| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| soft-tissue sarcoma |
| sarcomes des tissus mous |
|
| E.1.1.1 | Medical condition in easily understood language |
| soft-tissue sarcoma |
| sarcomes des tissus mous |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10039494 |
| E.1.2 | Term | Sarcoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the antitumor activity of combined administration of standard doxorubicin and double immune modulation with Bintrafusp alfa in terms of 6 month progression-free rate (as per RECIST v1.1 criteria) after blinded centralized radiological review, in patients with advanced STS. Antitumor activity will be assessed independently for 2 distinct subgroups of patients, depending on the presence (TLS+) or absence (TLS-) of mature tertiary lymphoid structures. |
| Evaluer l’activité antitumorale du bintrafusp alfa prescrit en association avec la doxorubicine en termes de taux de non-progression à 6 mois (selon les critères RECIST v1.1), après relecture centralisée réalisée en aveugle du bras de traitement, chez les patients porteurs de STM avancés. L’activité antitumorale sera évaluée indépendamment pour chaque sous-groupe de patients, en fonction de la présence (TLS+) ou de non (TLS-) de structures lymphoïdes tertiaires matures. |
|
| E.2.2 | Secondary objectives of the trial |
Independently for each subgroup (TLS+ or TLS-):
• To evaluate the antitumor activity of combined administration of doxorubicin in association with Bintrafusp alfa in terms of 6-month objective response (as per RECIST v1.1 criteria), best overall response (as per RECIST v1.1 criteria), 1-year progression free survival (PFS) (as per RECIST v1.1 criteria) and 1- year overall survival (OS).
• To evaluate the antitumor activity of combined administration of doxorubicin in association with Bintrafusp alfa in terms of Immune response (iRECIST - Seymour et al 2017).
• To evaluate the safety of combined administration of doxorubicin in association with Bintrafusp alfa (NCI-CTC v5). |
Indépendamment pour chaque sous-groupe (TLS+ ou TLS-)
•Evaluer l’activité antitumorale du bintrafusp alfa prescrit en association avec la doxorubicine en termes de réponse objective à 6 mois, de meilleure réponse, de survie sans progression à 1 an (selon les RECIST v1.1), et de survie globale à 1 an.
•Evaluer l’activité antitumorale du bintrafusp alfa prescrit en association avec la doxorubicine en termes de réponse immune (iRECIST – Seymour et al 2017)
•Evaluer le profil de toxicité de l’association bintrafusp alfa + doxorubicine (NCI-CTCAE v5).
•Etude de biomarqueurs (pharmacodynamie) à partir d’échantillons de sang, de tumeur et de seilles obtenus à différents temps de la prise en charge. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histologically confirmed soft-tissue sarcoma with unknown translocation (including the following histologies but not limited to undifferentiated pleomorphic sarcomas, dedifferentiated liposaromas or leiomyosarcomas).
2.Metastatic or unresectable locally advanced disease,
3.No previous systemic treatment for advanced/metastatic disease,
4.For TLS status: available archived FFPE tumor tissue sample or tumor material newly obtained by biopsy.
5.Age ≥ 18 years,
6.ECOG ≤ 1,
7.Life expectancy > 3 months,
8.Patients must have measurable disease defined as per RECIST v1.1,
9.Patient must comply with the collection of tumor biopsies and biomarkers study. Tumors must be accessible for biopsy,
10.Adequate hematological, renal, metabolic and hepatic function:
a)Hemoglobin ≥ 9 g/dl (patients may not have received prior red blood cell transfusion in the last 30 days); absolute neutrophil count ≥ 1.5 G/l, and platelet count ≥ 100 G/l.
b)Alanine aminotransferase, aspartate aminotransferase ≤ 1.5 x ULN (≤ 5 in case of extensive liver involvement) and alkaline phosphatase ≤ 2.5 x ULN
c)Total bilirubin ≤ ULN (≤ 3 in case of liver involvement)
d)Albumin ≥ 30 g/l
e)Creatinine level ≤ 1.5 x ULN or calculated creatinine clearance ≥ 40 ml/min (according to Cockroft Gault formula)
f)INR, PT ≤ 1.5 x ULN and aPTT ≤ 1.5 x ULN.
11.Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
12.Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for at least two months after discontinuation of treatment for women and four months for men.
13.No prior or concurrent malignant disease diagnosed or treated in the last 3 years except for a. Superficial/non-invasive bladder cancer, or basal or squamous cell carcinoma in situ treated with curative intent; b. endoscopically resected GI cancers limited to the mucosal layer without recurrence in > 1 year,
14.Recovery to grade ≤ 1 from any adverse event derived from previous treatment (excluding alopecia and vitiligo of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the NCI-CTCAE, version 5.0,
15.Voluntarily signed and dated written informed consent prior to any study specific procedure,
16.Patients with a social security in compliance with the French law. |
|
| E.4 | Principal exclusion criteria |
1.Previous treatment with doxorubicin, daunorubicin, epirubicin, idarubicin and/or any other anthracyclines or anthracediones at the maximum cumulative dose or any approved or investigational treatment targeting PD1, PD-L1 or TGFB1,
2.Known central nervous system malignancy,
3.Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
4.Participation to a study involving a medical or therapeutic intervention in the last 30 days,
5.Previous enrolment in the present study,
6.Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
7.Known hypersensitivity to any involved study drug or any of its formulation components,
8. Any history of anaphylaxis, or recent, within 5 months, history of uncontrollable asthma,
9.Individuals deprived of liberty or placed under legal guardianship,
10.Any of the following cardiac criteria:
a)Mean QTcF ≥ 470 msec, obtained from three consecutive ECGs,
b)Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG,
c)LVEF ≤ 50% per CTCAE v5
d)Any factors increasing the risk of QTc prolongation or arrhythmic events ,
e)Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, uncontrolled hypertension, congestive heart failure NYHA Grade ≥2, ventricular arrhythmias requiring continuous therapy, supraventricular arrhythmias including atrial fibrillation, which are uncontrolled, haemorrhagic or thrombotic stroke, including transient ischaemic attacks, cerebral vascular accident/stroke or any other central nervous system bleeding
11.Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
12.History of bleeding diathesis or recent major bleeding event (i.e. Grade ≥ 2 bleeding events within 30 days prior to treatment,
13.Prior organ transplantation including allogenic stem-cell transplantation, except transplants that do not require immunosuppression,
14.Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection requiring systemic therapy, drug-induced interstitial lung disease (ILD) or subject 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 subject’s tolerance for the study or ability to consistently participate in study procedures,
15.Active infection including tuberculosis,
16.Has known active hepatitis B or hepatitis C,
17.Has a known history of HIV infection,
18.Receipt of live attenuated vaccine within 30 days prior to the first dose of treatment. ,
19.Patients with current or history of deep vein thrombosis within 6 months prior to randomization,
20.Any contraindication to biopsy for the research,
21.Any other contraindication to Doxorubicin administration,
22.Patients with oral anticoagulation therapy based on Vitamin K antagonist.
23.Prior mediastinal radiation.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Efficacy will be assessed in terms of 6-month progression-free rate, as per the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). This endpoint is a validated endpoint in STS. Non-progression is defined as complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. Disease status at 6 months will be centrally reviewed for all patients by an expert radiologist blinded to the treatment. Reviewed data will be used for the primary efficacy analysis. |
L’activité antitumorale sera évaluée en termes de taux de non-progression à 6 mois (6- month progression-free rate, 6-month PFR).
Le taux de non-progression à 6 mois est défini par la proportion de patients avec une réponse complète ou partielle ou maladie stable (RECIST v1.1, >= 24 semaines).
Le critère principal sera évalué à partir des résultats de la relecture radiologique centralisée, en aveugle du traitement reçu.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The PFR at 6 months will be reported |
| Le taux de non-progression sera reporté à 6 mois |
|
| E.5.2 | Secondary end point(s) |
1 - Objective response is defined as complete response (CR) or partial response (PR) defined as per RECIST evaluation criteria v1.1. Claimed responses will have to be confirmed at least 4 weeks later to ensure responses identified are not the results of measurement errors.
2 -Duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started.
3 - Best overall response under treatment is defined as the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation as per RECIST v1.1 criteria. It is determined once all the data for the patient is known.
4 - Progression-Free Survival (PFS) is defined as the time from randomization to the first occurrence of disease progression (defined as per RECIST V1.1) or death (of any cause), whichever occurs first.
5 - Overall Survival (OS) is defined as the time from randomization to death (of any cause).
6 - Immune response is defined following (iRECIST - Seymour et al. 2017). Analysis of Immune-related response will be based on blinded central radiological review data.
7 - Safety will be graded using the common toxicity criteria from the NCI CTC-AE v5.0. |
1 - Réponse objective définie par la proportion de patients avec une réponse complète (RC) ou partielle (RP) (RECIST v1.1). Les réponses devront être confirmées au moins 4 semaines après.
2- La durée de la réponse est mesurée à compter de la date d’enregistrement de d’une réponse (RC/RP) jusqu’à la date de documentation objective d’une première rechute ou progression, en se basant pour référence pour la progression, la plus petite mesure de taille tumorale enregistrée depuis l’initiation du traitement.
3 - Meilleure réponse globale définie par la meilleure réponse (RECIST v1.1) observée entre l’initiation et la fin du traitement. Elle est déterminée une fois que toutes les données pour un même patient sont connues.
4 - Survie sans progression (PFS) définie par le délai entre la date de début de traitement et la date du premier des évènements suivants : progression ou décès (quelle que soit la cause).
5 - La survie globale (OS) est définie par le délai entre la date de début de traitement et la date de décès (quelle que soit la cause).
6 - La réponse immunologique est définie selon les critères iRECIST de Seymour et al. 2017. L’analyse de la réponse immunologique sera basée sur la revue centralisée des données (en insu du traitement).
7 - Le profil de tolérance sera évalué selon l’échelle de sévérité de la NCI-CTCAE v5.0. Les évènements indésirables graves ou non graves seront codés selon le dictionnaire MedDRA. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- Objective response at 6 months will be reported
2 - Duration of response will be reported once all the data for a patient is known
3 - Best overall response will be reported once all the data for a patient is known
4- Median PFS, 1-year PFS rates will be reported,
5- Median OS, 1-year OS rate will be reported,
6 - Immune response will be reported throughout the treatment period (an expected average of 6 months),
7- Safety will be assessed across the treatment period |
1- La réponse objective sera reportée à 6 mois
2 - La durée de la réponse sera reportée une fois que toutes les données pour un même patient seront connues
3 - La meilleure réponse sera reportée une fois que toutes les données pour un même patient seront connues
4- Le taux de PFS à 1 an et la médiane de PFS seront reportés
5- Le taux d'OS à 1 an et la médiane d'OS seront reportés,
6 - La réponse immunologique sera reportée tout au long de la période de traitement (moyenne estimée de 6 mois de traitement)
7- Le profil de tolérance sera évalué tout au long de la période de traitement |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Doxorubicine seule |
| Doxorubicin alone |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS |
| Dernière visite du dernier patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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