Study of TAS3681 in Metastatic Castration Resistant Prostate Cancer

A Phase 1, Open-Label, Non-Randomized, Safety, Tolerability and Pharmacokinetic Study of TAS3681 in Patients With Metastatic Castration Resistant Prostate Cancer

The purpose of this trial is to investigate the safety and tolerability of TAS3681, to find the maximum tolerated dose (MTD)/recommended dose of TAS3681 (Escalation Phase) and to further evaluate safety and preliminary efficacy of TAS3681 at the MTD/recommended dose (Expansion Phase).

Study Overview

• Status: Completed
• Conditions: Metastatic Castration Resistant Prostate Cancer
• Intervention / Treatment: Drug: TAS3681

Detailed Description

This is a first in human, multinational, Phase 1, open-label study of TAS3681 evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) for which there is no standard therapy. Eligible participants will be enrolled to evaluate safety and determine the MTD/recommended dose for TAS3681, including a preliminary evaluation of food effect and antitumor activity. The study will be conducted in 2 parts, Dose Escalation (Enrollment closed) and Expansion (Enrollment Closed). Patients who are continuing to receive clinical benefit may receive drug in the extension part of the study after escalation and expansion are completed.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Lyon, France, 69008
    • Centre Leon Berard
  • Lyon, France
    • Hospices Civils de Lyon
  • Marseille, France, 13273
    • Institut Paoli Calmettes
  • Montpellier, France, 34298
    • Institut régional du Cancer de Montpellier - ICM Val d'Aurelle
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75015
    • HEGP- Hôpital Européen Georges Pompidou
  • Rennes, France, 35042
    • Centre Eugenie Marquis
  • Suresnes, France, 92151
    • Hopital Foch
  • Villejuif Cedex, France, 94805
    • Gustave Roussy
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Barcelona, Spain, 08908
    • Institut Catala d Oncologia - L Hospitalet de Llobregat
  • Castellana, Spain, 12002
    • Hospital Provincial de Castellon
  • Madrid, Spain, 28034
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
  • Sabadell, Spain, 08208
    • Hospital Universitari Parc Tauli
  • Santander, Spain, 39008
    • Hospital Marques de Valdecilla
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Foundation
  • England
    • London, England, United Kingdom
      • Sarah Cannon Research Institute UK
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust- The Christie Clinic
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital (RMH) NHS Foundation Trust (DDU)
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital (RMH) NHS Foundation Trust
• United States
  • California
    • Sacramento, California, United States, 95817
      • Univeristy of California Davis Comprehensive Cancer Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists & Research Institute
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Greenebaum Cancer Center
  • Missouri
    • Jackson, Missouri, United States, 39213
      • UMMC-Cancer Center and Research Institute
  • Nebraska
    • Omaha, Nebraska, United States, 68130
      • GU Research Network / Urology Cancer Center
  • New Jersey
    • Edison, New Jersey, United States, 08837
      • Premier Oncology Group
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10065
      • MSKCC
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin-Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male ≥18 years of age

2. Histological or cytological evidence of metastatic castrate resistant prostate cancer (excluding neuroendocrine differentiation and small cell histology) who are castration resistant and have:

   1. Dose escalation: documented progression defined in PCWG3 and/or intolerance to abiraterone and/or enzalutamide therapy, as well as 1 or more chemotherapies.
   2. Expansion:

   I. Group A: documented progression after abiraterone or enzalutamide and chemotherapy consisting of no more than 2 prior taxane-based therapies

   ii. Group B: documented progression after only abiraterone or enzalutamide therapy without any chemotherapy

   iii. Measurable disease per RECIST 1.1 and/or bone metastases

3. ECOG performance status of ≤1 on Day 1 Cycle 1
4. Ongoing androgen deprivation with serum testosterone <50 ng/dL
5. Expansion Phase only: willingness to undergo baseline core biopsies, if feasible
6. Ability to take medication orally
7. Adequate organ function
8. Agree to use effective contraception during the study and for 30 days after the last dose of TAS3681
9. Willing to comply with scheduled visits and procedures

Exclusion Criteria:

1. QTcF ≥ 450 ms, history of QTc prolongation or predisposition for QTc prolongation or family history of sudden cardiac death or QT prolongation
2. History or presence of heart failure or left ventricular dysfunction with ejection fraction <40% within the previous 6 months; if >6 months cardiac function within normal limits and free of cardiac-related symptoms
3. History or presence of atrial fibrillation, atrial flutter, or paroxysmal supraventricular tachycardia; the presence or history of ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia
4. Presence of cardiac pacemaker or implantable cardioverter-defibrillator
5. History or presence of bradycardia or conduction abnormalities
6. History or presence of cardiac arrest or unexplained syncope
7. Hypokalemia
8. History of myocardial infarction or severe unstable angina
9. Any medication administered within 2 weeks prior to 1st dose of TAS3681 that is known to prolong the QT interval or be arrhythmogenic
10. Received G-CSF, radiotherapy for extended field, anticancer chemotherapy, investigational agents, or major surgery within 4 weeks of study drug administration; receipt of anticoagulant or CYP3A inhibitor within 2 weeks of study drug administration
11. Serious illness or medical condition that could affect the safety or tolerability of study treatments
12. Received prior treatment with TAS3681
13. User of herbal products
14. Any condition or reason that in the opinion of the investigator, interferes with the ability of the participant to participate in the trial
15. To be eligible to participate in the food effect assessment (Escalation Phase only), participants must not have a history or presence of any clinically significant abnormality involving the gastrointestinal tract and an inability to fast for a minimum of 8 hours

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TAS3681; All participants will receive TAS3681 in 28-day cycles. The Escalation phase includes participants who have progressed after abiraterone, enzalutamide and chemotherapy. Eleven dose escalation cohorts are planned, one of which includes a preliminary assessment of food effect. The MTD/recommended dose for further development will be used for participants in the Expansion Phase. The Expansion Phase will enroll participants who have progressed after abiraterone or enzalutamide with chemotherapy consisting of no more than 2 prior taxane-based therapies (Group A) or without any chemotherapy (Group B). Participants receive TAS3681 until discontinuation criteria are met.

Drug: TAS3681; TAS3681 will be provided as 100 mg tablets to be administered orally in 28-day cycles. The number of cycles is approximately 6, or until discontinuation criteria is met.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with dose-limiting toxicities		Through 1 month
Escalation Phase: Number of patients with treatment-emergent adverse events and significant ECG abnormalities	Based on treatment-emergent adverse events, serious adverse events (SAEs), clinical laboratory tests, vital signs, 12-lead electrocardiograms (ECGs)	Through 6 months (or until patient discontinuation)
Expansion Phase: Overall Response Rate (ORR)	ORR based on investigator-assessed radiographic response per PCWG3/modified RECIST 1.1	Through 6 months (or until patient discontinuation)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Escalation Phase: Prostate Specific Antigen (PSA) response		Up to 6 months (or until patient discontinuation)
Escalation Phase: Time to PSA progression		Up to 6 months (or until patient discontinuation)
Escalation Phase: Maximum concentration of TAS3681 in plasma		Through Day 15 in Cycle 1 (each cycle is 28 days)
Escalation Phase: Time to reach maximum concentration of TAS3681		At Day 15 in Cycle 1 (each cycle is 28 days)
Escalation Phase: Area under the concentration-time curve of TAS3681		Through Day 15 in Cycle 1 (each cycle is 28 days)
Escalation Phase: Terminal half-life time of TAS3681		Through Day 15 in Cycle 1 (each cycle is 28 days)
Escalation Phase: Accumulation ratio of TAS3681		Through Day 15 in Cycle 1 (each cycle is 28 days)
Escalation Phase: Tumor response per PCWG3/RECIST 1.1 including ORR, and duration of response (DOR)		Through 6 months ( or until patient discontinuation)
Expansion Phase: Prostate Specific Antigen (PSA) response		Up to 6 months (or until patient discontinuation)
Expansion Phase: Number of patients with treatment-emergent adverse events and significant ECG abnormalities	Based on treatment-emergent adverse events, serious adverse events (SAEs), clinical laboratory tests, vital signs, 12-lead ECGs	Through 6 months (or until patient discontinuation)
Expansion Phase: Maximum concentration of TAS3681 in plasma		Through Day 15 during Cycle 1 (each cycle is 28 days)
Expansion Phase: Time to reach maximum concentration of TAS3681		Through Day 15 during Cycle 1 (each cycle is 28 days)
Expansion Phase: Area under the concentration-time curve of TAS3681		Through Day 15 during Cycle 1 (each cycle is 28 days)
Expansion Phase: Terminal half-life time of TAS3681		Through Day 15 of Cycle 1 (each cycle is 28 days)
Expansion:Tumor response measures including duration of response (DOR), radiologic progression-free survival (rPFS), overall survival (OS), clinical benefit rate (CBR; percentage of participants with complete response, partial response or stable disease)		Through 6 months (or until patient discontinuation)

Other Outcome Measures

Outcome Measure	Time Frame
Change from baseline in Circulating Tumor Cell (CTC) number in blood	Baseline, end of week 4, at the end of every 12 weeks, and end of every 12 weeks through study completion, an average of 6 months
Number of patients with AR-v7 positivity in circulating tumor cells	Baseline
Severity and impact of pain on daily function using Brief Pain Inventory - Short Form (BPI-SF).	Through 6 months (or until patient discontinuation)

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): August 9, 2022
• Study Completion (Actual): April 26, 2024

Study Registration Dates

• First Submitted: September 25, 2015
• First Submitted That Met QC Criteria: September 30, 2015
• First Posted (Estimated): October 2, 2015

Study Record Updates

• Last Update Posted (Actual): September 3, 2024
• Last Update Submitted That Met QC Criteria: August 30, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Prostate Cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms
• Other Study ID Numbers: TO-TAS3681-101; 2015-002745-55 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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