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Azacitidine With or Without N...

Azacitidine With or Without Nivolumab or Midostaurin, or Decitabine and Cytarabine Alone in Treating Older Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Last Updated: 2025-01-16

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2/PHASE3

Total Enrollment

76 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-02-02

Study Completion Date

2024-06-26

Brief Summary

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This randomized phase II/III trial studies how well azacitidine with or without nivolumab or midostaurin, or decitabine and cytarabine alone work in treating older patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Drugs used in chemotherapy, such as azacitidine, decitabine, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Midostaurin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine with or without nivolumab or midostaurin, or decitabine and cytarabine alone may kill more cancer cells.

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Detailed Description

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PRIMARY OBJECTIVES:

I. To select, based on overall survival, any or all of the "Novel Therapeutic" regimens for further testing against azacitidine in patients age 60 and older with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with excessive blasts-2 (MDS-EB-2). (Phase II) II. To compare overall survival of the "Novel Therapeutic" regimens selected in the phase II portion of the trial to azacitidine in these patient populations. (Phase III)

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities of the regimens in these patient populations.

II. To estimate response rates, event-free survival, and relapse-free survival for these regimens in these patient populations.

TERTIARY OBJECTIVES:

I. To investigate associations between cytogenetic and molecular abnormalities (including FLT3) and outcomes for each of the regimens in these patient populations.

II. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 4 arms.

ARM A: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) daily on days 1-7 or on an interrupted schedule which ensures that all 7 days of therapy are received within a 12 day period. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive azacitidine as in Arm A and nivolumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive azacitidine as in Arm A and midostaurin orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM D:

INDUCTION: Patients receive decitabine IV over 2 hours on days 1-5 and cytarabine IV continuously on days 6-11. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients deemed stable at the discretion of the treating physician receive decitabine as in Induction. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for the 1st year, every 6 months for the 2nd and 3rd years, then annually until 5 years after randomization.

Conditions

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Acute Myeloid Leukemia Myelodysplastic Syndrome Myelodysplastic Syndrome/Acute Myeloid Leukemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm A (azacitidine)

Patients receive azacitidine SC or IV daily on days 1-7 or on an interrupted schedule which ensures that all 7 days of therapy are received within a 12 day period. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type ACTIVE_COMPARATOR

Azacitidine

Intervention Type DRUG

Given SC or IV

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Arm B (azacitidine, nivolumab)

Patients receive azacitidine as in Arm A and nivolumab IV over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Given SC or IV

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Nivolumab

Intervention Type BIOLOGICAL

Given IV

Arm C (azacitidine, midostaurin)

Patients receive azacitidine as in Arm A and midostaurin orally (PO) twice daily (BID) on days 8-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Azacitidine

Intervention Type DRUG

Given SC or IV

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Midostaurin

Intervention Type DRUG

Given PO

Arm D (decitabine, cytarabine)

INDUCTION: Patients receive decitabine IV over 2 hours on days 1-5 and cytarabine IV continuously on days 6-11. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients deemed stable at the discretion of the treating physician receive decitabine as in Induction. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type EXPERIMENTAL

Cytarabine

Intervention Type DRUG

Given IV

Decitabine

Intervention Type DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type OTHER

Correlative studies

Interventions

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Azacitidine

Given SC or IV

Intervention Type DRUG

Cytarabine

Given IV

Intervention Type DRUG

Decitabine

Given IV

Intervention Type DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type OTHER

Midostaurin

Given PO

Intervention Type DRUG

Nivolumab

Given IV

Intervention Type BIOLOGICAL

Other Intervention Names

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5 AZC 5-AC 5-Azacitidine 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar U-18496 Vidaza .beta.-Cytosine arabinoside 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-.beta.-D-Arabinofuranosylcytosine 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone 1-Beta-D-arabinofuranosylcytosine 1.beta.-D-Arabinofuranosylcytosine 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl- 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl- Alexan Ara-C ARA-cell Arabine Arabinofuranosylcytosine Arabinosylcytosine Aracytidine Aracytin Aracytine Beta-Cytosine Arabinoside CHX-3311 Cytarabinum Cytarbel Cytosar Cytosine Arabinoside Cytosine-.beta.-arabinoside Cytosine-beta-arabinoside Erpalfa Starasid Tarabine PFS U 19920 U-19920 Udicil WR-28453 5-Aza-2'-deoxycytidine Dacogen Decitabine for Injection Deoxyazacytidine Dezocitidine CGP 41251 CGP41251 N-Benzoyl-Staurosporine N-Benzoylstaurosporine PKC 412 PKC-412 PKC412 Rydapt ABP 206 BCD-263 BMS 936558 BMS-936558 BMS936558 CMAB819 MDX 1106 MDX-1106 MDX1106 NIVO Nivolumab Biosimilar ABP 206 Nivolumab Biosimilar BCD-263 Nivolumab Biosimilar CMAB819 ONO 4538 ONO-4538 ONO4538 Opdivo

Eligibility Criteria

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Inclusion Criteria

* REGISTRATION STEP 1-SPECIMEN SUBMISSION
* Patients must be suspected to have previously untreated acute myelogenous leukemia (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2)
* Patients must not be known to have AML in the central nervous system (CNS)
* Patients must have specimens submitted for FLT3 testing for randomization stratification; collection of pretreatment specimens must be completed within 1 day of registration to Step 1; specimens must be submitted via the Southwest Oncology Group (SWOG) Specimen Tracking System; FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification of randomization assignment must be received prior to Step 2 registration
* Patients must be offered participation in specimen banking; with patient consent, pretreatment specimens must be collected and submitted via the SWOG Specimen Tracking System
* Patients who have received prior therapy with midostaurin, any anti-PD-1 or anti-PD-L1 therapy, any deoxyribonucleic acid (DNA)-methyltransferase inhibitor (including hypomethylating agents such as azacitidine, decitabine, or other investigational agent that acts by inhibiting DNA or ribonucleic acid \[RNA\] methylation) for any condition, or prior intensive cytotoxic therapy for myelodysplastic syndrome (MDS), are not eligible
* Patients must be able to swallow oral medications without crushing or chewing
* Prior malignancy is allowed providing it does not require concurrent therapy

* Exception: active hormonal therapy is allowed
* Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception also includes (but is not limited to) heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or vasectomy; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

* Women must agree to avoid breast-feeding and women of child-bearing potential (WOCBP) must agree to use highly effective contraception while receiving study drug and for a period of 31 weeks after the last dose of study drug; sexually-active men must agree to use a condom while receiving study drug and for 31 weeks after the last dose of study drug; vasectomized men must also agree to use a condom to avoid delivering drug in the seminal fluid
* 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 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
* REGISTRATION STEP 2-RANDOMIZATION: Patients must be registered to Step 2 no more than 42 days after registration to Step 1 and no more than 42 days after collection of specimens for FLT3 testing
* REGISTRATION STEP 2-RANDOMIZATION: Patients must have morphologically confirmed, previously untreated acute myeloid leukemia (AML) or MDS with excess blasts-2 (MDS-EB-2)

* Patients with acute promyelocytic leukemia (APL), biphenotypic leukemia, blastic transformation of chronic myelogenous leukemia (CML or BCR/ABL), are not eligible
* Patients must have disease present in the blood or bone marrow; patients with only extramedullary disease in the absence of bone marrow or blood involvement are not eligible
* All tests for establishing baseline disease status eligibility must be based on blood and/or bone marrow examination performed within 42 days prior to randomization (registration Step 2)
* REGISTRATION STEP 2-RANDOMIZATION: Patients must not be known to have AML in the CNS
* REGISTRATION STEP 2-RANDOMIZATION: Patients must be deemed, in the judgment of the treating physician, to be ineligible for intensive induction therapy, or must have refused intensive induction therapy; rationale for clinical determination or notation of patient decision must be made
* REGISTRATION STEP 2-RANDOMIZATION: Pretreatment cytogenetics must be performed on all patients; collection of pretreatment specimens must be completed within 42 days prior to randomization (registration Step 2); reports of the results must be submitted
* REGISTRATION STEP 2-RANDOMIZATION: FLT3 results will be used for stratification purposes at the time of randomization; E-mail notification that FLT3 specimens have been processed must be received prior to randomization (registration Step 2)
* REGISTRATION STEP 2-RANDOMIZATION: Prior treatment with hydroxyurea is permitted; prior all-trans retinoic acid (ATRA) for suspected APL and prior intrathecal therapy are permitted, but must plan to be discontinued prior to initiating protocol therapy; patients with signs/symptoms of hyperleukocytosis or white blood cells (WBC) \>= 50,000/mcL can be treated with leukapheresis prior to randomization (registration to Step 2)
* REGISTRATION STEP 2-RANDOMIZATION: Patients may have received non-intensive therapy for antecedent hematologic disorders, including lenalidomide; patients may have received prior chemotherapy for prior cancers; these therapies must be discontinued at least 5 days prior to randomization (registration to Step 2)
* REGISTRATION STEP 2-RANDOMIZATION: Patients who are transfusion-dependent and patients receiving growth factor support are eligible; patients must discontinue growth factor support prior to initiation of protocol therapy
* REGISTRATION STEP 2-RANDOMIZATION: The following tests must be performed within 14 days prior to randomization (registration to Step 2) to establish baseline values:

* Performance status
* Complete blood count (CBC)/differential/platelets
* Creatinine clearance (Cockcroft-Gault)
* Total bilirubin
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
* Lactate dehydrogenase (LDH)
* Albumin
* Glucose
* Fibrinogen
* Electrocardiogram (ECG)
* REGISTRATION STEP 2-RANDOMIZATION: Patients must have complete history and physical examination within 28 days prior to randomization (registration to Step 2); history must include autoimmune disease status (to determine whether patient is eligible for Arm B)
* REGISTRATION STEP 2-RANDOMIZATION: Patients must not have active infection (systemic bacterial, fungal, or viral infection) that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement despite appropriate antibiotics or other treatment)
* REGISTRATION STEP 2-RANDOMIZATION: Patients must be eligible for at least one of the currently active investigational treatment arms (S1612B or S1612C); if the patient does not meet eligibility criteria for at least one active investigational arm, then the patient is not eligible for S1612
* REGISTRATION STEP 2-RANDOMIZATION: 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
* ARM B (AZACITIDINE + NIVOLUMAB)
* Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
* Patients must have AST and ALT =\< 2.5 x institutional upper limit of normal (IULN)
* Patients must have total bilirubin =\< 1.5 x IULN
* Patients must have baseline troponin test performed for eligibility; however, no associated values must be met in order for the patient to be eligible
* ARM C (AZACITIDINE + MIDOSTAURIN)
* Patients must have total bilirubin =\< 2.5 x IULN
* Patients must have creatinine clearance =\< 2.5 x IULN
* Patients must have corrected QT (QTc) interval \< 500/msec (by Bazett's formula) on baseline ECG
* Patients must not have any history of hypersensitivity to any drugs or metabolites of midostaurin
* All tests for establishing baseline values must be completed within 14 days prior to registration to Step 2 (randomization)

Minimum Eligible Age

60 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Laura C Michaelis

Role: PRINCIPAL_INVESTIGATOR

SWOG Cancer Research Network

Locations

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Anchorage Associates in Radiation Medicine

Anchorage, Alaska, United States

Site Status

Alaska Breast Care and Surgery LLC

Anchorage, Alaska, United States

Site Status

Alaska Oncology and Hematology LLC

Anchorage, Alaska, United States

Site Status

Alaska Women's Cancer Care

Anchorage, Alaska, United States

Site Status

Anchorage Oncology Centre

Anchorage, Alaska, United States

Site Status

Katmai Oncology Group

Anchorage, Alaska, United States

Site Status

Providence Alaska Medical Center

Anchorage, Alaska, United States

Site Status

University of Arizona Cancer Center-Orange Grove Campus

Tucson, Arizona, United States

Site Status

Banner University Medical Center - Tucson

Tucson, Arizona, United States

Site Status

University of Arizona Cancer Center-North Campus

Tucson, Arizona, United States

Site Status

CHI Saint Vincent Cancer Center Hot Springs

Hot Springs, Arkansas, United States

Site Status

John L McClellan Memorial Veterans Hospital

Little Rock, Arkansas, United States

Site Status

Kaiser Permanente-Deer Valley Medical Center

Antioch, California, United States

Site Status

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Burbank, California, United States

Site Status

Kaiser Permanente-Fremont

Fremont, California, United States

Site Status

Fresno Cancer Center

Fresno, California, United States

Site Status

Kaiser Permanente-Fresno

Fresno, California, United States

Site Status

Fremont - Rideout Cancer Center

Marysville, California, United States

Site Status

Kaiser Permanente-Modesto

Modesto, California, United States

Site Status

Kaiser Permanente Oakland-Broadway

Oakland, California, United States

Site Status

Kaiser Permanente-Oakland

Oakland, California, United States

Site Status

Stanford Cancer Institute Palo Alto

Palo Alto, California, United States

Site Status

Kaiser Permanente-Rancho Cordova Cancer Center

Rancho Cordova, California, United States

Site Status

Kaiser Permanente-Redwood City

Redwood City, California, United States

Site Status

Kaiser Permanente-Richmond

Richmond, California, United States

Site Status

Rohnert Park Cancer Center

Rohnert Park, California, United States

Site Status

Kaiser Permanente-Roseville

Roseville, California, United States

Site Status

The Permanente Medical Group-Roseville Radiation Oncology

Roseville, California, United States

Site Status

Kaiser Permanente Downtown Commons

Sacramento, California, United States

Site Status

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States

Site Status

Kaiser Permanente-South Sacramento

Sacramento, California, United States

Site Status

South Sacramento Cancer Center

Sacramento, California, United States

Site Status

Kaiser Permanente Sacramento Medical Center

Sacramento, California, United States

Site Status

Kaiser Permanente-San Francisco

San Francisco, California, United States

Site Status

Kaiser Permanente-Santa Teresa-San Jose

San Jose, California, United States

Site Status

Stanford Cancer Center South Bay

San Jose, California, United States

Site Status

Kaiser Permanente San Leandro

San Leandro, California, United States

Site Status

Kaiser Permanente-San Rafael

San Rafael, California, United States

Site Status

Kaiser San Rafael-Gallinas

San Rafael, California, United States

Site Status

Kaiser Permanente Medical Center - Santa Clara

Santa Clara, California, United States

Site Status

Kaiser Permanente-Santa Rosa

Santa Rosa, California, United States

Site Status

Kaiser Permanente Cancer Treatment Center

South San Francisco, California, United States

Site Status

Kaiser Permanente-South San Francisco

South San Francisco, California, United States

Site Status

Kaiser Permanente-Stockton

Stockton, California, United States

Site Status

Gene Upshaw Memorial Tahoe Forest Cancer Center

Truckee, California, United States

Site Status

Kaiser Permanente Medical Center-Vacaville

Vacaville, California, United States

Site Status

Kaiser Permanente-Vallejo

Vallejo, California, United States

Site Status

Kaiser Permanente-Walnut Creek

Walnut Creek, California, United States

Site Status

Rocky Mountain Cancer Centers-Aurora

Aurora, Colorado, United States

Site Status

Boulder Community Hospital

Boulder, Colorado, United States

Site Status

Rocky Mountain Cancer Centers-Boulder

Boulder, Colorado, United States

Site Status

Penrose-Saint Francis Healthcare

Colorado Springs, Colorado, United States

Site Status