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

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung; Lung Neoplasms
• Intervention / Treatment: Drug: Midazolam; Drug: TAK-788

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Victoria
    • Frankston, Victoria, Australia, 3199
      • Peninsula and Southeast Oncology
    • Melbourne, Victoria, Australia, 3004
      • Nucleus Network
• Netherlands
  • Groningen, Netherlands, 9700 RB
    • Universitair Medisch Centrum Groningen
  • Noord-holland
    • Amsterdam, Noord-holland, Netherlands, 1066 CX
      • Netherlands Cancer Institute
• Singapore
  • Singapore, Singapore, 188770
    • Raffles Hospital
  • Singapore, Singapore, 119074
    • The National University Cancer Institute - Singapore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Refractory or intolerant to standard available therapies.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
4. Minimum life expectancy of 3 months or more.

5. 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.

6. 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.
7. 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]).
8. 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.
9. Suitable venous access for study-required blood sampling (that is, including for PK, pharmacodynamics, and clinical laboratory tests).

Exclusion Criteria:

1. 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.
2. 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.
3. Received antineoplastic monoclonal antibodies including check point inhibitors within 28 days of the first dose of TAK-788.
4. 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.
5. 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.
6. 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.
7. 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.
8. Current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
9. Have uncontrolled hypertension. Participants with hypertension should be under treatment on study entry to control blood pressure.

10. 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.
11. Treatment with medications known to be associated with the development of torsades de pointes.
12. Gastrointestinal illness or disorder that could affect oral absorption of TAK-788 or midazolam.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: Midazolam + TAK-788; 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; Midazolam Oral Solution and Midazolam Intravenous Infusion.; Drug: TAK-788; TAK-788 Oral Capsules.; Other Names: AP32788
Experimental: Part B: TAK-788; 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; TAK-788 Oral Capsules.; Other Names: AP32788

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A, Cmax: Geometric Mean Maximum Observed Plasma Concentration (Cmax) for Midazolam Administered Orally With Mobocertinib (Cycle 1 Day 24) and Without Mobocertinib (Cycle 1 Day 1)	As planned, this pharmacokinetic (PK) outcome measure was only assessed in Part A.	Cycle 1: Days 1 and 24 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length is equal to [=] 30 days)
Part A, AUC∞: Geometric Mean Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam Administered Orally With Mobocertinib (Cycle 1 Day 24) and Without Mobocertinib (Cycle 1 Day 1)	As planned, this PK outcome measure was only assessed in Part A.	Cycle 1: Days 1 and 24 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 30 days)
Part A, Cmax: Geometric Mean Maximum Observed Plasma Concentration (Cmax) for Midazolam Administered Intravenously With Mobocertinib (Cycle 1 Day 25) and Without Mobocertinib (Cycle 1 Day 2)	As planned, this PK outcome measure was only assessed in Part A.	Cycle 1: Days 2 and 25 pre-dose and at multiple time points (up to 24 hours) post-dose (Cycle length = 30 days)
Part A, AUC∞: Geometric Mean Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Midazolam Administered Intravenously With Mobocertinib (Cycle 1 Day 25) and Without Mobocertinib (Cycle 1 Day 2)	As planned, this PK outcome measure was only assessed in Part A.	Cycle 1: Days 2 and 25 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 Administered Orally With Mobocertinib (Cycle 1 Day 24) and Without Mobocertinib (Cycle 1 Day 1)	As planned, this PK outcome measure was only assessed in Part A for midazolam 3 mg oral solution.	Cycle 1: Days 1 and 24 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 Administered Intravenously With Mobocertinib (Cycle 1 Day 25) and Without Mobocertinib (Cycle 1 Day 2)	As planned, this PK outcome measure was only assessed in Part A for midazolam 1 mg intravenous infusion.	Cycle 1: Days 2 and 25 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
Part A and B: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)		Part A:From Day 1 up to 30 days after the last dose of study drug in Cycle 1 (up to 2 months);Part B:From Day 1 of Cycle 2 up to 30 days after the last dose of study drug in Cycle 19 (up to Month 19) (Cycle length, Part A= 30 days; Part B=28 days)
Part A and B: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values	The clinically significant change from baseline in laboratory values was assessed by the investigator.	Part A: Day 1 of Cycle 1; Part B: Day 1 of every Cycle (Cycle 2 to Cycle 19) (Cycle length, Part A=30 days; Part B =28 days)
Part A and B: Number of Participants With Clinically Significant Change From Baseline in Vital Signs		Part A: Day 1 up to Day 26 in Cycle 1; Part B: Day 1 of every Cycle (Cycle 2 to Cycle 19) (Cycle length, Part A=30 days; Part B =28 days)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.
• Investigators: Study Director: Study Director, Millennium Pharmaceuticals, Inc.

Publications and helpful links

Helpful Links

• To obtain more information about this study, click this link.

Study record dates

Study Major Dates

• Study Start (Actual): December 23, 2019
• Primary Completion (Actual): December 17, 2020
• Study Completion (Actual): December 7, 2021

Study Registration Dates

• First Submitted: August 5, 2019
• First Submitted That Met QC Criteria: August 8, 2019
• First Posted (Actual): August 9, 2019

Study Record Updates

• Last Update Posted (Actual): April 12, 2024
• Last Update Submitted That Met QC Criteria: October 27, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Protein Kinase Inhibitors; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Tyrosine Kinase Inhibitors; Midazolam; Mobocertinib
• Other Study ID Numbers: TAK-788-1004; 2019-000725-44 (EudraCT Number); U1111-1225-0210 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No