E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | This trial studies the side effects and how well pevonedistat, azacitidine, fludarabine phosphate, and cytarabine work in treating patients with acute myeloid leukemia that has come back or has not responded to treatment or high-risk myelodysplastic syndrome that has come back. | |
E.1.1.1 | Medical condition in easily understood language | Drugs used in chemotherapy work differently to stop growth of cancer cells. Giving more than one drug and pevonedistat may work better in treating acute myeloid leukemia or myelodysplastic syndrome. | |
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10024330 | E.1.2 | Term | Leukemia acute | E.1.2 | System Organ Class | 100000004864 | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10024349 | E.1.2 | Term | Leukemia myeloid | E.1.2 | System Organ Class | 100000004864 | |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 | E.1.2 | Level | LLT | E.1.2 | Classification code | 10028534 | E.1.2 | Term | Myelodysplastic syndrome NOS | E.1.2 | System Organ Class | 100000004864 | |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial | I. To evaluate the tolerability and feasibility of MLN4924 (pevonedistat) added to the 3-drug backbone of azacitidine (aza), fludarabine, and cytarabine re-induction for pediatric patients with recurrent/refractory AML and MDS II. To define and describe the toxicities of MLN4924 (pevonedistat) when given in combination with azacitidine, fludarabine, and cytarabine to pediatric patients with relapsed/refractory AML and relapsed MDS. III. To characterize the pharmacokinetics of MLN4924 (pevonedistat) in children with recurrent or refractory AML and relapsed MDS | |
E.2.2 | Secondary objectives of the trial | I. To describe the antitumor activity of MLN4924 (pevonedistat) in combination with azacitidine, fludarabine, and cytarabine within the confines of a feasibility study. | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria | - Patients must have had histologic verification of AML at the original diagnosis. Patients must have one of the following: Recurrent disease in >= 1st relapse with >= 5% blasts in the bone marrow (M2/M3) marrow OR immunophenotypic evidence of disease with >= 0.1% blasts detected by flow cytometry, OR evidence of recurrent cytogenetic or molecular abnormalities consistent with relapse, with or without extramedullary disease Refractory AML is defined as > 5% blasts in the bone marrow (M2/M3) after > 2 induction attempts (i.e., 2 cycles of chemotherapy) Patients with advanced MDS, including MDS that has progressed to AML, and have experienced relapse are eligible - Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age - Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment. If after the required timeframe, the numerical eligibility criteria are met, e.g., blood count criteria, the patient is considered to have recovered adequately Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive >= 14 days must have elapsed after the completion of other cytotoxic therapy, with the exception of hydroxyurea, for patients not receiving standard maintenance therapy. Additionally, patients must have recovered from all acute toxic effects of prior therapy NOTE: Cytoreduction with hydroxyurea must be discontinued >= 24 hours prior to the start of protocol therapy Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil [ANC] counts): >= 7 days after the last dose of agent Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to Grade =< 1 Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must - be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair and the study-assigned research coordinator Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors) Stem cell Infusions (with or without traumatic brain injury [TBI]): Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD) Autologous stem cell infusion including boost infusion: >= 42 days Cellular Therapy: >= 30 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.) Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 42 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial brain metastases (BM) radiation Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131 iodine [I]-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy Patients must not have received prior exposure to MLN4924 (pevonedistat) - Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows: 1 month to < 6 months; 0.4 (male and female) 6 months to < 1 year; 0.5 (male and female) 1 to < 2 years; 0.6 (male and female) 2 to < 6 years; 0.8 (male and female) 6 to < 10 years; 1 (male and female) 10 to < 13 years; 1.2 (male and female) 13 to < 16 years; 1.5 (male) and 1.4 (female) >= 16 years ; 1.7 (male) and 1.4 (female) - Bilirubin (sum of conjugated + unconjugated) =< upper limit of normal (ULN) for age - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN. For the purpose of this study, the ULN for serum glutamate pyruvate transaminase (SGPT) is 45 U/L - Shortening fraction of >= 27% by echocardiogram, or - Ejection fraction of >= 50% by echocardiogram or radionuclide angiogram - No ventricular or supraventricular arrhythmia on electrocardiogram (EKG) - Prolonged rate corrected QT (QTc) interval < 500 msec - Pulse oximetry > 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest) - International normalized ratio (INR) =< 1.5 - All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines | |
E.4 | Principal exclusion criteria | - Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. - - - Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use 1 highly effective and 1 additional effective (barrier) method of contraception at the same time for the duration of study therapy and for 4 months after the completion of MLN4924 (pevonedistat) administration. True abstinence, when this is in line with the preferred and usual lifestyle of the subject, is acceptable. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception - Investigational drugs: Patients who are currently receiving another investigational drug are not eligible - Anti-cancer agents: Patients who are currently receiving other anti-cancer agents are not eligible (except hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy) - Anti-GVHD agents post-transplant: Patients who are receiving cyclosporine, tacrolimus or other systemic agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial. Topical immunosuppressive agents (e.g. topical steroids) are allowed. Physiologic replacement of hydrocortisone is allowed - Patients who have received drugs that are moderate to strong inducers of CYP3A4 within 14 days prior to study enrollment are not eligible. Strong inducers of CYP3A4 are not permitted during the study - Patients with known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection are not eligible. NOTE: Patients who have isolated positive hepatitis B core antibody (i.e. in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load - Patients with known hepatic cirrhosis or severe pre-existing hepatic impairment are not eligible - Patients with uncontrolled high blood pressure (i.e., >= 99% for age) are not eligible - Patients with any of the following diagnoses: Acute promyelocytic leukemia Down syndrome Juvenile myelomonocytic leukemia - Patients who have a documented active uncontrolled infection are not eligible - History of allergic reactions attributed to compounds of similar chemical or biologic composition as the study agent - Patients with human immunodeficiency virus (HIV) are not eligible unless they meet all of the following criteria: CD4 count > 350 cell/mm^3 Undetectable viral load Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections - Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s) are not eligible - Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s) are not eligible | |
E.5 End points |
E.5.1 | Primary end point(s) | 1. Incidence of adverse events [ Time Frame: Up to 35 days (1 cycle) ] 2. Dose-limiting toxicities (DLTs) [ Time Frame: Up to 35 days (1 cycle of treatment) ] 3. Pharmacokinetics (PK) of MLN4924 (pevonedistat) [ Time Frame: Days 1 and 5 of cycle 1 ] | |
E.5.1.1 | Timepoint(s) of evaluation of this end point | Multiple time points occuring as stated in Section E.5.1 | |
E.5.2 | Secondary end point(s) | |
E.5.2.1 | Timepoint(s) of evaluation of this end point | |
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 | Will this trial be conducted at a single site globally? | No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned | |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |