IFM2009-02-Pomalidomide and Dexamethasone Phase 2 Myeloma (IFM2009-02)

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Pomalidomide; Drug: Pomalidomide

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.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHRU-Hôpital Sud, avenue Laennec,
  • Bobigny, France, 93009
    • Hématologie, Hôpital Avicenne
  • Caen, France, 14033
    • Hématologie, CHU, avenue G.Clemenceau
  • Dijon, France, 21000
    • Hématologie Clinique, CHU, Hôpital d'Enfants
  • Grenoble, France, 38043
    • Hématologie, CHRU, Hôpital A.Michallon
  • Lille, France, 59037
    • Service des Maladies du Sang, CHRU
  • Lyon, France, 69437
    • Hôpital Edouard Herriot
  • Marseille, France, 13273
    • Hématologie, Institut Paoli Calmette
  • Nancy, France, 54511
    • Hématologie, CHRU, Hôpitaux de Brabois
  • Nantes, France, 44035
    • Maladies du Sang, CHRU, Hôtel Dieu
  • Paris, France, 75475
    • Service Immuno-Hématologie, Hôpital Saint-Louis
  • Paris, France, 75571
    • Maladies du Sang, CHU - Hôpital St Antoine
  • Pessac, France, 33604
    • Service des Maladies du Sang, Hôpital Haut-Levèque
  • Pierre Benite, France, 69495
    • Service d'Hématologie, Centre Hospitalier Lyon Sud
  • Reims, France, 51092
    • Hématologie Clinique, Hôpital Robert Debré, CHU Reims
  • Rennes, France, 35033
    • Hôpital Pontchaillou, CHU de Rennes
  • Rennes, France, 35056
    • Médecine Interne, CHRU, Hôpital Sud
  • Toulouse, France, 31059
    • Hématologie, CHRU, Hôpital Purpan
  • Tours, France, 37044
    • Onco-Hématologie, CHRU- Hôpital Bretonneau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Drug on 21 days per 28 days cycle; Pomalidomide 4 mg continuous daily oral route on 21 days per 28 days cycle. The proposed dose of dexamethasone is considered standard, 40mg/day once a week.	Drug: Pomalidomide; Pomalidomide 4 mg continuous daily oral route on 21 days per 28 days cycle. The proposed dose of dexamethasone is considered standard, 40mg/day once a week.; Other Names: Actimid; CC-4047; Drug: Pomalidomide; Pomalidomide 4 mg continuous daily oral route on 28 days of a 28 days cycle The proposed dose of dexamethasone is considered standard, 40mg/day once a week.; Other Names: Actimid; CC-4047
Active Comparator: Drug on 28 days per 28 days cycle; Pomalidomide 4 mg continuous daily oral route on 28 days of a 28 days cycle The proposed dose of dexamethasone is considered standard, 40mg/day once a week.	Drug: Pomalidomide; Pomalidomide 4 mg continuous daily oral route on 21 days per 28 days cycle. The proposed dose of dexamethasone is considered standard, 40mg/day once a week.; Other Names: Actimid; CC-4047; Drug: Pomalidomide; Pomalidomide 4 mg continuous daily oral route on 28 days of a 28 days cycle The proposed dose of dexamethasone is considered standard, 40mg/day once a week.; Other Names: Actimid; CC-4047

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	30 months

Secondary Outcome Measures

Outcome Measure	Time Frame
To determine response and safety profile of 2 dose-regimens of pomalidomide	30 months
To determine Safety of pomalidomide and dexamethasone	30 months
To determine Time to response and Response duration of pomalidomide and dexamethasone	30 months
To determine Time to disease progression to pomalidomide and dexamethasone	30 months
Overall Survival of pomalidomide and dexamethasone	30 months
To determine response in both arms with regards to cytogenetic of the bone marrow tumor plasma cells	30 months

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: Celgene Corporation
• Investigators: Principal Investigator: Bruno ROYER, MD PhD, CHRU-Hôpital Sud d'Amiens-AMIENS; Principal Investigator: Philippe RODON, MD PhD, Centre Hospitalier de Blois -BLOIS; Principal Investigator: Sabine BRECHIGNAC, MD PhD, Hôpital Avicenne-Bobigny- PARIS; Principal Investigator: Gerard MARIT, MD PhD, Hôpital Haut-Levèque de Pessac-BORDEAUX; Principal Investigator: Christian BERTHOU, MD PhD, Service d'Hématologie Clinique, CHU Morvan, BREST; Principal Investigator: Margaret MACRO, MD PhD, Hématologie, CHU, CAEN; Principal Investigator: Denis CAILLOT, MD PhD, Hématologie Clinique, CHU, Hôpital d'Enfants, DIJON; Principal Investigator: Brigitte PEGOURIE, MD PhD, Hématologie, CHRU, Hôpital A.Michallon, GRENOBLE; Principal Investigator: Catherine TRAULLE, MD PhD, Service d'Hématologie, Centre Hospitalier Lyon Sud, PIERRE BENIT; Principal Investigator: Anne Marie STOPPA, MD PhD, Hématologie, Institut Paoli Calmette, MARSEILLE; Principal Investigator: Cyrille HULIN, MD PhD, Hématologie, CHRU, Hôpitaux de Brabois, VANDOEUVRE; Principal Investigator: Philippe MOREAU, MD PhD, Maladies du Sang, CHRU, Hôtel Dieu, NANTES; Principal Investigator: Jean-Gabriel FUZIBET, MD PhD, Médecine Interne, Oncologie, Hôpital de l'Archet 1, NICE; Principal Investigator: Bernard GROSBOIS, MD PhD, Médecine Interne, CHRU, Hôpital Sud, RENNES; Principal Investigator: Brigitte KOLB, MD PfD, Hématologie Clinique, Hôpital Robert Debré, CHU Reims; Principal Investigator: Laurent GARDERET, MD PhD, Maladies du Sang, CHU - Hôpital St Antoine, PARIS; Principal Investigator: Jean-Paul FERMAND, MD PhD, Service Immuno-Hématologie, Hôpital Saint-Louis, PARIS; Principal Investigator: Michel ATTAL, MD PhD, Hématologie, CHRU, Hôpital Purpan, TOULOUSE; Principal Investigator: Lofti BENBOUBKER, MD PhD, Onco-Hématologie, CHRU- Hôpital Bretonneau, TOURS; Study Director: Xavier Leleu, MD PhD, Service des maladies du sang, CHRU de Lille

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2009
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: January 21, 2010
• First Submitted That Met QC Criteria: January 21, 2010
• First Posted (Estimate): January 22, 2010

Study Record Updates

• Last Update Posted (Estimate): November 4, 2015
• Last Update Submitted That Met QC Criteria: November 3, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Multiple myeloma; safety; response; pomalidomide; dexamethasone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Thalidomide; Pomalidomide
• Other Study ID Numbers: 2009_28/0924; 2009-013319-36 (EudraCT Number)