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Clinical Trial Results:
A randomized phase II study of Durvalumab (MEDI4736) and Tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma.

Summary
EudraCT number	2016-004750-15
Trial protocol	DE
Global end of trial date	12 Aug 2022

Results information
Results version number	v1(current)
This version publication date	26 Mar 2025
First version publication date	26 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

AIO-STS-0415

ISRCTN number

US NCT number

NCT03317457

WHO universal trial number (UTN)

Sponsor organisation name

AIO-Studien-gGmbH

Sponsor organisation address

Kuno-Fischer-Str. 8, Berlin, Germany, 14057

Public contact

AIO-Studien-gGmbH, AIO-Studien-gGmbH, 0049 30814534431, info@aio-studien-ggmbh.de

Scientific contact

AIO-Studien-gGmbH, AIO-Studien-gGmbH, 0049 30814534431, info@aio-studien-ggmbh.de

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

12 Aug 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Aug 2022

Global end of trial reached?

Yes

Global end of trial date

12 Aug 2022

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of tremelimumab and durvalumab (MEDI4736) in comparison to doxorubicin in treatment-naïve soft tissue sarcoma patients

Protection of trial subjects

This study was planned, analyzed and conducted according to the study protocol and in accordance with the International Conference on Harmonization (ICH) ‚Guideline for Good Clinical Practice E6(R1)‘, CPMP/ICH/135/95, based on the principles of the Declaration of Helsinki (1964) and its October 1996 amendment (Somerset West, South Africa). The study was duly conducted in compliance with the German Arzneimittelgesetz (AMG; German Drug Law), and the corresponding Directive 2001/20/EC. Subjects were fully informed regarding all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Apr 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 103

Worldwide total number of subjects

103

EEA total number of subjects

103

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

Screening details

In total, 118 patients were screened for eligibility for study participation. Of these, 104 were eligible, and 103 were randomized.

Period 1 title

Randomization to treatment start

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Durvalumab + tremelimumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Durvalumab was administered at a fixed dose of 1500 mg Q4W by i.v. infusion.

Investigational medicinal product name

Tremelimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Tremelimumab was administered at a fixed dose of 75 mg Q4W by i.v. infusion.

Doxorubicin

Arm description

Arm type

Active comparator

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin was given at 75 mg/m2 Q3W by i.v. infusion, up to a total of 6 cycles.

Number of subjects in period 1	Durvalumab + tremelimumab	Doxorubicin
Started	53	50
Completed	53	39
Not completed	0	11
No treatment started	-	11

Period 2 title

Treatment and Follow-Up

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Durvalumab + tremelimumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Infusion

Dosage and administration details

Durvalumab was administered at a fixed dose of 1500 mg Q4W by i.v. infusion.

Investigational medicinal product name

Tremelimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Tremelimumab was administered at a fixed dose of 75 mg Q4W by i.v. infusion.

Doxorubicin

Arm description

Arm type

Active comparator

Investigational medicinal product name

Doxorubicin

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Doxorubicin was given at 75 mg/m2 Q3W by i.v. infusion, up to a total of 6 cycles.

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: A considerable number of patients randomized to the control arm did not initiate treatment, while all patients randomized to experimental treatment did. Therefore, a modified intention-to-treat population was defined post-hoc as the relevant patient population for analysis and reporting, including baseline data. Period 1 reports all randomized patients, while period 2 reports all patients for whom intention to treat persisted after randomizaiton, which is the main patient set for reporting.

Number of subjects in period 2 ^[2]	Durvalumab + tremelimumab	Doxorubicin
Started	53	39
Completed	53	39

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: A considerable number of patients randomized to the control arm did not initiate treatment, while all patients randomized to experimental treatment did. Therefore, a modified intention-to-treat population was defined post-hoc as the relevant patient population for analysis and reporting, including baseline data. The patient set reported and thus the number of baseline patients is therefore smaller than the number of screened and of randomized patients.

Baseline characteristics

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Reporting group title

Durvalumab + tremelimumab

Reporting group description

Reporting group title

Doxorubicin

Reporting group description

Reporting group values	Durvalumab + tremelimumab	Doxorubicin	Total
Number of subjects	53	39	92
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
median (inter-quartile range (Q1-Q3))	61 (54 to 68)	62 (56 to 67)	-
Gender categorical
Units: Subjects
Female	28	22	50
Male	25	17	42

End points

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Reporting group title

Durvalumab + tremelimumab

Reporting group description

Reporting group title

Doxorubicin

Reporting group description

Reporting group title

Durvalumab + tremelimumab

Reporting group description

Reporting group title

Doxorubicin

Reporting group description

Primary: Overall survival

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End point title

Overall survival

End point description

Censoring rules: If no event was observed, the patient was censored at the day of last contact. If the date of the last contact was not available, the date of the last attended visit was used for the calculation.

End point type

Primary

End point timeframe

OS was defined as the time in months between the date of randomization and the date of death from any cause.

End point values	Durvalumab + tremelimumab	Doxorubicin
Number of subjects analysed	53	39
Units: Months
median (confidence interval 95%)	17.4 (9.1 to 23.5)	12.5 (9.6 to 15.6)

Logrank test of median overall survival

Comparison groups

Durvalumab + tremelimumab v Doxorubicin

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1829

Method

Logrank

Confidence interval

Secondary: Overall response rate

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End point title

Overall response rate

End point description

RECIST was modified so that progressive disease (PD) had to be confirmed at the next scheduled visit, preferably, and no earlier than 4 weeks after the initial assessment of PD in the absence of clinically significant deterioration. Treatment continued between the initial assessment of progression and confirmation for progression. The subsequent imaging was resumed at the pre-specified time point. In case of confirmed pogression, the date of the first imaging with sign of PD (according to RECIST) was counted as an event.

End point type

Secondary

End point timeframe

Response was assessed as best overall response according to radiologic assessment and modified RECIST criteria

End point values	Durvalumab + tremelimumab	Doxorubicin
Number of subjects analysed	53	39
Units: Patients
Complete response	0	1
Partial response	5	4
Stable disease	10	12
Non-CR/Non-PD	1	0
Progressive disease	39	19

No statistical analyses for this end point

Secondary: Progression-free survival (PFS)

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End point title

Progression-free survival (PFS)

End point description

Censoring rules: Patients without event were censored at the last evaluable tumor assessment, if available, and on the date of the last contact otherwise. Patients who had started any subsequent anti-cancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to the subsequent anti-cancer therapy, if available, and at the date of initiation of the subsequent anti-cancer therapy otherwise.

End point type

Secondary

End point timeframe

PFS was defined as the time in months between the date of randomization until the date of confirmed PD (based on investigator assessments) or the date of death from any cause (patients who died without a reported progression were considered to have progre

End point values	Durvalumab + tremelimumab	Doxorubicin
Number of subjects analysed	53	39
Units: Months
median (confidence interval 95%)	2.7 (2.4 to 2.9)	2.8 (2.6 to 4.9)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were to be reported from signing of informed consent until the first follow-up visit.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Durvalumab + tremelimumab

Reporting group description

Reporting group title

Doxorubicin

Reporting group description

Serious adverse events	Durvalumab + tremelimumab	Doxorubicin
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 53 (33.96%)	7 / 39 (17.95%)
number of deaths (all causes)	37	35
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension aggravated
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Fever
subjects affected / exposed	0 / 53 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fever of unknown origin
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion site extravasation
subjects affected / exposed	0 / 53 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Exacerbation of asthma
subjects affected / exposed	0 / 53 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 53 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Myocarditis
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cognitive disturbance
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 53 (1.89%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 53 (1.89%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 53 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary retention
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 53 (1.89%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteolytic lesion
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pathologic fracture of femur
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Febrile infection
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 53 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatremia
subjects affected / exposed	1 / 53 (1.89%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Durvalumab + tremelimumab	Doxorubicin
Total subjects affected by non serious adverse events
subjects affected / exposed	41 / 53 (77.36%)	28 / 39 (71.79%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain
subjects affected / exposed	4 / 53 (7.55%)	2 / 39 (5.13%)
occurrences all number	5	3
Vascular disorders
Hypertension
subjects affected / exposed	5 / 53 (9.43%)	1 / 39 (2.56%)
occurrences all number	9	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	13 / 53 (24.53%)	15 / 39 (38.46%)
occurrences all number	14	31
Fever
subjects affected / exposed	5 / 53 (9.43%)	3 / 39 (7.69%)
occurrences all number	5	3
Edema limbs
subjects affected / exposed	5 / 53 (9.43%)	1 / 39 (2.56%)
occurrences all number	5	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	9 / 53 (16.98%)	3 / 39 (7.69%)
occurrences all number	12	3
Dyspnoea
subjects affected / exposed	6 / 53 (11.32%)	2 / 39 (5.13%)
occurrences all number	8	3
Investigations
White blood cell decreased
subjects affected / exposed	2 / 53 (3.77%)	7 / 39 (17.95%)
occurrences all number	2	18
Neutrophil count decreased
subjects affected / exposed	0 / 53 (0.00%)	7 / 39 (17.95%)
occurrences all number	0	18
Alanine aminotransferase increased
subjects affected / exposed	5 / 53 (9.43%)	1 / 39 (2.56%)
occurrences all number	10	3
Nervous system disorders
Dysgeusia
subjects affected / exposed	4 / 53 (7.55%)	3 / 39 (7.69%)
occurrences all number	4	4
Blood and lymphatic system disorders
Anemia
subjects affected / exposed	11 / 53 (20.75%)	9 / 39 (23.08%)
occurrences all number	14	11
Gastrointestinal disorders
Nausea
subjects affected / exposed	8 / 53 (15.09%)	12 / 39 (30.77%)
occurrences all number	8	27
Vomiting
subjects affected / exposed	4 / 53 (7.55%)	7 / 39 (17.95%)
occurrences all number	4	12
Abdominal pain
subjects affected / exposed	7 / 53 (13.21%)	2 / 39 (5.13%)
occurrences all number	7	2
Diarrhea
subjects affected / exposed	6 / 53 (11.32%)	3 / 39 (7.69%)
occurrences all number	9	6
Mucositis oral
subjects affected / exposed	3 / 53 (5.66%)	4 / 39 (10.26%)
occurrences all number	3	12
Constipation
subjects affected / exposed	4 / 53 (7.55%)	2 / 39 (5.13%)
occurrences all number	4	4
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	11 / 53 (20.75%)	1 / 39 (2.56%)
occurrences all number	15	1
Alopecia
subjects affected / exposed	1 / 53 (1.89%)	7 / 39 (17.95%)
occurrences all number	1	8
Endocrine disorders
Hypothyroidism
subjects affected / exposed	6 / 53 (11.32%)	0 / 39 (0.00%)
occurrences all number	6	0
Hyperthyroidism
subjects affected / exposed	4 / 53 (7.55%)	1 / 39 (2.56%)
occurrences all number	4	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	6 / 53 (11.32%)	2 / 39 (5.13%)
occurrences all number	10	3
Infections and infestations
Urinary tract infection
subjects affected / exposed	2 / 53 (3.77%)	4 / 39 (10.26%)
occurrences all number	2	5
Upper respiratory tract infection
subjects affected / exposed	2 / 53 (3.77%)	3 / 39 (7.69%)
occurrences all number	2	3
Metabolism and nutrition disorders
Anorexia
subjects affected / exposed	6 / 53 (11.32%)	1 / 39 (2.56%)
occurrences all number	7	1

More information

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Were there any global substantial amendments to the protocol? Yes

29 Nov 2017

Strategy for evaluation of efficacy endpoints sharpened; Formal corrections, clarifications, and consistency

15 May 2018

Alignment with new information regarding IMPs received from manufacturer, e.g., toxicity management guidelines; Edits and clarifications

12 Jun 2019

Deletion of olaratumab as possible medication in combination with doxorubicin in the control arm due to revocation of olaratumab's marketing authorization; Shortening of observation period after IMP administration from 2-4 h to 1h; Extension of list of adverse events of special interest

20 Apr 2020

Edits to align the protocol with updates in the investigator's brochures, mainly relating to toxicity managment guidelines

10 May 2021

Alignment of protocol with IMP manufacturer's update of toxicity managment guidelines

24 Jun 2021

Alignment of protocol with IMP manufacturer's update of toxicity managment guidelines

Were there any global interruptions to the trial? No

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 randomized phase II study of Durvalumab (MEDI4736) and Tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall survival

Primary: Overall survival

Secondary: Overall response rate

Secondary: Overall response rate

Secondary: Progression-free survival (PFS)

Secondary: Progression-free survival (PFS)

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 randomized phase II study of Durvalumab (MEDI4736) and Tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall survival

Primary: Overall survival

Secondary: Overall response rate

Secondary: Overall response rate

Secondary: Progression-free survival (PFS)

Secondary: Progression-free survival (PFS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A randomized phase II study of Durvalumab (MEDI4736) and Tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma.