No features suggestive of MDS/AML on peripheral blood smear or bone marrow biopsy, if clinically indicated, within 28 days prior to administration of study treatment
For patients with AML or MDS, patient must have white blood cell count (WBC) ? 50,000/mL. Hydroxyurea is allowed to achieve this change but must be discontinued a minimum of five (5) days prior to baseline evaluation
For AML and MDS patients: patients with a dry tap on bone marrow aspiration during screening
Patients must have previously untreated MDS or AML according to the WHO 2016 classification.
Clinical indication for treatment with azacitidine for MDS or AML.
AML/MDS combination treatment (dose escalation and expansion): histologically or cytologically proven AML or MDS as defined by WHO criteria and IPSS-R, respectively, that is: R/R to standard therapy, or AML: who are unfit for, or unwilling to receive standard induction therapy, or MDS: eligible to receive azacitidine
Known history of MDS or AML
Pathologically confirmed myelodysplastic syndrome (MDS) diagnosis (regardless of initial International Prognostic Scoring System [IPSS] risk category) or oligoblastic acute myeloid leukemia (AML) with 21-30% bone marrow (BM) blasts in whom DNMTi have failed; patients who have developed AML after DNMTi therapy can be enrolled as long as they have initiated DNMTi therapy while they were in the MDS or oligoblastic AML (20-30% BM blasts) phase and the study chair agrees; failure of DNMTis is defined as: failure to achieve a complete response (CR), partial response (PR) or hematologic improvement (HI) after at least 4 cycles of DNMTi or progressed after such therapy
Patients with a diagnosis of acute myeloid leukemia (AML) not transformed from MDS or transformed from MDS with > 30% blasts in bone marrow or white blood cells (WBC) > 25 x 10^3/L
Phase 2 (expansion) subjects must have either MDS or relapsed/refractory AML
A diagnosis of recurrent, persistent, or progressive acute myelogenous leukemia (AML), defined as >= 5% blasts in a patient with known prior history of AML, or recurrent, persistent, or progressive myelodysplastic syndrome (MDS) according to World Health Organization (WHO) criteria
Patients with the TP53wt hematological tumors (AML, ALL, HR-MDS) who have failed prior therapies or who are considered inappropriate candidates for standard induction therapy.
Patients with MDS who transform to AML while on hypomethylator agents or patients with AML who progress on hypomethylator agents could be considered for arm A of this trial if \r\n* They choose not to be treated on or are ineligible for our competing trial of sEPHB4-HSA + hypomethylator (9L-16-6) \r\n* They are appropriate for high dose cytarabine treatment
Relapsed/refractory AML. Treatment-naive patients who are not eligible for standard induction chemotherapy may also be eligible after discussion with the PI if in the best interest of the patient. Patients with high-risk myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) (defined as >= 10% bone marrow blasts) may also be eligible after discussion with the PI.
Acute myelogenous leukemia (AML):\r\n* Complete first remission (CR1) at high risk for relapse such as any of the following:\r\n** Known prior diagnosis of myelodysplasia (MDS) or myeloproliferative disorder.\r\n** Therapy-related AML.\r\n** White cell count at presentation > 100,000.\r\n** Presence of extramedullary leukemia at diagnosis.\r\n** Any unfavorable subtype by French-American-British (FAB) or World Health Organization (WHO) classification.\r\n** High-risk cytogenetics (e.g. those associated with MDS, abnormalities of 5, 7, 8, complex karyotype) or high risk molecular abnormalities.\r\n** Requirement for 2 or more inductions to achieve CR1.\r\n** Any patient with newly diagnosed AML with intermediate risk cytogenetics who elects allograft with curative intent over consolidation chemotherapy.\r\n** Any patient unable to tolerate consolidation chemotherapy as would have been deemed\r\nappropriate by the treating physician.\r\n** Other high risk features not defined above.\r\n* Complete second remission (CR2).\r\n* Primary refractory or relapsed AML with less than 10% blasts before transplant. Persistent/relapsed AML with cytogenetic, flow cytometric, or molecular aberrations in >= 10% of cells are eligible.
AML patients with prior history of MDS or CMML who received therapy for the MDS or CMML and progressed to AML, are eligible at the time of diagnosis of AML regardless of any prior therapy for MDS; the World Health Organization (WHO) classification will be used for AML
ARMS A-G: RR AML: Patients with AML who are refractory or relapsed (any salvage) with no available therapies or not candidates for available therapies. For patients with prior MDS or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN) who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML.
Patients with previously untreated AML (except acute promyelocytic leukemia [APL]) who have at least one of the following:\r\n* Adverse genetic features as per the European Leukemia Net guidelines\r\n* Treatment related AML or AML with antecedent myelodysplastic syndrome (MDS); (patient who have received treatment with hypomethylating agents for MDS and have now transformed to AML are eligible)\r\n* Are over the age of 55 years and considered fit for chemotherapy\r\n* Patients with AML with MDS-related changes
Patients must have advanced AML, ALL or high-risk MDS meeting one of the following descriptions:\r\n* AML or ALL beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen)\r\n* AML or ALL representing primary refractory disease (i.e., having failed to achieve remission at any time following one or more prior treatment regimens)\r\n* AML evolved from myelodysplastic or myeloproliferative syndromes\r\n* MDS expressed as refractory anemia with excess blasts (RAEB)\r\n* Chronic myelomonocytic leukemia (CMML) by French-American-British (FAB) criteria
Patients must have a confirmed diagnosis of one of the following:\r\n* Newly diagnosed AML (excluding acute promyelocytic leukemia [APL]) \r\n* Newly diagnosed intermediate-2 (INT-2) or high-risk MDS\r\n* Relapsed or refractory AML, or INT-2 or high-risk MDS
Resolved acute effects of any prior AML/MDS therapy to baseline or ? Grade 1 CTCAE severity.
Patients with AML who are refractory (up to salvage 2) or relapsed (up to 2nd relapse); for patients with prior myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN) who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML
For patients with newly diagnosed disease: diagnosis of “high-grade” MDS (>= 10% blasts by morphology) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2016 World Health Organization (WHO) classification; for patients with relapsed/refractory disease: prior diagnosis of “high-risk” MDS or non-APL AML, with relapsed/refractory disease according to 2003 recommendations of the International Working Group, requiring first or subsequent salvage therapy; patients with mixed phenotype acute leukemia (MPAL) are eligible
May have previously received monotherapy with demethylating agents for MDS or AML or treatment with a mitoxantrone- or cladribine-based regimen for MDS or AML, including G-CLAM, but not demethylating agent as priming for or in combination with chemotherapy
Diagnosis of AML based on 2008 World Health Organization (WHO) criteria; AML may be de novo, following a prior hematologic disorder, including MDS or Philadelphia chromosome-negative myeloproliferative neoplasm, and/or therapy-related
Patients who have received prior chemotherapy for AML with the exception of hydroxyurea or leukapheresis for leukocytosis; prior hypomethylating or immunomodulatory agents for MDS are allowed
Patients with a secondary AML (defined as a history of prior radiation therapy or systemic chemotherapy, antecedent MDS, MPN or CMML)
Untreated secondary AML, including AML that has progressed from myelodysplastic syndrome (MDS)
Newly diagnosed disease with either a diagnosis of “high-risk” MDS (>= 10% blasts in marrow or blood), high-risk myeloproliferative neoplasm (MPN; >= 10% blasts in blood or bone marrow), or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; patients with biphenotypic AML are eligible; such “high-risk” MDS or MPN have natural history much closer to AML than to lower risk MDS or MPN and have responded similarly to “AML-type” therapy
Patient population (histological or cytologically confirmed diagnosis):\r\n* Untreated elderly (> 60 years) AML if in the intermediate and poor-risk cytogenetic group and not candidates (as judged by treating doctor of medicine [MD]) for or willing to undergo standard induction therapy (i.e. elderly unfavorable cytogenetic AML) or any untreated AML age > 65 years\r\n** Note: previous therapy with a hypomethylating agent (HMA) for a diagnosis of MDS is allowed\r\n* Relapsed or refractory AML (>= 18 years)\r\n* Any MDS (>= 18 years) having failed or been intolerant to prior hypomethylating agent (HMA) treatment\r\n** Failure is defined as any disease progression while on HMA, relapse after HMA treatment or no response after 4 cycles of 5-Azacitidine or decitabine\r\n** Patients with isolated 5q-/5q- syndrome must have failed, not tolerated, or lenalidomide in addition to having failed or been intolerant to HMA treatment\r\n*** Note: patients with chronic myelomonocytic leukemia (CMML) and MDS/myeloproliferative neoplasms (MPN) overlap are allowed if meeting other study eligibility criteria\r\n*** Note: for all patient groups, therapy as part of a plan as a bridge to transplant is allowed
Patients must have a diagnosis of acute myeloid leukemia (AML) according to World Health Organization (WHO) criteria; therapy-related and secondary AML (arising after a period of myelodysplastic syndrome [MDS]) allowed; prior treatment for MDS with hypomethylator-based therapy and lenalidomide allowed, but not allowed if used after the diagnosis of AML is made, since enrollment to this study is not for relapsed AML
Prior chemotherapy treatment for AML (prior treatment with hydroxyurea and/or leukapheresis to control white blood cell count, or all-trans retinoic acid [ATRA] for suspected acute promyelocytic leukemia [APML] is acceptable); prior chemotherapy for MDS or myeloproliferative neoplasms (MPN) such as azacitidine, decitabine, and thalidomide, is permitted, but such treatments once MDS or MPN has transformed to AML is not permitted
Phase II FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory patients: patients should have a diagnosis of AML (de novo or transformed from hematologic malignancies); patients with high-risk myelodysplastic syndrome (MDS) (defined as having >= 10% blasts in the bone marrow) or patients with chronic myelomonocytic leukemia (CMML) (having >= 10% blasts in the bone marrow) may also be eligible after discussion with principal investigator (PI); the patients should have one of the following features: 1. patients with AML should have failed any prior induction therapy or have relapsed after prior therapy; 2. patients with high-risk MDS or high-risk CMML should have failed any prior therapy for the MDS or CMML; 3. patients with MDS or CMML who received therapy for the MDS or CMML and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML; the World Health Organization (WHO) classification will be used for AML
In the phase I portion, patients with relapsed or refractory AML/MDS are also eligible, as per the treating physician’s discretion
Patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) who received therapy for the MDS or CMML and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML; the World Health Organization (WHO) classification will be used for AML; prior therapy for MDS or CMML will not be considered as a prior therapy for AML
In the phase I portion of the study all patients with relapsed or refractory AML are eligible; for the Phase II portion of the study, patients must have AML progressing from prior MPN (MPN-BP) or have myelodysplastic syndrome (MDS)/MPN with more than 20% blasts; temporary prior measures to control blood counts, such as apheresis or Hydrea are allowed; patients with newly diagnosed or previously treated disease are eligible as long as prior therapy does not include hypomethylating agents; prior therapy for ruxolitinib for MPN is allowed
PHASE II -- Patients aged 60 and older with newly diagnosed primary or secondary AML according to WHO classification, without any prior therapy for AML with the exception of (a) emergency leukapheresis and (b) emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until 24 hours before start of the trial treatment; Note: prior therapy for preexisting hematological condition e.g. MDS or myeloproliferative disease (MPD), including but not limited to hypomethylating agents is allowed until at least 2 weeks have elapsed from completion of that agent before the first dose of MEK 162; patients with relapsed AML, and relapsed MDS and CMML, after prior hypomethylating therapy are also eligible to participate
For Phase I Only: Refractory or relapsed disease defined as follows: Patients with MDS or CMML should have failed prior therapy (e.g., with a hypomethylating agent, clofarabine, and/or with lenalidomide); Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy; Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML; Patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive standard intensive therapy (ie, high-dose cytarabine-based chemotherapy).
For Phase II Only: Patients with MDS, CMML or AML who are either: Age 60 years or older and newly diagnosed, previously untreated. Prior therapy with hydroxyurea or single agent ara-C for the purpose of control of WBC is acceptable.; Age 18 years or older and with refractory or relapse disease who have received no more than one prior treatment regimen and will be receiving first salvage. For this purposes, a second induction cycle with the same drugs used during the first cycle, consolidation chemotherapy or stem cell transplant in CR (or CRp or CRi) will be considered part of the prior regimen. Prior therapy for MDS (or other malignancies) is not considered a prior regimen for AML in patients who progress from MDS (or other malignancies).;
For Phase II only: Patients (any age) with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The WHO classification will be used for AML
Patients must have a diagnosis of one of the following:\r\n* MDS (Arm A)\r\n** High-risk MDS defined as: > 5% blasts in bone marrow and/or the following cytogenetic categories: presence of inv(3)/t(3q)/del(3q), -7/del(7q), complex cytogenetics (3 or more abnormalities)\r\n* AML (Arm B)\r\n** Relapsed/refractory/unable to tolerate conventional chemotherapy
Clonal cytogenetic abnormalities associated with MDS or AML on bone marrow examination.
Patients with previously untreated AML or high risk myelodysplastic syndrome (MDS) (>= 10 % blasts or International Prognostic Scoring System [IPSS] >= intermediate-2); prior therapy with hydroxyurea, hematopoietic growth factors, azacytidine, all-trans retinoic acid (ATRA), or an isolated dose of cytarabine up to 2 g is allowed; patients with history of MDS transformed to AML are eligible regardless of their prior therapy for MDS provided this will be their first induction therapy for AML
Patients with active AML or MDS at the time of the study (anything less than a complete remission) are not eligible for this protocol
Subjects with evidence of relapsed or refractory acute myeloid leukemia (AML) OR treatment naive AML who are 75 years or older OR relapsed or refractory myelodysplastic syndrome (MDS)\r\n* For subjects with relapsed AML: evidence of >= 5% blasts in the bone marrow; or reappearance of blasts in the peripheral blood; or development of extramedullary disease (according to 2003 IWG criteria) who relapse after:\r\n** Allogeneic hematopoietic stem cell transplant, or\r\n** After one cycle of standard cytotoxic chemotherapy or two cycles of any hypomethylating agent-based therapy\r\n* For subjects with refractory AML: =< 2 prior induction regimens (example: patients who receive 7+3 followed by 5+2 would count as one induction regimen) or a minimum of two cycles of any hypomethylating agent-based therapy\r\n* For subjects with treatment-naive AML: must be 75 years and older with de novo or secondary AML to be considered eligible\r\n* For subjects with relapsed MDS: disease recurrence after CR, partial remission (PR) or hematologic improvement with bone marrow blasts >= 5% who relapse after:\r\n** Allogeneic hematopoietic stem cell transplant, or\r\n** After four cycles of any hypomethylating agent-based therapy\r\n* For subjects with refractory MDS: disease progression at any time after initiation of hypomethylating agent treatment or persistent bone marrow blasts >= 5% despite a minimum of four cycles of hypomethylating agent therapy
Having received more than one induction systemic therapy for AML or having received a standard dose or high dose ara-C containing regimen for MDS
Patients diagnosed with AML or MDS per below:
Confirmed diagnosis of refractory/relapsed AML or high-risk MDS
Meets one of the following disease criteria:\r\n* Primary (de novo) AML or higher-risk MDS with induction failure: No complete remission (CR) after 2 or more induction attempts with high dose chemotherapy or hypomethylating agents +/- other agents. Higher risk MDS defined as risk score > 4.5 based on the revised International Prognostic Scoring System (IPSS) criteria\r\n* Secondary AML (from antecedent hematologic malignancy or treatment-related): Not in CR after 1 or more cycles of chemotherapy\r\n* Relapsed AML: Blast count >= 5% in bone marrow or peripheral blood after prior attainment of CR; relapse at any time but >= 100 days following allogeneic hematopoietic cell transplantation (HCT)\r\n* Relapsed MDS: Morphologic evidence of relapse or increase in blasts >= 5% in bone marrow or peripheral blood after prior attainment of CR; relapse at any time but ?100 days following allogeneic HCT
Cohort Inclusion Criteria - Group A: Subjects must have previously untreated acute myeloid leukemia (AML) according to the WHO classification with no prior treatment other than hydroxyurea. Prior therapy for myelodysplastic syndrome (MDS), myeloproliferative syndromes (MPD), or aplastic anemia is permitted but not with hypomethylating agents.
Patients with secondary AML are eligible for enrollment onto the trial; secondary AML is defined as AML that has developed in a person with a history of antecedent blood count abnormalities, or myelodysplastic syndrome (MDS), or a myeloproliferative disorder (excluding chronic myeloid leukemia); or a history of prior chemotherapy or radiation therapy for a disease other than AML\r\n* NOTE: Prior therapy of MDS with decitabine, low-dose cytarabine, or azacitidine is excluded
TREATMENT: Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing veliparib
Patients with AML, relapsed or refractory to standard therapy or elderly patients with AML (age 65 or over). Patients who have AML and are younger than age 65 but considered unfit for conventional chemotherapy are eligible. Patients with de novo or treated MDS or chronic myelomonocytic leukemia (CMML) INT-1 or above are eligible. Patients may have had prior exposure to azacitidine but no more than one cycle of decitabine. Patients must have been off chemotherapy for 2 weeks prior to entering this study and have recovered from the toxicities of that therapy; a caveat to this is in the case of rapidly progressive disease. Hydroxyurea is permitted for control of elevated white blood cell (WBC) prior to treatment and can be continued for the first 4 weeks of therapy. Erythropoiesis stimulating agents (ESAs) and granulocyte colony stimulating factor (GCSF) are allowed before therapy. ESAs, GCSF or other growth factors are permitted on therapy.
Patients with MDS that has evolved to AML must be in remission
Patients with AML or MDS arising from myeloproliferative neoplasm can be enrolled after principal investigator (PI) approval on case to case basis, depends on the spleen size and degree of bone marrow fibrosis
Patients with MDS evolved into AML that is not in remission
Subject has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
Subjects with AML evolving from MDS may have received prior MDS therapy with demethylating agents
AML secondary to prior MDS, or
For patients registered to the relapsed/refractory cohort (Cohort 2), patients must have a previous morphologically confirmed diagnosis of acute myeloid leukemia (AML)\r\n* For patients registered to the myelodysplastic syndromes (MDS) transformed to AML cohort (Cohort 1), patients must have a previous morphologically confirmed diagnosis of MDS/chronic myelomonocytic leukemia (CMML); patients may have received previous non-intensive therapy (e.g. azacitidine, decitabine, low-dose cytarabine [LDAC], lenalidomide) given for treatment of MDS/CMML (with up to 20% blasts); at the time of registration they must have a morphologically confirmed diagnosis of AML\r\n* Note: This protocol uses the World Health Organization (WHO) diagnostic criteria for AML; patients with acute promyelocytic leukemia (APL, French American British [FAB], M3) or blastic transformation of chronic myelogenous leukemia are not eligible
Patients with prior malignancy (other than AML and MDS/CMML) are eligible; however, the patient must be in remission from the prior malignancy and have completed all chemotherapy and radiotherapy at least 6 months prior to registration; except for AML and MDS treatment, all treatment related toxicities must have been resolved; NOTE: for patients with prior history of malignancy who have received anthracyclines or mediastinal/pericardial radiation in the past, the risk versus benefit of therapy should be weighed, particularly in the setting of receiving consolidation therapy
Diagnosis of MDS, CMML, or RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ? 25,000 x 10^9/L and stable for at least 4 weeks without intervention) according to World Health Organization (WHO) criteria or French American British (FAB) classification either previously treated or previously untreated. The diagnosis must be confirmed via BM aspirate and/or biopsy within 6 weeks prior to Screening. Note: patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ? 25,000 x 10^9/L and stable for at least 4 weeks without intervention) are not eligible for the Phase II Part 1 RPTD component of the study and patients with CMML will not be eligible for Phase II Part 2 Expansion of the study.
Off all other treatments for MDS, CMML, or AML including an erythropoiesis-stimulating agent (ESA), for at least 4 weeks prior to Screening. Filgrastim (G-CSF) is allowed before and during the study, as clinically indicated.
Anemia due to factors other than MDS, CMML, or AML (including hemolysis or gastrointestinal bleeding).
Patients with AML or RAEB 2 High Risk MDS who are newly diagnosed according to the WHO 2008 Classification and previously untreated.
Patients with AML (arising from an antecedent hematologic disease [AHD]) or MDS who may have had one prior regimen with commercially available agents for the treatment of their prior hematologic disease. The patients may not have had a prior therapy for their AML.
Patients who have received prior induction chemotherapy for AML or myelodysplastic syndrome (MDS); temporary prior measures such as apheresis or hydroxyurea are allowed; patients who have received a limited and short-term exposure of ATRA (all trans retinoic acid) while AML-M3 (acute promyelocytic leukemia) was being ruled out, and which has been discontinued, will be eligible
Participants with MDS, CMML, or low blast AML, whose only site of disease is extramedullary, example, the skin.
Patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) who received therapy for the MDS or CMML and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML; the World Health Organization (WHO) classification will be used for AML
Patients with secondary AML or therapy related disease (t-AML) are eligible; patients who received decitabine or 5-azacytidine as prior treatment for myelodysplastic syndrome (MDS) remain eligible
Pathological diagnosis of AML according to World Health Organization (WHO) criteria (with at least 20% blasts in the peripheral blood or bone marrow): newly diagnosed de novo AML; except for acute promyelocytic leukemia (APL); newly diagnosed secondary AML, defined as having a history of an antecedent hematologic disorder (myelodysplastic syndromes [MDS], myeloproliferative disease [MPD] or history of cytotoxic treatment for non-hematologic malignancy) or apparent de novo AML with MDS-associated karyotype
To be considered at high risk for induction mortality patients must have 1 or 2 of the following risk factors (patients >= 60 must have at least 1 risk factor, patients < 60 must have at least 2 risk factors) present; at least one risk factor in every patient must be an AML-related factor: \r\n* AML-related factors include: \r\n** Antecedent hematologic disorder (AHD) (MDS, chronic myelomonocytic leukemia [CMML], or MPD) or history of exposure to cytotoxic chemotherapy [therapy-related (t)-AML]), or WHO-defined AML with MDS-related changes or apparent de novo AML with MDS-associated karyotype\r\n** Unfavorable cytogenetics as defined by the European Leukemia Net\r\n* Patient-related factors:\r\n** Age >= 70\r\n** ECOG performance status (PS) >= 2\r\n* Co-morbidities:\r\n** Serum creatinine > 1.3 g/dL
Patients with untreated acute myeloid leukemia (AML) (> or equal to 20% blasts in bone marrow and/or peripheral blood) or high risk MDS (> or equal to 10% blasts in bone marrow); A. patients with AML and history of MDS who have received prior therapy with a hypomethylating agent (including azacytidine) and/or with lenalidomide for prior MDS are eligible if the treating physician feels that participation in the study is in the patients' best interest; B. patients should have molecular evidence of the presence of FLT3-ITD mutation with a molecular burden of at least 10%
For patients with newly diagnosed disease: diagnosis of “high-risk” myelodysplastic syndrome (MDS) (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; for patients with relapsed/refractory disease: prior diagnosis of “high-risk” MDS or non-APL AML, with relapsed/refractory disease according to standard criteria requiring first or subsequent salvage therapy; patients with biphenotypic AML are eligible
Diagnosis of AML (AML de novo and post-MDS) or DLBCL
AML participants ? 60 years old in first relapse with a disease-free interval < 12 months, or further relapse. First relapse is also applicable to AML post-MDS patients who have received prior treatment for MDS, but have not received prior treatment for AML.
Patients with one of the following diagnoses:\r\n* Intermediate, high and very high risk (per International Prognostic Scoring System [IPSS]-revised [R]) untreated MDS or any MDS with >= 5% marrow blasts (by French American British [FAB] and World Health Organization [WHO] diagnostic criteria); NOTE: MDS/MPN overlap is allowed\r\n* CMML requiring treatment per doctor of medicine (MD) judgment\r\n* Low and very low risk MDS patients symptomatic and/or transfusion dependent, (>= 4 U red blood cells [RBC] over the preceding 12 week period) who have failed erythropoietin-stimulating agents (ESAs) or who have a low likelihood of responding to ESAs\r\n* MDS and CMML patients relapsed/refractory to hypomethylating agents as evidenced by one of the following:\r\n** Progressed at any time during treatment with hypomethylating agents\r\n** Failed to achieve a response after 6 cycles of 5-azacytidine or 4 cycles of decitabine\r\n** Progressed after treatment with hypomethylating agents had been discontinued\r\n*** NOTE: MDS/MPN overlap is allowed\r\n* Relapsed or refractory AML exposed to =< 3 prior regimens (note, induction and consolidation including stem cell transplantation count as one regimen)\r\n* For exploratory phase I LDE225 days 1-7 with azacitidine or LDE225 days 1-28 with decitabine cohorts only: untreated AML/CMML/MDS/MPN overlap or relapsed/refractory AML/CMML/MDS/MPN overlap WITHOUT prior exposure to a hypomethylating agent (HMA)\r\n* Elderly (age >= 60) untreated AML and not a candidate for induction therapy\r\n* Untreated AML < 60 year of age who are not candidates to undergo standard induction chemotherapy\r\n* Primary myelofibrosis (PMF) and post essential thrombocytopenia (ET)/polycythemia vera (PV) MF with a Dynamic International Prognostic Scoring System (DIPSS)-plus score of intermediate or high, or a > 10% blasts in the marrow and who are in need of therapy and who have failed previous treatment with a janus kinase 2 (JAK2) inhibitor and, if appropriate, have failed Interferon based treatment
Pathological diagnosis of AML (by World Health Organization [WHO] criteria) or higher risk MDS (includes intermediate [int]-2 and high risk MDS by International Prognostic Scoring System (IPSS) along with one of the following:\r\n* Patients with de novo or secondary MDS with progression/refractoriness after HMA treatment who have not transformed to AML\r\n* Patients with MDS and prior HMA treatment for MDS who transformed to AML \r\n* Patients with AML who are refractory/relapsed after HMA therapy for their AML are eligible
Subjects with a histologically confirmed diagnosis of MDS by FAB criteria, including both MDS and RAEB-T (AML with 20-30% blasts and multilineage dysplasia) by World Health Organization (WHO) classification are eligible.
Previously untreated AML (>= 20% blasts); patients with high-risk MDS (defined as having >= 10% blasts in the bone marrow) or patients with chronic myelomonocytic leukemia (CMML) (having >= 10% blasts in the bone marrow) may also be eligible after discussion with principal investigator (PI); prior therapy with hydroxyurea, biological or targeted therapy (e.g. fms-related tyrosine kinase 3 [FLT3] inhibitors, other kinase inhibitors), or hematopoietic growth factors is allowed, however prior therapy with chemotherapy agents for the disease under study is not allowed; patients may have received one dose of cytarabine (up to 2 g/m^2) administered at presentation for control of hyperleukocytosis; for patients with prior MDS or CMML who transformed to AML, therapy received for MDS is not considered as prior therapy for AML
Prior or concomitant chemotherapy for AML (with the exception of hydroxyurea and/or corticosteroid therapy for no more than 28 days (cumulative)). Please note that any prior therapy for MDS is allowed.
Patients must meet one of two disease criteria:\r\n* Acute myelogenous leukemia within one of the following categories:\r\n** Primary induction failure (PIF): patients who have not achieved a complete remission following initial diagnosis and after at least two induction cycles of chemotherapy consisting of cytarabine and an anthracycline or high-dose cytarabine\r\n** Relapsed AML: Patients are defined as having relapsed disease if they entered a complete remission confirmed with a bone marrow biopsy following initial treatment, and then were found to have morphological or cytogenetic evidence of recurrent disease on a subsequent bone marrow exam\r\n** Any complete remission (CR)2 or greater: CR must be defined using a bone marrow exam taken at least 21 days since the last chemotherapy (including a methyltransferase inhibitor), and may include CRp (morphologic CR without peripheral platelet recovery)\r\n** CR1 with high-risk features: includes patients with treatment-related AML, secondary AML (following myelodysplastic syndrome [MDS] or myeloproliferative neoplasms [MPN]), high-risk cytogenetic or molecular phenotype (by National Comprehensive Cancer Network [NCCN] criteria)\r\n** Untreated AML (> 20% blasts on a bone marrow) arising from a previous confirmed diagnosis of MDS or MPN (excluding breakpoint cluster region [BCR]-Abelson murine leukemia viral oncogene homolog 1 [ABL] positive disease)\r\n* Myelodysplastic syndromes within one of the following categories:\r\n** High-risk MDS at diagnosis as defined by the International Prognostic Scoring System (IPSS) or World Health Organization (WHO) classification based Prognostic Scoring System (WPSS)\r\n** Transfusion dependent MDS (either red blood cells [RBC] or platelet dependent) without a hematologic response to at least 4 months of MTI therapy; hematological response is defined as transfusion independence for two or more months\r\n** Progressive MDS following at least 4 months of MTI therapy; progression is defined as resumption of transfusion dependence after at least two months of transfusion independence OR increase of marrow blasts by 50% from pretreatment OR overall blasts over 10% of marrow cells at any time after treatment
AML with a history of myelodysplasia: MDSAML must have bone marrow documentation of prior MDS
Except for CMMoL, patients with history of myeloproliferative neoplasms (MPN) (defined as a history of essential thrombocytosis or polycythemia vera, or idiopathic myelofibrosis prior to the diagnosis of AML) or combined MDS/MPN are not eligible.
Patient must have non-M3 AML or MDS
Patients with antecedent MDS/MPN, defined by WHO criteria, without any prior therapy for AML, regardless of the number of therapies for MDS/ MPN
For the phase I portion of the study patients should have failed any number of prior therapies, which should include at least the following: 1. Patients with MDS should have failed prior therapy with a hypomethylating agent and/or with lenalidomide. 2. Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy. 3. Patients with MDS who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless of any prior therapy for AML. 4. Patients with any of the eligible diagnoses who have received no prior therapy are eligible if not candidates to receive standard therapy or if they refuse standard chemotherapy.
For the phase II Portion of the study, only patients who are previously untreated for AML. 1. Patients with history of MDS who received therapy for MDS and progressed to AML are eligible at the time of diagnosis of AML. Only induction chemotherapy administered for AML will be considered for considerations of eligibility regarding prior therapy. Patients who received therapy for MDS before transforming to AML (e.g., with hypomethylating agents or lenalidomide) are eligible.
Isolated myeloid sarcoma not meeting bone marrow criteria for AML or MDS
Patients must have advanced AML, ALL or high-risk MDS meeting one of the following descriptions:\r\n* AML or ALL beyond first remission (i.e., having relapsed at least one time after achieving remission in response to a treatment regimen)\r\n* AML or ALL representing primary refractory disease (i.e., having failed to achieve remission at any time following one or more prior treatment regimens)\r\n* AML evolved from myelodysplastic or myeloproliferative syndromes; or \r\n* MDS expressed as refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML) by French-American-British (FAB) criteria
Key Inclusion Criteria (Phase 1):\n\n        - Confirmed hematologic malignancy, including Acute Myeloid Leukemia (AML), Chronic\n        Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia\n        (ALL), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), Myelofibrosis (MF),\n        Myeloproliferative Neoplasms (MPN) or MDS/MPN overlap diseases. (Once Phase 2 has started\n        subjects with AML will be eligible for inclusion in the Phase 1 portion of the study only\n        if their malignancy has been shown to have c-Cbl mutation, trisomy 3, trisomy 11, inv(16),\n        or elevated FLT3. [Other AML and subjects with MDS will no longer be eligible for\n        inclusion in the Phase 1 portion of the study]).\n\n        Key Inclusion Criteria (Phase 2):\n\n          -  Part A: AML or MDS patients with an acceptable level of EphA3 expression\n\n          -  Part B: MF patients with an acceptable level of EphA3 expression\n\n        Key Inclusion Criteria (Both Phases):\n\n          -  Confirmed hematologic malignancy refractory to or progressed following standard\n             treatments, or subjects not considered medically suitable to receive standard of care\n             treatment or who refuse standard of care treatment\n\n          -  Acceptable level of EphA3 expression\n\n          -  Eastern Cooperative Oncology Group (ECOG) ?1\n\n          -  Acceptable laboratory results\n\n        Key Exclusion Criteria (Both Phases):\n\n          -  For subjects with AML, more than 2 prior therapies for AML (induction and\n             consolidation with or without a hypomethylating agent given in a maintenance setting\n             are considered 1 therapy)\n\n          -  History of or current central nervous system (CNS) involvement that may increase risk\n             of bleeding\n\n          -  Recent major surgery\n\n          -  Ongoing surgical or wound healing complications\n\n          -  Active clinically significant bleeding\n\n          -  Uncontrolled hypertension\n\n          -  Significant intercurrent illness\n\n          -  Known history of prolonged bleeding times or platelet dysfunction\n\n          -  Active infection requiring IV antibiotics, IV antifungals, or IV antivirals within 2\n             weeks prior to Cycle 1, Day 1
Key Inclusion Criteria (Phase 1):\n\n        - Confirmed hematologic malignancy, including Acute Myeloid Leukemia (AML), Chronic\n        Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Acute Lymphocytic Leukemia\n        (ALL), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), Myelofibrosis (MF),\n        Myeloproliferative Neoplasms (MPN) or MDS/MPN overlap diseases. (Once Phase 2 has started\n        subjects with AML will be eligible for inclusion in the Phase 1 portion of the study only\n        if their malignancy has been shown to have c-Cbl mutation, trisomy 3, trisomy 11, inv(16),\n        or elevated FLT3. [Other AML and subjects with MDS will no longer be eligible for\n        inclusion in the Phase 1 portion of the study]).\n\n        Key Inclusion Criteria (Phase 2):\n\n          -  Part A: AML or MDS patients with an acceptable level of EphA3 expression\n\n          -  Part B: MF patients with an acceptable level of EphA3 expression\n\n        Key Inclusion Criteria (Both Phases):\n\n          -  Confirmed hematologic malignancy refractory to or progressed following standard\n             treatments, or subjects not considered medically suitable to receive standard of care\n             treatment or who refuse standard of care treatment\n\n          -  Acceptable level of EphA3 expression\n\n          -  Eastern Cooperative Oncology Group (ECOG) ?1\n\n          -  Acceptable laboratory results\n\n        Key Exclusion Criteria (Both Phases):\n\n          -  For subjects with AML, more than 2 prior therapies for AML (induction and\n             consolidation with or without a hypomethylating agent given in a maintenance setting\n             are considered 1 therapy)\n\n          -  History of or current central nervous system (CNS) involvement that may increase risk\n             of bleeding\n\n          -  Recent major surgery\n\n          -  Ongoing surgical or wound healing complications\n\n          -  Active clinically significant bleeding\n\n          -  Uncontrolled hypertension\n\n          -  Significant intercurrent illness\n\n          -  Known history of prolonged bleeding times or platelet dysfunction\n\n          -  Active infection requiring IV antibiotics, IV antifungals, or IV antivirals within 2\n             weeks prior to Cycle 1, Day 1
Subjects with MDS/AML or with features suggestive of MDS/AML;
Patients with a diagnosis of acute myeloid leukemia (AML) (World Health Organization classification: >= 20% blasts in the bone marrow and/or peripheral blood) or myelodysplastic syndrome (MDS) (International Prognostic Scoring System intermediate-1 or higher) that at the time of allogeneic transplantation were in: - induction failure, relapsed disease or second or greater remission; patients in first complete remission that required more than 1 cycle of treatment to achieve the remission, or that have AML evolving from MDS, or that had the following abnormalities: FLT3 mutation, deletion of chromosome 5 or 7, mixed-lineage leukemia (MLL) gene rearrangement, or more than or equal to 3 cytogenetics abnormalities; patients with de novo or therapy-related MDS, chronic myelomonocytic leukemia (CMML) or AML are also eligible, regardless of cytogenetics or molecular rearrangements
Patients with AML, MDS, ALL, or CML must not have presence of circulating leukemic blasts detected by standard pathology
Patients must be in a documented CR/CRi from either their front-line or first salvage therapy as evidenced by =< 5% bone marrow blasts and absence of extramedullary disease; (for patients with prior MDS who then transformed to AML, therapy received for MDS is not considered prior therapy for AML)
Diagnosis of AML or MDS according to the WHO criteria
Confirmed diagnosis of AML, including treatment-related secondary AML (except prior MDS) according to World Health Organization (WHO) 2008 classification at treating institution
Bone marrow blast < 20% if MDS or ? 10% if AML; and
Diagnosis of untreated “high-risk” MDS (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; patients with biphenotypic AML are eligible; outside diagnostic material is acceptable as long as peripheral blood and/or bone marrow slides are reviewed at the study institution and cytogenetic/molecular information is available\r\n* Prior hydroxyurea for AML is permitted but should be discontinued prior to start of CPX-351 treatment\r\n* Azacitidine, decitabine, lenalidomide, and growth factors are permitted for low-risk MDS (< 10% blasts); all treatments for MDS should be discontinued prior to start of CPX-351 treatment
Patients must be chemo-naïve, i.e., not have received any prior induction chemotherapy for AML or myelodysplastic syndrome (MDS); temporary prior measures such as apheresis or hydroxyurea are allowed; prior anthracycline therapy is allowed, but must not exceed a dose of 200 mg/m^2 daunorubicin or equivalent; prior all-trans retinoic acid (ATRA) for suspected APL is allowed; prior methotrexate for central nervous system (CNS) involvement is allowed; patients with prior history of MDS must not have received azacitidine, decitabine, lenalidomide or vorinostat
Must have one of the following diagnoses:\r\n* Pathologically confirmed chronic myelomonocytic leukemia (CMML) or myelodysplastic syndromes (MDS) with high risk features at the time of referral for trial as defined by:\r\n** Intermediate (INT)-2 or high International Prognostic Scoring System (IPSS) score\r\n** Secondary MDS (defined as MDS developing in a patient with an antecedent hematologic disorder or any patient with prior chemotherapy or radiation exposure)\r\n** INT-1 MDS with excess blasts (>= 5% blasts in bone marrow [BM]) or red blood cell (RBC) transfusion-dependency\r\n** MDS progressing to oligoblastic acute myeloid leukemia (AML) with 21-30% BM blasts\r\n** CMML with >= 5% marrow blasts, or RBC or platelet transfusion-dependency, abnormal karyotype, or proliferative features (white blood cell count >=13,000/uL, splenomegaly on physical examination, or extramedullary disease)\r\n** All patients are required to have failed to respond or relapsed after an initial response to hypomethylating agents 5-azacitidine or decitabine or have refused to receive hypomethylating therapy; failure to respond is defined as failing to achieve a CR, PR or HI after at least 4 cycles of hypomethylating therapy; these patients could have received other therapies or not, but must have received hypomethylating therapy or have refused to receive hypomethylating therapy\r\n* Pathologically confirmed AML patients who have received one or two courses of induction chemotherapy or hypomethylating agent therapy AND no plans for further chemotherapy therapy, but remain with residual disease of < 5% blasts in BM, by morphology, cytogenetics, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR) or flow cytometry
Prior diagnosis of “high-risk” myelodysplastic syndrome (MDS) (>= 10% blasts) or AML other than acute promyelocytic leukemia (APL) with t(15;17) (q22;q12) or variants according to the 2008 World Health Organization (WHO) classification; patients with biphenotypic AML are eligible
May have previously received monotherapy with demethylating agents for MDS or AML
May have previously received chemotherapy with MEC for MDS or AML
Patients with secondary MDS/AML
Known history of MDS or AML Cohort 3 Exclusion Criteria:
Known history of MDS or AML
Acute myeloid leukemia (AML) in CR1 with intermediate-risk disease or high-risk features defined as: \r\n* Greater than 1 cycle of induction therapy required to achieve remission\r\n* Preceding myelodysplastic syndrome (MDS) or myeloproliferative disease\r\n* Presence of fms-related tyrosine kinase 3 (FLT3) mutations or internal tandem duplications\r\n* French-American-British (FAB) M6 or M7 classification\r\n* Adverse cytogenetics, -5, del 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 (> 3 abnormalities), peripheral blood blasts < 1000/microliter, AML patients must show response to most recent received chemotherapy
Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)\r\n * Patients with AML will be eligible in first relapse or 2nd or 3rd complete remission; patients not in remission must have < 25% blasts in the bone marrow prior to admission to the hematopoietic stem cell transplant (HSCT) unit; patients with MDS will be eligible if no other suitable donor can be identified\r\n * In general, patients will be preferentially transplanted using a matched unrelated donor or umbilical cord blood; AML/MDS patients will be eligible for this study if a suitable related or unrelated donor cannot be identified, the amount of time required to identify a suitable donor is deemed unacceptable, or the patient is not eligible for a myeloablative transplant regimen\r\n * Patients who relapse following a myeloablative transplant, but cannot receive DLI (e.g. cord blood recipients, graft loss) will also be eligible; such patients must be >= 6 months post initial transplant, achieve a CR or have < 25% blasts in the bone marrow prior to admission to the HSCT unit
Patients should have a diagnosis of AML (de novo or transformed from hematologic malignancies), myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with one of the following features: (A) patients with MDS or CMML should have failed prior therapy with a hypomethylating agent and/or with lenalidomide (cohorts 2 and 3); (B) patients with AML should have failed any prior therapy or have relapsed after prior therapy (cohorts 2 and 3); for patients in cohort 3 prior therapy should have included a FLT3 inhibitor; (C) patients with MDS or CMML who received therapy with a hypomethylating agent and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML; the World Health Organization (WHO) classification will be used for AML; these patients will be assigned to cohort 1; patients with MDS, CMML or AML who have received no prior therapy are eligible if age 65 and greater or if, at the time of enrollment, are not candidates to receive or refuse standard therapy (cohort 1 only)
Patients may have had prior treatment for myelodysplastic syndrome (MDS) or AML, including prior lenalidomide for MDS or AML or another condition
Phase I (completed): Participants must have a diagnosis of AML, MDS, ALL or MPAL and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT)\r\n* Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy\r\n* Patients with AML, MPAL or MDS are eligible at first or subsequent relapse, whereas patients with ALL are eligible at second or subsequent relapse or any relapse that is refractory to salvage chemotherapy\r\n* Patients with AML or ALL must have >= 5% leukemic blasts in the bone marrow or increasing levels of MRD in the bone marrow as assessed by flow cytometry; if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood
Patients with AML or high-risk MDS receiving non-intensive therapy including hypomethylating agents, single-agent chemotherapy, targeted therapy agents, single or combination non-intensive agents offered on a clinical trial, or any other chemotherapy offered for patients with AML and high-risk MDS that does not require a prolonged 4-6 week hospitalization including the following populations:\r\n* Newly diagnosed AML\r\n* Relapsed or primary refractory AML\r\n* Newly diagnosed high-risk MDS\r\n* Relapsed or primary refractory high-risk MDS
Patients with secondary AML arising out of myelodysplastic syndrome (MDS) (all subtypes under WHO classification), chronic myelomonocytic leukemia (CMML); therapy-related AML and those with a prior autologous hematopoietic cell transplantation are eligible
Secondary AML arising out of myeloproliferative neoplasms (as per the revised 2008 WHO classification of myeloid neoplasms and acute leukemias) and MDS/myeloproliferative (MPD) neoplasms other than CMML (as per the revised 2008 WHO classification of myeloid neoplasms and acute leukemias); refractory anemia with ringed sideroblasts with thrombocytosis (RARS-T) classified as MDS/myeloproliferative neoplasm (MPN) neoplasm, unclassifiable will be excluded; AML patients with presenting features suspicious of underlying unrecognized MPD such as marked splenomegaly (>= 20 cm) and or thrombocytosis (> 400,000 per microliter) will be excluded; patients with relapsed or refractory AML will be excluded
Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents or hypomethylating agents for this diagnosis. Patients with other prior cancer diagnoses are allowed as long as they have no measurable disease, are not undergoing active therapy, and have a life expectancy of ? 4 months.
Untreated AML, including patients with an antecedent hematologic disorder or secondary disease. Patients with prior MDS may have received therapy with immunomodulatory agents for this diagnosis.
Patients with either newly diagnosed AML or MDS who have either begun (within 4 days of starting study drug) or are planned to begin specific treatment for their AML/MDS; patients who are participating in other therapeutic clinical trials for their AML/MDS may participate in this trial
CD123/IL3RA expression on the subject’s AML or MDS blasts, determined locally within 3 months of first protocol treatment
With relapsed or refractory AML (hydroxyurea is not considered a prior treatment regimen) OR with treatment-naive AML who decline intensive induction chemotherapy or who are unfit due to co-morbidity or other factors OR with MDS and >= 10% myeloblasts in the bone marrow
Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of MDS, MDS/MPN, CMML or AML within 14 days of the first day of study drug treatment
In the Dose Expansion Segment, hypomethylating agent (HMA) treatment-naïve MDS subjects (including CMML), and intermediate-2 or high-risk MDS subjects (including CMML) relapsed or refractory to prior HMA treatment are allowed, and treatment-naïve AML subjects who are at least 65 years of age will be allowed if they also have at least one of the following criteria
AML secondary to MDS, chemotherapy, or radiation therapy
Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing veliparib