A Study to Assess the Relative Bioavailability, Effect of Food, and Gastric Potential Hydrogen (pH) Modification on the Pharmacokinetics (PK) of TAK-931 in Participants With Advanced Solid Tumors

A Phase 1, Open-Label Study to Assess the Relative Bioavailability, Effect of Food, and Gastric pH Modification on the Pharmacokinetics of TAK-931 in Patients With Advanced Solid Tumors

The purpose of this study is to estimate the relative bioavailability of TAK-931 tablets in reference to powder-in capsule (PIC) and to assess the effect of food and esomeprazole on the pharmacokinetics (PK) of TAK-931 as a tablet.

Study Overview

• Status: Completed
• Conditions: Neoplasms, Advanced Solid
• Intervention / Treatment: Drug: TAK-931 PIC; Drug: TAK-931 Tablet; Drug: Esomeprazole

Detailed Description

The drug being tested in this study is called TAK-931. TAK 931 is being tested to treat participants who have advanced solid tumors. This study will look at relative bioavailability, effect of food and gastric pH modification on the PK of TAK-931.

The study will enroll approximately 44 participants. The study will be conducted in 2 parts: Part 1 and Part 2. In Part 1 and Part 2, participants will be randomly assigned (by chance, like flipping a coin) in a crossover design. In Part 1, participants will be assigned to 1 of the 2 following treatment sequences:

• TAK-931 80 mg PIC + TAK-931 80 mg Tablet
• TAK-931 80 mg Tablet + TAK-931 80 mg PIC

Part 2 of the study will be initiated, once the preliminary PK data from Part 1 is available to determine the relative bioavailability of the tablet formulation in reference to PIC and to calculate the single dose of TAK-931 tablet to be used in Part 2.In Part 2, participants will be assigned to 1 of the 2 following treatment sequences:

• TAK-931 TBD Fed + TAK-931 TBD Fasted
• TAK-931 TBD Fasted + TAK-931 TBD Fed

This multi-center trial will be conducted in the Netherlands. The overall time to participate in this study is approximately 2 years. Participants will make multiple visits to the clinic and will be contacted for approximately 30 days after receiving their last dose of study drug or until the start of subsequent anticancer therapy, whichever occurs first for a follow up assessment.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Radboud university medical center, department of medical oncology
  • Noord-holland
    • Amsterdam, Noord-holland, Netherlands, 1066 CX
      • Netherlands Cancer Institute - Antoni van Leeuwenhoek, Department of Medical Oncology
  • Zuid-holland
    • Leiden, Zuid-holland, Netherlands, 2333 ZA
      • Leiden University Medical Center, Department of Clinical Oncology
    • Rotterdam, Zuid-holland, Netherlands, 3015 GD
      • Erasmus MC Cancer Institute, Department of Internal Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult participants with histologically or cytologically confirmed metastatic or locally advanced or metastatic solid tumors for whom there is no available standard treatment with proven survival benefit, this therapy is not indicated, or it is refused by the participant. Based on the nonclinical data, the following indications may have a higher probability of clinical benefit: high-grade serous ovarian cancer, uterine carcinosarcoma, squamous esophageal cancer, squamous non-small cell lung carcinoma (NSCLC), rectal adenocarcinoma, and in general tumors with known tumor protein 53 (TP53) gene mutations. For any of these preferred indications, participants should have exhausted standard therapeutic options with a proven survival benefit.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Recovered to Grade 1 or baseline from all toxic effects of previous therapy (except alopecia or neuropathy).
4. Suitable venous access for the study-required blood sampling including PK and pharmacodynamic sampling.
5. Must have a radiographically or clinically evaluable tumor, but measurable disease as defined by RECIST v1.1 is not required for participation in this study.

Exclusion Criteria:

1. Participants who require continuous use of proton pump inhibitors (PPIs) or histamine-2 (H2) receptor antagonists and participants who are taking PPIs within 5 days before the first dose of study drug.
2. Treatment with clinically significant enzyme inducers, such as phenytoin, carbamazepine, enzalutamide, mitotane, ritonavir, rifampin, or St John's wort within 14 days before the first dose of study drug.
3. With treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system-directed treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or CT) during the screening period.
4. Part 2 only: known hypersensitivity to PPIs (example, angioedema or anaphylaxis have occurred).
5. Part 2 only: not being able or willing to take one high fat breakfast as indicated in the protocol.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part1: TAK-931 80 mg PIC + TAK-931 80 mg Tablet; TAK-931 80 milligram (mg), PIC, orally, once on Day 1 Cycle 0 (16-day treatment cycle), followed by TAK-931 80 mg, tablet, orally, once on Day 3 Cycle 0, further followed by TAK-931 50 mg, PIC, orally, once daily from Day 5 to Day 16 Cycle 0. Participants will receive TAK-931 50 mg PIC, orally, once daily for up to 14 days in 21-day treatment cycles until progressive disease (PD), or unacceptable toxicity or any treatment discontinuation is determined.	Drug: TAK-931 PIC; TAK-931 PICs.; Drug: TAK-931 Tablet; TAK-931 Tablets.
Experimental: Part1: TAK-931 80 mg Tablet + TAK-931 80 mg PIC; TAK-931 80 mg, tablet, orally, once on Day 1 of Cycle 0 (16-day treatment cycle), followed by TAK-931 80 mg, PIC, orally, once on Day 3 Cycle 0, further followed by TAK-931 50 mg, PIC, orally, once daily from Day 5 to Day 16 Cycle 0. Participants will receive TAK-931 50 mg PIC, orally, once daily for up to 14 days in 21-day treatment cycles until PD, or unacceptable toxicity or any treatment discontinuation is determined.	Drug: TAK-931 PIC; TAK-931 PICs.; Drug: TAK-931 Tablet; TAK-931 Tablets.
Experimental: Part 2: TAK-931 Fed + TAK-931 Fasted + Esomeprazole 40 mg; TAK-931 tablet, orally, once under fed state on Day 1 Cycle 0 (22-day treatment cycle), followed by TAK-931 tablet, orally, once under fasted state on Day 3 Cycle 0, further followed by esomeprazole 40 mg, tablet, orally, once daily from Day 5 to Day 13 Cycle 0 and TAK-931 tablet, orally, once on Day 12, Day 14 to Day 22. Participants will receive TAK-931 tablets, orally, once daily for up to 14 days in 21-day treatment cycles until PD, unacceptable toxicity or any treatment discontinuation is determined. Dose of TAK-931 in Part 2 will be determined based on relative bioavailability data available from Part 1 of the study.	Drug: TAK-931 Tablet; TAK-931 Tablets.; Drug: Esomeprazole; Esomeprazole Tablets.
Experimental: Part 2: TAK-931 Fasted + TAK-931 Fed + Esomeprazole 40 mg; TAK-931 tablet, orally, once under fasted state on Day 1 Cycle 0 (22-day treatment cycle), followed by TAK-931 tablet, orally, once under fed state on Day 3 Cycle 0, further followed by esomeprazole 40 mg, tablet, orally, once daily from Day 5 to Day 13 Cycle 0 and TAK-931 tablet, orally, once on Day 12, Day 14 to Day 22. Participants will receive TAK-931 tablets, orally, once daily for up to 14 days in 21-day treatment cycles until PD, unacceptable toxicity or any treatment discontinuation is determined. Dose of TAK-931 in Part 2 will be determined based on relative bioavailability data available from Part 1 of the study.	Drug: TAK-931 Tablet; TAK-931 Tablets.; Drug: Esomeprazole; Esomeprazole Tablets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-931 Tablets in Reference to PIC	Cycle 0 Days 1 and 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle 0 length is equal to [=] 16 days)
Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-931 Tablets in Reference to PIC	Cycle 0 Days 1 and 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle 0 length = 16 days)
Part 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-931 Tablets in Reference to PIC	Cycle 0 Days 1 and 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle 0 length = 16 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-931 as PIC and Tablets		Cycle 0 Days 1 and 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle 0 length = 16 days)
Part 1, CL/F: Oral Clearance for TAK-931		Cycle 0 Days 1 and 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle 0 length = 16 days)
Part 1, T1/2z: Terminal Disposition Phase Half-life for TAK-931		Cycle 0 Days 1 and 3 pre-dose and at multiple time points (up to 48 hours) post-dose (Cycle 0 length = 16 days)
Part 1: Overall Response Rate (ORR)	ORR was defined as the percentage of participants achieving complete response (CR) and partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), CR was defined as disappearance of all lesions, PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of lesions, taking as reference the baseline sum LD.	Baseline up to 8 months
Part 1: Progression-free Survival (PFS)	PFS was defined as the time from the date of randomization to the date of first documentation of PD or death due to any cause, whichever occured first. Per RECIST V1.1, PD was defined as at least a 20% increase in the SoD (Sum of Diameters) of target lesions, taking as a reference the smallest (nadir) SoD since (and including) baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 millimeter (mm).	From the date of randomization to the date of first documentation of PD or death due to any cause, whichever occurred first (up to 8 months)
Part 1: Disease Control Rate (DCR)	DCR was defined as the percentage of participants with CR, PR plus stable disease (SD) greater than or equal to (>=) 1 post baseline computed tomography (CT) scan evaluation from treatment initiation to qualify for DCR. Per RECIST v 1.1, CR was defined as disappearance of all lesions. PR was defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD. PD was defined as at least a 20% increase in the SoD of target lesions, taking as a reference the smallest (nadir) SoD since (and including) baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.	Baseline up to 8 months
Part 1: Duration of Response (DOR)	DOR was defined as the time from the date of first documentation of a response to the date of first documentation of PD. Per RECIST v1.1, CR was defined as disappearance of all lesions, PR was defined as at least a 30% decrease in the sum of the LD of lesions, taking as reference the baseline sum LD. PD was defined as at least a 20% increase in the SoD of target lesions, taking as a reference the smallest (nadir) SoD since (and including) baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 mm.	From the date of first documentation of a response to the date of first documentation of PD ( up to 8 months)
Part 1: Percentage of Participants With Serious Adverse Events (SAEs), Treatment-emergent Adverse Events (TEAEs), and TEAEs Leading to Discontinuation or Dose Modification		From the start of the study drug up to Day 30 after the last dose of study drug (up to 8 months)
Part 1: Percentage of Participants With Grade 3 or Higher TEAEs	An AE was defined as any untoward medical occurrence in a participant who has enrolled in a study; it does not necessarily have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) was defined as an adverse event with an onset that occurs after receiving study drug. A severity grade was defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. As per NCI-CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.	From the start of the study drug up to Day 30 after the last dose of study drug (up to 8 months)
Part 1: Percentage of Participants With Shift From Baseline Values to Post-baseline Values in Laboratory Parameters		From the start of the study drug up to Day 30 after the last dose of study drug (up to 8 months)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2019
• Primary Completion (Actual): December 3, 2019
• Study Completion (Actual): December 3, 2019

Study Registration Dates

• First Submitted: October 12, 2018
• First Submitted That Met QC Criteria: October 12, 2018
• First Posted (Actual): October 17, 2018

Study Record Updates

• Last Update Posted (Actual): December 29, 2020
• Last Update Submitted That Met QC Criteria: December 2, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Esomeprazole
• Other Study ID Numbers: TAK-931-1003; 2017-004629-34 (EudraCT Number); U1111-1214-4266 (Registry Identifier: WHO); NL66709.091.18 (Registry Identifier: Netherlands (CCMO))

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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (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