Clinical trial NCT01053949: IFM2009-02-Pomalidomide and Dexamethasone Phase 2 Myeloma
Official title: A Multicenter Randomized Open Label Phase II Study of Pomalidomide and Dexamethasone in Relapse and Refractory Multiple Myeloma Patients Who Are Progressive and Did Not Achieve at Least a Partial Response to Bortezomib and Lenalidomide
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Multiple myeloma
dexamethasone
pomalidomide
response
safety
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Celgene Corporation
First posted: 2010-01-22
Enrollment: 84
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: To determine Response rate to pomalidomide and dexamethasone in MM patients who are progressive and did not achieve at least a partial response to bortezomib and lenalidomide
timeFrame: 30 months
Secondary outcomes:
measure: To determine response and safety profile of 2 dose-regimens of pomalidomide
timeFrame: 30 months
measure: To determine Safety of pomalidomide and dexamethasone
timeFrame: 30 months
measure: To determine Time to response and Response duration of pomalidomide and dexamethasone
timeFrame: 30 months
measure: To determine Time to disease progression to pomalidomide and dexamethasone
timeFrame: 30 months
measure: Overall Survival of pomalidomide and dexamethasone
timeFrame: 30 months
measure: To determine response in both arms with regards to cytogenetic of the bone marrow tumor plasma cells
timeFrame: 30 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHRU-Hôpital Sud, avenue Laennec,
city: Bobigny
country: France
facility: Hématologie, Hôpital Avicenne
city: Caen
country: France
facility: Hématologie, CHU, avenue G.Clemenceau
city: Dijon
country: France
facility: Hématologie Clinique, CHU, Hôpital d'Enfants
city: Grenoble
country: France
facility: Hématologie, CHRU, Hôpital A.Michallon
city: Lille
country: France
facility: Service des Maladies du Sang, CHRU
city: Lyon
country: France
facility: Hôpital Edouard HERRIOT
city: Marseille
country: France
facility: Hématologie, Institut Paoli Calmette
city: Nancy
country: France
facility: Hématologie, CHRU, Hôpitaux de Brabois
city: Nantes
country: France
facility: Maladies du Sang, CHRU, Hôtel Dieu
city: Paris
country: France
facility: Service Immuno-Hématologie, Hôpital Saint-Louis
city: Paris
country: France
facility: Maladies du Sang, CHU - Hôpital St Antoine
city: Pessac
country: France
facility: Service des Maladies du Sang, Hôpital Haut-Levèque
city: Pierre Benite
country: France
facility: Service d'Hématologie, Centre Hospitalier Lyon Sud
city: Reims
country: France
facility: Hématologie Clinique, Hôpital Robert Debré, CHU Reims
city: Rennes
country: France
facility: Hôpital PONTCHAILLOU, CHU de RENNES
city: Rennes
country: France
facility: Médecine Interne, CHRU, Hôpital Sud
city: Toulouse
country: France
facility: Hématologie, CHRU, Hôpital Purpan
city: Tours
country: France
facility: Onco-Hématologie, CHRU- Hôpital Bretonneau
Study officials:
affiliation: CHRU-Hôpital Sud d'Amiens-AMIENS
name: Bruno ROYER, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier de Blois -BLOIS
name: Philippe RODON, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Avicenne-Bobigny- PARIS
name: Sabine BRECHIGNAC, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Haut-Levèque de Pessac-BORDEAUX
name: Gerard MARIT, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Service d'Hématologie Clinique, CHU Morvan, BREST
name: Christian BERTHOU, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hématologie, CHU, CAEN
name: Margaret MACRO, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hématologie Clinique, CHU, Hôpital d'Enfants, DIJON
name: Denis CAILLOT, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hématologie, CHRU, Hôpital A.Michallon, GRENOBLE
name: Brigitte PEGOURIE, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Service d'Hématologie, Centre Hospitalier Lyon Sud, PIERRE BENIT
name: Catherine TRAULLE, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hématologie, Institut Paoli Calmette, MARSEILLE
name: Anne Marie STOPPA, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hématologie, CHRU, Hôpitaux de Brabois, VANDOEUVRE
name: Cyrille HULIN, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Maladies du Sang, CHRU, Hôtel Dieu, NANTES
name: Philippe MOREAU, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Médecine Interne, Oncologie, Hôpital de l'Archet 1, NICE
name: Jean-Gabriel FUZIBET, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Médecine Interne, CHRU, Hôpital Sud, RENNES
name: Bernard GROSBOIS, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hématologie Clinique, Hôpital Robert Debré, CHU REIMS
name: Brigitte KOLB, MD PfD
role: PRINCIPAL_INVESTIGATOR
affiliation: Maladies du Sang, CHU - Hôpital St Antoine, PARIS
name: Laurent GARDERET, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Service Immuno-Hématologie, Hôpital Saint-Louis, PARIS
name: Jean-Paul FERMAND, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hématologie, CHRU, Hôpital Purpan, TOULOUSE
name: Michel ATTAL, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Onco-Hématologie, CHRU- Hôpital Bretonneau, TOURS
name: Lofti BENBOUBKER, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Service des maladies du sang, CHRU de Lille
name: Xavier Leleu, MD PhD
role: STUDY_DIRECTOR
References:
citation: Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Brechignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myelome. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02. Blood. 2013 Mar 14;121(11):1968-75. doi: 10.1182/blood-2012-09-452375. Epub 2013 Jan 14.