Azacitidine With or Without Lenalidomide or Vorinostat in Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

This study is currently recruiting participants.
Verified March 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01522976
First received: January 27, 2012
Last updated: April 16, 2014
Last verified: March 2014

January 27, 2012
April 16, 2014
March 2012
June 2015   (final data collection date for primary outcome measure)
Response rate (RR) (any of complete hematological remission [CR], partial response [PR], or hematologic improvement [HI]) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
The final analysis will consist of two one-sided tests of whether the RR is improved in either of the combination arms compared to the single-agent azacitidine arm. Each test will be performed at the 0.05 level.
  • Overall survival of each treatment arm estimated by the Kaplan-Meier method [ Designated as safety issue: No ]
  • Association of cytogenetic abnormalities with outcomes of each treatment arm [ Designated as safety issue: No ]
  • Toxicity rates on each arm [ Designated as safety issue: Yes ]
  • Response rate (complete remission, partial remission, or hematologic improvement) of combination arms compared with single-agent azacitidine arm [ Designated as safety issue: No ]
  • Relapse-free survival of each treatment arm estimated by the Kaplan-Meier method [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01522976 on ClinicalTrials.gov Archive Site
  • Overall survival [ Time Frame: From the date of initial registration to date of death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    Will be estimated by the Kaplan-Meier method.
  • Relapse-free survival [ Time Frame: From the date of response to the date of first documentation of relapse from response, or death due to any cause, assessed up to 5 years ] [ Designated as safety issue: No ]
    Will be estimated by the Kaplan-Meier method.
  • Toxicity rates on each arm assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Frequency of pre-study cytogenetic abnormalities [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be examined in descriptive analyses.
  • Cytogenetic response rates [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Will be estimated in descriptive analyses.
Frequency of prestudy cytogenetic abnormalities [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Azacitidine With or Without Lenalidomide or Vorinostat in Patients With Higher-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia
A Randomized Phase II Study of Azacitidine in Combination With Lenalidomide (NSC-703813) vs. Azacitidine Alone vs. Azacititdine in Combination With Vorinostat (NSC-701852) for Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

This randomized phase II trial studies how well giving azacitidine works with or without lenalidomide or vorinostat in treating patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Lenalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether azacitidine is more effective with or without lenalidomide or vorinostat in treating myelodysplastic syndromes or chronic myelomonocytic leukemia.

PRIMARY OBJECTIVES:

I. To test whether the response rate (complete remission, partial remission, or hematologic improvement) of patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) who receive either the combination of lenalidomide and azacitidine or the combination of vorinostat and azacitidine is improved compared to patients who receive single-agent azacitidine.

SECONDARY OBJECTIVES:

I. To estimate relapse-free survival, overall survival and cytogenetic response rate of patients treated on each regimen.

II. To estimate the frequency and severity of toxicities of the three regimens in this patient population.

III. To investigate in a preliminary manner the frequency of subgroups from pre-study cytogenetic studies and correlate these subgroups with clinical outcomes in this patient population.

IV. To collect specimens for banking for use in future research studies.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7 or days 1-5 and 8-9, and lenalidomide orally (PO) once daily (QD) on days 1-21.

ARM II: Patients receive azacitidine as in arm I.

ARM III: Patients receive azacitidine as in arm I and vorinostat PO twice daily (BID) on days 3-9.

In all arms, courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Previously Treated Myelodysplastic Syndromes
  • Refractory Anemia With Excess Blasts
  • Secondary Myelodysplastic Syndromes
  • Drug: azacitidine
    Given SC or IV
    Other Names:
    • 5-AC
    • 5-azacytidine
    • azacytidine
    • Vidaza
  • Drug: lenalidomide
    Given PO
    Other Names:
    • CC-5013
    • IMiD-1
    • Revlimid
  • Drug: vorinostat
    Given PO
    Other Names:
    • L-001079038
    • SAHA
    • suberoylanilide hydroxamic acid
    • Zolinza
  • Experimental: Arm I (azacitidine and lenalidomide)
    Patients receive azacitidine SC or IV on days 1-7 or days 1-5 and 8-9, and lenalidomide PO QD on days 1-21. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: azacitidine
    • Drug: lenalidomide
  • Experimental: Arm II (azacitidine)
    Patients receive azacitidine as in arm I. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: azacitidine
  • Experimental: Arm III (azacitidine and vorinostat)
    Patients receive azacitidine as in arm I and vorinostat PO BID on days 3-9. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: azacitidine
    • Drug: vorinostat
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
267
Not Provided
June 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) based on one of the following:

    • French-American-British (FAB) classifications:

      • Refractory anemia with excess blasts (RAEB - defined as having 5-20% myeloblasts in the bone marrow)
      • CMML with 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood
    • World Health Organization (WHO) Classifications:

      • RAEB-1 (defined as having 5-9% myeloblasts in the bone marrow)
      • RAEB-2 (defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood)
      • CMML-1 (defined as having < 5% myeloblasts in the bone marrow and/or < 10% blasts in the blood)
      • CMML-2 (defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood)
    • International prognostic score (IPSS) of Intermediate 2 (1.5-2.0 points) or High (>= 2.5 points); a score of Intermediate 1 (0.5-1.0 points) is only allowable in the setting of >= 5% myeloblasts
    • Patients with acute myeloid leukemia (AML) are not eligible
    • Procedures to obtain specimens for establishing baseline disease must be done within 30 days prior to registration
  • Patients must not have received lenalidomide, azacitidine, vorinostat, or decitabine as treatment previously; any hematopoietic growth factors must be stopped for at least 14 days prior to registration

    • Patients may have received low-dose cytarabine for MDS treatment previously, but they must have discontinued its use for at least 28 days prior to registration
  • Patients must not have received radiation therapy, chemotherapy, or cytotoxic therapy to treat conditions other than MDS within 12 months prior to registration
  • Patients must not have undergone prior allogeneic stem cell or bone marrow transplantation at any time; patients that have undergone an autologous stem cell transplant are eligible
  • Patients must not have used or be using histone deacetylase (HDAC) inhibitor agents for anticancer treatment
  • Patients may not have received agents such as valproic acid for epilepsy within 30 days prior to registration
  • Patients must have Zubrod performance status of 0-2
  • Patients must not have any pre-existing neurotoxicity/neuropathy of >= grade 2 according to the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 4.0, or prior >= grade 3 allergic reaction/hypersensitivity or rash to thalidomide that has not resolved to < grade 2
  • Patients must not have any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent
  • Patients must not have history of thromboembolic event or other condition requiring current use of anticoagulation with Coumadin (warfarin) or low molecular-weight heparin
  • Patients must not have known or suspected hypersensitivity to mannitol
  • Patients must receive a 12-lead electrocardiogram (EKG), chest x-ray, serum creatinine, complete metabolic panel including serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT), electrolytes, and bilirubin testing within 28 days prior to registration in order to establish baseline measurements; questions regarding patient safety in regards to results of these tests should be directed to the Study Coordinator
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to registration; FCBP must agree to have a second pregnancy test within 24 hours prior to starting course 1 if randomized to receive lenalidomide

    • A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Patients must commit to the following if they are randomized to receive lenalidomide; 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 starting 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 by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
  • Patients not randomized to receive lenalidomide will not be required to undergo serial pregnancy testing or lenalidomide counseling after registration
  • No prior malignancy is allowed except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for three years
  • Cytogenetics requirements:

    • Southwestern Oncology Group (SWOG) (and other sites not affiliated with Cancer and Leukemia Group B [CALGB] or Eastern Cooperative Oncology Group [ECOG]): Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 14 days prior to registration to SWOG-S1117
    • CALGB: CALGB patients must enroll on CALGB 8461, the cytogenetics protocol
    • ECOG: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 30 days prior to registration to S1117
  • Banking requirements:

    • SWOG and ECOG (and other sites not affiliated with CALGB): Patients must be offered participation in specimen banking
    • CALGB: CALGB patients must be offered participation in CALGB 9665, the CALGB Leukemia Tissue bank protocol
    • National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG): NCIC CTG patients must be offered participation in specimen submission and banking
  • All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
  • As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
Both
18 Years and older
No
Not Provided
United States,   Canada
 
NCT01522976
NCI-2012-00242, NCI-2012-00242, SWOG-S1117, CDR0000723909, S1117, S1117, U10CA032102
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Mikkael Sekeres Southwest Oncology Group
National Cancer Institute (NCI)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP