Study of a Tankyrase Inhibitor RK-582 for Patients With Unresectable Metastatic Colorectal Cancer

Investigator-initiated Phase I Study of a Tankyrase Inhibitor RK-582 for Patients With Unresectable Metastatic Colorectal Cancer

Tankyrase, the fifth and sixth members of the poly(ADP-ribose) polymerase (PARP) family (PARP-5a/b), is responsible for poly(ADP-ribosyl)ation (PARylation), and was originally identified as a factor that promotes the function of telomerase, an enzyme that elongates telomeres. Subsequently, it was reported that tankyrase enhances Wnt/beta-catenin signaling by PARylation and subsequent degradation of AXIN, a negative regulator of Wnt/beta-catenin signaling, suggesting that tankyrase inhibitors may be a new treatment for colorectal cancer.

RK-582 was discovered through lead optimization from a tankyrase inhibitor that suppresses the growth of human colorectal cancer cells. It was confirmed that RK-582 selectively inhibited tankyrase among the PARP family enzymes, suppressed the growth of Wnt/beta-catenin signal-dependent human colorectal cancer cells at both the levels of cultured cells and xenograft tumors in immunodeficient mice, and accumulated AXIN to decrease beta-catenin and downregulate the target gene expression as pharmacodynamic biomarkers.

Based on these findings, RK-582 is thought to have potential as a new treatment for colorectal cancer patients. At present, however, the efficacy and safety of RK-582 in humans have not been confirmed. Thus, this clinical trial is conducted with the aim of investigating the tolerability and safety of RK-582 for patients with unresectable advanced or recurrent colorectal cancer as a first-in-human trial, in which RK-582 is administered to humans for the first time.

Study Overview

• Status: Recruiting
• Conditions: Unresectable Colorectal Neoplasm Metastasis
• Intervention / Treatment: Drug: RK-582

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Eiji Shinozaki; Phone Number: +81-3-3520-0111; Email: eiji.shinozaki@jfcr.or.jp

Study Locations

• Japan
  • Tokyo
    • Koto-ku, Tokyo, Japan, 135-8550
      • Recruiting
      • Cancer Institute Hospital of Jfcr
      • Contact: Eiji Shinozaki; Phone Number: +81-3-3520-0111; Email: eiji.shinozaki@jfcr.or.jp

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with histologically or cytologically diagnosed colorectal cancer
• Patients who are refractory or intolerant to standard treatment for unresectable advanced or recurrent colorectal cancer
• Patients with measurable disease according to RECIST guideline ver 1.1
• Patients who are able to take capsules orally

Exclusion Criteria:

• Patients with clinically relevant gastrointestinal, hepatic, musculoskeletal, respiratory, cerebral/cardiovascular, hematologic, oncologic, endocrine, immunologic, psychiatric, neurologic, or genitourinary diseases, or patients with conditions that are judged to threaten the safety of the participant or to affect the outcome of this clinical trial by the investigators
• Patients with medical history of interstitial lung disease
• Patients with chronic nausea, vomiting or diarrhea that may interfere with oral administration of the investigational drug
• Patients with pulmonary embolism or central deep vein thrombosis.
• Patients receiving treatment with strong CYP3A4 inhibitors or inducers.
• Patients diagnosed and treated for osteoporosis or patients with a bone mineral density of less than T-score -2.5 at the time of screening
• Patients with obvious bone metastases in the long bones, vertebrae, or other parts of the leg where gravity is applied

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: RK-582

Drug: RK-582; Dosing Frequency: Do single dose of RK-582 at the dose level specified for the cohort. Seven days after the first dose, Start repeated daily dose and continue until discontinuation criteria were met. Dose level per dose: Dose Level 1: 5 mg BID Dose level 2: 10 mg QD Dose level 3: 20 mg QD Dose level 4: 40 mg QD Dose Level 5: 60 mg QD Dose Level 6: 80 mg QD Dose Level 7: 100 mg QD Dose Level 8: 200 mg QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of dose-limiting toxicity	35 days after the first dose of RK-582
Number of participants with adverse events as assessed by CTCAE v5.0	Approximately 1 year after the first dose of RK-582

Secondary Outcome Measures

Outcome Measure	Time Frame
Area under the curve (AUC) after single or repeated dosing	22 days after the first dose of RK-582
Maximum plasma concentration (Cmax) after single or repeated dosing	22 days after the first dose of RK-582
Maximum concentration time (Tmax) after single or repeated dosing	22 days after the first dose of RK-582
Elimination rate constant (kel) after single or repeated dosing	22 days after the first dose of RK-582
Elimination half-life (t1/2) after single or repeated dosing	22 days after the first dose of RK-582
Apparent total body clearance (CLtot/F) after single or repeated dosing	22 days after the first dose of RK-582
Apparent volume of distribution (Vd/F) after single or repeated dosing	22 days after the first dose of RK-582
Objective response rate based on investigator's judgment as assessed by RECIST guideline ver. 1.1	Approximately 1 year after the first dose of RK-582
Percentage of subjects who achieved a complete or partial response on the best overall response as assessed by RECIST guideline ver. 1.1	Approximately 1 year after the first dose of RK-582
Duration of response as assessed by RECIST guideline ver. 1.1	Approximately 1 year after the first dose of RK-582
Disease control rate as assessed by RECIST guideline ver. 1.1	Approximately 1 year after the first dose of RK-582
Time to response as assessed by RECIST guideline ver. 1.1	Approximately 1 year after the first dose of RK-582
Progression-free survival as assessed by RECIST guideline ver. 1.1	Approximately 1 year after the first dose of RK-582
Overall survival	Approximately 30 months after the first dose of RK-582

Collaborators and Investigators

• Sponsor: Eiji Shinozaki
• Collaborators: Japan Agency for Medical Research and Development
• Investigators: Study Chair: Kensei Yamaguchi, Cancer Institute Hospital of Jfcr

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2025
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: February 25, 2025
• First Submitted That Met QC Criteria: February 28, 2025
• First Posted (Actual): March 3, 2025

Study Record Updates

• Last Update Posted (Actual): July 29, 2025
• Last Update Submitted That Met QC Criteria: July 25, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: colorectal cancer; colorectal neoplasm; tankyrase inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis
• Other Study ID Numbers: RK582CRCPI; jRCT2031240702 (Registry Identifier: Japan Registy of Clinical Trials)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No