IFM2009-02-Pomalidomide and Dexamethasone Phase 2 Myeloma
IFM2009-02-Pomalidomide and Dexamethasone Phase 2 Myeloma
The purpose of this study is to evaluate the response to pomalidomide and dexamethasone in
 relapse and refractory MM patients who are progressive and did not achieve at least a partial
 response to bortezomib and lenalidomide. This study will determine the efficacy and toxicity
 profile of 2 modalities of pomalidomide in patients with advanced myeloma, previously heavily
 treated characterized with adverse prognostic and that are in desperate need of novel
 therapeutics.
Multiple myeloma (MM) is an incurable disease that is characterized by the accumulation of
 clonal plasma cells in the bone marrow. The median overall survival for patients with MM is
 approximately 4-5 years. Despite front line treatment approaches, the disease eventually
 relapses. The recent US Food and Drug Administration (FDA) approvals of bortezomib (2003) and
 combination lenalidomide plus dexamethasone (2006) therapies for the treatment of previously
 treated MM has provided effective therapeutic options that give patients with relapsed or
 refractory MM the prospect for a prolongation of overall and progression-free survival times.
 However, MM remains an incurable disease. A clear unmet medical need still exists for
 additional novel therapeutic options for the treatment of previously treated MM.

 Pomalidomide belongs to the IMiDs class of compounds which thalidomide is the parent compound
 and lenalidomide the most recently approved agent. It is derived from thalidomide and shares
 a number of the beneficial pharmacologic properties with thalidomide. The efficacy of
 thalidomide has been limited by adverse effects. This toxicity profile seems dose and
 duration-related, spurring the development of IMiDs, which have the potential of improved
 potency and reduced toxicity. By modifying the thalidomide structure through the addition of
 an amino group at the 4 position of the phthaloyl ring to generate pomalidomide, a compound
 that is up to 50000 times more potent at inhibiting TNF-alpha than thalidomide was formed.

 Recently, preliminary efficacy and safety data from an ongoing phase 2 study, led by Martha
 Lacy, et al, at Mayo Clinic, were presented at the XII International Myeloma Workshop in
 Washington DC (01 March 2009). The study highlighted a 63 % objective response and a 5%
 complete response in patients taking pomalidomide (2 mg daily on days 1-28 of a 28-day cycle)
 plus dexamethasone (40 mg daily on days 1, 8, 15, 22 of each cycle) including patients with
 lenalidomide resistant refractory multiple myeloma. The results also showed that the
 treatment was well tolerated. Based on the encouraging data of this study, a phase 1/2b
 multi-center, randomized, open-label, dose escalation study (dose level from 2 mg to 5 mg
 daily on days 1-21 of a 28-day cycle)is conducted to determine the MTD of pomalidomide. This
 ongoing study will evaluate the safety and efficacy of oral pomalidomide alone, and in
 combination with dexamethasone, in patients with relapsed and refractory MM. The first
 results obtained in this study demonstrated that the maximum tolerated dose of pomalidomide
 was 4 mg once per day and highlighted that pomalidomide has significant efficacy in MM and
 can be safely administered to myeloma patients. Moreover, there are an increasing number of
 patients who are refractory or did not respond significantly or experienced significant
 toxicity to either bortezomib or lenalidomide.

 Based on these studies, we hypothesized that these patients might benefit from the
 combination of pomalidomide and dexamethasone. We have therefore designed a multicenter phase
 2 randomized open labelled study to determine response to pomalidomide and dexamethasone in
 relapse and refractory MM patients who are progressive and did not achieve at least a partial
 response to bortezomib and lenalidomide. This study will determine the efficacy and toxicity
 profile of 2 modalities of pomalidomide in patients with advanced myeloma, previously heavily
 treated characterized with adverse prognostic and that are in desperate need of novel
 therapeutics. This study will be conducted in accordance with "good clinical practice" (GCP)
 and all applicable regulatory requirements, including, where applicable, the 2008 version of
 the Declaration of Helsinki.
Key inclusion criteria:

 -  Must be able to understand and voluntarily sign an informed consent form

 -  Must be able to adhere to the study visit schedule and other protocol requirements

 -  18 years>=Age

 -  Life expectancy>6 months

 -  Patients must have Symptomatic and Progressive Myeloma following bortezomib and/or
 lenalidomide treatment, defined as detailed in protocol.

 -  Patients must have a clearly detectable and quantifiable monoclonal M-component value*

 -  ECOG performance status score of 0,1,or 2

 -  Adequate bone marrow function,documented within 72 hours prior to treatment without
 transfusion or growth factor support,defined as*

 -  Wash out period of at least 2 weeks from previous antitumor therapy or any
 investigational treatment

 -  Able to take antithrombotic medicines such as Low molecular weight heparin or Aspirin
 75mg

 -  Subjects affiliated with an appropriate social security system

 -  Agree to abstain from donating blood while taking study drug therapy and for one week
 following discontinuation of study drug therapy

 -  Agree not to share study medication with another person and to return all unused study
 drug to the investigator

 -  Female subjects of childbearing potential* must:Understand that the study medication
 is expected to have a teratogenic risk-Agree to use,and be able to comply with,
 effective contraception* without interruption,4 weeks before starting study
 drug,throughout the entire duration of study drug therapy (including dose
 interruptions) and for 4 weeks after the end of study drug therapy,even if she has
 amenorrhoea.This applies unless the subject commits to absolute and continued
 abstinence on a monthly basis-Understand that even if she has amenorrhea,she must
 follow all the advice on effective contraception-She understands the potential
 consequences of pregnancy and the need to rapidly consult if there is a risk of
 pregnancy-Agree to have a medically supervised pregnancy test with a minimum
 sensitivity of 25 mIU/mL on the day of the study visit or in the 3 days prior to the
 study visit once the subject has been on effective contraception for at least 4
 weeks-Agree to have a medically supervised pregnancy test every 4 weeks including 4
 weeks after the end of study treatment,except in the case of confirmed tubal
 sterilization. These pregnancy tests should be performed on the day of the study visit
 or in the 3 days prior to the study visit.This requirement also applies to women of
 childbearing potential who practice complete and continued abstinence

 -  Male subjects must:Agree to use condoms throughout study drug therapy,during any dose
 interruption and for one week after cessation of study therapy if their partner is of
 childbearing potential and has no contraception Agree not to donate semen during study
 drug therapy and for one week after end of study drug therapy

 Exclusion Criteria:

 -  Any other uncontrolled medical condition or comorbidity that might interfere with
 subject's participation

 -  Pregnant or breast feeding females

 -  Use of any other experimental drug or therapy within 15 days of screening.

 -  Known positive for HIV or infectious hepatitis,type A, B or C.

 -  Patients with non-secretory MM

 -  Prior history of malignancies, other than multiple myeloma, unless the patients has
 been free of the disease for >= 3 years.Exceptions include the following*

 -  Prior local irradiation within two weeks before screening

 -  Evidence of central nervous system involvement

 -  Any>grade 2 toxicity unresolved

 -  Peripheral neuropathy>=Grade 2

 -  Known Hypersensitivity to Thalidomide,Lenalidomide or Dexamethasone

 -  Ongoing active infection,especially ongoing pneumonitis

 -  Ongoing Cardiac dysfunction

 -  Inability or unwillingness to comply with birth control requirements

 -  Unable to take antithrombotic medicines at study entry

 -  Unable to take corticotherapy at study entry

 -  Refusal to participate in the study

 -  Persons protected by a legal regime(guardianship,trusteeship)

 (*)=described in protocol