Congrats : Combination of Nivolumab Plus Relatlimab in Patients with Advanced or Metastatic Soft-Tissue Sarcoma: a Proof-Of-Concept Randomized Phase Ii Study

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

27 Feb 2020 → 29 Mar 2026

Decision date (initial)

2024-09-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-509495-42-00

EudraCT number

2019-002332-81

ClinicalTrials.gov

NCT04095208

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Efficacy, Pharmacodynamic, Therapy, Safety

To evaluate the antitumor activity of Nivolumab in association with relatlimab in terms of 6-month progression-free rate (rate of complete or partial responses or stable disease at 6 months, as per RECIST 1.1 criteria) after centralized radiological review, in patients with advanced or metastatic soft-tissue sarcoma.

Secondary objectives 3

1. To evaluate the antitumor activity of Nivolumab in association with relatlimab in terms of: o Best overall response (as per RECIST 1.1), o 1- and 2-year Progression-free survival (PFS), o 1- and 2-year Overall survival (OS), o Growth modulation index (GMI).
2. To assess the safety profile of Nivolumab in association with relatlimab (NCI-CTCAE v5).
3. Exploratory: o To perform pharmacodynamic study on blood, tumor and stool samples, in order to but not limited to, perform integrative assessment of prognostic/predictive factors of response to treatment. o To compare progression-free survival between the two treatment arms.

Conditions and MedDRA coding

Adult participants with advanced unresectable or metastatic soft-tissue sarcoma.

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. Histology: participant with soft tissue sarcoma histologically confirmed and reviewed by the RRePS Network as recommended by the French NCI (Inca),
2. Presence of mature tertiary lymphoid structures (TLS). Except if presence of TLS have been already confirmed by Biopathological platform at Bergonié Institute, presence of TLS should be confirmed by central review based on FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample (archived or newly PROT_CONgRAtS_V6.0 du |10|10|2022| Page 8 sur 82 obtained by biopsy for research purpose). Note that the presence of TLS could be determined by central analysis if not available before.
3. For research purpose, have provided tissue of a tumor lesion from < 3 months old archival tissue sample (both frozen or FFPE) obtained on locally advanced disease, or metastasis, with no subsequent treatment since or presence of tumor lesion that can be biopsied,
4. Advanced non resectable / metastatic disease,
5. Documented progression according to RECIST criteria, unless the participant has no received prior systemic treatment for advanced disease. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical (CT scans or MRI) obtained at less than 6 months interval within the 12 months before inclusion.
6. At least one tumor site that can be biopsied for research purpose,
7. Previous treatment: no more than 2 previous lines of systemic therapy for advanced or metastatic disease
8. Participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement. Patients amenable to surgical resection by using pre-operative systemic therapy are not eligible to the present study
9. Age ≥ 18 years
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
11. Measurable disease according to RECIST v1.1 outside any previously irradiated field (except if progressive as per RECIST v1.1 at inclusion). At least one site of disease must be uni-dimensionally ≥ 10 mm
12. Life expectancy > 3 months
13. No symptomatic central nervous system disease
14. No chronic use of glucocorticoids, higher than 10 mg/day prednisone equivalent
15. Adequate hematological, renal, metabolic and hepatic function: a. Hemoglobin > 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); leucocytes ≥ 2 G/l, absolute neutrophil count (ANC) > 1.5 G/l and platelet count > 100 G/l, lymphocyte count > 0.5 G/l b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normality (ULN) (< 5 in case of liver metastasis). c. Total bilirubin < 1.5 x ULN OR Direct bilirubin < ULN for subjects with total bilirubin levels > 1.5 x ULN. d. Albumin > 25g/l. e. Serum creatinine < 1.5 x ULN OR Calculated creatinine clearance (CrCl) > 60 ml/min (calculated per institutional standard) for subject with creatinine levels > 1.5 x ULN. f. INR < 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants g. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants, h. Thyroid functions (T3, T4 and TSH) ≤ 1.5 x ULN and ≥ LLN
16. Left ventricular ejection fraction (LVEF) ≥ 50% assessed by TTE or MUGA (TTE preferred test) within 6 months from study entry
17. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma
18. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy, except for TKI which should be discontinued for > 2 weeks before treatment start
19. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 5.0)
20. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study entry. Pregnancy test should be repeated within 24 hours prior to receiving the first dose of study medication
21. Women must agree to use a medically acceptable method of contraception throughout the treatment period and for 6 months weeks after discontinuation of treatment. Men must agree to use a medically acceptable method of contraception throughout the treatment period and for 8 months after discontinuation of treatment. Acceptable methods for contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year
22. Voluntary signed and dated written informed consents prior to any specific study procedure
23. Patients with a social security in compliance with the French law

Exclusion criteria 26

1. Previous treatment with an PD1/PDL1, LAG-3
2. Previous enrolment in the present study
3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases
4. Women who are pregnant or breast feeding
5. Participant unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons
6. Known hypersensitivity to any involved study drug or of its formulation components
7. Participation to a study involving a medical or therapeutic intervention in the last 30 days
8. Uncontrolled cardiac arrhythmia or hypertension, as per investigator discretion
9. Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following: a. Myocardial infarction or stroke/transient ischemic attack within the 6 months prior to study entry. b. Uncontrolled angina within the 3 months prior to study entry. c. Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes, or poorly controlled atrial fibrillation). d. Corrected QT (QTc) prolongation > 480 msec. e. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled venous thrombus). f. Cardiovascular disease-related requirement for daily supplemental oxygen. g. History of two or more myocardial infarction or two or more coronary revascularization procedures. h. Subjects with history of myocarditis, regardless of etiology. i. Troponin T (TnT) or I (TnI) > ULN
10. Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-cytotoxic T-lymphocyte-associated protein [CTLA]-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after endocrinopathy)
11. Active or prior documented inflammatory bowel disease (e.g. crohn disease, ulcerative colitis)
12. Current or prior use of immunosuppressive medication within 28 days before the first dose of nivolumab, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent (use for brain metastases is not permitted 28 days prior to start of therapy)
13. Active or prior documented autoimmune disease within the past 3 years. Note: Subjects with active, known or suspected autoimmune disease such as vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
14. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
15. History of idiopathic pulmonary fibrosis, history of non-infectious pneumonitis that required steroids, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
16. Has an active neurological disease, as well as an history of encephalitis, meningitis or uncontrolled seizures in the 12 months prior to study entry
17. Has en history of myocarditis
18. Has known active hepatitis B or hepatitis C
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies)
20. Has a known history of tuberculosis
21. Participant with oral anticoagulation therapy
22. Prior organ transplantation, including allogeneic stem cell transplantation
23. Has an active infection requiring systemic treatment within two weeks prior study entry
24. Has received a live vaccine within 30 days prior to the first dose of trial treatment
25. Individuals deprived of liberty or placed under legual guardianship
26. Body weight < 40 kg

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Efficacy of nivolumab in association with relatlimab (Arm A) as well of efficacy of nivolumab alone (Arm B) will be assessed, independently for each arm, in terms of 6-month progression-free rate (6-month PFR). This endpoint is a validated endpoint in STS (Van Glabbeke, EJC 2002):
2. 1a) PFR is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST 1.1. The PFR at 6 months will be reported. Note that confirmation of claimed responses at 4 weeks later is not required.
3. 1b) Disease status at 6 months will be centrally reviewed for all patients by an expert radiologist blinded to the treatment. Centralized radiological reviewed data will be used for the primary efficacy analysis.
4. 1c) No statistical comparison of efficacy between arms will be performed.

Secondary endpoints 11

1. Anti-tumor activity will be assessed, independently for each arm, in terms of additional efficacy endpoints:
2. 1a) Best overall response is defined as the best response across all time points (RECIST 1.1). The best overall response is determined once all the data for the patient is known (RECIST 1.1). Note that confirmation of claimed responses at 4 weeks later is not required.
3. 1b) Progression-free survival (PFS) is defined as the delay between the start date of treatment and the date of progression (as per RECIST 1.1) or death (from any cause), whichever occurs first. Median PFS, 1- and 2-year PFS rates will be reported independently for each arm.
4. 1c) Overall survival (OS) defined as the delay between the start date of treatment and the date of death (of any cause). Median OS, 1- and 2-year OS rate will be reported independently for each arm.
5. 1d) GMI is defined for each patient as ratio of its PFS on the nivolumab+BMS-986016 treatment combination to its PFS on the previous line of therapy, in patients with documented progression at inclusion. This accounts for inter-patient variability, the patient serving as his/her own control and implies by the natural history of the disease that the PFS tends to become shorter in successive lines of therapy. It is thought that an anti-cancer agent should be considered effective if the GMI is >1.3
6. The safety profile of the association. Events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0. Both AE and SAE will be coded according to the standardized medical terminology MedDRA.
7. Ancillary pharmacodynamic study:
8. 7a) Blood : samples will be collected at predefined time points for assessment of serum cytokines levels, as well as levels of Kynurenine and Kynurenine to Tryptophan ratio (ELISA and LC/MS) and lymphocytes subpopulations monitoring (flow cytometry)
9. 7b) Tumor: Mandatory Fresh pre-treatment and on-treatment tumor biopsies (FFPE + FF) will be collected to perform Hematoxylin and eosin staining (H&E) and IHC assessments including, but not limited to the following markers: IDO1, CSF-1R, PDL1, LAG3, CD68, CD163, CD8, Ki67 and other exploratory markers. The analysis will be prioritized based on the amount of material available.
10. 7c) Stool samples will be collected at baseline to evaluate the potential role of the gut microbiome in modulating the immune response (16S rRNA).
11. Exploratory analysis: 6-month PFS rates will be evaluated and compared across the two arms.

Investigational products

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

Test 2

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 · 5 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

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

Documents 5 files

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

Application history

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