Study to Compare Azacitidine Plus Pevonedistat Versus Azacitidine in Patients With Acute Myeloid Leukemia Not Eligible for Standard Chemotherapy

Prospective, 1:1 randomized multicentre, open label, phase III clinical trial to evaluate efficacy and safety of pevonedistat in combination with azacytidine versus azacytidine in the treatment of naïve adult patients with acute myeloid leukemia who are not eligible for standard induction therapy due to age, co-morbidities or risk-factors.

Subjects will be randomized to one of the two treatment arms in a 1:1 ratio, both of which will have treatment cycles of 28 days:

* Arm A: Pevonedistat (PEVO) 20 mg/m2 IV on days 1, 3, and 5 plus Azacitidine (AZA) 75 mg/m2 subcutaneous (SC) administered on a 5-on/2-off \[weekend\]/2-on schedule in 28-day cycles (IV AZA can be administered for any patients who have non-tolerated local reactions)
* Arm B: AZA 75 mg/m2 SC on a 5-on/2-off \[weekend\]/2-on schedule in 28-day cycle (IV AZA can be administered for any patients who have non-tolerated local reactions)

466 subjects will be randomized in the study. Subjects will continue their study treatment until documented disease progression per Investigator assessment, unacceptable toxicity, withdrawal of consent, or the subject meets other protocol criteria for discontinuation

• Pevonedistat (Drug): Pevonedistat 20 mg/m2 intravenous on days 1, 3, and 5 (28-day cycles)
• Azacitidine (Drug): Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off \[weekend\]/2-on schedule (28-day cycle). Intravenous for patients who have non-tolerated local reactions

Primary outcomes

• Overall survival (OS) [through study completion, an average of 1 year]: Time from the date of randomization to the date of death.

Secondary outcomes

• Event-free survival (EFS) [through study completion, an average of 1 year]: Time from randomization to the date of the occurrence of any of the following events: progressive disease, failure to achieve complete response or complete remission with incomplete blood count recovery at 6 months after initiation of treatment, relapse from complete response (CR)/ incomplete complete response (CRi) or death from any cause, whichever occurs first
• Composite complete remission [through study completion, an average of 1 year]: The proportion of subjects with complete response plus complete remission with incomplete blood count recovery
• Overall response rate [through study completion, an average of 1 year]: The proportion of subjects with complete response plus complete remission with incomplete blood count recovery plus partial response
• Cumulative incidence of relapse [through study completion, an average of 1 year]: Calculated using the competing risk method (Fine \& Gray)
• Health status/quality of life [through study completion, an average of 1 year]: Global health status/quality of life based on patient reported outcome EORTC Quality of life questionnaire (QLQ)-C30 and supplemental items.
• Health status/quality of life [through study completion, an average of 1 year]: Global health status/quality of life based on patient reported outcome: EQ-5D-5L questionnaire.
• Use of medical resources determined by the use of antibiotics [through study completion, an average of 1 year]: Compare the use of antibiotics during the study between treatment groups
• Use of medical resources determined by the use of transfusions [through study completion, an average of 1 year]: Compare the use of transfusions during the study between treatment groups
• Use of medical resources determined by the number of hospital admissions [through study completion, an average of 1 year]: Compare the number of hospital admissions during the study between treatment groups
• Pharmacokinetic [At day 1, 3 and 5 of cycle 1, cycle 2 and cycle 3 (each cycle is 28 days)]: Plasma concentration of Pevonedistat
• Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [through study completion (an average of 1 year)]: Adverse events of Pevonedistat plus Azacitidine versus Azacitidine regimen
• Quality of composite complete remission determined by the minimal residual disease determined by RT-qPCR in the NPM1+ and CBF subsets and in bone marrow by MPFC in the remaining patients [through study completion, an average of 1 year]: To evaluate the quality of composite complete remission determining the minimal residual disease in patients with complete remission and complete remission with incomplete blood count recovery
• Overall survival based on somatic mutations [through study completion, an average of 1 year]: To explore relationship of somatic mutations at baseline with overall survival
• Event free survival based on somatic mutations [through study completion, an average of 1 year]: To explore relationship of somatic mutations at baseline with event free survival
• Overall response rate based on somatic mutations [through study completion, an average of 1 year]: To explore relationship of somatic mutations at baseline with the overall response rate
• Overall survival based on cytogenetic abnormalities [through study completion, an average of 1 year]: To explore relationship of cytogenetic abnormalities at baseline with overall survival
• Event free survival based on cytogenetic abnormalities [through study completion, an average of 1 year]: To explore relationship of cytogenetic abnormalities at baseline event free survival
• Overall response rate based on cytogenetic abnormalities [through study completion, an average of 1 year]: To explore relationship of cytogenetic abnormalities at baseline with the overall response rate
• Red blood cells transfusion transfusion Independence (no use of red blood cells transfusion for a period of at least 8 weeks) [through study completion, an average of 1 year]: To determine if PEVO + AZA increase the duration of red blood cells transfusion Independence (transfusion independence requires that the patient receive no red blood cells transfusions for a period of at least 8 weeks)
• Platelet transfusion Independence (no use of platelets transfusión for a period of at least 8 weeks) [through study completion, an average of 1 year]: To determine if PEVO + AZA increase the duration of platelets transfusion Independence (transfusion independence requires that the patient receive no platelets transfusions for a period of at least 8 weeks)
• Biomarkers (CBF) predictive of PEVO activity [through study completion, an average of 1 year]: To assess biomarkers (CBF) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
• Biomarkers (FLT3-ITD) predictive of PEVO activity [through study completion, an average of 1 year]: To assess biomarkers (FLT3-ITD) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
• Biomarkers (NPM1) predictive of PEVO activity [through study completion, an average of 1 year]: To assess biomarkers (NPM1) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
• Biomarkers (P53) predictive of PEVO activity [through study completion, an average of 1 year]: To assess biomarkers (P53) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease
• Biomarkers (IDH1/IDH2 ) predictive of PEVO activity [through study completion, an average of 1 year]: To assess biomarkers (IDH1/IDH2) predictive of PEVO activity evaluated by the overall response rate and minimal residual disease

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male or female patients 18 years or older
2. Morphological diagnosis of Acute Myeloid Leukemia (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 be ineligible for treatment with a standard Ara-C and anthracycline induction regimen due to age or co-morbidities defined by one of the following:

   1. ≥ 75 years of age
   2. Or ≥ 18 to 74 years of age with at least one of the following:

      * ECOG Performance Status of 2 or 3;
      * Cardiac history of cardiac heart failure requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina;
      * 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;
      * Glomerular filtration rate (GFR) ≥ 30 mL/min to < 50 ml/min or levels of creatinine between the upper limit of the normal range (ULN) and 2.5 mg/dL (≤ 250 μmol/l).
      * Hepatic impairment with total bilirubin > 1.5 to ≤ 3 × ULN or with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2.5×ULN to ≤ 5×ULN
      * Non active/controlled prior neoplastic disease
      * 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):

   * Total bilirubin ≤ 1.5 × ULN 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.
   * ALT and AST ≤ 2.5×ULN or ≤ 5×ULN if elevation is attributed to underlying leukemia.
   * Adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min (calculated by the Cockcroft Gault formula, (see Appendix 5).
   * 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, must agree, from Study Day 1 through at least 4 months after the last dose of study drug, to practice effective barrier contraception during the entire study treatment period and 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 \[e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
10. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

1. Previous treatment for myelodysplastic síndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) or myeloproliferative neoplasms (MPN), with chemotherapy or other antineoplastic agents including HMAs (up to 2 cycles of Hypomethylating agents (HMA) 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.
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.

   * The reason a patient is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation is described in the inclusion criteria section
   * The reason a patient is not eligible for intensive chemotherapy must be documented in the electronic case report form (eCRF).
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:

    * Cluster of differentiation 4 (CD4) count > 350 cells/mm3
    * Undetectable viral load
    * Maintained on modern therapeutic regimens utilizing non-cytochrome P450 (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 strong Cytochrome P450, family 3, subfamily A (CYP3A) inducers (see Appendix 8) within 14 days before the first dose of pevonedistat.
20. Patients with uncontrolled coagulopathy or bleeding disorder.
21. High blood pressure which cannot be controlled by standard treatments
22. Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to institutional guidelines.
23. As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control and no signs of systemic inflammatory response beyond low grade fever that makes patient clinically unstable in the opinion of the investigator. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control.
24. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment.
25. Systemic antineoplastic therapy for malignant conditions other than myeloid neoplasms within 14 days before the first dose of any study drug.

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