Phase 1
Completed N=17
A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems
Myelodysplastic Syndromes · Leukemia, Myelomonocytic, Chronic · Leukemia, Myeloid, Acute · Renal insufficiency
Source: ClinicalTrials.gov NCT03814005 ↗
Enrolled (actual)
17
Serious AEs
35.3%
Results posted
Sep 2024
Primary outcomePrimary: Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose — 1168.616; 1293.467; 1050.553 hour*nanogram per milliliter(h*ng/mL)
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose |
1168.616; 1293.467; 1050.553 | — |
| PRIMARY Part A, AUClast: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration for Pevonedistat Following a Single Dose |
1120.759; 1267.523; 1020.344 | — |
| PRIMARY Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose |
262.9; 180.2; 148.9 | — |
| SECONDARY Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose |
6.957; 8.493; 9.612; 8.795; 10.248; 8.98 | — |
| SECONDARY Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose |
74.73; 44.74; 128.00; 141.55; 75.80 | — |
| SECONDARY Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat |
5.800; 7.073; 5.529 | — |
| SECONDARY Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose |
645.4; 918.6; 834.8 | — |
| SECONDARY Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose |
0.325; 0.500; 0.250 | — |
| SECONDARY Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose |
0.706; 1.020; 0.694 | — |
| SECONDARY Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose |
574.168; 396.240; 884.974; 848.866; 431.699 | — |
| SECONDARY Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose |
822.457; 1331.654; 751.448 | — |
| SECONDARY Parts A and B, CL: Total Clearance for Pevonedistat |
32.149; 29.167; 34.476; 32.721; 51.628; 32.361 | — |
| SECONDARY Part B, CL/F: Apparent Clearance for Azacitidine |
171.301; 106.238; 180.744 | — |
| SECONDARY Part B, CLR: Renal Clearance for Pevonedistat |
0.298; 0.492; 0.069; 0.516; 0.062 | — |
| SECONDARY Part B, CLR: Renal Clearance for Azacitidine |
0.909; 0.161; 0.445 | — |
| SECONDARY Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat |
219.288; 293.614; 353.570; 351.749; 729.013; 336.922 | — |
| SECONDARY Part B, Vz/F: Apparent Volume of Distribution of Azacitidine |
190.871; 167.610; 211.139 | — |
| SECONDARY Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR) |
13; 0; 0; 0; 0; 0 | — |
| SECONDARY Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI) |
38; 0; 0; 0; 0; 0 | — |
| SECONDARY Part B: Percentage of HR MDS and AML Participants With Overall Response |
50; 0; 0 | — |
| SECONDARY Part B: Duration of CR, PR and HI |
NA | — |
| SECONDARY Part B: Percentage of Solid Tumors Participants With CR or PR |
— | — |
Eligibility Criteria
Inclusion Criteria
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 =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), =60 (Mild and Moderate hepatic arm).
- Total Bilirubin =60 (mild and moderate hepatic arm).
- Total bilirubin =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).
Data sourced from ClinicalTrials.gov (NCT03814005). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.