Drug-Drug Interaction Study of TAK-788 and Midazolam in Participants With Advanced Non-small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The purpose of this study is to characterize the effect of repeated oral administration of TAK-788 160 milligram (mg) once daily on the single oral and intravenous dose pharmacokinetics (PK) of midazolam.

Detailed Description
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The drug being tested in this study is called TAK-788. The study will characterize the effect of repeated oral administration of TAK-788 160 mg on the single oral- and intravenous-dose PK of midazolam, and will assess the safety and tolerability of TAK-788 in participants with advanced NSCLC. The study will enroll approximately 26 participants. The study will be conducted in 2 parts: Part A (Cycle 1: PK Cycle) and Part B (Cycle 2 to Cycle 24: Treatment Cycles). In Part A, participants will receive midazolam as an oral dose and intravenous infusion, along with oral dose of TAK-788 in a single 30-day cycle. After completion of Part A, eligible participants may enter Part B. In Part B, participants will continue to receive oral dose of TAK-788 that they were receiving and tolerating at the end of Part A in a 28-day treatment cycle for up to 23 cycles of treatment, or until progressive disease (PD), intolerable toxicity, or another discontinuation criterion is met. Based on the opinion of investigator, if a participant continue to experience clinical benefit, treatment with TAK-788 may be continued after PD. This multi-center trial will be conducted in Australia, Singapore and the Netherlands. The overall time to participate in this study is 3 years. Participants will make multiple visits to the clinic and will be followed up for 30 days after the last dose of study drug for a follow-up assessment.

Official Title
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A Phase 1, Open-Label, Multicenter, Drug-Drug Interaction Study of TAK-788 and Midazolam, a Sensitive CYP3A Substrate, in Patients With Advanced Non-Small Cell Lung Cancer

Conditions
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Lung Neoplasms, Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Midazolam
* Drug: TAK-788


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed locally advanced NSCLC in which the participant is not a candidate for definitive therapy; or, the participant has recurrent or metastatic (Stage IV) disease. Refractory or intolerant to standard available therapies. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. Minimum life expectancy of 3 months or more. Adequate organ function as defined by the following criteria: Total serum bilirubin less than or equal to (<=) 1.5*upper limit of normal (ULN) (<=3*ULN for participants with Gilbert syndrome or if liver function abnormalities are due to underlying malignancy) Alanine aminotransferase and aspartate aminotransferase <=2.5*ULN (or <=5*ULN if liver function abnormalities are due to underlying malignancy) Estimated creatinine clearance greater than or equal to (>=) 30 milliliter per minute (mL/min) (calculated by using the Cockcroft-Gault equation) Serum albumin >= 2 gram/deciliter (g/dL) Serum lipase/amylase <=1.5*ULN; and Serum amylase <=1.5*ULN unless the increased serum amylase is due to salivary isoenzymes. Adequate bone marrow function as defined by the following criteria: Absolute neutrophil count >=1.5*10^9 per liter (/L) Platelet count >=75*10^9/L; and Hemoglobin >=9.0 g/dL. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval with Fridericia's correction (QTcF) of <= 450 millisecond (msec) in males or <= 470 msec in females. (as conducted and interpreted in accordance to local institutional practices and confirmed by principal investigator [PI]). All toxicities from prior anticancer therapy must have resolved to <= Grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 or have resolved to baseline, at the time of first dose of TAK-788. Note: treatment-related Grade 2 or 3 alopecia and treatment-related Grade 2 peripheral neuropathy are allowed if deemed irreversible. Suitable venous access for study-required blood sampling (that is, including for PK, pharmacodynamics, and clinical laboratory tests). Exclusion Criteria: Received a strong or moderate cytochrome P450 3A (CYP3A) inhibitor or strong or moderate CYP3A inducer within 2 weeks prior to the first dose of TAK-788. Received small-molecule anticancer therapy (including but not limited to cytotoxic chemotherapy and investigational agents) within 2 weeks prior to the first dose of TAK-788. Received antineoplastic monoclonal antibodies including check point inhibitors within 28 days of the first dose of TAK-788. Received radiotherapy <=14 days prior to the first dose of TAK-788. However, participants are allowed to receive any of the following treatments up to 7 days prior to the first dose: (a) Stereotactic radiosurgery (SRS) (b) stereotactic body radiation therapy (SBRT) or (c) palliative radiation outside the chest and brain. Major surgery within 28 days prior to the first dose of TAK-788. Minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed. Diagnosed with another primary malignancy other than NSCLC except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or another primary malignancy and is definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy. Have known active brain metastases (have either previously untreated intracranial central nervous system (CNS) metastases or previously treated intracranial CNS metastases with radiologically documented new or progressing CNS lesions). Brain metastases are allowed if they have been treated with surgery and/or radiation and have been stable without requiring corticosteroids to control symptoms within 7 days before the first dose of TAK-788, and have no evidence of new or enlarging brain metastases. Current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic). Have uncontrolled hypertension. Participants with hypertension should be under treatment on study entry to control blood pressure. Significant, uncontrolled, or active cardiovascular disease, including, but not limited to the following: Myocardial infarction within 6 months prior to the first dose of study drug; Unstable angina within 6 months prior to the first dose of study drug; Congestive heart failure within 6 months prior to the first dose of study drug. Cardiac ejection fraction <50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA); History of clinically significant (as determined by the treating physician) atrial arrhythmia; Any history of ventricular arrhythmia; or Cerebrovascular accident or transient ischemic attack within 6 months prior to the first dose of study drug. Treatment with medications known to be associated with the development of torsades de pointes. Gastrointestinal illness or disorder that could affect oral absorption of TAK-788 or midazolam.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Midazolam + TAK-788<br>Midazolam 3 mg, solution, orally, once on Days 1 and 24 and midazolam 1 mg, infusion, intravenously, once on Days 2 and 25 along with TAK-788 160 mg, capsule, orally, once daily from Day 3 through 30 in Cycle 1. | Drug: Midazolam<br>* Midazolam Oral Solution and Midazolam Intravenous Infusion.<br>Drug: TAK-788<br>* TAK-788 Oral Capsules.<br>* Other names: AP32788;|
| Experimental: Part B: TAK-788<br>TAK-788 160 mg, capsules, orally, once daily in a 28-day treatment cycle from Cycle 2 to Cycle 24, or until progressive disease (PD), intolerable toxicity, or another discontinuation criterion is met, whichever is sooner. Eligible participants from Part A may enter into Part B. Based on the investigator's opinion, if a participant continues to experience clinical benefit, treatment with TAK-788 may be continued after PD. | Drug: TAK-788<br>* TAK-788 Oral Capsules.<br>* Other names: AP32788;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: AUC∞: Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for Midazolam |  | Cycle 1: Days 1 and 24 (oral dose) and Days 2 and 25 (intravenous dose) pre-dose and at multiple time points (up to 24 hours) post-dose (cycle length is equal to [=] 30 days) | 
| Part A: Cmax: Maximum Observed Plasma Concentration for Midazolam |  | Cycle 1: Days 1 and 24 (oral dose) and Days 2 and 25 (intravenous dose) pre-dose and at multiple time points (up to 24 hours) post-dose (cycle length = 30 days) | 
| Part A: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Midazolam |  | Cycle 1: Days 1 and 24 (oral dose) and Days 2 and 25 (intravenous dose) pre-dose and at multiple time points (up to 24 hours) post-dose (cycle length = 30 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | From the first dose of study drug through the 30-day follow-up period, for a total time frame of up to approximately 25 months | 
| Number of Participants with Clinically Significant Change From Baseline in Laboratory Values |  | From the first dose of study drug through the 30-day follow-up period, for a total time frame of up to approximately 25 months | 
| Number of Participants with Clinically Significant Change From Baseline in Vital Signs |  | From the first dose of study drug through the 30-day follow-up period, for a total time frame of up to approximately 25 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy