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CompletedNCT03814005Updated Sep 5, 2024Results posted

A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems

A Phase 1 interventional study of Azacitidine and Pevonedistat in Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic and Leukemia, Myeloid, Acute, sponsored by Takeda. Completed at 8 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-09-05.

Sponsored by Takeda · Phase 1, Interventional, and Other

Phase
Phase 1
Study type
Interventional
Enrollment
17
Allocation
Non-randomized
Ages
18 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Myelodysplastic Syndromes
  • Leukemia, Myelomonocytic, Chronic
  • Leukemia, Myeloid, Acute
  • Renal Insufficiency
  • Liver Disease
  • Neoplasms

Keywords

  • Drug therapy
03

In context

Myelodysplastic Syndromes

2,165 studies on the registry are indexed under Myelodysplastic Syndromes; 322 are open to participants now.

This study's enrollment of 17 is below the median of 39 across 1,771 interventional studies indexed under Myelodysplastic Syndromes.

Browse Myelodysplastic Syndromes studies →

Lead sponsor

Takeda is the lead sponsor of 1,025 studies on the registry; 92 are open to participants now.

Of its 177 completed or terminated interventional studies of FDA-regulated products, 153 (86%) have results posted.

Browse Takeda studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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).
05

Study design

Phase
Phase 1
Primary purpose
Other
Allocation
Non-randomized
Intervention model
Sequential assignment
Masking
None (open label)
Enrollment
17 participants (actual)

Study arms

  • Experimental
    Control Arm

    Pevonedistat 20 milligram per square meter (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, further followed by 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 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.

    Drug: Azacitidine · Drug: Pevonedistat

  • Experimental
    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, further followed by 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 until symptomatic deterioration or PD, discontinuation for any reason, study stopped by the sponsor, or up to 12 cycles.

    Drug: Azacitidine · Drug: Pevonedistat

  • Experimental
    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, further followed by 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.

    Drug: Azacitidine · Drug: Pevonedistat

Interventions

  • DrugAzacitidine

    Azacitidine subcutaneous or intravenous injection.

  • DrugPevonedistat

    Pevonedistat intravenous infusion.

    Also known as: TAK-924 and MLN4924

06

What researchers measure

Primary outcomes

  1. 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

  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

    Time frame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose

  3. 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

Secondary outcomes

  1. 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)

  2. 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)

  3. 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

  4. 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)

  5. 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)

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. 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)

  12. 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)

  13. 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)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 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)

  19. 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)

07

Results

Posted Sep 5, 2024

Participant flow

Participants took part in the study at 5 investigative sites in United States and Spain from 10 July 2019 to 19 April 2022.

Part A: Day 1 to Day 4
Participant flow — Part A: Day 1 to Day 4
MilestoneControl ArmRenal ArmMild Hepatic Arm
Started1043
Response-evaluable population812
Completed1043
Not completed000
Washout Period : Day 4 to Day 7
Participant flow — Washout Period : Day 4 to Day 7
MilestoneControl ArmRenal ArmMild Hepatic Arm
Started1043
Completed1043
Not completed000
Part B: Day 8 to Day 343
Participant flow — Part B: Day 8 to Day 343
MilestoneControl ArmRenal ArmMild Hepatic Arm
Started1043
Completed000
Not completed1043
Withdrew: Adverse event200
Withdrew: Withdrawal by subject003
Withdrew: Progressive disease420
Withdrew: Unsatisfactory therapeutic response200
Withdrew: Symptomatic deterioration120
Withdrew: Reason not specified100

Outcome measures

PrimaryPart 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
Reported as:
Geometric mean · hour*nanogram per milliliter(h*ng/mL)
Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose
hour*nanogram per milliliter(h*ng/mL)Part A: Control Arm: Pevonedistat 20 mg/m^2Part A: Renal Arm: Pevonedistat 20 mg/m^2Part 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 Dose1168.616 ± 69.48111293.467 ± 22.06851050.553 ± 69.4854
PrimaryPart 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
Reported as:
Geometric mean · h*ng/mL
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
h*ng/mLPart A: Control Arm: Pevonedistat 20 mg/m^2Part A: Renal Arm: Pevonedistat 20 mg/m^2Part 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 Dose1120.759 ± 73.39561267.523 ± 22.15281020.344 ± 71.9314
PrimaryPart 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
Reported as:
Geometric mean · nanograms per milliliter(ng/mL)
Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose
nanograms per milliliter(ng/mL)Part A: Control Arm: Pevonedistat 20 mg/m^2Part A: Renal Arm: Pevonedistat 20 mg/m^2Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2
Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose262.9 ± 188.54180.2 ± 37.66148.9 ± 30.09
SecondaryParts 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)
Reported as:
Median · hours (h)
Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose
hours (h)Part A: Control Arm: Pevonedistat 20 mg/m^2Part A: Renal Arm: Pevonedistat 20 mg/m^2Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2Part B: Control Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part 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 Dose6.957 (4.25 to 13.88)8.493 (7.31 to 10.29)9.612 (7.49 to 11.03)—8.795 (7.03 to 9.22)10.248 (9.78 to 10.72)—8.98 (8.98 to 8.98)—6.477 (3.93 to 13.37)—6.79 (6.79 to 6.79)
SecondaryPart 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)
Reported as:
Geometric mean · ng/mL
Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose
ng/mLPart B: Control Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose—74.73 ± 14.94144.74 ± 24.579—128.00 ± NA—141.55 ± 37.468—75.80 ± NA
SecondaryParts 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
Reported as:
Geometric mean · percentage of plasma fraction unbound
Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat
percentage of plasma fraction unboundPart A: Control Arm: Pevonedistat 20 mg/m^2Part A: Renal Arm: Pevonedistat 20 mg/m^2Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2
Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat5.800 ± 18.28807.073 ± 12.22695.529 ± 2.0462
SecondaryPart 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)
Reported as:
Geometric mean · ng/mL
Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose
ng/mLPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose645.4 ± 34.40918.6 ± 98.14834.8 ± 38.23
SecondaryPart 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)
Reported as:
Median · hours (h)
Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose
hours (h)Part B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose0.325 (0.08 to 0.75)0.500 (0.32 to 0.53)0.250 (0.12 to 0.75)
SecondaryPart 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)
Reported as:
Median · hours (h)
Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose
hours (h)Part B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose0.706 (0.57 to 1.47)1.020 (0.79 to 1.76)0.694 (0.67 to 1.13)
SecondaryPart 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)
Reported as:
Geometric mean · h*ng/mL
Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose
h*ng/mLPart B: Control Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 20 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—574.168 ± 19.6797396.240 ± 14.4663—884.974 ± NA—848.866 ± 25.6831—431.699 ± NA
SecondaryPart 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)
Reported as:
Geometric mean · h*ng/mL
Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose
h*ng/mLPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose822.457 ± 31.13381331.654 ± 63.1278751.448 ± 35.3760
SecondaryParts 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)
Reported as:
Geometric mean · liters per hour (L/h)
Parts A and B, CL: Total Clearance for Pevonedistat
liters per hour (L/h)Part A: Control Arm: Pevonedistat 20 mg/m^2Part A: Renal Arm: Pevonedistat 20 mg/m^2Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2Part B: Control Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Parts A and B, CL: Total Clearance for Pevonedistat32.149 ± 64.548929.167 ± 31.512534.476 ± 56.9322—32.721 ± 36.010451.628 ± 9.1794—32.361 ± NA—44.259 ± 24.9426—65.746 ± NA
SecondaryPart 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)
Reported as:
Geometric mean · L/h
Part B, CL/F: Apparent Clearance for Azacitidine
L/hPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B, CL/F: Apparent Clearance for Azacitidine171.301 ± 34.6321106.238 ± 74.8634180.744 ± 21.1071
SecondaryPart 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)
Reported as:
Geometric mean · L/h
Part B, CLR: Renal Clearance for Pevonedistat
L/hPart B: Control Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2
Part B, CLR: Renal Clearance for Pevonedistat—0.298 ± 51.05580.492 ± 36.0553—0.069 ± NA—0.516 ± 147.7469—0.062 ± NA
SecondaryPart 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)
Reported as:
Geometric mean · L/h
Part B, CLR: Renal Clearance for Azacitidine
L/hPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B, CLR: Renal Clearance for Azacitidine0.909 ± 134.39590.161 ± 207.85150.445 ± 167.4353
SecondaryParts 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)
Reported as:
Geometric mean · Liters (L)
Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat
Liters (L)Part A: Control Arm: Pevonedistat 20 mg/m^2Part A: Renal Arm: Pevonedistat 20 mg/m^2Part A: Mild Hepatic Arm: Pevonedistat 20 mg/m^2Part B: Control Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 10 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Mild Hepatic Arm: Pevonedistat 15 mg/m^2 + Azacitidine 75 mg/m^2Part B: Control Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part B: Renal Arm: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Part 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 Pevonedistat219.288 ± 124.3584293.614 ± 36.3707353.570 ± 55.0197—351.749 ± 23.5066729.013 ± 3.2642—336.922 ± NA—370.563 ± 44.2326—573.044 ± NA
SecondaryPart 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)
Reported as:
Geometric mean · L
Part B, Vz/F: Apparent Volume of Distribution of Azacitidine
LPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B, Vz/F: Apparent Volume of Distribution of Azacitidine190.871 ± 60.0093167.610 ± 92.9284211.139 ± 8.4099
SecondaryPart 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)
Reported as:
Number · percentage of participants
Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR)
percentage of participantsPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
CR or CRi1300
PR000
SecondaryPart 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)
Reported as:
Number · percentage of participants
Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI)
percentage of participantsPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
MDS CR3800
MDS PR000
MDS HI000
SecondaryPart 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)
Reported as:
Number · percentage of participants
Part B: Percentage of HR MDS and AML Participants With Overall Response
percentage of participantsPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B: Percentage of HR MDS and AML Participants With Overall Response5000
SecondaryPart 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)
Reported as:
Median · days
Part B: Duration of CR, PR and HI
daysPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Part B: Duration of CR, PR and HINA (NA to NA)——
SecondaryPart 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)

No measurements were reported for this outcome.

Adverse events

Collected over From the study start up to end of study (up to approximately 2 years 9 months). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Part A: Control Arm0/10 (0%)0/10 (0%)2/10 (20%)
Part A: Renal Arm0/4 (0%)0/4 (0%)1/4 (25%)
Part A: Mild Hepatic Arm0/3 (0%)0/3 (0%)1/3 (33.3%)
Part B: Control Arm2/10 (20%)7/10 (70%)10/10 (100%)
Part B: Renal Arm2/4 (50%)3/4 (75%)4/4 (100%)
Part B: Mild Hepatic Arm0/3 (0%)2/3 (66.7%)3/3 (100%)
Most frequent serious events
Showing 10 of 22
Most frequent serious events
EventPart A: Control ArmPart A: Renal ArmPart A: Mild Hepatic ArmPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Acute kidney injuryRenal and urinary disorders0/100/40/30/102/40/3
PyrexiaGeneral disorders0/100/40/30/101/41/3
Rectal haemorrhageGastrointestinal disorders0/100/40/30/100/41/3
Febrile neutropeniaBlood and lymphatic system disorders0/100/40/33/101/40/3
Acute myeloid leukaemiaNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/100/40/30/101/40/3
Chronic kidney diseaseRenal and urinary disorders0/100/40/30/101/40/3
DiarrhoeaGastrointestinal disorders0/100/40/30/101/40/3
SepsisInfections and infestations0/100/40/30/101/40/3
Tumour lysis syndromeMetabolism and nutrition disorders0/100/40/30/101/40/3
Back painMusculoskeletal and connective tissue disorders0/100/40/31/100/40/3
Most frequent other events
Showing 10 of 123
Most frequent other events
EventPart A: Control ArmPart A: Renal ArmPart A: Mild Hepatic ArmPart B: Control ArmPart B: Renal ArmPart B: Mild Hepatic Arm
Blood creatinine increasedInvestigations0/100/40/30/103/40/3
Blood bilirubin increasedInvestigations0/100/40/30/101/42/3
Conjunctival haemorrhageEye disorders0/100/40/30/100/42/3
EpistaxisRespiratory, thoracic and mediastinal disorders0/100/40/32/101/42/3
PyrexiaGeneral disorders1/100/41/36/100/42/3
AnaemiaBlood and lymphatic system disorders0/100/40/31/102/40/3
ConstipationGastrointestinal disorders0/100/41/33/102/41/3
DiarrhoeaGastrointestinal disorders0/100/40/33/102/40/3
FatigueGeneral disorders0/100/40/34/102/41/3
CoughRespiratory, thoracic and mediastinal disorders0/100/40/34/100/40/3

Baseline characteristics

Safety population included all participants who received at least 1 dose of study drug.

Age, Continuous
Age, Continuous(years)Control ArmRenal ArmMild Hepatic ArmTotal
Mean70.1 ± 11.7571.5 ± 6.8679.7 ± 3.0672.1 ± 10.05
Sex: Female, Male
Sex: Female, Male(Participants)Control ArmRenal ArmMild Hepatic ArmTotal
Female0112
Male103215
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Control ArmRenal ArmMild Hepatic ArmTotal
Hispanic or Latino0000
Not Hispanic or Latino104317
Unknown or Not Reported0000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Control ArmRenal ArmMild Hepatic ArmTotal
American Indian or Alaska Native0000
Asian1012
Native Hawaiian or Other Pacific Islander0000
Black or African American1001
White84214
More than one race0000
Unknown or Not Reported0000
Region of Enrollment
Region of Enrollment(Participants)Control ArmRenal ArmMild Hepatic ArmTotal
United States63211
Spain4116
Height
Height(centimeter (cm))Control ArmRenal ArmMild Hepatic ArmTotal
Mean170.3 ± 5.99175.0 ± 11.13170.2 ± 22.00171.4 ± 10.40
Weight
Weight(kilogram (kg))Control ArmRenal ArmMild Hepatic ArmTotal
Mean75.0 ± 7.7774.5 ± 14.2171.7 ± 19.4374.3 ± 10.98
08

Study locations

8 sites
  • Icahn School of Medicine at Mount Sinai
    New York, New York 10029, United States
  • University of North Carolina at Chapel Hill
    Chapel Hill, North Carolina 27514, United States
  • ICO lHospitalet Hospital Duran i Reynals
    LHospitalet de Llobregat, Barcelona 8908, Spain
  • Hospital Universitario Vall d'Hebron - PPDS
    Barcelona, 8035, Spain
  • Hospital de San Pedro de Alcantara
    Cáceres, 10003, Spain
  • C.H. Regional Reina Sofia
    Córdoba, 14004, Spain
  • Complejo Asistencial Universitario de Salamanca H. Clinico
    Salamanca, 37007, Spain
  • Hospital Universitario Virgen del Rocio - PPDS
    Seville, 41013, Spain
09

References and documents

Study documents

  • Study protocol · Jun 1, 2021
  • Statistical analysis plan · Feb 23, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting information: Study protocol, Statistical analysis plan, Informed consent form, Clinical study report

Access criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Data sharing details ↗ · vivli.org

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Sep 5, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT03814005
Lead sponsor
Takeda
Responsible party
Sponsor
First posted
Jan 23, 2019
Start date
Jul 10, 2019
Primary completion
Mar 19, 2021
Completion
Apr 19, 2022
Results posted
Sep 5, 2024
Last update
Sep 5, 2024

Study contacts

Medical Director
study director · Takeda

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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