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

NCT03708211 — Phase 1, Completed, 20 participants, Millennium Pharmaceuticals, Inc.
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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

RegistryNCT03708211
StatusCompleted
PhasePhase 1
Study typeInterventional; randomized, crossover, masking: none, other
Enrollment20 (Actual)
SponsorMillennium Pharmaceuticals, Inc. (Industry)
ConditionsNeoplasms, Advanced Solid
InterventionsTAK-931 PIC, TAK-931 Tablet, Esomeprazole (Drug)
Datesstart 2019-03-28, primary completion 2019-12-03, completion 2019-12-03, first posted 2018-10-17, last updated 2020-12-29
Locations4 sites in Netherlands

Related Papers Related Patents Related Grants Related Experts
All trials for Neoplasms, Advanced Solid All trials of TAK-931 PIC All trials of TAK-931 Tablet

-Summary

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.

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+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.

+Arms and interventions

ArmTypeInterventionsDescription
Part1: TAK-931 80 mg PIC + TAK-931 80 mg TabletExperimentalDrug: TAK-931 PIC; Drug: TAK-931 TabletTAK-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.
Part1: TAK-931 80 mg Tablet + TAK-931 80 mg PICExperimentalDrug: TAK-931 PIC; Drug: TAK-931 TabletTAK-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.
Part 2: TAK-931 Fed + TAK-931 Fasted + Esomeprazole 40 mgExperimentalDrug: TAK-931 Tablet; Drug: EsomeprazoleTAK-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.
Part 2: TAK-931 Fasted + TAK-931 Fed + Esomeprazole 40 mgExperimentalDrug: TAK-931 Tablet; Drug: EsomeprazoleTAK-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.
  • TAK-931 PIC (Drug): TAK-931 PICs.
  • TAK-931 Tablet (Drug): TAK-931 Tablets.
  • Esomeprazole (Drug): Esomeprazole Tablets.

+Outcome measures

Primary outcomes

  • 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 outcomes

  • 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) [Baseline up to 8 months]: 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.
  • Part 1: Progression-free Survival (PFS) [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)]: 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).
  • Part 1: Disease Control Rate (DCR) [Baseline up to 8 months]: 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.
  • Part 1: Duration of Response (DOR) [From the date of first documentation of a response to the date of first documentation of PD ( up to 8 months)]: 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.
  • 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 [From the start of the study drug up to Day 30 after the last dose of study drug (up to 8 months)]: 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.
  • 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)]

+Eligibility

Sex: All, ages: 18 Years to any

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.

+Posted results

Participant flow

MilestonePart 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg TabletPart 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC
Started128
Completed00
Not completed128

Outcome results

  • Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-931 Tablets in Reference to PIC (Primary), Geometric mean, nanogram per milliliter (ng/mL): TAK-931 80 mg PIC 251.45 +/- 41.91; TAK-931 80 mg Tablet 270.09 +/- 36.44
  • 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 (Primary), Geometric mean, hour*nanogram per milliliter (h*ng/mL): TAK-931 80 mg PIC 1869.0329 +/- 44.7484; TAK-931 80 mg Tablet 1898.9016 +/- 45.2980
  • Part 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-931 Tablets in Reference to PIC (Primary), Geometric mean, h*ng/mL: TAK-931 80 mg PIC 1901.1447 +/- 44.6999; TAK-931 80 mg Tablet 1925.8648 +/- 45.2966
  • Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-931 as PIC and Tablets (Secondary), Median, hour: TAK-931 80 mg PIC 1.6830 (0.917 to 4.117); TAK-931 80 mg Tablet 1.9830 (0.483 to 4.033)
  • Part 1, CL/F: Oral Clearance for TAK-931 (Secondary), Geometric mean, liter per hour (L/h): TAK-931 80 mg PIC 42.0799 +/- 44.6999; TAK-931 80 mg Tablet 41.5397 +/- 45.2966
  • Part 1, T1/2z: Terminal Disposition Phase Half-life for TAK-931 (Secondary), Geometric mean, hour: TAK-931 80 mg PIC 7.3250 +/- 25.4121; TAK-931 80 mg Tablet 7.3683 +/- 18.6369
  • Part 1: Overall Response Rate (ORR) (Secondary), Number, percentage of participants: Part 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg Tablet 0; Part 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC 0
  • Part 1: Progression-free Survival (PFS) (Secondary), Median, months: Part 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg Tablet 1.9 (1.7 to 2.8); Part 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC 2.0 (1.4 to 3.6)
  • Part 1: Disease Control Rate (DCR) (Secondary), Number, percentage of participants: Part 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg Tablet 18.2; Part 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC 25.0
  • Part 1: Duration of Response (DOR) (Secondary)
  • Part 1: Percentage of Participants With Serious Adverse Events (SAEs), Treatment-emergent Adverse Events (TEAEs), and TEAEs Leading to Discontinuation or Dose Modification (Secondary), Number, percentage of participants: Part 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg Tablet 16.7; Part 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC 25.0
  • Part 1: Percentage of Participants With Grade 3 or Higher TEAEs (Secondary), Number, percentage of participants: Part 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg Tablet 41.7; Part 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC 37.5
  • Part 1: Percentage of Participants With Shift From Baseline Values to Post-baseline Values in Laboratory Parameters (Secondary), Number, percentage of participants: Part 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg Tablet 83.3; Part 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC 87.5

Adverse events

Time frame: TEAEs are adverse events (AE) that started after the first dose of study drug up to 30 days after the last dose of study drug (up to 8 months)

ArmDeathsSerious adverse eventsOther adverse events
Part 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg Tablet0/12 (0.0%)2/12 (16.7%)9/12 (75.0%)
Part 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC1/8 (12.5%)2/8 (25.0%)6/8 (75.0%)

Serious adverse events by term

TermOrgan systemPart 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg TabletPart 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC
IleusGastrointestinal disorders2/120/8
Bundle branch block leftCardiac disorders0/121/8
Rectal cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)0/121/8
Cholecystitis infectiveInfections and infestations1/120/8

Other adverse events by term

TermOrgan systemPart 1, Sequence A: TAK-931 80 mg PIC + TAK-931 80 mg TabletPart 1, Sequence B: TAK-931 80 mg Tablet + TAK-931 80 mg PIC
NauseaGastrointestinal disorders3/124/8
ConstipationGastrointestinal disorders2/124/8
VomitingGastrointestinal disorders2/123/8
DiarrhoeaGastrointestinal disorders1/121/8
Abdominal painGastrointestinal disorders0/121/8
Dry mouthGastrointestinal disorders0/121/8
DyspepsiaGastrointestinal disorders1/120/8
Gastrointestinal disorderGastrointestinal disorders1/120/8
FatigueGeneral disorders6/126/8
Oedema peripheralGeneral disorders0/121/8
AlopeciaSkin and subcutaneous tissue disorders4/122/8
Dry skinSkin and subcutaneous tissue disorders1/120/8
Night sweatsSkin and subcutaneous tissue disorders0/121/8
PruritusSkin and subcutaneous tissue disorders1/120/8
RashSkin and subcutaneous tissue disorders0/121/8
Rash maculo-papularSkin and subcutaneous tissue disorders1/120/8
Weight decreasedInvestigations1/122/8
Aspartate aminotransferase increasedInvestigations0/121/8
Blood creatinine increasedInvestigations1/120/8
Neutrophil count decreasedInvestigations0/121/8
Platelet count decreasedInvestigations0/121/8
Decreased appetiteMetabolism and nutrition disorders0/123/8
HypokalaemiaMetabolism and nutrition disorders0/121/8
HypophosphataemiaMetabolism and nutrition disorders1/120/8
Oral candidiasisInfections and infestations0/121/8
Otitis mediaInfections and infestations1/120/8
PneumoniaInfections and infestations1/120/8
Rash pustularInfections and infestations1/120/8
Back painMusculoskeletal and connective tissue disorders1/121/8
Pain in extremityMusculoskeletal and connective tissue disorders1/121/8
HeadacheNervous system disorders1/121/8
AphasiaNervous system disorders1/120/8
Disturbance in attentionNervous system disorders1/120/8
DizzinessNervous system disorders1/120/8
Facial nerve disorderNervous system disorders1/120/8
Peripheral sensory neuropathyNervous system disorders0/121/8
DyspnoeaRespiratory, thoracic and mediastinal disorders1/121/8
CoughRespiratory, thoracic and mediastinal disorders1/120/8
Oropharyngeal painRespiratory, thoracic and mediastinal disorders1/120/8
Rhinitis allergicRespiratory, thoracic and mediastinal disorders0/121/8
NeutropeniaBlood and lymphatic system disorders1/121/8
AnaemiaBlood and lymphatic system disorders0/121/8
LeukopeniaBlood and lymphatic system disorders1/120/8
Dry eyeEye disorders1/121/8
Hepatic painHepatobiliary disorders1/120/8
Limb injuryInjury, poisoning and procedural complications1/120/8
Chronic kidney diseaseRenal and urinary disorders0/121/8
HypertensionVascular disorders1/120/8

+Locations (4)

FacilityCityCountryStatus
Radboud University Medical Center, Department of Medical OncologyNijmegen, GelderlandNetherlands
Netherlands Cancer Institute - Antoni van Leeuwenhoek, Department of Medical OncologyAmsterdam, North HollandNetherlands
Leiden University Medical Center, Department of Clinical OncologyLeiden, South HollandNetherlands
Erasmus MC Cancer Institute, Department of Internal OncologyRotterdam, South HollandNetherlands

+Publications

  • Results publication: Steeghs N, Pruis M, van Herpen C, Lu V, Redman J, Zhou X. A phase 1 open-label study to assess the relative bioavailability of TAK-931 tablets in reference to powder-in-capsule in patients with advanced solid tumors. Invest New Drugs. 2023 Feb;41(1):53-59. doi: 10.1007/s10637-022-01318-3. Epub 2022 Nov 21. PMID 36409435

+Study documents

+Investigators

  • Medical Director, Study director, Millennium Pharmaceuticals, Inc.

+Funding

NIH grants: 2017