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

This study has suspended participant recruitment.
(Temporarily stopped for assessment.)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01522976
First received: January 27, 2012
Last updated: September 23, 2014
Last verified: July 2014
  Purpose

This randomized phase II/III 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.


Condition Intervention Phase
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Previously Treated Myelodysplastic Syndromes
Refractory Anemia With Excess Blasts
Secondary Myelodysplastic Syndromes
Drug: azacitidine
Drug: lenalidomide
Drug: vorinostat
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II/III Study of Azacitidine in Combination With Lenalidomide (NSC-703813) vs. Azacitidine Alone vs. Azacitidine in Combination With Vorinostat (NSC-701852) for Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Response rate (RR) (any of complete hematological remission, partial remission, or hematologic improvement) (Phase II) [ 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 (OS) (Phase III) [ 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 ]
    Cox regression models stratified by the randomization factor will be used for all analyses.


Secondary Outcome Measures:
  • OS (Phase II) [ 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 NCI Common Terminology Criteria for Adverse Events 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.


Estimated Enrollment: 592
Study Start Date: March 2012
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.
Drug: azacitidine
Given SC or IV
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
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.
Drug: azacitidine
Given SC or IV
Other Names:
  • 5-AC
  • 5-azacytidine
  • azacytidine
  • Vidaza
Drug: vorinostat
Given PO
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza

Detailed Description:

PRIMARY OBJECTIVES:

I. To select based on response rate (complete remission, partial remission, or hematologic improvement) either the combination of lenalidomide and azacitidine or the combination of vorinostat and azacitidine for further testing against single-agent azacitidine among patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). (Phase II) II. To compare overall survival between the combination arm selected in the Phase II portion of the trial to single-agent azacitidine among patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). (Phase III)

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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:

      • Refractory anemia with excess blasts-1 (RAEB-1 - defined as having 5-9% myeloblasts in the bone marrow)
      • Refractory anemia with excess blasts-2 (RAEB-2 - defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood)
      • Chronic myelomonocytic leukemia-1 (CMML-1 - defined as having < 5% myeloblasts in the bone marrow and/or < 10% blasts in the blood)
      • Chronic myelomonocytic leukemia-2 (CMML-2 - defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood) OR
    • 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
    • NOTE: 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 may have received prior hydroxyurea per CMML treatment previously, but they must have discontinued its use for at least 7 days prior to registration; these patients will not be eligible if white blood cell (WBC) > 30,000/mm^3
  • 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 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 or computed tomography (CT) scan, serum creatinine, complete metabolic panel including serum glutamic oxaloacetic transaminase (SGOT) or serum glutamate pyruvate 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 Chair
  • 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

    • Further, patients 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; 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); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure
    • NOTE: Patients not randomized to receive lenalidomide will not be required to undergo serial pregnancy testing or lenalidomide counseling after registration
  • 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
  • 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 Alliance or Eastern Cooperative Oncology Group [ECOG]-American College of Radiology Imaging Network [ACRIN]): Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 30 days prior to registration to S1117; specimens must be submitted to the site's preferred Clinical Laboratory Improvement Amendments (CLIA)-approved cytogenetics laboratory; reports of the results must be submitted as described; note that cytogenetics are required at other timepoints; NOTE: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) sites may submit specimens to College of American Pathologists (CAP) or Ontario Laboratory Accreditation (OLA)-approved laboratories providing the lab is licensed to perform fluorescent in situ hybridization (FISH) analysis
    • Alliance: Alliance patients must enroll on Cancer and Leukemia Group B (CALGB) 8461, the cytogenetics protocol; CALGB 8461 provides sample procurement and submission instructions to Alliance-approved institutional cytogeneticists; note that cytogenetics are required at other timepoints
    • ECOG-ACRIN: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 30 days prior to registration to S1117; specimens must be submitted to the site's preferred CLIA-approved cytogenetics laboratory; karyotypes and reports must be submitted for review to the Mayo Clinic Cytogenetics Laboratory in Rochester; note that cytogenetics testing is required at other timepoints
  • Banking requirements:

    • SWOG, Alliance and ECOG-ACRIN (and other sites not affiliated with NCIC CTG): Patients must be offered participation in specimen banking; with patient consent, specimens must be submitted as outlined
    • Alliance: (Temporarily Closed 2/28/14): As of February 28, 2014, CALGB 9665 has been temporarily closed, so Alliance patients under consideration for S1117 are NOT to be registered to CALGB 9665 and no specimens for patients enrolled after February 28, 2014 are to be submitted via this ancillary study; these patients should submit specimens per SWOG instructions; patients already enrolled on CALGB 9665 should continue to submit specimens per instructions in CALGB 9665
    • NCIC CTG: NCIC CTG patients must be offered participation in specimen submission and banking; with patient consent, specimens must be submitted as outlined
  • All patients or their legally authorized representative 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 Oncology Patient Enrollment Network (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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01522976

  Show 301 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Mikkael Sekeres Southwest Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01522976     History of Changes
Other Study ID Numbers: NCI-2012-00242, NCI-2012-00242, SWOG-S1117, CDR0000723909, S1117, S1117, U10CA180888, U10CA032102
Study First Received: January 27, 2012
Last Updated: September 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Leukemia
Syndrome
Anemia, Refractory
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Anemia, Refractory, with Excess of Blasts
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Neoplasms by Histologic Type
Disease
Pathologic Processes
Anemia
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Lenalidomide
Thalidomide
Vorinostat
Azacitidine
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on October 01, 2014