Patient population
vitiligo, TB, tumor, Sarcoidosis, fever, Graves’ disease, stroke, malignancy, non-melanoma skin cancer, uveitis, Crohn’s disease, allowed)Active infection, factors/prior transfusions)Creatinine, Tumor, autoimmune or inflammatory disorders, HBV infection, toxicity, primary breast tumor, hypothyroidism, Gilbert syndrome, infarction, thrombo-embolic, TNBC, hepatitis C, Hepatitis, diverticulitis, primary tumor, lentigo maligna, colitis, de-novo metastatic disease, celiac disease, primary malignancy, Wegener syndrome, Hashimoto syndrome, HCV RNA.Human immunodeficiency virus, idiopathic pneumonitis, intercurrent illness, headache, alopecia
RHEUMATOID ARTHRITIS, VITILIGO, TUMOR, RECURRENCE, CARCINOMATOUS MENINGITIS, HER2-POSITIVE BREAST CANCER, INFLAMMATORY BOWEL DISEASE, SARCOIDOSIS, SYMPTOMATIC CONGESTIVE HEART FAILURE, STROKE, HYPOPHYSITIS, UVEITIS, CARDIAC ARRHYTHMIA, DRUG-INDUCED PNEUMONITIS, IDIOPATHIC PULMONARY FIBROSIS, CARCINOMA IN SITU, HYPERSENSITIVITY REACTIONS, LIVER METASTASES, TUMOR, ORGANIZING PNEUMONIA, SKIN CONDITION, SYNDROME, HYPOTHYROIDISM, GILBERT SYNDROME, INFARCTION, HEPATITIS B, BRAIN METASTASES, DIVERTICULOSIS, DEEP VEIN THROMBOSIS (DVT), HEPATITIS C, HEPATITIS, DIVERTICULITIS, PRIMARY TUMOR, LENTIGO MALIGNA, METASTASES, COLITIS, CELIAC DISEASE, UNCONTROLLED HYPERTENSION, METASTASIS, UNSTABLE ANGINA PECTORIS, TRANSIENT ISCHEMIC ATTACK, DISEASE, WEGENER SYNDROME, SYSTEMIC LUPUS ERYTHEMATOSUS, EVENT, METASTATIC DISEASE, GRANULOMATOSIS WITH POLYANGIITIS, PEPTIC ULCER DISEASE, ALOPECIA, BRONCHIOLITIS OBLITERANS
Eligible patients were enrolled from 16 centers in Belgium and France. The complete list of inclusion and exclusion criteria is provided below.Inclusion criteria:Age of ≥18 yearsFemaleLife expectancy of a least 12 weeksBody weight above 35 kgThe locally recurrent or metastatic relapse must be histologically confirmed TNBC in patients not previously treated with systemic treatment and which cannot be treated with curative intent. Newly diagnosed patients with de-novo metastatic disease are eligibleEstrogen receptor (ER) and progesterone receptor (PR) negativity (<1% positive staining cells in the invasive tumor) determined locally using IHC per ASCO/CAP criteriaHuman epidermal growth factor receptor 2 (HER2) negativity (negative IHC staining [score 0 or 1] or negative fluorescence in situ hybridization [FISH] based on the ASCO/CAP guidelines and recommendations) and determined locallyNote: patients initially diagnosed with hormone receptor–positive and/or HER2-positive breast cancer OR de novo metastatic patients with a primary tumor hormone receptor-positive (weak positivity or ER negativity and PR positivity) considered as non-clinically relevant are eligible if the tumor biopsy obtained from a local recurrence or distant metastasis site confirms the TNBC disease.Confirmed tumor PD-L1 and CD73 IHC assessment as documented through central testing of a representative tumor tissue specimen for stratification purposes (only for phase II).Provision of recurrence/metastatic tissue samples from resections, core-needle biopsies or excisional, incisional, punch, or forceps biopsies:At least 1 FFPE [Formalin-Fixed paraffin-embedded] tumor tissue and 1 frozen core as a priority, if feasible 2 additional fresh tumor tissue cores should be collected too.Fine-needle aspiration (FNA) (defined as samples that do not preserve tissue architecture and yield cell suspension and/or smears), brushing, and cell pellets from cytology samples are not acceptable.Note 1: If the subject has just performed a metastatic lesion biopsy, the patient is eligible only if a FFPE tissue sample (or at least 20 unstained slides, freshly cut for the purposes of the study) of the metastatic/recurrent lesion is available. In this situation only, frozen cores are not mandatory.Note 2: In case of a de-novo metastatic disease, if the biopsy of a metastatic lesion is not feasible, the patient is eligible if primary tumor lesion samples (FFPE + frozen cores) are available.Provision of an archived FFPE diagnostic biopsy or surgical primary breast tumor sample (or at least 20 unstained slides, freshly cut for the purposes of the study).Note: In case of neoadjuvant treatment (before surgery), the diagnostic biopsy is preferable.At least 6 months elapsed between the completion of surgical and/or systemic treatment with curative intent (e.g., the date of primary breast tumor surgery or the date of last adjuvant chemotherapy administration (radiotherapy is not included), whichever occurred last) and first documented local or distant disease recurrence (NOTE: not applicable for de-novo metastatic disease)At least one measurable disease based on RECIST v1.1. Tumor lesions in a previously irradiated area are considered measurable, if progression has been demonstrated in such lesionsAdequate organ function:Absolute neutrophil count (ANC) ≥ 1500/μl (without the addition of growth factors)Platelets [PLT] ≥100,000/μl (without the addition of growth factors/prior transfusions)Hemoglobin (Hb) ≥ 10 g/dl (without the addition of growth factors/prior transfusions)Creatinine ≤1.5 × upper limit of normal (ULN) OR estimated glomerular filtration rate (eGFR) ≥ 60 ml/min as calculated using the method standard for the institution. If eGFR is lower than 60 ml/min, a 24-h urine creatinine clearance can be performed to rule out an underestimation of the eGFR.Total serum bilirubin (TBL) ≤ 1.5 × ULN unless the subject has documented Gilbert syndrome in which case up to 3 x ULN is acceptableAspartate and alanine aminotransferase (AST/ALT) ≤ 2.5 × ULN unless liver metastases are present, in which case it must be ≤5 × ULNInternational Normalized Ratio (INR) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as INR and activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulantsPerformance status (PS) of 0 or 1 on the ECOG Performance scaleFemale subjects of childbearing potential (FSCP) must be willing to use one highly effective method of contraception for the course of the study through 6 months after the last study drug administration. FSCP must have a negative serum pregnancy test done within the 28 days before treatment start. FSCP are those who have not been surgically sterilized or have not been free of menses for at least 1 year.Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trialAbsence of any concurrent illness that would preclude the evaluation of safetyAgreement to provide tissue and blood samples for research purposesWritten informed consent must be given according to ICH/GCP, and national/local regulations before patient enrolmentInclusion criterion applicable to FRANCE onlyAffiliated to the French Social Security SystemExclusion criteria:Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:Patients with vitiligo or alopeciaPatients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacementAny chronic skin condition that does not require systemic therapyPatients without active disease in the last 5 years may be included but only after consultation with the sponsorPatients with celiac disease controlled by diet aloneCurrent or prior treatment with immunosuppressive medication within 14 days prior to enrolment. The following are exceptions to this criterion:Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalentSteroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)Any live, attenuated vaccine administered within 28 days prior to enrolment or anticipation that such a live attenuated vaccine will be required during the studyChronic daily treatment with non-steroidal anti-inflammatory drug (NSAID) (occasional use for the symptomatic relief of medical conditions, for example, headache, fever is allowed)Active infection includingTuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)Hepatitis B (known positive HBV surface antigen (HBsAg) result). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.Human immunodeficiency virus (positive HIV 1/2 antibodies).Treatment with systemic immunostimulatory agents, including but not limited to, interferon (IFN)-alpha, IFN-beta, interleukin (IL)−2, conjugated IL-2 cytokines within 42 days or five half-lives of the drug, whichever is longer, prior to screeningPrevious treatment with immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1 including durvalumab, anti-cytotoxic T-lymphocyte-associated molecule-4), anti-CD73 antibodies, adenosine A2A receptor antagonists, or prior treatment with CD137 agonists/OX-40 agonists or any other antibody or drug targeting T cell co-stimulation or other immunomodulatory therapiesAny unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo and the laboratory values defined in the inclusion criteriaKnown hypersensitivity reactions to the study drugs or to any of the excipients, pre-medications (acetaminophen/paracetamol, diphenhydramine or equivalent anti-histamine and methylprednisolone or equivalent glucocorticoid) and to other platinum containing compoundsUntreated central nervous system (CNS) metastases and/or carcinomatous meningitis.Subjects with previously treated brain metastases with local treatment (stereotactic radiosurgery or whole brain radiation therapy) may participate provided they have stable brain metastases on a recent brain MRI (performed during the 2 weeks prior inclusion) and have measurable disease outside the CNS.Note: Known brain metastases are considered active (and not eligible for trial), if any of the following criteria are applicable:Recent brain imaging demonstrates progression of existing and/or appearance of new lesionsNeurological symptoms attributed to brain metastases have not returned to baselineSteroids were used for management of symptoms related to brain metastases within 14 days of enrolmentCompletion of local therapy for brain metastases within 28 days of enrolmentMajor surgical procedure (as defined by the principal investigator) within 28 days prior to enrolment. Note: Local surgery of isolated lesions for palliative intent is acceptable.Uncontrolled intercurrent illness, including but not limited to,Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia. Patients previously treated with anthracyclines are eligible if a recent cardiac work up (<6 months) demonstrated a normal left ventricular ejection fraction (LVEF ≥ 50%).Interstitial lung diseaseSerious chronic gastrointestinal conditions associated with diarrheaPsychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consentPast medical conditions, including,Class II-IV congestive heart failureMyocardial infarction within 12 months prior enrolment,Deep vein thrombosis (DVT) or thrombo-embolic event within 12 months prior to enrolmentHistory of stroke or transient ischemic attack requiring medical therapyIntra-abdominal inflammatory process within the last 12 months prior to enrolment such as, but not limited to, diverticulitis, peptic ulcer disease, or colitisHistory of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitisHistory of another primary malignancy except for malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated carcinoma in situ without evidence of diseaseStatus post allogeneic bone marrow transplantation or solid organ transplantationPregnant or lactating women.Vulnerable persons according to the article L.1121-6 of the Public Health Code, adults who are the subjects of a measure of legal protection or unable to express their consent according to article L.1121-8 of the Public Health Code (Exclusion criterion applicable to FRANCE only).