DESIGN DE L ETUDE Environ 406 patients seront randomisés dans l un des 3 bras de l étude selon le schéma cidessous

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1 AN OPEN-LABEL, RANDOMIZED PHASE 3 TRIAL OF COMBINATIONS OF NIVOLUMAB, ELOTUZUMAB, POMALIDOMIDE AND DEXAMETHASONE IN RELAPSED AND REFRACTORY MULTIPLE MYELOMA ETUDE CA Sponsor: BMS CONTACTS AUX HUG : Unité de recherche en Onco-Hématologie, Fondation DFDL Coordinatrice de l étude : Mme Bénédicte Fleury, Investigateur responsable: Dr Thomas Matthes, Secrétariat: Mme Florence Marti-Klay, DESIGN DE L ETUDE Environ 406 patients seront randomisés dans l un des 3 bras de l étude selon le schéma cidessous :

2 OBJECTIF DE L ETUDE Evaluer l efficacité, la sécurité et la tolérance du nivolumab associé au pomalidomide et à la dexaméthasone par rapport à un traitement du MM par pomalidomide et dexaméthasone seuls. CRITERES D INCLUSION/EXCLUSION # INCLUSION CRITERIA Subject is, in the investigator s opinion, willing and able to comply with the protocol requirements Subject has given voluntary written informed consent before performance of any studyrelated procedure not part of normal medical care, with the understanding that consent 2 may be withdrawn by the subject at any time without prejudice to their future medical care Must have received 2 prior lines of therapy which must have included an immune modulatory drug (IMiD) and a proteasome inhibitor (PI) alone or in combination. Subject 3 must have received at least 2 consecutive cycles of an IMiD and at least 2 consecutive cycles of a PI. The dose of the prior IMiD (eg lenalidomide) to which the subject has relapsed or been refractory must be the induction dose and NOT a maintenance dose (Note: adjusted induction dose for intolerance reasons or for renal impairment is accepted) 4 Documented refractory or relapsed and refractory (R/R) multiple myeloma 5 Refractory (progressed on or within 60 days of the last dose of treatment) to their last line of treatment Subjects must have failed treatment with a proteasome inhibitor and an IMiD in one of the following ways i) Refractory = Refractory (progressed on treatment or within 60 days of the last dose of 6 treatment, regardless of the achievement of initial response) to a proteasome inhibitor and an IMiD, and to their last line of treatment ii) Relapsed and refractory = patients had achieved at least a partial response to previous treatment with proteasome inhibitor or IMiD, or both, but then progressed after 60 days of the last dose of treatment, and were refractory to their last treatment Measurable disease at screening, Serum IgG, IgA, or IgM M-protein > 0.5 g/dl (5 g/l) Urine M-Protein 200 mg (0.2 g) excreted in a 24-hour 7 based on central lab results within collection sample 28 days of randomization, defined Involved serum free light chain (sflc) 00 mg/l (0 as one or more of the following: mg/dl) provided the FLC ratio is abnormal 8 Eastern Cooperative Oncology Group (ECOG) performance status 2 Subject Re-enrollment: This study permits the re-enrollment of a subject that has 9 discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must be re-consented 0 Males and Females at least 8 years or legal age of consent per local regulations Women of childbearing potential (WOCBP) must have two negative serum or urine pregnancy tests (minimum sensitivity 25 miu/ml or equivalent units of HCG). One 0-4 days prior to start of the study drug and one within 24 hours prior to the start of study drug i) WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug plus 5 half-lives of study drug plus 30 days (duration of ovulatory cycle) for a total of 5 months (except the Pd arm- where only 4 weeks is required) post treatment completion ii) Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 5 half-lives of study drug plus 90 days (duration of sperm turnover) for a total of 7 months (except the Pd arm -where only 4 weeks is required) post-treatment completion 2

3 2 Women must not be breastfeeding 3 Male patients must not donate sperm, for up to 7 months (4 weeks only for Pd arm) post treatment completion Azoospermic males and WOCBP who are not heterosexually active are exempt from 4 contraceptive requirements. However they must still undergo pregnancy testing as described in this section 5 All subjects must not donate blood for 90 days post treatment completion 6 All subjects must be willing and able to comply with Pomalyst REMS program, where applicable 7 All subjects must agree not to share study medication # EXCLUSION CRITERIA Subjects with solitary bone or extramedullary plasmacytoma as the only evidence of plasma cell dyscrasia Subjects with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), primary amyloidosis (without active multiple 2 myeloma), Waldenstrom s macroglobulinemia, or POEMS syndrome (plasma cell dyscrasia with poly neuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Subjects with active plasma cell leukemia (defined as either 20% of peripheral blood 3 white blood cell count comprised of plasma/cd38+ cells or an absolute plasma cell count of 2 x 09/L) Women who are of childbearing potential not complying to the above described 4 contraceptive measures or are breastfeeding, and sexually active fertile men whose partners are WOCBP if they are not complying to the above described contraceptive measures Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator, including: i) NYHA functional classification III or IV, congestive heart failure, unstable or poorly controlled 5 angina, uncontrolled hypertension, serious arrhythmia, or myocardial infarction in the past 2 months ii) Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity 6 Active infection Subjects with an active, known or suspected autoimmune disease. Subjects with type I 7 diabetes mellitis, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll Subjects with a condition requiring systemic treatment with either corticosteroids (> 0 mg daily prednisone equivalent) or other immunosuppressive medications within 4 days 8 of initiation of study drug. Inhaled or topical steroids, and adrenal replacement steroid doses > 0 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease 9 Unable to tolerate thromboembolic prophylaxis while on the study 0 Serious hypersensitivity reaction (as per investigator assessment) to prior IMiD (thalidomide or lenalidomide) Grade 2 peripheral neuropathy (per NCI CTCAE v4.0) 2 Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection 3

4 Known history of positive test for human immunodeficiency virus (HIV) or known acquired 3 immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated by local regulation 4 Gastrointestinal disease that may significantly alter the absorption of pomalidomide Prior or concurrent invasive malignancy, except for the following: i) Adequately treated basal cell or squamous cell skin cancer 5 ii) Adequately treated in-situ cancer iii) Any cancer (other than those noted above) from which the subject has been disease free for > 3 years prior to study entry 6 Prior treatment with pomalidomide or nivolumab (or any PD- or PD-L inhibitor). 7 Use of any anti-myeloma drug therapy, within 4 days of the initiation of study drug treatment. Bisphosphonate use permitted if initiated prior to first dose of study medication 8 All prior drug-related AEs should have resolved or returned to baseline for the subject to be eligible 9 Prior autologous stem cell transplant within 2 weeks of the first dose of study drug Prior allogeneic stem cell transplant or graft versus host disease (GVHD) within 2 20 months of the first dose of study drug, or subjects on topical or systemic immunosuppressive therapy for GVHD Treatment with corticosteroids within 2 weeks of the first dose of study drug, except for the equivalent of 0 mg prednisone per day or corticosteroids with minimal to no systemic absorption (ie, topical or inhaled steroids) or for short course ( 4 days) of 40 2 mg dexamethasone or equivalent for emergency use (baseline M proteins must be drawn after this short course and prior to randomization). Adrenal replacement steroid doses > 0 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease Major cardiac surgery within 8 weeks prior to the first dose of study drug; all other major 22 surgery within 4 weeks prior to the first dose of study drug. (Kyphoplasty is not considered major surgery); subjects should have been fully recovered from any surgical related toxicities Absolute neutrophil count (ANC) <,000 cells/μl (.0 x 09/L) (Growth factors cannot be used within week of first drug administration. No pegylated growth factors within 3 weeks of first drug administration) Platelet count < 75,000 cells/μl (75 x 0 9 /L) (< 30 x 0 9 /L if 50% of bone marrow nucleated cells were plasma cells). Qualifying laboratory value must occur at most recent measurement prior to study entry. No transfusions are allowed within 72 hours prior to qualifying laboratory value 23 Screening Laboratory evaluations Hemoglobin < 8 g/dl (No transfusions are allowed within within the following parameters: 72 hours prior to qualifying laboratory value) Total Bilirubin >.5 X upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin up to 3.0 X ULN) AST (SGOT) and ALT (SGPT) > 3.0x ULN Renal function: Estimated creatinine clearance by Cockcroft-Gault formula < 30 ml/min Corrected serum calcium.5 mg/dl within 2 weeks of initiation of study drug (despite appropriate measures such a short course of steroids, bisphosphonates, hydration, calcitonin) 24 History of allergy or hypersensitivity to study drug components 4

5 25 History of severe hypersensitivity reaction to any monoclonal antibody Prisoners or subjects who are involuntarily incarcerated. 26 Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a subject. Strict conditions apply and Bristol-Myers Squibb approval is required 27 Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness 5