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
Prior treatment with more than 1 cycle of azacitidine or decitabine.
Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment.
Adult subjects with advanced MDS or CMML requiring therapy who were previously treated with either azacitidine or decitabine for at least 4 cycles and deemed to have failed therapy due to progression of disease using International Working Group (IWG) criteria (“refractory”) or losing their previously documented response to the therapy (“relapsed”) and who are ineligible for allogeneic stem cell transplant
Must have received at least 1 cycle of induction therapy for front-line AML including cytarabine continuous infusion + anthracycline +/- cladribine or etoposide for 1 or 2 cycles, high dose cytarabine with or without fludarabine, cladribine or clofarabine, >= 4 cycles of azacitidine/decitabine or the equivalent experimental therapy (the latter as confirmed by the principal investigator [PI])
Patients must be eligible for treatment with decitabine
Previous exposure to 5-AC (azacitidine) or decitabine
MDS/CMML, relapsed from, or refractory to, prior HMA therapy; the latter defined as failure to achieve clinical remission (CR), partial remission (PR) or hematologic improvement (HI) after previous HMA therapy (? 4 cycles of azacitidine or decitabine), or progression during, or toxicity to previous HMA therapy precluding further HMA treatment, and,
Disease that is refractory to or relapsed from either a hypomethylating agent (e.g. decitabine or azacitidine) or a standard AML-type intensive regimen
Relapse/refractory is defined as at least 1 course of treatment for AML excluding any patients treated with azacitidine or decitabine
Any prior treatment with azacitidine or decitabine
(Arm A only): Subject must be hypomethylating agent naive (i.e. prior azacitidine, decitabine, SGI-110 is exclusionary). Receipt of other MDS-directed therapy such as lenalidomide is allowed
Has previous treatment for higher-risk myelodysplastic syndromes (HR MDS) or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug.
Prior exposure to decitabine or azacitidine will be an exclusion criterion for the use of decitabine or azacitidine alone
Adult subjects with advanced MDS requiring treatment with HMA and either refractory to at least 4 cycles or progressing after previously documented response\r\n* Patient must be treated within 6 months of the last HMA treatment and must be willing to be treated with the same agent they last received on this study\r\n* Prior treatment with novel HMA analog of decitabine on clinical trial is allowed; in such cases, decitabine will be used as the standard of care agent
Patient with history of prior exposure to decitabine
For patients in the relapse or refractory cohort, any other therapy not being a hypomethylating agent after hypomethylating agents (HMA) failure or more than 4 months since completion of last cycle of hypomethylating agent. Please note that hypomethylating agent may include second generation compounds such as SGI-110, oral decitabine or oral azacitidine and will also include combinations with investigational agents
Any previous treatment with a hypomethylating agent, including decitabine, azacitidine, or SGI-110
Prior treatment with either decitabine or azacitidine
Patients may have received treatment (e.g. azacitidine/decitabine, lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm
Prior DNA methyl transferase inhibitor administration (azacitidine, decitabine or guadecitabine) for AML or for antecedent MDS is allowed if this clinical trial is considered the best treatment option, but azacitidine, decitabine or guadecitabine must have been stopped at least 3 weeks prior to day 1 of treatment on the study
Previous receipt of azacitidine, decitabine, anthracyclines, cytarabine, or other nucleoside analogues for treatment of AML or MPN/MDS other than as noted for cytarabine
Azacitidine, decitabine or other demethylating agents
No response, progression, or relapse (according to 2006 International Working Group [IWG] criteria) following at least 4 cycles of either azacitidine or decitabine, which were completed within the last 2 years - AND/OR - intolerance to azacitidine or decitabine defined as drug-related >= grade 3 hepatic or renal toxicity leading to treatment discontinuation during the preceding 2 years
Patients who received more than one full course of prior hypomethylating agents azacitidine or decitabine
Prior decitabine for the treatment of cancer
Patients who received 1-2 cycles of hypomethylating therapy (decitabine azacitidine) are eligible
Patients must not be currently receiving any chemotherapy agents (except hydroxyurea)\r\n* Intrathecal cytarabine (ARA-C) and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system)\r\n* Patients cannot have received more than 3 prior lines of therapy for their hematologic malignancy; patient may have previously had azacitidine or decitabine and still be eligible
Prior therapy with decitabine will be allowed unless the patient experienced progression to AML while being treated with decitabine
Prior treatment with guadecitabine for any indication, or more than 2 cycles of prior decitabine or azacitidine.
Inclusion Criteria:\n\n          1. Previously participated in, and received oral azacitidine, and continues to fulfill\n             the eligibility criteria in one of the parent oral azacitidine clinical trials.\n\n             The Investigator believes the subject is tolerating treatment with oral azacitidine\n             monotherapy and continued oral azacitidine treatment is of benefit to the subject.\n\n          2. Understand and voluntarily sign an informed consent document prior to any study\n             related assessments or procedures being conducted.\n\n          3. Willing and able to adhere to the study visit schedule and other protocol\n             requirements.\n\n          4. Females of childbearing potential (FCBP) may participate, provided they meet the\n             following conditions:\n\n               1. Have two negative pregnancy tests as verified by the Investigator prior to\n                  starting study therapy. She must agree to ongoing pregnancy testing during the\n                  course of the study, and after end of study treatment. This applies even if the\n                  subject practices true abstinence from heterosexual contact.\n\n               2. Either commit to true abstinence from heterosexual contact (which must be\n                  reviewed on a monthly basis and source documented) or agree to use, and be able\n                  to comply with, effective contraception without interruption, 28 days prior to\n                  starting investigational product, during the study therapy (including dose\n                  interruptions), and for 3 months, or longer if required by local regulations,\n                  after discontinuation of study therapy.\n\n          5. Male subjects must:\n\n               1. Practice true abstinence (which must be reviewed on a monthly basis) or agree to\n                  use a condom during sexual contact with a pregnant female or a female of\n                  childbearing potential while participating in the study, during dose\n                  interruptions and for at least 3 months, or longer if required by local\n                  regulations, following Investigational Product (IP) discontinuation, even if he\n                  has undergone a successful vasectomy.\n\n        Subjects must satisfy the following criteria to participate in the Survival Follow-up\n        phase:\n\n          1. In order to be enrolled for the survival follow-up in the Follow-up Phase of the\n             rollover study, subjects must have been in a parent oral azacitidine study where\n             monitoring for survival was required and have signed informed consent for follow-up\n             phase.\n\n          2. Understand and voluntarily sign an informed consent document for this study.\n\n          3. Willing and able to adhere to the study visit schedule and other protocol\n             requirements.\n\n        Exclusion Criteria:\n\n        The presence of any of the following will exclude a subject from receiving investigational\n        product in the study:\n\n          1. Concomitant use of drugs that are prohibited.\n\n          2. Prior chemotherapy (including injectable azacitidine) or radiotherapy or any\n             investigational agent after the last dose of oral azacitidine administered as part of\n             the parent oral azacitidine study.\n\n          3. Subjects have met one or more criteria for discontinuation as stipulated in the parent\n             oral azacitidine study.\n\n          4. Subjects received oral azacitidine in combination with another compound during a\n             parent oral azacitidine study (Subjects form multi-arm parent oral azacitidine studies\n             will be allowed to enroll into the rollover study, if the subject is receiving\n             single-agent oral azacitidine at the time of transition into the rollover study).\n\n          5. A subject's transition into rollover study ? 45 days after End of the Study visit of\n             the parent oral azacitidine study\n\n          6. Pregnant or lactating females. There are no exclusion criteria to prevent entry or\n             remaining on the follow-up phase of this study
Patients must have failed prior therapy with either a hypomethylating agent (e.g., azacytidine, decitabine) alone or in combination with other agents. Patients with abnormalities in chromosome 5q, should have failed either a hypomethylating agent or lenalidomide.
Patients may have received low-intensity treatment (e.g. azacitidine/decitabine, lenalidomide, growth factors) for antecedent low-grade myeloid neoplasm (i.e. < 10% blasts in blood and bone marrow)
Pathologically confirmed diagnosis of MDS by World Health Organization (WHO) criteria (including secondary and therapy-related disease) who have failed standard therapy, who are intolerant of prior therapy, or who refuse standard therapy; any prior therapy, including ibrutinib and/or lenalidomide (unless intolerant of one or both of these medications), is permitted\r\n* Hypomethylating agent failure is defined as disease progression or stable disease as best response to an adequate course of treatment (at least four cycles) with an injectable hypomethylating agent (azacitidine or decitabine)
Clinical indication for treatment with azacitidine.
Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:
Subjects who may still be sensitive to repeated treatment with decitabine or azacitidine such as subjects who had response to prior decitabine or azacitidine treatment, but relapsed >6 months after stopping treatment with these agents.
Patients who have received previous treatment for antecedent hematological disorders (AHD) with 5-azacitidine, decitabine, or low dose cytarabine will be excluded
The absolute neutrophil count (ANC) must be > 1000 mm^3 prior to starting every cycle of treatment with decitabine; decitabine may be delayed for up to 4 weeks between cycles (i.e. may be administered as infrequently as every (q) 8 weeks) while waiting for counts to recover
The platelet count must be > 75,000 mm^3 prior to starting every cycle of treatment with decitabine; decitabine may be delayed for up to 4 weeks between cycles (i.e. may be administered as infrequently as every (q) 8 weeks) while waiting for counts to recover
Subjects who have received prior therapy with hypomethylating agents (5-azacytidine, decitabine, SGI-110)
Progression at any time after initiation of azacitidine or decitabine treatment OR
Failure to achieve complete or partial response or hematological improvement after at least six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine OR
Relapse after initial complete or partial response or hematological improvement after six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine administered within the past 2 years For participants in Cohorts C1 and C2:
Deoxyribonucleic acid (DNA) methyltransferase inhibitors (azacitidine or decitabine) must have been stopped at least 3 weeks prior to day 1 of treatment on the study
Patients with relapsed or refractory AML age >= 18 years are also eligible for treatment; patients may have been treated for antecedent hematologic disorder with myeloid growth factors, recombinant erythropoietin, thalidomide, lenalidomide, 5-azacitidine or the 5 day schedule of decitabine; patients who have received the 10 day schedule of decitabine for treatment an antecedent hematologic disorder or AML are not eligible
Hypomethylating agent (azacitidine and/or decitabine) failure, defined as lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator
Prior azacitidine, decitabine, or midostaurin
Prior exposure to azacitidine, decitabine or prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative.
Known or suspected hypersensitivity to azacitidine or mannitol or any other ingredient used in the manufacture of oral azacitidine (see the current azacitidine IB).
Have known or suspected hypersensitivity to azacitidine or any other ingredient used in the manufacturing of Azacitidine.
Received other treatments for MDS within 28 days prior to first dose (example [eg], azacitidine, decitabine, lenalidomide, Erythropoiesis-Stimulating Agent (ESA) (8 weeks for long-acting ESAs)
Previous treatment with decitabine or azacitidine or other hypomethylating agent.
a) Prior treatment with a hypomethylating agent (example [eg], azacitidine, decitabine); b) Prior treatment with lenalidomide; c) Has received an erythropoiesis-stimulating agent (ESA) or any chemotherapy, immunomodulatory, or immunosuppressive therapy within 4 weeks prior to study entry (8 weeks for long-acting ESAs)
Prior treatment with >= 4 cycles of a hypomethylating agent (decitabine or azacitidine) without response OR documented disease progression on or after hypomethylating agent therapy
Previous treatment with specific chemotherapy (cytarabine, idarubicin, daunorubicin) or hypomethylating drug (decitabine or azacitidine) for a hematological disorder; EXCEPTIONS: prior hydroxyurea allowed; secondary AML is allowed
Participant has been previously treated with azacitidine (any formulation), decitabine, or any other hypomethylating agent.
Subject has been previously treated with azacitidine (any formulation), decitabine, or any other hypomethylating agent.
Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only)
Patients may have received up to 3 prior cycles of hypomethylator therapy (i.e. decitabine or azacitidine) prior to enrollment and may have received supportive care measures (growth factors, erythropoietin stimulating agents, transfusion, etc)
Patients must have completed at least 4 cycles of hypomethylating agent therapy (e.g azacitidine or decitabine) with failure to achieve at least a partial response, or with the presence of ongoing cytopenias per IWG (platelet count < 100x10^9/L, hemoglobin <11g/L or ANC <1x10^9/L). Patients with progressive disease on HMA-therapy prior to this time point are also eligible at the time of documented progression. Therapy with decitabine analogs (i.e. SGI-110) will be considered as decitabine for the purposes of this study.
Patients receiving concomitant treatment with other anti-neoplastic agents, with the exception of hydroxyurea; however, prior treatment with DNMTi therapy (i.e., decitabine or azacitidine) for MDS or other antecedent hematologic malignancy is allowed\r\n* NOTE: if the patient has been initiated on the protocol defined regimen (i.e. decitabine without a FLT3 inhibitor) before the FLT3 mutation status was known, the patient may be registered on the protocol and start midostaurin on day 11
Prior therapy with decitabine or azacitidine
Patients must be 28 days from the end of the last induction course or at least 14 days from completion of previous methyltransferase inhibitor therapy (azacitidine or decitabine) at the time of registration
Patient must have undergone =< 2 cycles of prior hypomethylating agent (decitabine or azacitidine)
No response, progression, or relapse (according to 2006 International Working Group [IWG] criteria) following at least 4 cycles of either azacitidine or decitabine, or following at least 2 cycles of SGI-110, which were completed within the last 2 years - AND/OR - intolerance to azacitidine or decitabine, or SGI-110 defined as drug-related >= grade 3 hepatic or renal toxicity leading to treatment discontinuation during the preceding 2 years
At least one prior HMTA treatment with either azacitidine or decitabine and subsequent loss of response to HMTA, progression while on HMTA, or no response to HMTA, defined as failure to achieve at least hematologic improvement (HI) after 4 cycles of treatment
One course of hypomethylating agent therapy (i.e.; up to 7 doses of azacitidine or 3-5 days of decitabine) within 30 days prior to enrollment (Day 1)
Eligible for therapy with either decitabine or azacitidine
Eligible for therapy with azacitidine.
Patients with a diagnosis of myelodysplastic syndrome with >= 10% bone marrow blasts with no response or progression of disease after at least 4 cycles of a hypomethylating agent (5-azacytidine or decitabine)
Previous therapy with cytotoxic agents for AML; persons with previous treatments for myelodysplasia/myeloproliferation such as hydroxyurea, interferon, hypomethylating agents (5-azacitidine or decitabine), lenalidomide, or Janus kinase/signal transducers and activators of transcription (JAK/STAT) inhibitors may participate but must have > 1 week off therapy prior to enrollment
Subjects with any prior exposure to the hypomethylating agents (5-azacitadine or decitabine) are excluded
For Cohort 3 subjects, prior treatment with hypomethylating agents (eg, azacitidine, decitabine)
Previous treatment with azacitidine (any formulation), decitabine, any other hypomethylating agent.
Patients may have received azacitidine, decitabine, or lenalidomide but no “cytotoxic therapy” such as ara-C or anthracyclines; data suggest that failure to respond to azacitidine reduces probability of response to 3+7; hence in the interest of having a relatively homogeneous population, while patients who have received and failed azacitidine or decitabine will be eligible for this study, they will be analyzed separately from patients who have not received these drugs
Use of any of the following after transplantation and prior to starting oral Azacitidine:
Azacitidine, decitabine or other demethylating agents
Previous treatment with azacitidine or decitabine
Prior therapy with decitabine or azacitidine
Patients who were treated with 5'-azacitidine without response prior to transplant would be eligible to participate on this protocol
Adequate course of treatment with an injectable hypomethylating agent (azacitidine for injection or decitabine) as the last therapeutic intervention for MDS (MYELODYSPLASTIC SYNDROMES) prior to beginning screening for this study. Adequate is defined as:
having received at least 6 consecutive 4-week treatment cycles with azacitidine for injection, or
having received at least 4 consecutive 6-week treatment cycles with decitabine (3-day regimen) or at least 6 consecutive 4-week treatment cycles with decitabine (5-day regimen), or
having demonstrated inability to tolerate treatment with an injectable hypomethylating agent because of unacceptable drug-related toxicity after at least 3 months of attempted treatment: Three 28-day cycles of azacitidine for injection or decitabine 5-day regimen; two 42-day cycles of decitabine 3-day regimen.
Documented disease progression or stable disease as best response to treatment (or attempted treatment) with azacitidine for injection or decitabine. Those achieving an objective response to treatment regimen with an injectable Hypomethylating agent (HMA) are excluded from participation in this study. Definitions of disease progression are modified from IWG (INTERNATIONAL WORKING GROUP) 2006 criteria and include:
Have the last dose of the prior treatment regimen (injectable HMA (HYPOMETHYLATING AGENT) - azacitidine for injection or decitabine) not more than 16 weeks prior to screening for this study (date of informed consent signature).
No less than 3 weeks between the last dose of the prior treatment regimen (injectable HMA (HYPOMETHYLATING AGENT) - azacitidine for injection or decitabine) and the planned date of first dose of IP (IINVESTIGATIONAL PRODUCT).
Agree to practice true abstinence2 (which must be reviewed on a monthly basis and source documented) or agree to the use of highly effective methods of contraception from 28 days prior to starting azacitidine, and must agree to continue using such precautions while taking azacitidine (including dose interruptions) and for up to 90 days after the last dose of azacitidine. Cessation of contraception after this point should be discussed with a responsible physician
Prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative at any time in the subject's prior history
Prior treatment with a hypomethylating agent (including but not limited to azacitidine or decitabine), unless last treatment with hypomethylating agent was > 3 months prior to start of protocol treatment OR has received =< 2 cycles of hypomethylating agent without disease progression during those =< 2 cycles and last dose was not within 14 days of first protocol treatment
Prior exposure to azacitidine, decitabine or investigational hypomethylating agent
For International Prognostic Staging System (IPSS) high-risk or intermediate-2 MDS, participants must be intolerant of hypomethylating agents or not have responded to 4 treatment cycles of decitabine or 6 treatment cycles of azacitidine, or must have progressed at any point after initiation of a hypomethylating agent.
In the Dose Expansion Segment, which includes the 10-day regimen, subjects who have received 2 complete full dose cycles or more of a hypomethylating agent (HMA) decitabine or azacitidine (except for intermediate-2 or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment).