Description:
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.
Title
- Brief Title: 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
- Official Title: A Randomized Phase II/III Trial of "Novel Therapeutics" Versus Azacitidine in Newly Diagnosed Patients With Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS), Age 60 or Older LEAP: Less-Intense AML Platform Trial
Clinical Trial IDs
- ORG STUDY ID:
NCI-2017-00436
- SECONDARY ID:
NCI-2017-00436
- SECONDARY ID:
S1612
- SECONDARY ID:
S1612
- SECONDARY ID:
U10CA180888
- NCT ID:
NCT03092674
Conditions
- Acute Myeloid Leukemia
- Myelodysplastic Syndrome
- Myelodysplastic Syndrome With Excess Blasts-2
Interventions
| Drug | Synonyms | Arms |
|---|
| Azacitidine | 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, Onureg, U-18496, Vidaza | Arm A (azacitidine) |
| Cytarabine | .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 | Arm D (decitabine, cytarabine) |
| Decitabine | 5-Aza-2''-deoxycytidine, Dacogen, Decitabine for Injection, Deoxyazacytidine, Dezocitidine | Arm D (decitabine, cytarabine) |
| Midostaurin | CGP 41251, CGP41251, N-Benzoyl-Staurosporine, N-Benzoylstaurosporine, PKC-412, PKC412, Rydapt | Arm C (azacitidine, midostaurin) |
| Nivolumab | BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo | Arm B (azacitidine, nivolumab) |
Purpose
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.
Detailed Description
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 1 year,
every 6 months for 2 years, then annually for 2 years.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Arm A (azacitidine) | Active Comparator | 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. | |
| Arm B (azacitidine, nivolumab) | Experimental | 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 (azacitidine, midostaurin) | Experimental | 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 (decitabine, cytarabine) | Experimental | 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. | |
Eligibility Criteria
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)
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 60 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Overall survival (OS) (Phase II) |
| Time Frame: | Day of registration on study until death from any cause, assessed for up to 5 years |
| Safety Issue: | |
| Description: | A stratified log-rank test of the null hypothesis (hazard ratio=1) with a one-sided alpha of 15% will be used to test an experimental arm versus azacitidine for further phase III testing. |
Details
| Phase: | Phase 2/Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
August 19, 2021
