A Clinical Study to Compare the Effectiveness and Safety of Azacitidine Versus Pevonedistate Plus Azacitidine in Adults with Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Low-Blast Acute Myelogenous Leukemia

Phase 1

Conditions: Higher-risk myelodysplastic syndromes (MDS), Chronic myelomonocytic leukemia (CMML), Low-blast acute myelogenous leukemia (AML)
MedDRA version: 20.0Level: LLTClassification code 10054350Term: Chronic myelomonocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10024348Term: Leukemia myelogenousSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.1Level: LLTClassification code 10024330Term: Leukemia acuteSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: HLTClassification code 10028536Term: Myelodysplastic syndromesSystem Organ Class: 100000004851
MedDRA version: 20.0Level: PTClassification code 10067387Term: Myelodysplastic syndrome transformationSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10009018Term: Chronic myelomonocytic leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10028533Term: Myelodysplastic syndromeSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2015-000221-37-CZ

Lead Sponsor: Millennium Pharmaceuticals, Inc. (Takeda)

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 117

Inclusion Criteria

1. Male or female patients 18 years or older.
2. Morphologically confirmed diagnosis of MDS, nonproliferative CMML (ie, with WBC <20,000/µL), or low-blast AML based on 1 of the following:
French-American-British (FAB) Classifications:
- Refractory anemia with excess blasts (RAEB – defined as having 5% to 20%
myeloblasts in the bone marrow).
- CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19%
blasts in the blood.
OR
World Health Organization (WHO) Classifications:
- Refractory anemia with excess blasts-1 (RAEB-1 – defined as having 5% to 9%
myeloblasts in the bone marrow).
- Refractory anemia with excess blasts-2 (RAEB-2 – defined as having 10% to
19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).
- Chronic Myelomonocytic Leukemia-2 (CMML-2 – defined as having 10% to
19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood).
- Chronic Myelomonocytic Leukemia-1 (Although CMML-1 is defined as having
<10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these
patients may enroll only if bone marrow blasts =5%).
- WHO-defined AML with 20% to 30% myeloblasts in the bone marrow (defined in this protocol as Low-Blast AML”) and < 30% myeloblasts in peripheral blood who are considered by investigator to be appropriate for azacitidine-based therapy.

3. For MDS and CMML patients, prognostic Risk Category, based on the Revised International Prognostic Scoring System (IPSS-R):
- Very high (>6 points),
- High (>4.5 - 6 points), or
- Intermediate (>3 – 4.5 points): a patient determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of =5% bone marrow myeloblasts.
Patients with indeterminate cytogenetics findings at Screening should be
assigned a cytogenetics prognostic variable of 2 points (ie, intermediate)
for determining overall Prognostic Risk Category/Score
4. ECOG performance status of 0 to 2

5. 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):
- Albumin >2.7 g/dL.
- Total bilirubin syndrome. Patients with Gilbert’s syndrome may enroll if direct bilirubin = 1.5 x
ULN of the direct bilirubin.
- ALT and AST <2.5 × ULN.
- Creatinine clearance >50 mL/min
- Hemoglobin >8 g/dL. Patients may be transfused to achieve this value. Elevated indirect bilirubin due to post-transfusion hemolysis is allowed.

6. For CMML patients: WBC count <20,000/µL before administration of the first dose of study drug on Cycle 1 Day 1; patients must have been off hydroxyurea for at least 1 week prior to WBC count assessment.

7. Ability to undergo the study-required bone marrow sample collection procedures.

8. Suitable venous access for the study-required blood sampling (ie, including PK and biomarker sampling).

9. - Are postmenopausal for at least 1 year before the Screening visit, or
- Are surgically sterile, or
- If they are of childbearing potential, agree to practice 1 highly effective
method
and 1 additional effective (barrier) method of contraception, at
the same time, from the time of signing the informed consent through 4
months
after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the
preferred and usual lifestyle

Exclusion Criteria

1. Previous treatment with decitabine or azacitidine or other
hypomethylating agent.
2. Acute promyelocytic leukemia as diagnosed by morphologic
examination of bone marrow, by fluorescent in situ hybridization or
cytogenetics of peripheral blood or bone marrow, or by other accepted
analysis.
3. Eligible for allogenic stem cell transplantation.
4. Patients with MDS, CMML, or low-blast AML, whose only site of disease
is
extramedullary, eg, the skin.
5. Any serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with the completion of study
procedures or could limit patient expected survival to less than 6
months.
6. Treatment with any anti-leukemic/anti-MDS therapies (eg,
lenalidomide, cytarabine, anthracyclines, purine analogs) or with any
investigational products within 14 days before the first dose of any study
drug.
7. Known hypersensitivity to mannitol.
8. Active uncontrolled infection or severe infectious disease, such as
severe pneumonia, meningitis, or septicemia. 9. Major surgery within 14 days before first dose or a scheduled surgery
during study period; insertion of a venous access device (eg, catheter,
port) is not considered major surgery.
10. Diagnosed or treated for another malignancy within 2 years before
randomization or previously diagnosed with another malignancy and
have any evidence of residual disease. Patients with nonmelanoma skin
cancer or carcinoma in situ of any type are not excluded if they have
undergone resection.
11. Life-threatening illness unrelated to cancer.
12. Prothrombin time (PT) or aPTT > 1.5 ULN or active uncontrolled
coagulopathy or bleeding disorder.
13. Known human immunodeficiency virus (HIV) seropositive.
14. Known hepatitis B surface antigen seropositive, or known or
suspected active hepatitis C infection. Note: Patients who have isolated
positive hepatitis B core antibody (ie, in the setting of negative hepatitis
B surface antigen and negative hepatitis B surface antibody) must have
an undetectable hepatitis B viral load.
15. Known hepatic cirrhosis or severe pre-existing hepatic impairment. 16. Known cardiopulmonary disease defined as unstable angina,
clinically significant arrhythmia, congestive heart failure (New York
Heart Association [NYHA] Class III or IV; see Section 15.3), and/or
myocardial infarction within 6 months prior to first dose, or severe
pulmonary hypertension. As an example, well-controlled atrial
fibrillation would not be an exclusion whereas uncontrolled atrial
fibrillation would be an exclusion.
17. Treatment with strong CYP3A inhibitors or inducers within 14 days
before the first dose of pevonedistat.
18. Systemic antineoplastic therapy or radiotherapy for other malignant
conditions within
12 months before the first dose of any study drug, except for
hydroxyurea.
19. Female patients who are 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.
20. 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).
21. 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).

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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