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

ID#: NCT03814005

Age: 18 years - 66+

Gender: All

Healthy Subjects: No

Study Phase: Phase 1

Recruitment Status: Recruiting

Start Date: July 10, 2019

End Date: April 06, 2021

Contact Information:
Takeda Study Registration Call Center
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.

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
- 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
- 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 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).