Idarubicin + Cytarabine and Lenalidomide in Patients With Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML)

All three drugs are FDA approved to treat patients in the United States of America. Idarubicin and Cytarabine combination therapy is a standard treatment for patients with acute myeloid leukemia (AML). Lenalidomide is FDA approved to retreat patients with Multiple Myeloma or Myelodysplastic syndrome with a specific change in their DNA. Loss of a specific part of DNA is also seen in some patients with AML.

This is a phase 1/2, dose-escalation trial of Lenalidomide given in combination with idarubicin + cytarabine. During phase 1, we will enroll patients with AML involving del 5q31; 2) patients with MDS RAEB-2 associated with monosomy 5 or segmental deletion involving 5q31, either alone or with additional cytogenetic abnormalities, and 3) older patients with any type of karyotypic profile in whom an effective and reliable standard of care remains to be developed. All 3 groups of patients define a population of patients with very poor prognoses. Dose escalation of lenalidomide will use a standard 3x3 design. Dose escalation of Lenalidomide only will take place, while the doses of idarubicin and cytarabine will be constant. This trial will have an induction component, consolidation component, and maintenance component. Overall safety and MTD will be determined from the induction phase only.

During phase 2, we will enroll only patients with AML age ≥ 60 years. During phase 2, the efficacy of this combination of Lenalidomide + idarubicin + cytarabine, at the maximum tolerated dose (MTD) for Lenalidomide (determined during phase 1), will be tested.

• Idarubicin (Drug), also known as Antineoplastic Agent: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms.
• Cytarabine (Drug), also known as Antineoplastic Agent: Intravenous infusion of Idarubicin as outlined in Phase I and Phase II Treatment Arms.
• Lenalidomide (Revlimid®) (Drug), also known as Revlimid®: Lenalidomide as outlined in Phase I and Phase II Treatment Arms.

Primary outcomes

• Phase I: Recommended Phase II Dose [18 months]: For the Phase I component, no formal statistical analysis was planned. The primary endpoint is to determine the maximum tolerated dose (MTD) and recommended Phase II dose of lenalidomide given in combination with standard idarubicin + cytarabine induction therapy.
• Phase II: Complete Response Rate of Participants Treated at Maximum Tolerated Dose (MTD) [24 months]: Percentage of participants achieving CR/CRi. Complete Response (CR) plus Complete Response with Incomplete Count Recovery (CRi) rates. Response rates (CR + CRi) of lenalidomide following idarubicin and cytarabine induction therapy in older patients with previously untreated AML. A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of 100,000/μL. CRi: After chemotherapy, patients fulfill all of the criteria for CR except for residual neutropenia (1,000/μL) or thrombocytopenia (100,000/μL).

Secondary outcomes

• Rate of Lenalidomide Related Toxicity During Maintenance Therapy [24 months]: Rate of toxicities of lenalidomide as maintenance therapy according to the National Cancer Institute Common Toxicity Criteria (CTC) V3. Adverse Events: Possibly Related; Probably Related, or Definitely Related to study treatment. Events are categorized as Grade 1 or 2, or as Grade 3 or 4.
• Median Progression-Free Survival (PFS) [24 months]: Progression-free survival (PFS), defined as the time from study entry to disease progression, relapse, or death due to any cause, whichever is earlier, will be summarized with the Kaplan-Meier curve.
• Median Overall Survival (OS) [Up to 24 Months]: Overall Survival (OS), defined for those patients who have achieved CR or CRi as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, to be analyzed similarly. Descriptive analysis was planned for this measure.

Other outcomes

• Rate of Cytogenetic Remission Following Induction Therapy [24 Months]: Rate of cytogenetic remission following induction therapy. Descriptive analysis was planned for this measure.
• Median Relapse-Free Survival (RFS) [24 Months]: Relapse-Free Survival (RFS), defined for those patients who have achieved CR or CRi as the time from study entry to disease progression, relapse or death due to any cause, whichever is earlier, will be analyzed similarly. Descriptive analysis was planned for this measure.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Understand and voluntarily sign an informed consent form
* Able to adhere to the study visit schedule and other protocol requirements
* Disease-specific criteria (Phase I):

  * Previously untreated Acute Myeloid Leukemia (AML), associated with monosomy 5 or segmental deletion involving 5q31, either alone or with additional cytogenetic abnormalities
  * Previously untreated AML (age ≥ 60 years)
  * Myelodysplastic Syndrome, Refractory Anemia with Excess Blasts-2 (MDS,RAEB-2, 10-19% blasts in the bone marrow) associated with monosomy 5 or segmental deletion involving 5q31, either alone or with additional cytogenetic abnormalities
  * For MDS, patients must have had progression with or failed response to front-line therapy with a nucleoside analogue (azacitidine, decitabine).
* Disease Specific Criteria (Phase II)
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry
* Left ventricular ejection fraction (LVEF) ≥ 50%
* Laboratory test results within these ranges:

  * Serum creatinine ≤ 2.0 mg/dL
  * Total bilirubin ≤ 1.5 mg/dL (Gilbert's syndrome excluded)
  * Aspartic transaminase (AST) and Alanine transaminase (ALT) ≤ 2 x upper limit of normal (ULN)
* Disease free of prior malignancies for ≥ 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix or breast
* Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide. For FCBP who have a medical need to proceed with therapy immediately, the pregnancy test that would normally be done 10-14 days prior to initiation of lenalidomide may be done as late as 7 days prior to initiation of lenalidomide. Both this test and the pregnancy testing done within 24 hours prior to initiation of lenalidomide must be negative. FCBP 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. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. *For patients who have latex allergies or whose partner(s) have latex allergies, alternatives will be discussed.
* Must be able to swallow capsules and no evidence of gastrointestinal (GI) tract abnormality that would alter absorption of oral medications
* Understand and voluntarily sign an informed consent form
* Life expectancy >3 months
* All study patients 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)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 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. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form
* Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).
* Unwilling or unable to participate with Food and Drug Administration (FDA) mandated birth control and pregnancy guidelines
* Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
* Use of any other experimental drug or therapy within 28 days of baseline
* Known hypersensitivity to thalidomide
* The development of erythema nodosum, if characterized by a desquamating rash, while taking thalidomide or similar drugs
* Any prior use of lenalidomide
* AML with cytogenetics including t(15;17), t(8;21), or inv(16)
* White blood count (WBC) count ≥ 50,000 on hydroxyurea therapy
* Previous history of induction chemotherapy for AML or allogeneic stem cell transplant
* Predicted inability to tolerate standard induction chemotherapy with idarubicin and cytarabine
* History of spontaneous thromboembolic event requiring use of anticoagulation with warfarin (coumadin) or low molecular-weight heparin within 3 years
* Known positive for human immunodeficiency virus (HIV) or infectious hepatitis, type A, B or C

Participant flow

Outcome results

• Phase I: Recommended Phase II Dose (Primary), Number, mg/day: Phase I Participants 20
• Phase II: Complete Response Rate of Participants Treated at Maximum Tolerated Dose (MTD) (Primary), Number, percentage of participants: All Participants Treated at MTD 54
• Rate of Lenalidomide Related Toxicity During Maintenance Therapy (Secondary), Count of participants, Participants: Maintenance Phase Participants 1
• Median Progression-Free Survival (PFS) (Secondary), Median, months: All Participants Treated at MTD 7.55 (5.53 to 10.53)
• Median Overall Survival (OS) (Secondary), Median, months: All Participants Treated at MTD 11.22 (7.61 to 13.74)
• Rate of Cytogenetic Remission Following Induction Therapy (Other pre specified)
• Median Relapse-Free Survival (RFS) (Other pre specified)

Adverse events

Time frame: 4 years, 8 months

Serious adverse events by term

Other adverse events by term

48 more terms not shown.

• Jeffrey Lancet, M.D., Principal investigator, H. Lee Moffitt Cancer Center and Research Institute