Myelodysplastic SyndromesPhase 1NCT03814005
A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems
A Phase 1 study testing Azacitidine and Pevonedistat in people with Myelodysplastic Syndromes and Leukemia, Myelomonocytic, Chronic, run by Takeda at 8 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute
- What is being tested?
- Azacitidine and Pevonedistat
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 8 sitesin 2 countries
- Study dates
- 10 Jul 2019to 19 Apr 2022
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- All participants:
- Has expected survival of at least 3 months from the date of enrollment in the study.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
- Has recovered (that is, Grade <=1 toxicity) from the reversible effects of prior anticancer therapy.
- 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.
- Suitable venous access for the study-required blood sampling (that is, PK sampling).
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- For hematologic malignancies:
- Previously untreated hematologic malignancies not suitable for induction therapy.
- Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cell [WBC] <13,000 /mcL) at the study entry, based on one of the following:
- French-American-British (FAB) Classifications:
- Refractory anemia with excess blasts (RAEB), defined as having 5% to 20% myeloblasts in the bone marrow.
- CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
- OR
- World Health Organization (WHO) Classifications:
- RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow.
- RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
- CMML-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
- CMML-1 (although CMML-1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these participants may enroll only if bone marrow blasts >=5%).
- With MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):
- Very high (>6 points).
- High (>4.5-6 points).
- Intermediate (>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts.
- 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.
- With relapsed or refractory MDS, have previously been treated with an hypomethylating agent.
- 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:
- 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.
- 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.
- 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).
Who cannot join
- All participants:-
- With end-stage renal disease requiring hemodialysis.
- Has Gilbert syndrome.
- Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. Prophylactic treatment with antibiotics is allowed.
- Has life-threatening illness unrelated to cancer.
- Known human immunodeficiency virus (HIV) seropositive.
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- Treatment with strong cytochrome P450 (CYP)3A inducers within 14 days before the first dose of pevonedistat.
- 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.
- 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).
- Has severe symptomatic pulmonary hypertension requiring pharmacologic therapy or participants with chronic respiratory disease that requires continuous oxygen.
- For hematologic malignancies:
- 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.
- 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.
- With either clinical evidence of or history of central nervous system (CNS) involvement by AML.
- 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:
- Has prior treatment with radiation therapy involving >=25% of the hematopoietically active bone marrow.
- 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).
Trial locations and contacts
8 sites in 2 countries.
8 sites in 2 countries
Spain6 sites
Hospital Universitario Vall d'Hebron - PPDS
Barcelona, 8035
Hospital de San Pedro de Alcantara
Cáceres, 10003
C.H. Regional Reina Sofia
Córdoba, 14004
ICO lHospitalet Hospital Duran i Reynals
LHospitalet de Llobregat, Barcelona, 8908
Complejo Asistencial Universitario de Salamanca H. Clinico
Salamanca, 37007
Hospital Universitario Virgen del Rocio - PPDS
Seville, 41013
United States2 sites
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27514
Icahn School of Medicine at Mount Sinai
New York, New York, 10029
About this study
Official title: A Phase 1/1b Study of Pevonedistat in Combination With Select Standard of Care Agents in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myelogenous Leukemia, or Advanced Solid Tumors With Severe Renal Impairment or Mild or Moderate Hepatic Impairment
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.
Read more
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.
- Conditions
- Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute, Renal Insufficiency, Liver Disease, Neoplasms
- Being tested
- Azacitidine, Pevonedistat
- Keywords
- Drug therapy
- Medical subject headings
- Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute, Renal Insufficiency, Liver Diseases, Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
Azacitidine subcutaneous or intravenous injection.
PevonedistatDrug
Also called TAK-924 and MLN4924
Pevonedistat intravenous infusion.
| Study group | Role | What they receive |
|---|---|---|
| Control Arm | Experimental | 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. Receives: Drug: Azacitidine; Drug: Pevonedistat |
| Renal Arm | Experimental | 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. Receives: Drug: Azacitidine; Drug: Pevonedistat |
| Mild Hepatic Arm | Experimental | 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. Receives: Drug: Azacitidine; Drug: Pevonedistat |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose
Measured: 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
Measured: 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
Measured: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Secondary outcomes (19)
Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose
Measured: 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: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose
Measured: 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
Measured: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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 Azacitidine
Measured: 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, Vss: Volume of Distribution at Steady-state of Pevonedistat
Measured: 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
Measured: 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)
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.
Measured: 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)
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.
Measured: 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)
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.
Measured: 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)
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.
Measured: From first documentation of response up to disease progression (up to 2 years 9 months)
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.
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2019
- Study start10 Jul 2019
- Primary completion19 Mar 2021
- Study completion19 Apr 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Myelodysplastic SyndromesStudies of the same condition, open and under way.
- More trials run by TakedaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Takeda
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03814005
- Sponsor's protocol ID
- Pevonedistat-1016
- Other IDs
- U1111-1220-1396, 2018-004049-17, 2018
- Status last verified
- Aug 2024
- First submitted
- 21 Jan 2019
- Last updated
- 5 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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.
Study at a glance
From the registry record, last updated by the sponsor on 5 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1/1b Study of Pevonedistat in Combination With Select Standard of Care Agents in Patients With Higher-Risk Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Acute Myelogenous Leukemia, or Advanced Solid Tumors With Severe Renal Impairment or Mild or Moderate Hepatic Impairment
- ClinicalTrials.gov ID
- NCT03814005
- Acronym / sponsor ID
- Pevonedistat-1016
- Conditions
- Myelodysplastic Syndromes, Leukemia, Myelomonocytic, Chronic, Leukemia, Myeloid, Acute, Renal Insufficiency, Liver Disease, Neoplasms
- Keywords
- Drug therapy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- TakedaIndustry (pharma, biotech, devices)
- Study start
- 10 Jul 2019 (actual)
- Primary completion
- 19 Mar 2021 (actual)
- Study completion
- 19 Apr 2022 (actual)
- First posted
- 23 Jan 2019 (actual)
- Results
- Posted 5 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Control Arm | Experimental | Drug: Azacitidine, Drug: PevonedistatPevonedistat 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. |
| Renal Arm | Experimental | Drug: Azacitidine, Drug: PevonedistatPevonedistat 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. |
| Mild Hepatic Arm | Experimental | Drug: Azacitidine, Drug: PevonedistatPevonedistat 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (35 listed)
- Has expected survival of at least 3 months from the date of enrollment in the study.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
- Has recovered (that is, Grade <=1 toxicity) from the reversible effects of prior anticancer therapy.
- 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.
- Suitable venous access for the study-required blood sampling (that is, PK sampling).
Key exclusion criteria (18 listed)
- All participants:-
- With end-stage renal disease requiring hemodialysis.
- Has Gilbert syndrome.
- Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. Prophylactic treatment with antibiotics is allowed.
- Has life-threatening illness unrelated to cancer.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzacitidineAzacitidine subcutaneous or intravenous injection. | Drug | Control Arm, Mild Hepatic Arm, Renal Arm |
| PevonedistatAlso: TAK-924 and MLN4924Pevonedistat intravenous infusion. | Drug | Control Arm, Mild Hepatic Arm, Renal Arm |
Primary outcome
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
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
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
19 secondary outcomes
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)
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)
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
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR)
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)
Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI)
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)
Part B: Percentage of HR MDS and AML Participants With Overall Response
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)
Part B: Duration of CR, PR and HI
Time frame: From first documentation of response up to disease progression (up to 2 years 9 months)
Part B: Percentage of Solid Tumors Participants With CR or PR
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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- To obtain more information on the study, click here/on this linkLink provided by the sponsor.
- Individual participant dataSharing planned: 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Takeda
8 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Azacitidine and Pevonedistat in people with Myelodysplastic Syndromes and Leukemia, Myelomonocytic, Chronic, run by Takeda at 8 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 35 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Spain, United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Sep 2024.