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

NCT ID: NCT03814005

Last Updated: 2024-09-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 17 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-10
• Study Completion Date: 2022-04-19

Brief Summary

Pevonedistat is a medicine to treat people with blood cancers or solid tumors.

The main aim of the study is to learn about the levels of pevonedistat in the blood of participants with blood cancers or solid tumors, who also have severe kidney problems or mild to moderate liver problems. The information from this study will be used to work out the best dose of pevonedistat to give people with these conditions in future studies. At the first visit, the study doctor will check who can take part in the study.

This study is in 2 parts: A and B.

Part A Participants will be placed into 1 of 4 treatment groups depending on how severe their kidney and liver problems are. All participants will receive 1 dose of pevonedistat as a slow injection in their vein (infusion). Then, the study doctors will check the levels of pevonedistat in the blood of the participants for 3 days after the infusion. They will also check if the participants have any side effects from pevonedistat.

Participants will be asked to continue to Part B. Those who don't want to continue will visit the clinic 30 days later for a final check-up.

Part B Participants who agree to participate into Part B will receive an infusion of pevonedistat on specific days during a 21-day or 28-day cycle. The cycle time will depend on what type of cancer the participants have. Participants will also be treated with standard of care medicines for their kidney and liver problems during this time. In the first cycle, the study doctors will also check the levels of pevonedistat in the blood and urine of participants for 3 days after the infusion. Participants will continue with cycles of treatment together with standard of care medicines until their condition gets worse or they have too many side effects from the treatment.

When treatment has finished, participants will visit the clinic 10 days later for a final check-up.

Detailed Description

The drug being tested in this study is called pevonedistat. The study will characterize the PK of pevonedistat, assess the safety, and determine the dose of pevonedistat, in combination with azacitidine, docetaxel OR paclitaxel plus carboplatin in participants with higher-risk myelodysplastic syndromes (HRMDS), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), acute myelogenous leukemia (AML), or advanced solid tumors who also have severe renal impairment or mild or moderate hepatic impairment.

The study will enroll approximately 42 participants. Participants with solid tumors or hematologic malignancies will be assigned to one of the four treatment groups on the basis of their renal and hepatic function:

• Control Arm (Normal Renal and Hepatic Function)
• Renal Arm (Severe Renal Impairment)
• Mild Hepatic Arm (Mild Hepatic Impairment)
• Moderate Hepatic Arm (Moderate Hepatic Impairment)

The study will be conducted in 2 parts: Part A and Part B. Part A will include single dose administration of pevonedistat. Eligible participants from Part A who will opt to continue treatment in Part B will be treated with pevonedistat in combination with standard of care (SOC) agents (azacitidine, docetaxel OR paclitaxel plus carboplatin) in Part B.

Intrapatient dose escalation of pevonedistat and SOC agents will be based on the safety data from Cycle 1 of Part B as mentioned below:

• In renal arm (severe renal impairment ) based on the safety data from Cycle 1 of Part B, pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of Cycle 2 Part B and in subsequent Cycles, to a maximum dose of 25 mg/m^2. Participants may be eligible for intrapatient dose escalation to paclitaxel 175 mg/m^2 in Cycle 2 or beyond if the lower dose is well tolerated. Intrapatient dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.
• In mild hepatic arm (mild hepatic impairment), the starting dose for pevonedistat and azacitidine in combination are not escalated in the cohort. Intrapatient dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.
• In moderate hepatic arm (moderate hepatic impairment) based on the safety data from Cycle 1 of Part B, pevonedistat may be increased to 15 mg/m^2 on Days 1, 3, and 5 of Cycle 2 Part B and in subsequent Cycles, to a maximum dose of 20 mg/m^2. Intrapatient dose escalation of carboplatin to AUC5 will be allowed if treatment with AUC4 in Cycle 1 of Part B is safe and tolerable.

This multi-center trial will be conducted in the United States and Spain. The overall time to participate in this study is approximately 3.5 years. Participants will attend end of the study visit 30 days after the last dose of study drug or before the start of subsequent therapy, if that occurs sooner for safety follow up.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Azacitidine subcutaneous or intravenous injection.

Pevonedistat

Intervention Type: DRUG

Pevonedistat intravenous infusion.

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.

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Azacitidine subcutaneous or intravenous injection.

Pevonedistat

Intervention Type: DRUG

Pevonedistat intravenous infusion.

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.

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Azacitidine subcutaneous or intravenous injection.

Pevonedistat

Intervention Type: DRUG

Pevonedistat intravenous infusion.

Interventions

Azacitidine

Azacitidine subcutaneous or intravenous injection.

Intervention Type: DRUG

Pevonedistat

Pevonedistat intravenous infusion.

Intervention Type: DRUG

Other Intervention Names

TAK-924 and MLN4924

Eligibility Criteria

Inclusion Criteria

All participants:

1. Has expected survival of at least 3 months from the date of enrollment in the study.

2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

3. Has recovered (that is, Grade <=1 toxicity) from the reversible effects of prior anticancer therapy.

4. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) <=1.5 * upper limit of the normal range (ULN) at screening or within 7 days before the first dose of study drug.

5. Suitable venous access for the study-required blood sampling (that is, PK sampling).

For hematologic malignancies:

6. Previously untreated hematologic malignancies not suitable for induction therapy.

7. Morphologically confirmed diagnosis of MDS or nonproliferative CMML (that is, with white blood cell [WBC] <13,000 /mcL) at the study entry, based on one of the following:

French-American-British (FAB) Classifications:

• Refractory anemia with excess blasts (RAEB), defined as having 5% to 20% myeloblasts in the bone marrow.
• CMML with 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.

OR

World Health Organization (WHO) Classifications:

• RAEB-1, defined as having 5% to 9% myeloblasts in the bone marrow.
• RAEB-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
• CMML-2, defined as having 10% to 19% myeloblasts in the bone marrow and/or 5% to 19% blasts in the blood.
• CMML-1 (although CMML-1 is defined as having <10% myeloblasts in the bone marrow and/or <5% blasts in the blood, these participants may enroll only if bone marrow blasts >=5%).

8. With MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):

• Very high (>6 points).
• High (>4.5-6 points).
• Intermediate (>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts.

9. With WHO-defined AML at study entry, including leukemia secondary to prior chemotherapy or resulting from an antecedent hematologic disorder, have failed to achieve CR or have relapsed after prior therapy and are not candidates for potentially curative treatment.

10. With relapsed or refractory MDS, have previously been treated with an hypomethylating agent.

11. Laboratory value requirements per study arms are:

• Estimated glomerular filtration rate (eGFR) (milliliter per minute per 1.73 square meter [mL/min/1.73^m]) >=90 (Control arm), <30 (Renal arm) , >=60 (Mild and Moderate hepatic arm).
• Total Bilirubin <= ULN (Control arm), <= ULN (Renal arm), ULN <Bilirubin <=1.5 * ULN (not secondary to transfusions) (Mild hepatic arm) and 1.5 * ULN <bilirubin <=3.0 * ULN (not secondary to transfusions) (Moderate hepatic arm).
• Alanine aminotransferase (ALT) <= ULN (Control arm), <=2.5 * ULN (Renal arm) and any value (for mild and moderate hepatic arm).

For advanced solid tumors:

12. Have a histologically or cytologically confirmed metastatic or locally advanced solid tumor that is appropriate for treatment with pevonedistat in combination with either docetaxel or carboplatin plus paclitaxel in Part B of this study, or have progressed despite standard therapy, or whom conventional therapy is not considered effective.

13. Computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 28 days of the first dose of the study drug.

14. Laboratory value requirements per study arms are:

• eGFR (mL/min/1.73m^2) <30 (Renal arm) and >=60 (mild and moderate hepatic arm).
• Total bilirubin <=ULN (Renal arm), ULN <bilirubin <=1.5 * ULN (Mild hepatic arm) and 1.5 * ULN <bilirubin <=3.0 * ULN (Moderate hepatic arm).
• ALT <=1.5 * ULN (for participants who receive pevonedistat plus docetaxel only) or <=2.5 * ULN (for participants who receive pevonedistat plus carboplatin plus paclitaxel only) (Renal arm) and any value (Mild and Moderate hepatic arm).

Exclusion Criteria

All participants:-

1. With end-stage renal disease requiring hemodialysis.

2. Has Gilbert syndrome.

3. Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. Prophylactic treatment with antibiotics is allowed.

4. Has life-threatening illness unrelated to cancer.

5. Known human immunodeficiency virus (HIV) seropositive.

6. Treatment with strong cytochrome P450 (CYP)3A inducers within 14 days before the first dose of pevonedistat.

7. Has left ventricular ejection fraction (LVEF) <50% within 6 months prior to study enrollment. If a result within this time frame is unavailable, LVEF must be determined by echocardiography or multigated acquisition scan at screening.

8. Has severe uncontrolled ventricular arrhythmias or torsade de pointes; electrocardiographic evidence of acute ischemia or active conduction system abnormalities; or clinically significant arrhythmia (as an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion).

9. Has severe symptomatic pulmonary hypertension requiring pharmacologic therapy or participants with chronic respiratory disease that requires continuous oxygen.

For hematologic malignancies:

10. Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis.

11. With AML with a WBC count >=50,000/mcL. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they otherwise meet the eligibility criteria.

12. With either clinical evidence of or history of central nervous system (CNS) involvement by AML.

13. With hematologic malignancies, PT or aPTT >1.5 * ULN or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment.

For advanced solid tumors:

14. Has prior treatment with radiation therapy involving >=25% of the hematopoietically active bone marrow.

15. Has CNS metastasis, except for participants who have received prior treatment (radiation or resection) and have stable CNS disease (example: stable MRI, no steroid requirement).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Takeda

Locations

Icahn School of Medicine at Mount Sinai

New York, New York, United States

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

ICO lHospitalet Hospital Duran i Reynals

LHospitalet de Llobregat, Barcelona, Spain

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, , Spain

Hospital de San Pedro de Alcantara

Cáceres, , Spain

C.H. Regional Reina Sofia

Córdoba, , Spain

Complejo Asistencial Universitario de Salamanca H. Clinico

Salamanca, , Spain

Hospital Universitario Virgen del Rocio - PPDS

Seville, , Spain

Countries

United States; Spain

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.takeda.com/study-detail/5f6b603a4db2bf003ab4a2d1

To obtain more information on the study, click here/on this link

Other Identifiers

U1111-1220-1396

Identifier Type: OTHER

Identifier Source: secondary_id

2018-004049-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

Pevonedistat-1016

Identifier Type: -

Identifier Source: org_study_id