IPD in RRMM Characterized With Genomic Abnormalities of Adverse Prognostic (IFM2014-01)

Multicenter Open Label Phase 2 Single Arm Study of Ixazomib, Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma Characterized With Genomic Abnormalities of Adverse Adverse Prognostic

AXONAL, Nantes University Hospital, University Hospital, Grenoble, Euraxi Pharma, QPS Holdings LLC, Bristol-Myers Squibb, Takeda

This study is a Multicenter, Open-label, Phase II study of ixazomib, plus Pomalidomide and Dexamethasone regimen (IPD) in RRMM with adverse Genomic Abnormalities.

There is no escalation dose study, the maximum tolerated dose has already been determined in previous phase 1 escalation dose studies. The proposed dose of dexamethasone is considered standard. Patients will receive the IPd regimen until progression. The hypothesis is that this IPd regimen based combination will eventually improve time to disease progression, with no additional toxicity, as compared to other available regimens, in this subgroup of patients with myeloma characterized with a very adverse prognosis. Study design. This trial will study the efficacy and safety of IPd regimen in Relapsed and Refractory Multiple Myeloma with adverse Genomic Abnormalities until progression in 2 separate phases. Induction phase: 17 cycles - 21-days cycles Ixazomib 3 mg D1, D4, D8 and D11 Pomalidomide 4mg D1 to D14 Dexamethasone 40 mg/d D1, D8 and D15 if patient aged <75 years Dexamethasone 20 mg/d D1, D8 and D15 if patient aged ≥ 75 years Maintenance phase: until progression - 28-days cycles Ixazomib 4mg D1, D8 and D15 Pomalidomide 4mg D1 to D21 It is not planned for the patients to receive autologous stem-cell transplantation as part of the study trial

Single arm treatment organized in 2 separate phases Induction phase : association of Ixazomib, Pomalidomide & Dexamethasone (IPD) 21-days cycles - maximum of 17 cycles Ixazomib (tablets) 3 mg D1, D4, D8 and D11 Pomalidomide (tablets) 4mg D1 to D14 Dexamethasone (tablets) 40 mg/d D1, D8 and D15 if patient aged <75 years or Dexamethasone (tablets) 20 mg/d D1, D8 and D15 if patient aged ≥ 75 years Maintenance phase : association of Ixazomib and Pomalidomide (IP) 28-days cycles until disease progression Ixazomib (tablets) 4mg D1, D8 and D15 Pomalidomide (tablets) 4mg D1 to D21

Treatment with association of Ixazomib, Pomalidomide and Dexamethasone (IPD) Induction phase : 21-days cycles - maximum of 17 cycles Ixazomib (tablets) 3 mg D1, D4, D8 and D11 Pomalidomide (tablets) 4mg D1 to D14 Dexamethasone (tablets) 40 mg/d D1, D8 and D15 if patient aged <75 years Dexamethasone (tablets) 20 mg/d D1, D8 and D15 if patient aged ≥ 75 years Treatment with association of Ixazomib and Pomalidomide (IP) Maintenance phase : 28-days cycles until disease progression Ixazomib (tablets) 4mg D1, D8 and D15 Pomalidomide (tablets) 4mg D1 to D21

Time to progression (TTP), defined as time from the first induction cycle to confirmed progressive disease (PD) per the International Myeloma Working Group criteria, or death due to progressive disease, whichever occurs first. It is noted that the events (PD or death due to PD) may include those that occur in the maintenance phase. The analysis will be performed on an Intent-To-Treat (ITT) basis and then per protocol

from Cycle 1 Day 1 of Induction phase (each Cycle is 21 days) until documented disease progression or death due to disease progression, whichever came first, assessed through study completion, an average of 18 months

Incidence of Serious Adverse Events and Adverse Events as assessed by CTCAE version 4.0, dose reduction or modification

A safety Analysis will be performed after the 10th patient enrolled has finished the first cycle of treatment, without any enrollment break. The Independent Data Monitoring Committee (IDMC) will then analyzed the following: Frequency of Total Serious Adverse Events (SAE) Frequency of Adverse Events (AEs) Grade 3 or higher Frequency of dose reductions Frequency of dose discontinuations Data Monitoring Committee. No enrollment break is planned unless requested by the IDMC. The IDMC will analyze: The interim safety analysis after the10th patient enrolled has finished the first cycle of treatment. Safety review along study if asked by the sponsor.

after the 10th patient has completed the first cycle of treatment (Cycle is 21 days), an average of 5 months after the beginning of the study and then every 6 months through study end

Plasma concentrations of ixazomib after twice-weekly dosing in combination with Pomalidomide and Dexamethasone

Sparse Pharmacokinetics samples for the measurement of plasma concentrations of ixazomib will be collected in this study for the purposes of population PK and exposure-response analyses

Post-induction and post-maintenance overall response rate (ORR) defined as the proportions of subjects who have achieved PR or better by the end of treatment per the IMWG criteria

after completion of induction treatment of the last patient included, an average of 2 years after the beginning of the study and post maintenance treatment of the last patient included, an average of 3 years and half after the beginning of the study

rate of VGPR or better, defined as the proportions of subjects who have achieved PR or better by the end of induction phase per the IMWG criteria

after completion of induction treatment of the last patient included, an average of 2 years after the beginning of the study and post maintenance treatment of the last patient included, an average of 3 years and half after the beginning of the study

CR rate defined as the proportions of subjects who have achieved CR by the end of Induction phase per IMWG criteria

after completion of induction treatment of the last patient included, an average of 2 years after the beginning of the study and post maintenance treatment of the last patient included, an average of 3 years and half after the beginning of the study

at the end of the study, time to response and level of response to IPD for responders patients will be analyzed

Overall Survival (OS) rate defined as the time in months from start of treatment and death or the termination of the study, whichever came first

from the start of study treatment to death or the termination of the study, whichever came first, an average of 5 years

Progression free survival (PFS) defined as the time in months from start of treatment and disease progression

Event Free survival (EFS) to IPD defined as the time in months from start of treatment and disease recurrence or onset of disease symptoms

from the start of study treatment to death or the termination of the study, whichever came first, an average of 5 years

Response rate defined as the proportions of subjects who show a PR or better from start of treatment and the termination of the study

Survival rate defined as the proportions of subjects who are still alive at the termination of the study

Definition of molecular characteristics assessed by performing whole exome sequencing (WES) and RNA-sequencing (RNA-seq)

Comparison of molecular characteristics by performing whole exome sequencing (WES) and RNA-sequencing (RNA-seq)

Inclusion Criteria: Male or female patients 18 years or older. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. Life expectancy > 3 months. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2. Presence - at diagnosis or at relapse - of one of the following adverse genomic abnormalities determined using Interphase fluorescence in situ hybridization and Single nucleotide polymorphism (FISH/SNP) techniques at a significant rate validated centrally by Pr AVET - LOISEAU: deletion 17p and/ or translocation (4; 14) Must have an RRMM and have received a Lenalidomide line of treatment Must have a Progressive Multiple Myeloma (MM) according to IMWG consensus recommendations for multiple myeloma treatment response criteria (DURIE 2007, RAJKUMAR 2011) : Increase of 25% from lowest response value in any one of the following: Serum M-component (absolute increase must be ≥ 0.5 g/dL), Urine M-component (absolute increase must be ≥ 200 mg/24 hours), Only in subjects without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC (Free Light-Chain) levels (absolute increase must be >10 mg/dL) Bone marrow plasma cell percentage: the absolute percentage must be >10% Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the PC (Plasma Cell) proliferative disorder Must have a measurable disease as defined by the following: IgG (immunoglobulin G) and IgA (immunoglobulin A) (serum M-component > 5g/l) IgD (immunoglobulin D) (serum M-component > 0.5g/l) Light chain (Bence Jones > 200mg/24h) For MM without measurable serum or urine M protein, involved FLC ≥100 mg/l and FLC abnormal ratio. Patients must meet the following clinical laboratory criteria: Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment. Total bilirubin ≤1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN. Calculated creatinine clearance ≥ 30 mL/min MDRD (Modification of Diet in Renal Disease) formula should be used for calculating creatinine clearance values: http://mdrd.com/ Able to undergo antithrombotic prophylactic treatment. HBPM (low weight heparin) is preferred. In case of anti-Vitamin K Agent, INR (international normalized ratio) must be used Female patients who: Have been postmenopausal for at least 2 years before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, OR Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal and post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree to one of the following: Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal and post-ovulation methods] and withdrawal are not acceptable methods of contraception.) Patients agree: not to share study medication with any other person and to return all unused study drugs to the investigator. to abstain from donating blood while taking the study drug therapy and for one week following discontinuation of the study drug therapy. Must be able to adhere to the study visit schedule and other protocol requirements including the pregnancy prevention program as detailed in section 13.4 of protocol Affiliated with an appropriate social security system. Exclusion Criteria: Any other uncontrolled medical condition or comorbidity that might interfere with subject's participation. Patients not having receive Lenalidomide Pregnant or breast feeding females Known positive for HIV or active hepatitis type B or C. Patients with non-secretory MM Patient with terminal renal failure that require dialysis and clearance creatinine < 30ml/min Prior history of malignancies, other than multiple myeloma, unless the patients has been free of the disease for ≥ 5 years. Prior local irradiation within two weeks before first dose* *However, an exception (that is patients allowed to remain in the treatment phase of the study) is made for radiation therapy to a pathological fracture site to enhance bone healing or to treat post-fracture pain that is refractory to narcotic analgesics because pathologic bone fractures do not by themselves fulfill a criterion for disease progression.) Evidence of central nervous system (CNS) involvement Unable to take corticotherapy at study entry, Ixazomib or pomalidomide Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment Ongoing Cardiac dysfunction: specify e.g. uncontrolled hypertension, MI (Myocardial Infarction) within 6 months, unstable Angina pectoris, Cardiac arrhythmia Grade 2 or higher Patients planned to receive a transplantation while on IPd protocol Patients who have had Ixazomib and Pomalidomide therapy as a previous line Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial. Failure to have fully recovered (ie, ≤ Grade 1 toxicity) from the reversible effects of prior chemotherapy. Inability or unwillingness to comply with birth control requirements Unable to take antithrombotic medicines at study entry Major surgery within 14 days before enrollment. Systemic treatment, within 14 days before the first dose of ixazomib and Pomalidomide, with strong CYP3A (Cytochrome P450 3A) inducers (rifampicin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib and Pomalidomide including difficulty swallowing. Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period. Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not. Subjects under juridical protection guardianship or tutelage measure

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