Clinical trial NCT03814005: A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Myelodysplastic Syndromes
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid, Acute
Renal Insufficiency
Liver Disease
Neoplasms
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2019-01-23
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

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.

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).

Primary outcomes:
measure: Part A, AUC∞: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Pevonedistat Following a Single Dose
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: 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
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Part A, Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following a Single Dose
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Secondary outcomes:
measure: Parts A and B, t1/2z: Terminal Disposition Phase Half-life for Pevonedistat Following Single and Multiple Dose
timeFrame: 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)
measure: Part B: Cmax: Maximum Observed Plasma Concentration for Pevonedistat Following Multiple Dose
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)
measure: Parts A, fu: Fraction of Unbound Drug in Plasma for Pevonedistat
timeFrame: Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Part B, Cmax: Maximum Observed Plasma Concentration for Azacitidine Following Multiple Dose
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
measure: Part B, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Azacitidine Following Multiple Dose
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
measure: Part B, t1/2z: Terminal Disposition Phase Half-life for Azacitidine Following Multiple-dose
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
measure: Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Pevonedistat Following Multiple Dose
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle length= 28 days)
measure: Part B, AUCτ: Area Under the Concentration-time Curve From Time Zero to the End of the Dosing Interval for Azacitidine Following Multiple Dose
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 7 hours) post-dose (Cycle length= 28 days)
measure: Parts A and B, CL: Total Clearance for Pevonedistat
timeFrame: 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)
measure: Part B, CL/F: Apparent Clearance for Azacitidine
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
measure: Part B, CLR: Renal Clearance for Pevonedistat
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
measure: Part B, CLR: Renal Clearance for Azacitidine
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
measure: Parts A and B, Vss: Volume of Distribution at Steady-state of Pevonedistat
timeFrame: 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)
measure: Part B, Vz/F: Apparent Volume of Distribution of Azacitidine
timeFrame: Cycle 1 Day 3 pre-dose and at multiple time points (up to 8 hours) post-dose (Cycle length= 28 days)
measure: Part B: Percentage of AML Participants With Complete Response/ Remission (CR) or CR With Incomplete Blood Count Recovery (CRi) or Partial Response (PR)
timeFrame: 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)
measure: Part B: Percentage of MDS and CMML Participants With CR, PR or Hematologic Improvement (HI)
timeFrame: 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)
measure: Part B: Percentage of HR MDS and AML Participants With Overall Response
timeFrame: 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)
measure: Part B: Duration of CR, PR and HI
timeFrame: From first documentation of response up to disease progression (up to 2 years 9 months)
measure: Part B: Percentage of Solid Tumors Participants With CR or PR
timeFrame: 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)
Other outcomes:
Locations:
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: LHospitalet de Llobregat
country: Spain
facility: ICO lHospitalet Hospital Duran i Reynals
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Caceres
country: Spain
facility: Hospital de San Pedro de Alcantara
city: Cordoba
country: Spain
facility: C.H. Regional Reina Sofia
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca H. Clinico
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References: