A Study of Pevonedistat in Combination With Select Standard of Care Agents in Participants With Higher-risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myelogenous Leukemia, Or Advanced Solid Tumors With Severe Renal Impairment or Mild or Moderate Hepatic Impairment
- Inclusion Criteria: All participants: 1. Has expected survival of at least 3 months from the date of enrollment in the study. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 3. Has recovered (that is, Grade <=1 toxicity) from the reversible effects of prior anticancer therapy. 4. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) <=1.5 * upper limit of the normal range (ULN) at screening or within 7 days before the first dose of study drug. 5. Suitable venous access for the study-required blood sampling (that is, PK sampling). For hematologic malignancies: 6. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cell [WBC] <13,000 /mcL) at the study entry, based on one 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: - RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow. - RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood. - CMML-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood. - CMML-1 (although CMML-1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these participants may enroll only if bone marrow blasts >=5%). With MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R): - Very high (>6 points). - High (>4.5-6 points). - Intermediate (>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts. 7. With WHO-defined AML at study entry, including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, have failed to achieve CR or have relapsed after prior therapy and are not candidates for potentially curative treatment. 8. With relapsed or refractory MDS, have previously been treated with an hypomethylating agent. 9. Laboratory value requirements per study arms are: - Estimated glomerular filtration rate (eGFR) (milliliter per minute per 1.73 square meter [mL/min/1.73^m]) >=90 (Control arm), <30 (Renal arm) , >=60 (Mild and Moderate hepatic arm). - Total Bilirubin <= ULN (Control arm), <= ULN (Renal arm), ULN <Bilirubin <=1.5 * ULN (not secondary to transfusions) (Mild hepatic arm) and 1.5 * ULN <bilirubin <=3.0 * ULN (not secondary to transfusions) (Moderate hepatic arm). - Alanine aminotransferase (ALT) <= ULN (Control arm), <=2.5 * ULN (Renal arm) and any value (for mild and moderate hepatic arm). For advanced solid tumors: 10. Have a histologically or cytologically confirmed metastatic or locally advanced solid tumor that is appropriate for treatment with pevonedistat in combination with either docetaxel or carboplatin plus paclitaxel in Part B of this study, or have progressed despite standard therapy, or whom conventional therapy is not considered effective. 11. Computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 28 days of the first dose of the study drug. 12. Laboratory value requirements per study arms are: - eGFR (mL/min/1.73m^2) <30 (Renal arm) and >=60 (mild and moderate hepatic arm). - Total bilirubin <=ULN (Renal arm), ULN <bilirubin <=1.5 * ULN (Mild hepatic arm) and 1.5 * ULN <bilirubin <=3.0 * ULN (Moderate hepatic arm). - ALT <=1.5 * ULN (for participants who receive pevonedistat plus docetaxel only) or <=2.5 * ULN (for participants who receive pevonedistat plus carboplatin plus paclitaxel only) (Renal arm) and any value (Mild and Moderate hepatic arm). Exclusion Criteia: All participants:- 1. Participants with end-stage renal disease requiring hemodialysis. 2. Has Gilbert syndrome. 3. Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. Prophylactic treatment with antibiotics is allowed. 4. Has life-threatening illness unrelated to cancer. 5. Known human immunodeficiency virus (HIV) seropositive. 6. Has left ventricular ejection fraction (LVEF) <50% within 6 months prior to study enrollment. If a result within this time frame is unavailable, LVEF must be determined by echocardiography at screening. 7. Has severe uncontrolled ventricular arrhythmias or torsade de pointes; electrocardiographic evidence of acute ischemia or active conduction system abnormalities; or clinically significant arrhythmia (as an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion). 8. Has severe symptomatic pulmonary hypertension requiring pharmacologic therapy or participants with chronic respiratory disease that requires continuous oxygen. For hematologic malignancies: 9. Has 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. 10. With AML with a WBC count >=50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they otherwise meet the eligibility criteria. 11. With either clinical evidence of or history of central nervous system (CNS) involvement by AML. 12. With hematologic malignancies, PT or aPTT >1.5 * ULN or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment. For advanced solid tumors: 13. Has prior treatment with radiation therapy involving >=25% of the hematopoietically active bone marrow. 14. Has CNS metastasis, except for participants who have received prior treatment (radiation or resection) and have stable CNS disease (example: stable MRI, no steroid requirement).
The drug being tested in this study is called pevonedistat. The study will characterize the
PK of pevonedistat, assess the safety, and determine the dose of pevonedistat, in combination
with azacitidine, docetaxel OR paclitaxel plus carboplatin in participants with higher-risk
myelodysplastic syndromes (HRMDS), myelodysplastic syndromes (MDS), chronic myelomonocytic
leukemia (CMML), acute myelogenous leukemia (AML), or advanced solid tumors who also have
severe renal impairment or mild or moderate hepatic impairment.
The study will enroll approximately 42 participants. Participants with solid tumors or
hematologic malignancies will be assigned to one of the four treatment groups on the basis of
their renal and hepatic function:
- Control Arm (Normal Renal and Hepatic Function)
- Renal Arm (Severe Renal Impairment)
- Mild Hepatic Arm (Mild Hepatic Impairment)
- Moderate Hepatic Arm (Moderate Hepatic Impairment)
The study will be conducted in 2 parts: Part A and Part B. Part A will include single dose
administration of pevonedistat. Eligible participants from Part A who will opt to continue
treatment in Part B will be treated with pevonedistat in combination with standard of care
(SOC) agents (azacitidine, docetaxel OR paclitaxel plus carboplatin) in Part B.
Dose escalation of pevonedistat and SOC agents will be based on the safety data from Cycle 1
of Part B as mentioned below:
- In renal arm (severe renal impairment ) based on the safety data from Cycle 1 of Part B,
pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of Cycle 2 Part B and in
subsequent Cycles, to a maximum dose of 25 mg/m^2. Participants may be eligible for
intrapatient dose escalation to paclitaxel 175 mg/m^2 in Cycle 2 or beyond if the lower
dose is well tolerated. Intrapatient dose escalation of carboplatin to AUC5 will be
allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.
- In mild hepatic arm (mild hepatic impairment), the starting dose for pevonedistat and
azacitidine in combination are not escalated in the cohort. Intrapatient dose escalation
of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is
safe and tolerable.
- In moderate hepatic arm (moderate hepatic impairment) based on the safety data from
Cycle 1 of Part B, pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of
Cycle 2 Part B and in subsequent Cycles, to a maximum dose of 20 mg/m^2. Intrapatient
dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1
of Part B is safe and tolerable.
This multi-center trial will be conducted in the United States and Spain. The overall time to
participate in this study is approximately 3.5 years. Participants will attend end of the
study visit 30 days after the last dose of study drug or before the start of subsequent
therapy, if that occurs sooner for safety follow up.
Trial Phase Phase I
Trial Type Not provided by clinicaltrials.gov
Millennium Pharmaceuticals, Inc.
- Primary ID Pevonedistat-1016
- Secondary IDs NCI-2019-06215, 2018-004049-17, U1111-1220-1396
- Clinicaltrials.gov ID NCT03814005