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Revlimid®, and Metronomic Melphalan in the Management of Higher Risk Myelodysplastic Syndromes (MDS) and CMML: a Phase 2 Study"

Phase 2
18 Years
Not Enrolling
Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic, Angiogenesis

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Trial Information

Revlimid®, and Metronomic Melphalan in the Management of Higher Risk Myelodysplastic Syndromes (MDS) and CMML: a Phase 2 Study"



1. Determine the overall response rates of low dose melphalan used in combination with
lenalidomide in higher risk MDS


1. Determine the frequency of hematologic improvement of low dose melphalan used in
combination with lenalidomide in higher risk MDS·

2. Determine the safety and tolerability of low dose melphalan used in combination with
lenalidomide in higher risk MDS·

3. Determine the effects of low dose melphalan used in combination with lenalidomide on
biomarkers of angiogenesis in higher risk MDS·

4. Determine the frequency of cytogenetic remissions of low dose melphalan used in
combination with lenalidomide in higher risk MDS


This study is a single center, open-label, non-randomized Phase II study. Patients with
higher risk MDS are included. This patient population will be defined by either high
intermediate or high risk IPSS scores or proliferative CMML with symptomatic cytopenias or
hypersplenism (IPSS score does not apply). If cytogenetics are unavailable, patients with
transfusion dependent RAEB-1 will be eligible.

This is an open label, single center non-randomized Phase II study of melphalan 2 mg po and
lenalidomide, 10 mg po daily on days 1 - 21 of a 28 day cycle in adult patients with higher
risk MDS. Patients may continue to receive drug for a maximum of 12 months or until one of
the following occur: death; disease progression (for definition, see appendix D);
intercurrent illness that prevents further administration of treatment; unacceptable adverse
event(s); patient decides to withdraw from the study; or if general or specific changes in
the patient's condition make the patient unsuitable for further treatment, or if after 4
cycles the patient is not deriving clinical benefit from the treatment in the judgment of
the investigator. After 12 months, responding patients may continue on oral lenalidomide
alone daily (at the dose tolerated by the patient) for 21 days of a 28 day cycle until
disease progression, toxicity or death.

Response to treatment and disease progression will be assessed by collecting and evaluating
bone marrow aspirates within 10 days of the first dose of cycles 3 and 5 and every three
cycles thereafter (every 12 weeks) until confirmation of a complete response. Once
confirmed 1 month later, patients will not undergo bone marrow assessments until there is
evidence of progression.

Blood tests will include weekly CBC with differential and platelet count, electrolytes, BUN
and creatinine for the first 8 weeks, then every 2 weeks until on stable doses, then every 4
weeks thereafter or as clinically indicated. Liver profile will be measured monthly. Bone
marrow biopsies/aspirates will be centrally reviewed during or at the end of the study.
Approximately 30 days after receiving the last dose of study drug, patients will be
reassessed for toxicity, patient status and relapse/progression if applicable. Thereafter,
patients will be re-assessed every 3 months until death or loss to follow-up.

Biomarkers of angiogenesis will be measured at the following frequencies: CECs and CEPs at
baseline, monthly x 3 then q 3 monthly x 2 then at time of progression or coming off
study.Marrow and peripheral blood soluble VEGF and VEGFR-1 and 2 will be measured by ELISA
at the same frequency as the bone marrows.Cytogenetics will be performed at baseline, at 3
months and at completion of the study.

STUDY DURATION: 12 months for lenalidomide + melphalan; option to remain on lenalidomide
alone if ongoing response at 12 months TOTAL SAMPLE SIZE: 20

Inclusion Criteria:

1. Understand and voluntarily sign an informed consent form.

2. Age 18 years or older at the time of signing the informed consent form.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Must have a diagnosis of high-intermediate or high risk MDS (de novo or secondary) or
CMML fitting any of the following classifications (including CMML with wbc < 12,000 x
109/L) and IPSS > 1.5 or proliferative form of CMML (wbc > 12,000 x 109/L for which
the IPSS does not apply). If the patient has unsuccessful cytogenetics, patients
with WHO classification of transfusion dependent RAEB-1 will be eligible (see
appendix B and C for WHO MDS classification).

5. All previous cancer therapy, including radiation, hormonal therapy and surgery, must
have been discontinued at least 4 weeks (6 weeks for 5-Azacitidine or bone marrow
transplant) prior to treatment in this study.

6. ECOG performance status of <= 2 at study entry (see Appendix A).

7. Laboratory test results within these ranges:

- Serum calcium <3.0 mmol/L

- Serum creatinine < 1.5 mg/dL

- Total bilirubin < 1.5 mg/dL

- AST (SGOT) and ALT (SGPT) < 2 x ULN

Exclusion Criteria:

1. Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form.

2. Pregnant or breast-feeding females. (Lactating females must agree not to breast feed
while taking lenalidomide).

3. Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

4. Use of any other experimental drug or therapy within 28 days of baseline.

5. Known hypersensitivity to thalidomide or melphalan.

6. The development of erythema nodosum is characterized by a desquamating rash while
taking thalidomide or similar drugs.

7. Any prior use of lenalidomide.

8. Concurrent use of other anti-cancer agents or treatments.

9. Known positive for HIV or infectious hepatitis, types A, B or C.

10. Must not have a diagnosis of AML (> 20% blasts) or other progressive malignant

11. Must not have received treatment with, erythropoietin, or granulocyte
colony-stimulating factors within seven days of study initiation (21 days for
pegfilgrastim or Aranesp). Note: use of corticosteroids (topical and inhaled) is
permitted and prophylactic steroids are allowed for transfusion reactions, but
ongoing oral corticosteroids are not permitted.

12. Serious or non-healing wound, ulcer, or bone fracture.

13. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 28 days of treatment.

14. Any history of cerebrovascular accident (CVA) or transient ischemic attack within 12
months prior to study entry.

15. Histories of myocardial infarction, cardiac arrhythmia, stable/unstable angina,
symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or
stenting within 12 months prior to study entry.

16. History of pulmonary embolism within the past 12 months.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Response Rate (RR) (as defined by modified international working group standardized response criteria)

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Rena J Buckstein, MD FRCPC

Investigator Role:

Principal Investigator

Investigator Affiliation:

Odette Cancer Center


Canada: Canadian Institutes of Health Research

Study ID:




Start Date:

January 2008

Completion Date:

December 2012

Related Keywords:

  • Myelodysplastic Syndromes
  • Leukemia, Myelomonocytic, Chronic
  • Angiogenesis
  • Myelodysplastic syndrome
  • Chronic myelomonocytic leukemia
  • High intermediate risk and high risk IPSS score
  • Angiogenesis
  • Metronomic chemotherapy
  • Myelodysplastic Myeloproliferative Diseases
  • Leukemia
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia