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A Study of the Efficacy and Safety of Lenalidomide Combined to Escalating Doses of Chemotherapy in Intermediate-2-or High Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) With Del 5q (GFM-Chimio-Rev)

Primary Purpose

Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia

Status
Unknown status
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Lenalidomide
Sponsored by
Groupe Francophone des Myelodysplasies
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelodysplastic Syndrome focused on measuring MDS, AML, deletion 5q, Documented diagnosis of MDS, or CMML, with WBC < 13,000/mm3 that meets IPSS criteria for intermediate-2, or high-risk disease, or AML with an associated del 5q[31], (the deleted chromosomal region must include 5q[31]),, with or without additional cytogenetic abnormalities

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Must understand and voluntarily sign an informed consent form
  3. Must be able to adhere to the study visit schedule and other protocol requirements
  4. No contra indication to anthracycline based chemotherapy
  5. Documented diagnosis of MDS, or CMML with WBC < 13,000/mm3 that meets IPSS criteria for intermediate-2 or high-risk disease, or AML with an associated del 5q[31] (the deleted chromosomal region must include 5q[31]), with or without additional cytogenetic abnormalities
  6. Female subjects of childbearing potential must:

    • Understand that the study medication could have a potential teratogenic risk
    • Agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout 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 confirmed on a monthly basis. The following are effective methods of contraception:

      • Implant, Levonorgestrel-releasing intrauterine system (IUS) (prophylactic antibiotics should be considered at the time of insertion particularly in patients with neutropenia due to risk of infection) , Medroxyprogesterone acetate depot, Tubal sterilization, Ovulation inhibitory progesterone-only pills (i.e., desogestrel), Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses.
      • Combined oral contraceptive pills are not recommended. If a subject was using combined oral contraception, she must switch to one of the methods above. The increased risk of VTE continues for 4 to 6 weeks after stopping combined oral contraception.
    • Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days from the start of study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence.
    • 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 tests should be performed not more than 3 days before the start of next treatment. This requirement also applies to women of childbearing potential who practice complete and continued abstinence
  7. 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.
  8. All subjects must:

    • 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

Exclusion Criteria:

  1. Pregnant or lactating females.
  2. Contra indication to anthracycline based chemotherapy.
  3. Proliferative (WBC ≥ 13,000/mL) CMML.
  4. Prior ≥ grade-2 NCI CTCAE (v 3.0) allergic reaction to thalidomide.
  5. Prior desquamating (blistering) rash while taking thalidomide.
  6. Prior history of malignancy other than MDS unless the subject has been free of disease for ≥ 5 years.
  7. Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days .
  8. Less than 6 months since prior allogeneic bone marrow transplantation.
  9. Less than 3 months since prior autologous bone marrow or stem cell transplantation.
  10. Recombinant human erythropoietin (rHuEPO) therapy received within 28 days.
  11. Known HIV-1 positivity.
  12. Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he or she participates in the study.
  13. Creatinine Clearance< 50 ml/min
  14. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 3.0 x upper limit of normal (ULN)
  15. Serum total bilirubin > 1.5 mg/dL (expect for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS).
  16. Subjects with ≥ grade-2 neuropathy

Sites / Locations

  • CH Angers
  • hopital Victor Dupouy
  • Centre Hospitalier de La Cote Basque
  • Hôpital Avicenne
  • CHU Haut-Lévèque
  • Centre hospitalier de Chambéry
  • CHU de Clermont-Ferrand
  • Centre henri Mondor
  • Centre Hospitalier du Mans
  • Centre Hospitalier de Lens
  • centre hospitalier de Lens
  • Hôpital Limoges
  • Centre Hospitalier Lyon Sud
  • Institut Paoli Calmettes
  • CHU Brabois
  • CHU de nantes
  • Hôpital Archet1
  • Hoiptal St Louis
  • Hopital Cochin-Hematology
  • Centre Hospitalier Joffre
  • Centre Henri Becquerel
  • Hôpital Hautepierre
  • Hopital Purpan Service d'Hématologie Clinique
  • CH de Valence
  • Institut gustave Roussy

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Aracytidine, Daunaurubicine, Lenalidomide

Arm Description

Outcomes

Primary Outcome Measures

Response (CR, mCR and Cri, according to IWG criteria for AML and IWG 2006 criteria for MDS) to the combination of lenalidomide and chemotherapy in adult high and int 2 MDS (IPSS) or AML with deletion 5q[31]

Secondary Outcome Measures

Duration of response
Progression to AML
Survival and safety of the combination of lenalidomide and chemotherapy

Full Information

First Posted
April 21, 2009
Last Updated
April 23, 2015
Sponsor
Groupe Francophone des Myelodysplasies
Collaborators
Celgene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT00885508
Brief Title
A Study of the Efficacy and Safety of Lenalidomide Combined to Escalating Doses of Chemotherapy in Intermediate-2-or High Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) With Del 5q
Acronym
GFM-Chimio-Rev
Official Title
A Phase II Study of the Efficacy and Safety of Lenalidomide Combined to Escalating Doses of Chemotherapy in Intermediate-2-or High Risk MDS and AML With Del 5q
Study Type
Interventional

2. Study Status

Record Verification Date
April 2015
Overall Recruitment Status
Unknown status
Study Start Date
February 2009 (undefined)
Primary Completion Date
December 2015 (Anticipated)
Study Completion Date
December 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Groupe Francophone des Myelodysplasies
Collaborators
Celgene Corporation

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In this trial, the investigators will test the combination of escalating doses of chemotherapy (starting at relatively low dose) with lenalidomide in intermediate-2-or high risk MDS and AML with del 5 q31. It is hoped that this combined therapy will further increase response rate in intermediate-2-or high risk MDS and AML with del 5 q31, without major toxicity in comparison to historical results obtained with chemotherapy alone in the same subset of patients.
Detailed Description
Patients will receive lenalidomide combined to DNR- AraC chemotherapy. The first 31 patients will receive DNR 45 mg/m2/d, during 3 days, and AraC 200mg/m2/d CI during 7 days. Progression or not to the next cohort DNR 60 mgm2/d x3d and AraC 200mg/m2d x7d , or on the contrary reduction to the lower cohort DNR 30 mgm2/d x3d and AraC 200mg/m2d x5d will be decided after inclusion of fixed numbers of patients ,after review of toxicity and efficacy by an independent safety review committee (SRC). Efficacy would be defined as a response rate ≥50%. After inclusion of the first 31 patients, the SRC will choose the cohort dose the last 33 patients will receive, based on toxicity and efficacy criteria. Induction treatment Lenalidomide 10 mg once daily PO during 3 weeks . DNR 30-45-or 60 mg/m2 /d (depending on the cohort during 3 days (IV push)- AraC 200mg/m2/d during 5- 7 or 7 days (continuous infusion)+ G-CSF (lenograstim): 263 ug/d from day 9, until recovery from aplasia (maximum 30 days). Evaluation will be performed after recovery from aplasia, on day 40 at the latest (with marrow aspirate and karyotype). Patients in hematological CR, CRi or marrow CR will proceed to consolidation treatment :Once the cohort dose has been decided by the SRC, a second cohort of 33 patients will be enrolled Consolidation treatment (in patients who achieved CR, Cri, or marrow CR) 6 monthly courses of : DNR (at the daily dose required to achieve CR) day1, combined to AraC 60 mg/m2/12h SC during 5 days will be given. Lenalidomide 10 mg/ d during the first 2 weeks of the course. Maintenance treatment Lenalidomide 10 mg/d 2 weeks every month until relapse (dose reduced if cytopenias) In patients still responding after 52 weeks, the drug will continue to be supplied, and follow up until death will be continued in all patients. SECOND PART OF THE TRIAL AFTER AMENDMENT Treatment schedule of the 2nd Part of the trial In dose level 4, 20 patients will receive lenalidomide 25 mg/d during 21 days combined to DNR- AraC chemotherapy (DNR 60 mgm2/d x3d and AraC 200mg/m2d x7d) during induction. During consolidation, patients will receive Lenalidomide 25 mg/d during 14 days, combined with DNR 60 mgm2/d x1d and AraC 60 mg/m2 x2/d x5d. finally, during maintenance, patients will receive Lenaidomide 25 mg/d x14d every months, until relapse. Progression or not to the next cohort (Lenaidomide 50 mg) will be decided after inclusion of 20 patients, after review of toxicity and efficacy by an independent safety review committee (SRC) (Briefly, given median times to reach ANC and platelets > 500 and 50000/mm3, respectively of about 27 days in our previous trial with chemotherapy alone (Gardin, Blood), DLT would be defined by having greater than 3 of 10 patients recovering those levels after more than 40 days, or the occurrence of unexpected grade III-IV non hematological toxicity). Efficacy would be defined as a response rate ≥60%. In dose level 5, 20 patients will receive lenalidomide 50 mg/d during 21 days combined to DNR- AraC chemotherapy (DNR 60 mgm2/d x3d and AraC 200mg/m2d x7d) during induction. During consolidation, patients will receive Lenalidomide 50 mg/d during 14 days, combined with DNR 60 mgm2/d x1d and AraC 60 mg/m2 x2/d x5d. finally, during maintenance, patients will receive Lenaidomide 50 mg/d x14d every months, until relapse.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia
Keywords
MDS, AML, deletion 5q, Documented diagnosis of MDS, or CMML, with WBC < 13,000/mm3 that meets IPSS criteria for intermediate-2, or high-risk disease, or AML with an associated del 5q[31], (the deleted chromosomal region must include 5q[31]),, with or without additional cytogenetic abnormalities

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
85 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Aracytidine, Daunaurubicine, Lenalidomide
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Intervention Description
Induction treatment Lenalidomide 10 mg once daily PO during 3 weeks . in combination with classical 7+3 chemotherapy. Consolidation treatment 6 monthly courses of : Lenalidomide 10 mg/ d during the first 2 weeks in combination with classical 5+1 consolidation chemotherapy Maintenance treatment Lenalidomide 10 mg/d 2 weeks every month until relapse In absence of toxicity, 20 additionnal patients will be included with lenalidomide dose of 25mg/J, then 20 other additionnals patients with Lenalidomide 50mg/J
Primary Outcome Measure Information:
Title
Response (CR, mCR and Cri, according to IWG criteria for AML and IWG 2006 criteria for MDS) to the combination of lenalidomide and chemotherapy in adult high and int 2 MDS (IPSS) or AML with deletion 5q[31]
Time Frame
At the end of induction
Secondary Outcome Measure Information:
Title
Duration of response
Time Frame
At 1 and 2 years
Title
Progression to AML
Time Frame
At 1 and 2 years
Title
Survival and safety of the combination of lenalidomide and chemotherapy
Time Frame
At 1 and 2 years

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years Must understand and voluntarily sign an informed consent form Must be able to adhere to the study visit schedule and other protocol requirements No contra indication to anthracycline based chemotherapy Documented diagnosis of MDS, or CMML with WBC < 13,000/mm3 that meets IPSS criteria for intermediate-2 or high-risk disease, or AML with an associated del 5q[31] (the deleted chromosomal region must include 5q[31]), with or without additional cytogenetic abnormalities Female subjects of childbearing potential must: Understand that the study medication could have a potential teratogenic risk Agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout 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 confirmed on a monthly basis. The following are effective methods of contraception: Implant, Levonorgestrel-releasing intrauterine system (IUS) (prophylactic antibiotics should be considered at the time of insertion particularly in patients with neutropenia due to risk of infection) , Medroxyprogesterone acetate depot, Tubal sterilization, Ovulation inhibitory progesterone-only pills (i.e., desogestrel), Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses. Combined oral contraceptive pills are not recommended. If a subject was using combined oral contraception, she must switch to one of the methods above. The increased risk of VTE continues for 4 to 6 weeks after stopping combined oral contraception. Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days from the start of study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. 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 tests should be performed not more than 3 days before the start of next treatment. 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. All subjects must: 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 Exclusion Criteria: Pregnant or lactating females. Contra indication to anthracycline based chemotherapy. Proliferative (WBC ≥ 13,000/mL) CMML. Prior ≥ grade-2 NCI CTCAE (v 3.0) allergic reaction to thalidomide. Prior desquamating (blistering) rash while taking thalidomide. Prior history of malignancy other than MDS unless the subject has been free of disease for ≥ 5 years. Use of cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days . Less than 6 months since prior allogeneic bone marrow transplantation. Less than 3 months since prior autologous bone marrow or stem cell transplantation. Recombinant human erythropoietin (rHuEPO) therapy received within 28 days. Known HIV-1 positivity. Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he or she participates in the study. Creatinine Clearance< 50 ml/min Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 3.0 x upper limit of normal (ULN) Serum total bilirubin > 1.5 mg/dL (expect for unconjugated hyperbilirubinemia due to Gilbert's disease or secondary to MDS). Subjects with ≥ grade-2 neuropathy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lionel Adès, MD
Organizational Affiliation
Groupe Francophone des Myelodysplasies
Official's Role
Principal Investigator
Facility Information:
Facility Name
CH Angers
City
Angers
ZIP/Postal Code
49 000
Country
France
Facility Name
hopital Victor Dupouy
City
Argenteuil
ZIP/Postal Code
95107
Country
France
Facility Name
Centre Hospitalier de La Cote Basque
City
Bayonne
ZIP/Postal Code
64100
Country
France
Facility Name
Hôpital Avicenne
City
Bobigny
ZIP/Postal Code
93 000
Country
France
Facility Name
CHU Haut-Lévèque
City
Bordeaux
ZIP/Postal Code
33604
Country
France
Facility Name
Centre hospitalier de Chambéry
City
Chambéry
ZIP/Postal Code
73011
Country
France
Facility Name
CHU de Clermont-Ferrand
City
Clermont-Ferrand
ZIP/Postal Code
63058
Country
France
Facility Name
Centre henri Mondor
City
Creteil
ZIP/Postal Code
94010
Country
France
Facility Name
Centre Hospitalier du Mans
City
Le Mans cedex
ZIP/Postal Code
72037
Country
France
Facility Name
Centre Hospitalier de Lens
City
Lens
ZIP/Postal Code
32307
Country
France
Facility Name
centre hospitalier de Lens
City
Lens
ZIP/Postal Code
62307
Country
France
Facility Name
Hôpital Limoges
City
Limoges
ZIP/Postal Code
87046
Country
France
Facility Name
Centre Hospitalier Lyon Sud
City
Lyon
ZIP/Postal Code
69495
Country
France
Facility Name
Institut Paoli Calmettes
City
Marseille
ZIP/Postal Code
13009
Country
France
Facility Name
CHU Brabois
City
Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
CHU de nantes
City
Nantes
ZIP/Postal Code
44093
Country
France
Facility Name
Hôpital Archet1
City
Nice
ZIP/Postal Code
06202
Country
France
Facility Name
Hoiptal St Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
Hopital Cochin-Hematology
City
Paris
ZIP/Postal Code
75679
Country
France
Facility Name
Centre Hospitalier Joffre
City
Perpignan
ZIP/Postal Code
66046
Country
France
Facility Name
Centre Henri Becquerel
City
Rouen
ZIP/Postal Code
76038
Country
France
Facility Name
Hôpital Hautepierre
City
Strasbourg
ZIP/Postal Code
67098
Country
France
Facility Name
Hopital Purpan Service d'Hématologie Clinique
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
CH de Valence
City
Valence
ZIP/Postal Code
26953
Country
France
Facility Name
Institut gustave Roussy
City
Villejuif
ZIP/Postal Code
94805
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
28034993
Citation
Ades L, Prebet T, Stamatoullas A, Recher C, Guieze R, Raffoux E, Bouabdallah K, Hunault M, Wattel E, Stalnikiewicz L, Toma A, Dombret H, Vey N, Sebert M, Gardin C, Chaffaut C, Chevret S, Fenaux P. Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myelodysplasies. Haematologica. 2017 Apr;102(4):728-735. doi: 10.3324/haematol.2016.151894. Epub 2016 Dec 29.
Results Reference
derived
Links:
URL
http://www.gfmgroup.org
Description
Website of the french group of MDS

Learn more about this trial

A Study of the Efficacy and Safety of Lenalidomide Combined to Escalating Doses of Chemotherapy in Intermediate-2-or High Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) With Del 5q

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