Clinical trial NCT03330106: A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors
Official title: A Randomized, Crossover Phase 1 Study to Evaluate the Effects of Pevonedistat on the QTc Interval in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Neoplasm
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2017-11-06
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: The purpose of this study is to characterize the effects of 25 and 50 milligram per square meter (mg/m\^2) pevonedistat on the Fridericia corrected QT interval (QTcF) of the electrocardiogram (ECG).

Detailed description: The drug being tested in this study is called pevonedistat. Pevonedistat in combination with standard of care will be used to treat participants who have advanced solid tumors. This study will assess the effects of pevonedistat on the QTc interval in participants with advanced solid tumors.

The study will enroll approximately 45 participants. The study will be conducted in two Parts: Part A and Part B. Part A will have a 2-way crossover design and will involve the collection of triplicate ECGs. In Part A, participants will be randomly assigned to one of the two treatment groups as follow:

* Pevonedistat 25 mg/m\^2 + Pevonedistat 50 mg/m\^2
* Pevonedistat 50 mg/m\^2 + Pevonedistat 25 mg/m\^2

Eligible participants from Part A will continue treatment in optional Part B with pevonedistat in combination with SoC, docetaxel or carboplatin plus paclitaxel. The investigator will decide which pevonedistat combination a participant will receive.

* Pevonedistat 25 mg/m\^2 + Docetaxel
* Pevonedistat 20 mg/m\^2 + Carboplatin + Paclitaxel

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 9.6 months. Participants will make a final visit to the clinic 30 days after receiving their last dose of study drug for a follow-up assessment.

Eligibility criteria: Inclusion Criteria:

1. Participants must have a histologically or cytologically confirmed metastatic or locally advanced solid tumor(s) appropriate for treatment with one of the 2 combination therapies in Part B of this study, have progressed despite standard therapy, or for whom conventional therapy is not considered effective.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Expected survival longer than 3 months from enrollment in the study.
4. Recovered (that is, grade less than or equal to \[\<=\] 1 toxicity) from the reversible effects of prior anticancer therapy.
5. Suitable venous access for the study-required blood sampling (including pharmacokinetic \[PK\] sampling).

Exclusion Criteria:

1. Treatment with strong cytochrome P3A (CYP3A) inducers within 14 days before the first dose of pevonedistat. Participants must have no history of amiodarone use within 6 months before the first dose of pevonedistat nor require the use of these medications during the study.
2. Treatment with QT-prolonging drugs with a risk of causing torsades de pointes (TdP. Participants taking drugs with a possible or conditional risk of QT prolongation or drugs that are to be avoided by participants with congenital long QT syndrome may be considered if on a stable dose, pending discussion and agreement between the investigator and the sponsor.
3. History of Brugada syndrome, risk factors for TdP, or family history of long QT syndrome.
4. Implantable cardioverter defibrillator.
5. Cardiac pacemaker with heart rate (HR) set at a fixed rate and treatment with concomitant medication that may limit increase in HR in response to hypotension (example, high-dose beta blocker).
6. Known moderate to severe aortic stenosis, moderate to severe mitral stenosis, or other valvulopathy (ongoing).
7. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.

Entry Criteria for Continuation to Optional Part B:

After completing Part A of the study, participants may choose to enter the optional Part B of the study. To be eligible for the optional Part B, participants must have completed Part A and be reassessed to determine if they meet the entry criteria for optional Part B. Only participants who meet the following criteria may enter into Part B:

* ECOG performance status of 0 to 1.
* Absolute neutrophil count (ANC) greater than or equal to (\>=) 1500 per cubic millimeter (/mm\^3).
* Platelet count \>=100,000/mm\^3.
* Laboratory values for hemoglobin, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and serum creatinine or calculated/measured creatinine clearance.
* Diarrhea symptoms resolved to Grade 1 or better.
* QTc interval \<480 millisecond (msec).
* Computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis within 28 days of Cycle 1 Day 1.

Primary outcomes:
measure: Part A: Change From Time-matched Baseline in Fridericia-corrected QT Interval (QTcF) After Pevonedistat Administration
timeFrame: Baseline up to Day 8
Secondary outcomes:
measure: Part A: Change From Time-matched Baseline in Individual Corrected QT Interval (QTcI) After Pevonedistat Administration
timeFrame: Predose, and at multiple time points up to 24 hours post dose on Day 1 or Day 8 in Part A
measure: Part A: Change From Time-matched Baseline in QRS After Pevonedistat Administration
timeFrame: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
measure: Part A: Change From Time-matched Baseline in PR After Pevonedistat Administration
timeFrame: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
measure: Part A: Change From Time-matched Baseline in Heart Rate (HR) After Pevonedistat Administration
timeFrame: Predose, and at multiple time points post dose up to 24 hours on Day 1 or Day 8 in Part A
measure: Part A: Cmax: Maximum Observed Plasma Concentration for Pevonedistat
timeFrame: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
measure: Part A: AUC(0-24): Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Postdose for Pevonedistat
timeFrame: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
measure: Part A: Terminal Phase Elimination Half-life (t1/2) for Pevonedistat
timeFrame: Days 1 or 8 predose and at multiple time points (up to 24 hours) post dose in Part A
measure: Part B: Overall Response Rate (ORR)
timeFrame: Up to Cycle 45 (end of treatment) (Cycle length=21 days)
Other outcomes:
Locations:
city: Santa Monica
country: United States
facility: Sarcoma Oncology Center
state: California
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Dallas
country: United States
facility: Mary Crowley Medical Research
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Zhou X, Richardson DL, Dowlati A, Goel S, Sahebjam S, Strauss J, Chawla S, Wang D, Mould DR, Samnotra V, Faller DV, Venkatakrishnan K, Gupta N. Effect of Pevonedistat, an Investigational NEDD8-Activating Enzyme Inhibitor, on the QTc Interval in Patients With Advanced Solid Tumors. Clin Pharmacol Drug Dev. 2023 Mar;12(3):257-266. doi: 10.1002/cpdd.1194. Epub 2022 Nov 16.