The Effect of Tesetaxel on the QTc Interval and the Effect of Food, Itraconazole, and Rifampin on Tesetaxel Pharmacokinetics in Patients With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is a 3-cohort, multicenter, Phase 1 study of the effect of tesetaxel, an investigational, orally administered taxane, on the corrected QT (QTc) interval and the potential effect of food, a cytochrome P450 (CYP) 3A inhibitor (itraconazole), and a CYP3A inducer (rifampin) on tesetaxel pharmacokinetics (PK) in adult patients with advanced solid tumors.

Detailed Description
-----------------
Cohort 1: Cohort 1 is a 2-period, 2-sequence, crossover study designed to assess the effect of food on the PK of tesetaxel and tesetaxel metabolites. Patients were randomized in a 1:2 ratio to receive tesetaxel on Day 1 of two 21-day cycles under fed and fasting conditions in one of two opposing sequences (Sequence 1A and Sequence 1B). Cohort 2: Cohort 2 is a 2-period, single-sequence, crossover study designed to assess the potential PK drug-drug interaction (DDI) of a strong CYP3A inhibitor (itraconazole) on tesetaxel and tesetaxel metabolites. Patients receive tesetaxel during Cycle 1 followed by a reduced dose of tesetaxel plus itraconazole during Cycle 2. Cohort 3: Cohort 3 is a 2-period, single-sequence, crossover study designed to assess the potential PK DDI of a strong CYP3A inducer (rifampin) on tesetaxel and tesetaxel metabolites. Patients receive tesetaxel during Cycle 1 followed by tesetaxel plus rifampin during Cycle 2. Patients in all cohorts also participate in a study designed to assess the effect of tesetaxel and tesetaxel metabolites on cardiac repolarization as measured by the change from baseline in the QTc interval over the first cycle of treatment. Patients who are tolerating and benefitting from treatment with tesetaxel have the opportunity to continue onto an optional treatment extension.

Official Title
-----------------
An Open-Label Study of the Effect of Tesetaxel on the QTc Interval and the Effect of Food, Itraconazole, and Rifampin on Tesetaxel Pharmacokinetics in Patients With Advanced Solid Tumors

Conditions
-----------------
Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: Tesetaxel
* Drug: Tesetaxel
* Drug: Itraconazole
* Drug: Rifampin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female or male patients at least 18 years of age Histologically or cytologically confirmed solid tumor Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 Adequate cardiac conduction by ECG Adequate bone marrow, hepatic, and renal function Exclusion Criteria: Presence of risk factors for QTc prolongation Presence of neuropathy Grade > 1 Anticancer treatment ≤ 14 days prior to randomization Major surgery ≤ 28 days prior to randomization Less than 2 weeks or 5 plasma half-lives (whichever is greater) since last use of: A moderate or strong inhibitor or inducer of CYP3A A CYP3A substrate with a narrow therapeutic range or that is contraindicated with either itraconazole or rifampin

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1, Sequence 1A: Fed then fasted<br>Cycle 1: Tesetaxel on Day 1 of a 21-day cycle under fed conditions Cycle 2: Tesetaxel on Day 1 of a 21-day cycle under fasted conditions | Drug: Tesetaxel<br>* Tesetaxel orally on Day 1 of a 21-day cycle<br>|
| Experimental: Cohort 1, Sequence 1B: Fasted then fed<br>Cycle 1: Tesetaxel on Day 1 of a 21-day cycle under fasted conditions Cycle 2: Tesetaxel on Day 1 of a 21-day cycle under fed conditions | Drug: Tesetaxel<br>* Tesetaxel orally on Day 1 of a 21-day cycle<br>|
| Experimental: Cohort 2: Tesetaxel plus itraconazole<br>Cycle 1: Tesetaxel on Day 1 of a 21-day cycle Cycle 2: Tesetaxel on Day 1 of a 21-day cycle and itraconazole on Day -3 through Day 14 of a 21-day cycle | Drug: Tesetaxel<br>* Tesetaxel orally on Day 1 of a 21-day cycle<br>Drug: Itraconazole<br>* Itraconazole orally once daily from Day -3 to Day 14 of a 21-day cycle<br>|
| Experimental: Cohort 3: Tesetaxel plus rifampin<br>Cycle 1: Tesetaxel on Day 1 of a 21-day cycle Cycle 2: Tesetaxel on Day 1 of a 21-day cycle and rifampin on Day -6 through Day 14 of a 21-day cycle | Drug: Tesetaxel<br>* Tesetaxel orally on Day 1 of a 21-day cycle<br>Drug: Rifampin<br>* Rifampin orally once daily from Day -6 to Day 14 of a 21-day cycle<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cohorts: The change from baseline in Fridericia's corrected QT (ΔQTcF) interval |  | Approximately 3 weeks | 
| Cohort 1, Sequences 1A and 1B: Maximum observed plasma concentration (Cmax) for tesetaxel under fed and fasted conditions |  | Approximately 6 weeks | 
| Cohort 1, Sequences 1A and 1B: Area under the plasma concentration-time curve from 0 to the last measurable plasma concentration (AUC0-t) for tesetaxel under fed and fasted conditions |  | Approximately 6 weeks | 
| Cohort 2: Cmax for tesetaxel in the presence and absence of itraconazole |  | Approximately 6 weeks | 
| Cohort 2: AUC from 0 to 336 hours (AUC0-336h) for tesetaxel in the presence and absence of itraconazole |  | Approximately 6 weeks | 
| Cohort 3: Cmax for tesetaxel in the presence and absence of rifampin |  | Approximately 6 weeks | 
| Cohort 3: AUC0-336h for tesetaxel in the presence and absence of rifampin |  | Approximately 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cohorts: Cmax for tesetaxel metabolites |  | Approximately 6 weeks | 
| All Cohorts: AUC for tesetaxel metabolites |  | Approximately 6 weeks | 
| All Cohorts: Treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs) |  | Baseline through 30 days after last administration of Study treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
tesetaxel, itraconazole, rifampin, food effect, QTc interval, food-drug interaction, drug-drug interaction, PK, tesetaxel metabolites, advanced solid tumor