Dose-escalating, Safety, Tolerability and PK Study of TAS-119 in Combination With Paclitaxel in Patients With Advanced Solid Tumors

A Phase 1, Open-Label, Non-Randomized, Dose-Escalating Safety, Tolerability and Pharmacokinetic Study of TAS-119 in Combination With Paclitaxel in Patients With Advanced Solid Tumors

The purpose of this study is to determine the safety of TAS-119 and determine the most appropriate dose in combination with Paclitaxel for subsequent studies in patients with advanced solid tumors.

TAS-119 is a novel, selective Aurora A kinase inhibitor, which has previously been demonstrated to enhance the activity of paclitaxel in preclinical studies

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: TAS-119; Drug: Paclitaxel

Detailed Description

Background and rationale for study:

In nonclinical pharmacology studies TAS-119 significantly enhanced the antitumor activity of the microtubule stabilizer paclitaxel and TAS-119 is being developed for use in combination with paclitaxel.

TAS-119 selectively inhibits the kinase inhibitor Aurora A. AurA regulates cell division by controlling the transition from G2 to M phase. Overexpression of AurA is associated with resistance to taxanes.

The study will be conducted in two sequential phases:

Dose Escalation Phase with the purpose to determine the maximum tolerated dose and the recommended Phase 2 dose of TAS-119 given in combination with paclitaxel

An Expansion Phase in which additional patients will be enrolled to further evaluate the safety and preliminary efficacy of the recommended Phase 2 dose of TAS-119 in combination with paclitaxel, during which a subgroup of patients will be evaluated for DDI between paclitaxel and TAS-119 via PK assessment.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital Anschutz Cancer Pavilion
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Division of Oncology Siteman Cancer Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Ingram Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Is a male or female ≥ 18 years of age, that has provided written informed consent.
2. Has histologically or cytologically confirmed advanced, unresectable metastatic solid tumor(s) for which the patients have no available therapy likely to provide clinical benefit, or for which paclitaxel is considered a standard of care.

3. Has adequate organ function as defined by the following criteria:

   • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3.0 × upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastasis, AST (SGOT) and ALT (SGPT) ≤ 5 × ULN.
   • Total serum bilirubin ≤ 1.5 × ULN.
   • Absolute neutrophil count ≥ 1,500/mm3 (excluding measurements obtained within 7 days after administration of granulocyte colony-stimulating factor [G-CSF]).
   • Platelet count ≥ 100,000/mm3 (IU: ≥ 100 × 109/L) (excluding measurements obtained within 7 days after a transfusion of platelets).
   • Hemoglobin ≥ 9.0 g/dL
   • Total serum creatinine ≤ 1.5 × ULN
   • Serum albumin ≥ 3.0 mg/dL.

Exclusion Criteria:

1. Previous inability to tolerate any dose of paclitaxel (i.e., the subject required a paclitaxel dose reduction or discontinuation).
2. Has received any treatments prohibited in this trial within specified time frames
3. Has a serious illness or medical condition(s) that would affect safety or tolerability of the study treatments
4. Has history of Grade 2 or greater peripheral neuropathy during the 3 months prior to enrollment.
5. Has known hypersensitivity to TAS-119 or its components.
6. Has known hypersensitivity to Cremophor® EL, paclitaxel or its components.
7. Is a pregnant or lactating female.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAS-119; TAS-119 tablets, oral, dose-escalating, 28-day cycle. Paclitaxel (90mg/m2) is administered IV in combination with TAS-119 in each of the arms.	Drug: TAS-119; Drug: Paclitaxel; A dose of 90 mg/m2 is used in combination with various doses of TAS-119.; Other Names: Taxol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of TAS-119 in combination with paclitaxel	Standard safety monitoring and grading using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 will be used. The safety and tolerability of TAS-119 will be evaluated by the number and severity of adverse events, vital signs, physical exam, and clinical laboratory assessments.	Safety monitoring will begin at the time of the first dose of TAS-119, and will continue until all patients are discontinued from treatment or until 12 months from the last patient enrolled (up to 3 years).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response according to RECIST guidelines (version 1.1, 2009)	The determination of antitumor efficacy will be based on objective tumor assessments made by the investigator according to RECIST guidelines (version 1.1, 2009).	Computed tomography (CT) scans for tumor imaging will be performed at the end of every 2 treatment cycles (8 weeks) and an average of 4 cycles (16 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the concentration time curve (AUC)	During Dose Escalation Phase PK blood samples will be collected from each arm during Cycle 1 (predose up to 24 hours post-dose). In the Expansion Phase, the first 12 patients (DDI Subgroup) of each arm will undergo PK sampling in Cycle 1 (predose up to 24 hours) and Cycle 2 (predose up to 48 hours post-dose).	During Dose Escalation Phase PK blood samples for determination of TAS-119 PK profile will be collected during Cycle 1. In the Expansion Phase, the first 12 patients (DDI Subgroup) will undergo PK sampling in Cycle 1 and Cycle 2 (up to 31 days).
Maximum Plasma Concentration (Cmax)	During Dose Escalation Phase PK blood samples will be collected from each arm during Cycle 1 (predose up to 24 hours post-dose). In the Expansion Phase, the first 12 patients (DDI Subgroup) of each arm will undergo PK sampling in Cycle 1 (predose up to 24 hours) and Cycle 2 (predose up to 48 hours post-dose).	During Dose Escalation Phase PK blood samples for determination of TAS-119 PK profile will be collected during Cycle 1. In the Expansion Phase, the first 12 patients (DDI Subgroup) will undergo PK sampling in Cycle 1 and Cycle 2 (up to 31 days).
Time of maximum observed serum concentration (Tmax)	During Dose Escalation Phase PK blood samples will be collected from each arm during Cycle 1 (predose up to 24 hours post-dose). In the Expansion Phase, the first 12 patients (DDI Subgroup) of each arm will undergo PK sampling in Cycle 1 (predose up to 24 hours) and Cycle 2 (predose up to 48 hours post-dose).	During Dose Escalation Phase PK blood samples for determination of TAS-119 PK profile will be collected during Cycle 1. In the Expansion Phase, the first 12 patients (DDI Subgroup) will undergo PK sampling in Cycle 1 and Cycle 2 (up to 31 days).

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2014
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 1, 2018

Study Registration Dates

• First Submitted: April 28, 2014
• First Submitted That Met QC Criteria: May 6, 2014
• First Posted (Estimate): May 8, 2014

Study Record Updates

• Last Update Posted (Actual): February 21, 2020
• Last Update Submitted That Met QC Criteria: February 19, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: advanced solid tumors; Paclitaxel; AurA; tumor; Dose Escalation; Taxane; Aurora A kinase inhibitor; TAS-119
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel
• Other Study ID Numbers: TO-TAS-119-101