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Clofarabine Followed by Lenalidomide for Treatment of High Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia

Phase 1
18 Years
Open (Enrolling)
Myeldysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia, Bone Marrow Diseases, Neutropenia, Acute Myeloid Leukemia (AML)

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Trial Information

Clofarabine Followed by Lenalidomide for Treatment of High Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia

High risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute
myelogenous leukemia (AML) are hetereogeneous myeloid malignancies that are associated with
a poor prognosis. Due to advanced age and medical comorbidities, the majority of MDS, CMML,
and AML patients are not candidates for potentially curative standard treatments such as
allogeneic stem cell transplantation (SCT) or intensive chemotherapy (ICT). New therapeutic
approaches that improve response rates, have lesser toxicity, and extend survival are
clearly needed for high risk MDS and AML patients.

Clofarabine is a myelosuppressive, second generation purine nucleoside analogue which has
shown meaningful efficacy at variable dosing levels for high risk MDS and AML patients with
a favorable toxicity profile compared to intensive chemotherapy. Lenalidomide is an oral
structural analogue of thalidomide with a complex mechanism of action including
immunomodulatory, anti-angiogenic, and direct cytotoxic effects which is a well-established
treatment for MDS and has shown agent single efficacy at higher doses for AML.
Lenalidomide's therapeutic benefit in AML has been the greatest in patients with low
presenting total leukocyte and circulating blast counts. We hypothesize that the initial
cytoreductive effects of clofarabine may augment the effectiveness of subsequent
lenalidomide therapy and create a favorable immunologic milieu for patients eligible for
lenalidomide maintenance therapy. This open-label, single institution phase I trial will
evaluate a sequential combination of IV clofarabine with oral lenalidomide for the treatment
of high risk MDS, CMML, and AML. Subjects will receive a single course of IV clofarabine (5
milligrams per metered square per day times 5) for cytoreduction. This will be followed by
oral lenalidomide consolidation with dose escalation from 25 mg daily for 21/28 days for 1
cycle in the first cohort up to 50 mg daily for 28/28 days for 2 cycles in the fourth
cohort. In the absence of dose limiting toxicity or disease progression, Subjects will
receive lenalidomide maintenance, starting at a dose of 10 mg daily in 28 day cycles, with
dose adjustments, for up to 12 cycles.

The overall objective is to determine the safety of sequential therapy with clofarabine and
lenalidomide in subjects with high risk MDS, CMML, and AML. The primary study endpoint will
be the toxicity profile of this novel treatment combination in each cohort. Secondary
endpoints will include characterization of response and duration, overall survival, and the
feasibility of maintenance lenalidomide therapy for responding subjects.

Inclusion Criteria


- Age greater than or equal to 18 years old

- Unequivocal diagnosis of MDS (including chronic myelomonocytic leukemia- CMML)
according to WHO criteria with IPSS risk categorization for MDS subjects of
intermediate-2 to high confirmed by bone marrow evaluation within 30 days prior to
study enrollment


Unequivocal diagnosis of AML according to WHO criteria to include secondary and relapsed
or refractory disease confirmed by bone marrow evaluation within 30 days prior to study

- ECOG Performance Status less than or equal to 2

- Must have failed at least one prior therapy before study enrollment

- Ability to comprehend the investigational nature of the study and provide informed

- All study participants must be registered into the mandatory RevAssist program, and
be willing and able to comply with the requirements of RevAssist

- Females of childbearing potential (FCBP)(Cross) must have a negative serum or urine
pregnancy test with a sensitivity of at least 50 milli-International units per
milliliter within 10 - 14 days and again within 24 hours prior to prescribing
lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by
RevAssist) and must either commit to continued abstinence from heterosexual
intercourse or begin TWO acceptable methods of birth control, one highly effective
method and one additional effective method AT THE SAME TIME, at least 28 days before
she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing.
Men must agree to use a latex condom during sexual contact with a FCBP even if they
have had a successful vasectomy.


- Prior Allogeneic Stem Cell Transplant

- Diagnosis of acute promyelocytic leukemia

- Diagnosis of atypical chronic myeloid leukemia BCR-ABL1 negative, juvenile
myelomonocytic leukemia, yelodysplastic/myeloproliferative neoplasm unclassifiable)

- Prior therapy with clofarabine at any dose

- Prior therapy with lenalidomide at doses greater than or equal to 25 milligrams daily

- Clinically significant active infection not responding adequately to therapy

- HIV Positive

- Uncontrolled concurrent hepatic, renal, cardiac, pulmonary, neurologic, infectious,
or metabolic disease of such severity, which in the opinion of the PI, would preclude
the subjects's ability to tolerate protocol therapy

- Ejection fraction less than 40% by Echocardiogram or MUGA

- Calculated creatinine clearance less 60 milliliters per minute

- Serum bilirubin greater than 1.5 times upper limit of normal

- Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) greater than 3
times upper limit normal

- Decreased oxygen saturation at rest (e.g. pulse oximeter less than 88% or PaO2 less
than or equal to 55 millimeters of mercury)

- Patients with any condition that prevents their ability to swallow and retain
lenalidomide tablets

- Severe psychiatric illness or complex social situations that would limit the
patient's ability to tolerate and/or comply with study requirements

- Current pregnancy or breastfeeding

Type of Study:


Study Design:

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

Outcome Measure:

Identification of the maximum tolerated dose.

Principal Investigator

Minocher M Battiwalla, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Heart, Lung, and Blood Institute (NHLBI)


United States: Federal Government

Study ID:




Start Date:

June 2012

Completion Date:

June 2015

Related Keywords:

  • Myeldysplastic Syndrome (MDS)
  • Chronic Myelomonocytic Leukemia
  • Bone Marrow Diseases
  • Neutropenia
  • Acute Myeloid Leukemia (AML)
  • Myelodysplastic Syndromes
  • Acute Myeloid Leukemia (AML)
  • Chronic Myelomonocytic Leukemia (CMML)
  • Bone Marrow Diseases
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Neutropenia



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892