toxicity survey was reduced from 36 to 6 months post-surgery.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A phase II trial assessing Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in a pre-operative setting for resectable and untreated head and neck squamous cell carcinoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Pathological response (PathR)

Primary: Pathological response (PathR)

Secondary: Evaluation of the impact of inking the tumor margins during baseline endoscopy to avoid surgical plan changes putatively induced by tumor shrinking under therapy

Secondary: Evaluation of the impact of inking the tumor margins during baseline endoscopy to avoid surgical plan changes putatively induced by tumor shrinking under therapy

Post-hoc: Survival

Post-hoc: Survival

Post-hoc: Endoscopy to surgery interval

Post-hoc: Endoscopy to surgery interval

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A phase II trial assessing Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in a pre-operative setting for resectable and untreated head and neck squamous cell carcinoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Pathological response (PathR)

Primary: Pathological response (PathR)

Secondary: Evaluation of the impact of inking the tumor margins during baseline endoscopy to avoid surgical plan changes putatively induced by tumor shrinking under therapy

Secondary: Evaluation of the impact of inking the tumor margins during baseline endoscopy to avoid surgical plan changes putatively induced by tumor shrinking under therapy

Post-hoc: Survival

Post-hoc: Survival

Post-hoc: Endoscopy to surgery interval

Post-hoc: Endoscopy to surgery interval

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase II trial assessing Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in a pre-operative setting for resectable and untreated head and neck squamous cell carcinoma.