Acute Myeloid Leukemia MedDRA version: 21.0 Level: LLT Classification code 10000886 Term: Acute myeloid leukemia System Organ Class: 100000004864
Conditions
Interventions
Product Name: Pevonedistat
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Pevonedistat
CAS Number: 905579-51-3
Current Sponsor code: Millennium Pharmaceuticals, Inc.
O
Sponsors
Fundación PETHEMA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patients 18 years or older 2. Morphological diagnosis of AML (WHO criteria 2008) 3. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 3 (ECOG 0-2 for patients greater than or equal to 75 years old) 4. Newly diagnosed AML 5. Patient must be considered ineligible for treatment with a standard Ara-C and anthracycline induction regimen due to age or co-morbidities defined by one of the following: a. = 75 years of age b. Or 18 to 74 years of age with at least one of the following: o ECOG Performance Status of 2 or 3 o Cardiac history of cardiac heart failure requiring treatment or Ejection Fraction = 50% or chronic stable angina o Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) = 65% or Forced Expiratory Volume in 1 second (FEV1) = 65% or significant history of chronic pulmonary obstructive disease o GFR = 30 mL/min to 1.5 to = 3 × ULN or with ALT and/or AST > 2.5×ULN to = 5×ULN o Non active/controlled prior neoplastic disease o Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed, documented, and approved by the Sponsor before study enrollment 6. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug): o Total bilirubin = 1.5 × ULN (upper limit of normal) except in patients with Gilbert’s syndrome or = 3 × ULN if elevation is attributed to underlying leukemia. Patients with Gilbert’s syndrome may enroll with direct bilirubin =3 × ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed o ALT and AST =2.5×ULN or = 5×ULN if elevation is attributed to underlying leukemia o Adequate renal function as demonstrated by a creatinine clearance = 30 mL/min (calculated by the Cockcroft Gault formula, (see Appendix 5) o Albumin >2.7 g/dL 7. Subject has a white blood cell count <50 × 109/L. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy 8. Female subjects must be either postmenopausal for at least 1 year before screening (see Appendix 12 for definition) OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception (see Appendix 11), at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding 9. Male subjects even if surgically sterilized (i.e., status post vasectomy), who are sexually active,
Exclusion criteria
Exclusion criteria: 1. Previous treatment for MDS or Chronic Myelomonocytic Leukemia (CMML) or MPN, with chemotherapy or other antineoplastic agents including HMAs (up to 2 cycles of HMAs) such as decitabine or azacitidine 2. Subject has history MPN with BCR-ABL1 translocation and AML with BCR-ABL1 translocation 3. Genetic diagnosis of acute promyelocytic leukemia 4. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation 5. Patients with either clinical evidence of or history of central nervous system involvement by AML 6. Diagnosed or treated for another malignancy within 1 year before randomization or previously diagnosed with another malignancy and have any evidence of residual disease which may compromise the administration of AZA or AZA+PEVO 7. Psychological, social, or geographic factors that otherwise preclude the patient from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up 8. Subject has a white blood cell count > 50 × 109/L 9. Contraindications for PEVO or AZA 10. Known hypersensitivity to pevonedistat or its excipients 11. Female patients who intend to donate eggs (ova) during the course of this study or for 4 months after receiving their last dose of study drug(s) 12. Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug 13. Male patients who intend to donate sperm or father a child during the course of this study or for 4 months after receiving their last dose of study drug(s) 14. Subject is known to be positive for HIV (HIV testing is not required for eligibility assessment). Known HIV positive patients who meet the following criteria will be considered eligible: • CD4 count > 350 cells/mm3 • Undetectable viral load • Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents • No history of AIDS-defining opportunistic infections 15. Subject is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral load within 3 months(Hepatitis B or C testing is not required for eligibility assessment) 16. Known hepatic cirrhosis or severe preexisting hepatic impairment 17. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV; see Appendix 7), and/or ST elevation myocardial infarction within 6 months before first dose, or severe symptomatic pulmonary hypertension requiring pharmacologic therapy, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled 18. Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study 19. Treatment with stron
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate if Pevonedistat plus Azacitidine improves overall survival (OS), when compared with single-agent Azacitidine, in the treatment of naïve subjects with AML who are ineligible for standard induction chemotherapy.;Secondary Objective: To evaluate: EFS Subjects achieving CCR Time to PD, relapse after CR or CRi, or death CCR after 2, 4 and 6 cycles Rate of CR, CRi, and OR Rate of CR, CRi, and ORR at 2, 4 and 6 cycles Duration of response Time to event (CR, CRi, PR, PD) 6-month and 1-year survival rates DFS RFS CIR ORR, EFS, and OS in patients who have TP53 mutations Increase in the frequency of MRD neg status in patients who achieve CR or CRi Quality of CCR by MRD in bone marrow Increase in 30 and 60 day survival rates Overall health status/QoL and fatigue domain scores Plasma concentration-time data for PEVO Safety/toxicity of the regimens Impact on the use of medical resources Rate and duration of RBC/platelet or both transfusion independence Inpatient hospital admission related to AML Iimprovement on EFS Biomarkers predictive of PEVO activity, depth and duration of response Health utilization and calculate utility values (EQ-5D-5L) Improvement in functioning and symptoms (EORTC QLQ-C30);Primary end point(s): Overall survival (OS);Timepoint(s) of evaluation of this end point: Throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Composite CR (CCR) • Event-free survival (EFS) according to FDA definition • Early mortality (first 30 and 60 days) • 6 months and 1 year survival rates • CR, CRi and CRh rates • CR, CRi and CCR at 2, 4 and 6 cycles of treatment • Time to CR, CRi, PR, PD • ORR • ORR after 2, 4 and 6 cycles of treatment • Duration of response • Disease-free survival (DFS) • Relapse-free survival (RFS) • Cumulative incidence of relapse (CIR) • Global health status/quality of life (GHS/QoL) and fatigue assessed using subscales/items from the EORTC QLQ-C30 instrument • Medical resources during treatment phase: this includes inpatient hospital admissions, use of antibiotics, duration of hospitalization • Rates of RBC and platelet transfusion independence, duration of RBC transfusion independence and platelet transfusion independence and platelet and RBC transfusion independence • CR and CRi with negative measurable residual disease (MRD) • ORR, EFS, and OS in patients who have TP53 mutations, 17p deletions, and/or are determined to be in an adverse cytogenetic risk group in both treatment arms. • Event-free survival (EFS) according to ELN definition • Analysis of potential biomarkers predictive of PEVO activity, depth and duration of response will be performed • Correlation of response with EFS and OS • Time to improvement in functioning and symptoms using the EORTC QLQ-C30, and the supplemental items of the EORTC item bank: fatigue, shortness of breath, and physical functioning. • Evaluation of health utilization and calculate utility values using a preference-based PRO instrument EQ-5D-5L. • Safety/toxicity of the PEVO+AZA regimen vs AZA: Hematologic and non-hematologic toxicity (e.g. adverse events (AEs), serious AEs (SAEs), clinical laboratory tests, performance status).;Timepoint(s) of evaluation of this end point: Cycles 2, 4, 6 and every 3 cycles thereafter. 30 and 60 days for Early mortality. 6 months and 1 year for survival rates. PRO instruments ( | — |
Countries
Portugal
Contacts
Public ContactClinical Trials Unit
Dynamic
Outcome results
None listed