Clinical trial comparing azacitidine plus pevonedistat versus azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for standard induction chemotherapy

Phase 1

• Conditions: Acute Myeloid Leukemia; MedDRA version: 21.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2019-001323-12-PT
• Lead Sponsor: Fundación PETHEMA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-04-17
• Last Update Posted: 22 March 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 466

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 < 50 ml/min or levels of creatinine between the upper limit of the normal range (ULN) and 2.5 mg/dL(= 250 µmol/L)
o Hepatic impairment with total bilirubin > 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

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified