Trust : Bintrafusp Alfa and Doxorubicin Hydrochloride in Treating Patients with Advanced Sarcoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Bergonie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Feb 2022 → ongoing

Decision date (initial)

2024-10-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509497-30-00

EudraCT number

2020-005703-39

ClinicalTrials.gov

NCT04874311

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacogenomic, Therapy, Safety, Efficacy

To evaluate the antitumor activity of combined administration of standard doxorubicin and double immune modulation with Bintrafusp alfa in terms of 6-month progressionfree 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.

Secondary objectives 5

1. Independently for each subgroup (TLS+ or TLS-):
2.  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).
3.  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).
4.  To evaluate the safety of combined administration of doxorubicin in association with Bintrafusp alfa (NCI-CTC v5). The combination of Bintrafusp alfa with doxorubicin is not anticipated to have overlapping toxicity, pharmacodynamic or pharmacokinetic interaction, a formal phase I trial is therefore not required. However, a safety run-in for tolerability will be implemented in the protocol to guarantee the absence of safety signals after the inclusion of the first 6, 12 and 18 patients (regardless of TLS status).
5.  Mandatory biomarker study: To perform pharmacodynamic/mechanism of action biomarkers analysis as well as predictive biomarkers analysis on pre-treatment and on-treatment tumor biopsies.

Conditions and MedDRA coding

Adult patients with locally advanced/unresectable and/or metastatic soft-tissue sarcomas.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Histologically confirmed soft-tissue sarcoma with unknown translocation (including the following histologies but not limited to undifferentiated pleomorphic sarcomas, dedifferentiated liposaromas or leiomyosarcomas). Diagnosis must be reviewed or confirmed by the RRePS Network (Réseau de référence en pathologie des sarcomes et des viscères) as recommended by the French NCI (Institut National du Cancer, Inca).
2. Metastatic or unresectable locally advanced disease,
3. No previous systemic treatment for advanced/metastatic disease,
4. For TLS status: available archived FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample or tumor material newly obtained by biopsy. Except if TLS analysis have been already performed by Biopathological platform at Bergonié Institute or on site by a pathologist specifically trained by a representative of Biopathological platform at Bergonié Institute, presence or absence of TLS should be confirmed by central review based on FFPE (Formalin-Fixed ParaffinEmbedded) tumor tissue sample (archived or newly obtained by biopsy for research purpose),
5. Age ≥ 18 years,
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,
7. Life expectancy > 3 months,
8. Patients must have measurable disease (lesion in previously irradiated filed can be considered as measurable if progressive at inclusion according to RECIST v1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as > 10 mm with spiral CT scan.,
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 [RBC] transfusion in the last 30 days); absolute neutrophil count (ANC) ≥ 1.5 G/l, and platelet count ≥ 100 G/l. b) Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement and/or liver metastasis for AP and ≤ 5 x ULN in case of liver metastasis for AST and ALT) 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 (CrCl) ≥ 40 ml/min (according to Cockroft Gault formula) f) Normal international normalized ratio (INR), PT ≤ 1.5 x ULN and activated partial thromboplastine time (aPTT) ≤ 1.5 x ULN.
11. Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization. Serum or urine pregnancy test must be repeated within 72 hours prior to receiving the first dose of study medication,
12. Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for at least seven months after discontinuation of treatment for women and four months for men. Acceptable methods of contraception will be described in the full protocol.
13. No prior or concurrent malignant disease diagnosed or treated in the last 3 years except for: 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.
14. .Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia and vitiligo of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (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.

Exclusion criteria 23

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 (CNS),
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 resting corrected QT interval (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 by MUGA or echocardiogram) d) Any factors increasing the risk of QTc prolongation or arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years old or any concomitant medication known to prolong the QT interval, 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: a) Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible b) Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day c) Administration of steroids through a route known to result in a minimal systemic exposure (intranasal, topical, local (e.g., intro-ocular, inhalation or intra-articular) are acceptable. d) Steroids as premedication for hypersensitivity reactions (e;g;, CT scan premedication) are allowed.
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 (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice),
16. Has known active hepatitis B or hepatitis C,
17. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV1/2 antibodies),
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of treatment. Note: Patients, if enrolled, should not receive live vaccine within 30 days prior to the first dose of treatment, whilst receiving study treatments and up to 30 days after the last dose. Seasonal flu vaccines that do not contain a live virus are permitted,
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. Low molecular weight heparin and heparin are allowed.
23. Prior mediastinal radiation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 (30). 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.

Secondary endpoints 7

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. Median PFS and 1-year PFS will be reported.
5. Overall Survival (OS) is defined as the time from randomization to death (of any cause). Median OS and 1-year OS will be reported.
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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Bergonie

Sponsor organisation

Institut Bergonie

Address

229 Cours De L Argonne

City

Bordeaux

Postcode

33000

Country

France

Scientific contact point

Organisation

Institut Bergonie

Contact name

Pr Antoine ITALIANO

Public contact point

Organisation

Institut Bergonie

Contact name

Aurore BARTHOD-MALAT

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications