Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Low-Blast Acute Myelogenous Leukemia
- Conditions
- Higher-Risk Myelodysplastic Syndromes (MDS)Chronic Myelomonocytic Leukemia (CMML)Low-Blast Acute Myelogenous Leukemia (AML)MedDRA version: 21.0Level: LLTClassification code 10054350Term: Chronic myelomonocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: 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: 100000004851MedDRA version: 21.1Level: PTClassification code 10067387Term: Myelodysplastic syndrome transformationSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.0Level: PTClassification code 10009018Term: Chronic myelomonocytic leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)MedDRA version: 21.1Level: 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
- EUCTR2017-000318-40-GB
- Lead Sponsor
- Millennium Pharmaceuticals, Inc. (Takeda)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 450
1.Male or female patients 18 years or older.
2.Morphologically confirmed diagnosis of MDS or nonproliferative CMML (ie, with WBC <13,000/µL) or low-blast AML based on 1 of the following:
French-American-British (FAB) Classifications:
- 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%-9% myeloblasts in the bone marrow.
- Refractory anemia with excess blasts-2 (RAEB-2), defined as having 10%-19% myeloblasts in the bone marrow and/or 5%-19% blasts in the blood.
- Chronic Myelomonocytic Leukemia-2 (CMML-2), defined as having 10%-19% myeloblasts in the bone marrow and/or 5%-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%-30% myeloblasts in the bone marrow (defined in this protocol as low-blast AML) and =30% myeloblasts in peripheral blood who are deemed by the investigator to be appropriate for azacitidine-based therapy.
3. All patients with MDS or CMML must also have one of the following 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.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
5. Patients with AML (20%-30% blasts) must have a TRM score =4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers
Calculation of TRM score:
- 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age =71 years).
- + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
- + 0 for (platelets <50), +1 for (platelets =50).
6. Female patients who:
- 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 one highly effective method of contraception and one additional effective (barrier) method, 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 of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 120 days (or if the drug has a very long half-life, for 90 days plus five half-lives) after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods
1. Previous treatment for HR MDS or CMML, or low-blast AML with chemotherapy or other antineoplastic agents including HMAs 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. 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. Patients with AML with a WBC count >50,000/ µL. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria.
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 may consist of one or more of the following factors:
- Age >75.
- Comorbidities.
- Inability to tolerate intensive chemotherapy (eg, patients with AML with 20%-30% blasts and TRM =4).
- Physician decision (eg, lack of available stem cell donor).
The reason a patient is not eligible should 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. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of study procedures or could limit expected patient survival to less than 6 months.
7. Treatment with any investigational products or participation in any interventional studies within 14 days before the first dose of any study drug.
8. Known hypersensitivity to pevonedistat or its excipients.
9. Known hypersensitivity to azacitidine or its excipients.
10. Active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia.
11. 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.
12. 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.
13. Life-threatening illness unrelated to cancer.
14. Prothrombin time (PT) or aPTT >1.5×ULN or active uncontrolled coagulopathy or bleeding disorder. Patients therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.
15. Known human immunodeficiency virus (HIV) seropositive.
16. 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.
17. Known hepatic cirrhosis or severe preexisting hepatic impairment.
18. Known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary
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