CombinatiOn of NivolumAb plus Relatlimab in patients with Advanced or metastatic soft-tissue Sarcoma: a proof-of-concept randomized phase II study

Phase 1

• Conditions: Advanced soft-tissue sarcoma; MedDRA version: 20.0 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0 Level: LLT Classification code 10039494 Term: Sarcoma NOS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2019-002332-81-FR
• Lead Sponsor: Institut Bergonié

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2019-09-18
• Last Update Posted: 1 February 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Not specified
• Target Recruitment: 67

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

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified