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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


Phase 2
N/A
N/A
Open (Enrolling)
Both
Myelodysplastic Syndrome, Chronic Myelomonocytic Leukemia, Acute Myeloid Leukemia

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Trial Information

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


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.

1. 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

2. 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.

3. 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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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]

Outcome Time Frame:

At the end of induction

Safety Issue:

No

Principal Investigator

Lionel Adès, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Groupe Francophone des Myelodysplasies

Authority:

France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:

GFM-Chimio-Rev-08

NCT ID:

NCT00885508

Start Date:

April 2009

Completion Date:

April 2013

Related Keywords:

  • Myelodysplastic Syndrome
  • Chronic Myelomonocytic Leukemia
  • Acute Myeloid Leukemia
  • 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
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute

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