Leukemia, Myeloid, Acute, Leukemia, Myelomonocytic, Chronic, Liver Disease, Myelodysplastic Syndromes, Neoplasms, Renal Insufficiency
Conditions
Keywords
Drug therapy
Brief summary
Pevonedistat is a medicine to treat people with blood cancers or solid tumors. The main aim of the study is to learn about the levels of pevonedistat in the blood of participants with blood cancers or solid tumors, who also have severe kidney problems or mild to moderate liver problems. The information from this study will be used to work out the best dose of pevonedistat to give people with these conditions in future studies. At the first visit, the study doctor will check who can take part in the study. This study is in 2 parts: A and B. Part A Participants will be placed into 1 of 4 treatment groups depending on how severe their kidney and liver problems are. All participants will receive 1 dose of pevonedistat as a slow injection in their vein (infusion). Then, the study doctors will check the levels of pevonedistat in the blood of the participants for 3 days after the infusion. They will also check if the participants have any side effects from pevonedistat. Participants will be asked to continue to Part B. Those who don't want to continue will visit the clinic 30 days later for a final check-up. Part B Participants who agree to participate into Part B will receive an infusion of pevonedistat on specific days during a 21-day or 28-day cycle. The cycle time will depend on what type of cancer the participants have. Participants will also be treated with standard of care medicines for their kidney and liver problems during this time. In the first cycle, the study doctors will also check the levels of pevonedistat in the blood and urine of participants for 3 days after the infusion. Participants will continue with cycles of treatment together with standard of care medicines until their condition gets worse or they have too many side effects from the treatment. When treatment has finished, participants will visit the clinic 10 days later for a final check-up.
Detailed description
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. Intrapatient 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.
Interventions
DRUGAzacitidine
Azacitidine subcutaneous or intravenous injection.
DRUGPevonedistat
Pevonedistat intravenous infusion.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. Previously untreated hematologic malignancies not suitable for induction therapy. 7. 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%). 8. 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. 9. 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. 10. With relapsed or refractory MDS, have previously been treated with an hypomethylating agent. 11. 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: 12. 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. 13. 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. 14. 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 criteria
All participants:- 1. 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. Treatment with strong cytochrome P450 (CYP)3A inducers within 14 days before the first dose of pevonedistat. 7. 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 or multigated acquisition scan at screening. 8. 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). 9. Has severe symptomatic pulmonary hypertension requiring pharmacologic therapy or participants with chronic respiratory disease that requires continuous oxygen. For hematologic malignancies: 10. 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. 11. 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. 12. With either clinical evidence of or history of central nervous system (CNS) involvement by AML. 13. 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: 14. Has prior treatment with radiation therapy involving \>=25% of the hematopoietically active bone marrow. 15. 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).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose | Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose |
| Part A, AUClast: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose | Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose |
| Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose | Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose | Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days) | — |
| Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose | Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days) | — |
| Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose | Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days) | — |
| Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose | Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days) | — |
| Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose | Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days) | — |
| Parts A and B, CL: Total Clearance for Pevonedistat | Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length is 28 Days) | — |
| Part B, CL/F: Apparent Clearance for Azacitidine | Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days) | — |
| Part B, CLR: Renal Clearance for Pevonedistat | Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days) | — |
| Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days) | — |
| Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days) | — |
| Part B, Vz/F: Apparent Volume of Distribution of Azacitidine | Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days) | — |
| Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) | Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days) | Disease response in AML are based on international working group (IWG) for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in AML. For AML participants, all CR includes both CR and CRi. CR: morphologic leukemia-free state with absolute neutrophil count (ANC) of greater than (\>) 1000 per microliter (/mcL) and platelets of greater than or equal to (\>=) 100,000/mcL, and no residual evidence of extramedullary leukemia. CRi: After chemotherapy, some participants fulfill all criteria for CR except for residual neutropenia (less than \[\<\] 1000/mcL) or thrombocytopenia (\<100,000/mcL). PR: requires all hematologic values for a CR but with a decrease of at least 50 percent (%) in the percentage of blasts to 5% to 25% in the bone marrow aspirate. A value of less than or equal to (\<=) 5% blasts may also be considered a PR if Auer rods are present. |
| Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days) | Disease response in MDS and CMML was based on best overall response (CR+PR+HI) as determined by investigator using revised IWG response criteria for MDS and CMML. CR: morphologic leukemia-free state with absolute neutrophil count (ANC) of greater than (\>) 1000 per microliter (/mcL) and platelets of greater than or equal to (\>=) 100,000/mcL, and no residual evidence of extramedullary leukemia. PR: requires all hematologic values for a CR but with a decrease of at least 50 percent (%) in the percentage of blasts to 5% to 25% in the bone marrow aspirate. A value of less than or equal to (\<=) 5% blasts may also be considered a PR if Auer rods are present. HI: erythropoietic (HI-E): Hemoglobin increase of ≥ 1.5 g/dL untransfused, for red blood cells (RBC) transfusions performed for hemoglobin ≤ 9.0: reduction in RBC units transfused in 8 weeks by ≥ 4 units compared to the number of units transfused in the 8 weeks prior to treatment. No participants with CMML were enrolled in this study. |
| Part B: Percentage of HR MDS and AML Participants With Overall Response | Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days) | Overall Response Rate is defined as CR+CRi+PR+HI. CR:≤5% myeloblasts with normal maturation of all bone marrow(BM)cell lines,≥11g/dL Hgb,≥100\*10\^9/L pl,≥1.0\*10\^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still \>5%;HI:Hgb increase(inc) ≥1.5g/dL if baseline(BL)\<11 g/dL;pl inc≥30\*10\^9/L if BL\>20\*10\^9/L or inc from \<20\*10\^9/L to \>20\*10\^9/L and by 100%;neutrophil inc by 100%;absolute inc of \>0.5\*10\^9/L if BL\<100\*10\^9/L.For AML-CR:morphologic leukemia-free state \>1.0\*10\^9 neutrophils,≥100\*10\^9/L pl,transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia (\<1000/μL) or thrombocytopenia (\<100,000/μL);PR:all CR hematological values but ≥50% decrease in BM aspirate. |
| Part B: Duration of CR, PR and HI | From first documentation of response up to disease progression (up to 2 years 9 months) | Duration of response in participants with disease response (CR+PR+HI) for hematologic malignancies is time between first documentation of response and disease progression. Duration of response will be determined by the investigator using the revised IWG response criteria. |
| Part B: Percentage of Solid Tumors Participants With CR or PR | Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days) | Disease response in solid tumors was based on best overall response (CR+PR) as determined by investigator using the RECIST version 1.1 criteria. CR: disappearance of all target lesions with any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \<10 millimeter (mm) and disappearance of all nontarget lesions and normalization of tumor marker level with all lymph nodes must be nonpathological in size (\<10 mm short axis); PR: At least a 30% decrease from baseline in the sum of diameters of target lesions, taking as reference the baseline sum of diameters and Persistence of one or more nontarget lesion(s) or/and maintenance of tumor marker level above the normal limits. No participants with solid tumors were enrolled in this study. |
| Part B, CLR: Renal Clearance for Azacitidine | Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days) | — |
| Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose | Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days) | — |
| Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat | Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose | — |
Countries
Spain, United States
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in United States and Spain from 10 July 2019 to 19 April 2022.
Pre-assignment details
Participants with myelodysplastic syndromes (MDS), and acute myelogenous leukemia (AML) who also had severe renal impairment or mild hepatic impairment were enrolled in this study to receive single dose of pevonedistat in Part A followed by a wash out period and pevonedistat in combination with standard of care agent in Part B. No participants with chronic myelomonocytic leukemia (CMML) and solid tumors were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Control Arm Pevonedistat 20 milligram per square meter (mg/m\^2), infusion, intravenously (IV), once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days. Following Part A participants received azacitidine 75 mg/m\^2, injection, subcutaneously (SC) in Cycle 1 or SC or IV in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with pevonedistat 20 mg/m\^2, infusion, IV, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies in Part B until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. | 10 |
| Renal Arm Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days. Following Part A participants received azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8-9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 15 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies in Part B until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. | 4 |
| Mild Hepatic Arm Pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Day 1 of Part A in participants with hematologic malignancies, followed by a washout period of approximately 4 to 7 days. Following Part A participants received azacitidine 75 mg/m\^2, injection, subcutaneously in Cycle 1 or subcutaneously or intravenously in Cycle 2 and subsequent cycles, once on Day 1 through Day 7 or Day 1 through Day 5, and on Days 8 and 9 in combination with a starting dose of pevonedistat 10 mg/m\^2 to a maximum dose of pevonedistat 20 mg/m\^2, infusion, intravenously, once, on Days 1, 3, and 5 in each 28-day treatment cycle in participants with hematologic malignancies until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles. | 3 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Part B: Day 8 to Day 343 | Adverse Event | 2 | 0 | 0 |
| Part B: Day 8 to Day 343 | Progressive Disease | 4 | 2 | 0 |
| Part B: Day 8 to Day 343 | Reason not Specified | 1 | 0 | 0 |
| Part B: Day 8 to Day 343 | Symptomatic Deterioration | 1 | 2 | 0 |
| Part B: Day 8 to Day 343 | Unsatisfactory Therapeutic Response | 2 | 0 | 0 |
| Part B: Day 8 to Day 343 | Withdrawal by Subject | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Renal Arm | Total | Control Arm | Mild Hepatic Arm |
|---|---|---|---|---|
| Age, Continuous | 71.5 years STANDARD_DEVIATION 6.86 | 72.1 years STANDARD_DEVIATION 10.05 | 70.1 years STANDARD_DEVIATION 11.75 | 79.7 years STANDARD_DEVIATION 3.06 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 17 Participants | 10 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 175.0 centimeter (cm) STANDARD_DEVIATION 11.13 | 171.4 centimeter (cm) STANDARD_DEVIATION 10.4 | 170.3 centimeter (cm) STANDARD_DEVIATION 5.99 | 170.2 centimeter (cm) STANDARD_DEVIATION 22 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 14 Participants | 8 Participants | 2 Participants |
| Region of Enrollment Spain | 1 Participants | 6 Participants | 4 Participants | 1 Participants |
| Region of Enrollment United States | 3 Participants | 11 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 3 Participants | 15 Participants | 10 Participants | 2 Participants |
| Weight | 74.5 kilogram (kg) STANDARD_DEVIATION 14.21 | 74.3 kilogram (kg) STANDARD_DEVIATION 10.98 | 75.0 kilogram (kg) STANDARD_DEVIATION 7.77 | 71.7 kilogram (kg) STANDARD_DEVIATION 19.43 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 4 | 0 / 3 | 2 / 10 | 2 / 4 | 0 / 3 |
| other Total, other adverse events | 2 / 10 | 1 / 4 | 1 / 3 | 10 / 10 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 0 / 10 | 0 / 4 | 0 / 3 | 7 / 10 | 3 / 4 | 2 / 3 |
Outcome results
Primary
Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose
Time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Population: Pharmacokinetic (PK) population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose | 1168.616 hour*nanogram per milliliter(h*ng/mL) | Geometric Coefficient of Variation 69.4811 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose | 1293.467 hour*nanogram per milliliter(h*ng/mL) | Geometric Coefficient of Variation 22.0685 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose | 1050.553 hour*nanogram per milliliter(h*ng/mL) | Geometric Coefficient of Variation 69.4854 |
Primary
Part A, AUClast: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose
Time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part A, AUClast: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose | 1120.759 h*ng/mL | Geometric Coefficient of Variation 73.3956 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part A, AUClast: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose | 1267.523 h*ng/mL | Geometric Coefficient of Variation 22.1528 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part A, AUClast: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose | 1020.344 h*ng/mL | Geometric Coefficient of Variation 71.9314 |
Primary
Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose
Time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose | 262.9 nanograms per milliliter(ng/mL) | Geometric Coefficient of Variation 188.54 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose | 180.2 nanograms per milliliter(ng/mL) | Geometric Coefficient of Variation 37.66 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose | 148.9 nanograms per milliliter(ng/mL) | Geometric Coefficient of Variation 30.09 |
Secondary
Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose | 822.457 h*ng/mL | Geometric Coefficient of Variation 31.1338 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose | 1331.654 h*ng/mL | Geometric Coefficient of Variation 63.1278 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose | 751.448 h*ng/mL | Geometric Coefficient of Variation 35.376 |
Secondary
Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose | 574.168 h*ng/mL | Geometric Coefficient of Variation 19.6797 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose | 396.240 h*ng/mL | Geometric Coefficient of Variation 14.4663 |
| Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose | 884.974 h*ng/mL | — |
| Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose | 848.866 h*ng/mL | Geometric Coefficient of Variation 25.6831 |
| Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose | 431.699 h*ng/mL | — |
Secondary
Part B, CL/F: Apparent Clearance for Azacitidine
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B, CL/F: Apparent Clearance for Azacitidine | 171.301 L/h | Geometric Coefficient of Variation 34.6321 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, CL/F: Apparent Clearance for Azacitidine | 106.238 L/h | Geometric Coefficient of Variation 74.8634 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, CL/F: Apparent Clearance for Azacitidine | 180.744 L/h | Geometric Coefficient of Variation 21.1071 |
Secondary
Part B, CLR: Renal Clearance for Azacitidine
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B, CLR: Renal Clearance for Azacitidine | 0.909 L/h | Geometric Coefficient of Variation 134.3959 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, CLR: Renal Clearance for Azacitidine | 0.161 L/h | Geometric Coefficient of Variation 207.8515 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, CLR: Renal Clearance for Azacitidine | 0.445 L/h | Geometric Coefficient of Variation 167.4353 |
Secondary
Part B, CLR: Renal Clearance for Pevonedistat
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, CLR: Renal Clearance for Pevonedistat | 0.298 L/h | Geometric Coefficient of Variation 51.0558 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, CLR: Renal Clearance for Pevonedistat | 0.492 L/h | Geometric Coefficient of Variation 36.0553 |
| Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Part B, CLR: Renal Clearance for Pevonedistat | 0.069 L/h | — |
| Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Part B, CLR: Renal Clearance for Pevonedistat | 0.516 L/h | Geometric Coefficient of Variation 147.7469 |
| Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Part B, CLR: Renal Clearance for Pevonedistat | 0.062 L/h | — |
Secondary
Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose | 645.4 ng/mL | Geometric Coefficient of Variation 34.4 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose | 918.6 ng/mL | Geometric Coefficient of Variation 98.14 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose | 834.8 ng/mL | Geometric Coefficient of Variation 38.23 |
Secondary
Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose | 74.73 ng/mL | Geometric Coefficient of Variation 14.941 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose | 44.74 ng/mL | Geometric Coefficient of Variation 24.579 |
| Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose | 128.00 ng/mL | — |
| Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose | 141.55 ng/mL | Geometric Coefficient of Variation 37.468 |
| Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose | 75.80 ng/mL | — |
Secondary
Part B: Duration of CR, PR and HI
Duration of response in participants with disease response (CR+PR+HI) for hematologic malignancies is time between first documentation of response and disease progression. Duration of response will be determined by the investigator using the revised IWG response criteria.
Time frame: From first documentation of response up to disease progression (up to 2 years 9 months)
Population: Response-evaluable population included participants who received at least 1 dose of study drug, had a baseline disease assessment, and had at least 1 postbaseline disease assessment to analyze response. Overall number of participants analyzed is the number of participants with disease response (CR+PR+HI) for hematologic malignancies.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B: Duration of CR, PR and HI | NA days |
Secondary
Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR)
Disease response in AML are based on international working group (IWG) for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in AML. For AML participants, all CR includes both CR and CRi. CR: morphologic leukemia-free state with absolute neutrophil count (ANC) of greater than (\>) 1000 per microliter (/mcL) and platelets of greater than or equal to (\>=) 100,000/mcL, and no residual evidence of extramedullary leukemia. CRi: After chemotherapy, some participants fulfill all criteria for CR except for residual neutropenia (less than \[\<\] 1000/mcL) or thrombocytopenia (\<100,000/mcL). PR: requires all hematologic values for a CR but with a decrease of at least 50 percent (%) in the percentage of blasts to 5% to 25% in the bone marrow aspirate. A value of less than or equal to (\<=) 5% blasts may also be considered a PR if Auer rods are present.
Time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days)
Population: Response-evaluable population included participants who received at least 1 dose of study drug, had a baseline disease assessment, and had at least 1 postbaseline disease assessment to analyze response. Percentages are rounded off to whole number at the nearest decimal.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) | CR or CRi | 13 percentage of participants |
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) | PR | 0 percentage of participants |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) | CR or CRi | 0 percentage of participants |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) | PR | 0 percentage of participants |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) | CR or CRi | 0 percentage of participants |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) | PR | 0 percentage of participants |
Secondary
Part B: Percentage of HR MDS and AML Participants With Overall Response
Overall Response Rate is defined as CR+CRi+PR+HI. CR:≤5% myeloblasts with normal maturation of all bone marrow(BM)cell lines,≥11g/dL Hgb,≥100\*10\^9/L pl,≥1.0\*10\^9/L neutrophils,0% blasts in peripheral blood;PR:all CR criteria met except BM blasts ≥50% decrease over pretreatment but still \>5%;HI:Hgb increase(inc) ≥1.5g/dL if baseline(BL)\<11 g/dL;pl inc≥30\*10\^9/L if BL\>20\*10\^9/L or inc from \<20\*10\^9/L to \>20\*10\^9/L and by 100%;neutrophil inc by 100%;absolute inc of \>0.5\*10\^9/L if BL\<100\*10\^9/L.For AML-CR:morphologic leukemia-free state \>1.0\*10\^9 neutrophils,≥100\*10\^9/L pl,transfusion independence,no residual evidence of extramedullary leukemia;CR with incomplete blood count recovery:fulfill CR criteria except residual neutropenia (\<1000/μL) or thrombocytopenia (\<100,000/μL);PR:all CR hematological values but ≥50% decrease in BM aspirate.
Time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days)
Population: Response-evaluable population included participants who received at least 1 dose of study drug, had a baseline disease assessment, and had at least 1 postbaseline disease assessment to analyze response. Percentages are rounded off to whole number at the nearest decimal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of HR MDS and AML Participants With Overall Response | 50 percentage of participants |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of HR MDS and AML Participants With Overall Response | 0 percentage of participants |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of HR MDS and AML Participants With Overall Response | 0 percentage of participants |
Secondary
Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI)
Disease response in MDS and CMML was based on best overall response (CR+PR+HI) as determined by investigator using revised IWG response criteria for MDS and CMML. CR: morphologic leukemia-free state with absolute neutrophil count (ANC) of greater than (\>) 1000 per microliter (/mcL) and platelets of greater than or equal to (\>=) 100,000/mcL, and no residual evidence of extramedullary leukemia. PR: requires all hematologic values for a CR but with a decrease of at least 50 percent (%) in the percentage of blasts to 5% to 25% in the bone marrow aspirate. A value of less than or equal to (\<=) 5% blasts may also be considered a PR if Auer rods are present. HI: erythropoietic (HI-E): Hemoglobin increase of ≥ 1.5 g/dL untransfused, for red blood cells (RBC) transfusions performed for hemoglobin ≤ 9.0: reduction in RBC units transfused in 8 weeks by ≥ 4 units compared to the number of units transfused in the 8 weeks prior to treatment. No participants with CMML were enrolled in this study.
Time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days)
Population: Response-evaluable population included participants who received at least 1 dose of study drug, had a baseline disease assessment, and had at least 1 postbaseline disease assessment to analyze response. Percentages are rounded off to whole number at the nearest decimal.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS PR | 0 percentage of participants |
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS CR | 38 percentage of participants |
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS HI | 0 percentage of participants |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS PR | 0 percentage of participants |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS CR | 0 percentage of participants |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS HI | 0 percentage of participants |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS CR | 0 percentage of participants |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS HI | 0 percentage of participants |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) | MDS PR | 0 percentage of participants |
Secondary
Part B: Percentage of Solid Tumors Participants With CR or PR
Disease response in solid tumors was based on best overall response (CR+PR) as determined by investigator using the RECIST version 1.1 criteria. CR: disappearance of all target lesions with any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to \<10 millimeter (mm) and disappearance of all nontarget lesions and normalization of tumor marker level with all lymph nodes must be nonpathological in size (\<10 mm short axis); PR: At least a 30% decrease from baseline in the sum of diameters of target lesions, taking as reference the baseline sum of diameters and Persistence of one or more nontarget lesion(s) or/and maintenance of tumor marker level above the normal limits. No participants with solid tumors were enrolled in this study.
Time frame: Cycle 2 Day 22, Cycles 5, 8, and 11 (between Days 15 and 28), and every 6 cycles (up to 2 years 9 months) (Cycle length= 28 days)
Population: No participants with solid tumors were enrolled in this study.
Secondary
Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose | 0.706 hours (h) |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose | 1.020 hours (h) |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose | 0.694 hours (h) |
Secondary
Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose | 0.325 hours (h) |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose | 0.500 hours (h) |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose | 0.250 hours (h) |
Secondary
Part B, Vz/F: Apparent Volume of Distribution of Azacitidine
Time frame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Part B, Vz/F: Apparent Volume of Distribution of Azacitidine | 190.871 L | Geometric Coefficient of Variation 60.0093 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Part B, Vz/F: Apparent Volume of Distribution of Azacitidine | 167.610 L | Geometric Coefficient of Variation 92.9284 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Part B, Vz/F: Apparent Volume of Distribution of Azacitidine | 211.139 L | Geometric Coefficient of Variation 8.4099 |
Secondary
Parts A and B, CL: Total Clearance for Pevonedistat
Time frame: Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length is 28 Days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 32.149 liters per hour (L/h) | Geometric Coefficient of Variation 64.5489 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 29.167 liters per hour (L/h) | Geometric Coefficient of Variation 31.5125 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 34.476 liters per hour (L/h) | Geometric Coefficient of Variation 56.9322 |
| Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 32.721 liters per hour (L/h) | Geometric Coefficient of Variation 36.0104 |
| Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 51.628 liters per hour (L/h) | Geometric Coefficient of Variation 9.1794 |
| Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 32.361 liters per hour (L/h) | — |
| Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 44.259 liters per hour (L/h) | Geometric Coefficient of Variation 24.9426 |
| Part B: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, CL: Total Clearance for Pevonedistat | 65.746 liters per hour (L/h) | — |
Secondary
Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose
Time frame: Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 6.957 hours (h) |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 8.493 hours (h) |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 9.612 hours (h) |
| Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 8.795 hours (h) |
| Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 10.248 hours (h) |
| Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 8.98 hours (h) |
| Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 6.477 hours (h) |
| Part B: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose | 6.79 hours (h) |
Secondary
Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat
Time frame: Part A: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Part B: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 219.288 Liters (L) | Geometric Coefficient of Variation 124.3584 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 293.614 Liters (L) | Geometric Coefficient of Variation 36.3707 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 353.570 Liters (L) | Geometric Coefficient of Variation 55.0197 |
| Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 351.749 Liters (L) | Geometric Coefficient of Variation 23.5066 |
| Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 729.013 Liters (L) | Geometric Coefficient of Variation 3.2642 |
| Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 336.922 Liters (L) | — |
| Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 370.563 Liters (L) | Geometric Coefficient of Variation 44.2326 |
| Part B: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2 | Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat | 573.044 Liters (L) | — |
Secondary
Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat
Time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Population: PK population included all participants who had sufficient dosing in Part A and Part B Cycle 1, had sufficient concentration-time data to permit reliable estimation of PK parameters, and who had not received any excluded concomitant medications through the completion of Part A. Overall number analyzed is the number of participants available for analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Control Arm: Pevonedistat 20 mg/m^2 | Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat | 5.800 percentage of plasma fraction unbound | Geometric Coefficient of Variation 18.288 |
| Part A: Renal Arm: Pevonedistat 20 mg/m^2 | Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat | 7.073 percentage of plasma fraction unbound | Geometric Coefficient of Variation 12.2269 |
| Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 | Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat | 5.529 percentage of plasma fraction unbound | Geometric Coefficient of Variation 2.0462 |