| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced soft-tissue sarcoma |
| Sarcome des tissus mous localement avancé et/ou métastatique |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced soft-tissue sarcoma |
| Sarcome des tissus mous localement avancé et/ou métastatique |
|
| 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 | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the antitumor activity of Nivolumab in association with relatlimab in terms of:
oBest overall response (as per RECIST 1.1),
* 1- and 2-year Progression-free survival (PFS),
* 1- and 2-year Overall survival (OS),
* Growth modulation index (GMI).
- To assess the safety profile of Nivolumab in association with relatlimab (NCI-CTCAE v5).
- Exploratory:
* To perform pharmacodynamic study on blood and tumor samples, in order to but not limited to, perform integrative assessment of prognostic/predictive factors of response to treatment.
* To compare progression-free survival between the two treatment arms.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histology: participant with soft tissue sarcoma histologically confirmed and reviewed by the RRePS Network as recommended by the French NCI (Inca),
2. For TLS status determination: available archived FFPE (Formalin-Fixed Paraffin-Embedded) tumor tissue sample not previously treated. In case of archived material is not available, presence of tumor lesion that can be biopsied for research purpose,
3. Presence of high-level of tertiary lymphoid structures (by central review),
4. 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,
5. Advanced non resectable / metastatic disease,
6. 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.
7. At least one tumor site that can be biopsied for research purpose,
8. Previous treatment: no more than 2 previous lines of systemic therapy for advanced or metastatic disease
9. 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,
10. Age ≥ 18 years,
11. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1,
12. 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,
13. Life expectancy > 3 months,
14. No symptomatic central nervous system disease,
15. No chronic use of glucocorticoids, higher than 10 mg/day prednisone equivalent,
16. 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,
17. Left ventricular ejection fraction (LVEF) ≥ 50% assessed by TTE or MUGA (TTE preferred test) within 6 months from study entry,
18. 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,
19. 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
20. 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),
21. 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.
22. 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.
23. Voluntary signed and dated written informed consents prior to any specific study procedure,
24. Patients with a social security in compliance with the French law. |
|
| E.4 | Principal exclusion criteria |
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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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):
- PFR is defined as the rate of complete or partial response (CR, PR) or stable disease (SD), as per RECIST 1.1.
- 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The PFR at 6 months will be reported. Note that confirmation of claimed responses at 4 weeks later is not required. |
|
| E.5.2 | Secondary end point(s) |
1- Efficacy will be assessed, independently for each arm, in terms of best overall response. Best overall response is defined as the best response across all time points as per RECIST 1.1,
2- Efficacy will be assessed, independently for each arm, in terms of progression-free survival (PFS).
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,
3- Efficacy will be assessed, independently for each arm, in terms of overall survival (OS). OS defined as the delay between the start date of treatment and the date of death (of any cause),
4- Efficacy will be assessed, independently for each arm, in terms of Growth modulation index (GMI). GMI is defined for each patient as the ratio of its PFS on the nivolumab + Relatlimab treatment combination to its PFS on the previous line of therapy, in patients with documented progression at inclusion,
5- The safety profile of the association will assessed using the Common Terminology Criteria for Adverse Events (CTCAE) from the NCI v5.0.
Toxicity will be graded using the commonterminology criteria from the NCI v5.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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,
2- Median PFS, 1- and 2-year PFS rates will be reported independently for each arm,
3- Median OS, 1- and 2-year OS rate will be reported independently for each arm,
4- This method 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 greater than 1.3,
5- Safety will be assessed across the treatment period |
|
| 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 | No |
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| 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 | No |
| 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 | 5 |
| 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
|
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
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