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

Official title

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

Overview

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.

Interventions

• 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

Primary outcome measures

• Percentage of dose-limiting toxicity [Time frame: 35 days after the first dose of RK-582]
• Number of participants with adverse events as assessed by CTCAE v5.0 [Time frame: Approximately 1 year after the first dose of RK-582]

Secondary outcome measures (12)

• Area under the curve (AUC) after single or repeated dosing [Time frame: 22 days after the first dose of RK-582]
• Maximum plasma concentration (Cmax) after single or repeated dosing [Time frame: 22 days after the first dose of RK-582]
• Maximum concentration time (Tmax) after single or repeated dosing [Time frame: 22 days after the first dose of RK-582]
• Elimination rate constant (kel) after single or repeated dosing [Time frame: 22 days after the first dose of RK-582]
• Elimination half-life (t1/2) after single or repeated dosing [Time frame: 22 days after the first dose of RK-582]
• Apparent total body clearance (CLtot/F) after single or repeated dosing [Time frame: 22 days after the first dose of RK-582]
• Apparent volume of distribution (Vd/F) after single or repeated dosing [Time frame: 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 [Time frame: 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 [Time frame: Approximately 1 year after the first dose of RK-582]
• Duration of response as assessed by RECIST guideline ver. 1.1 [Time frame: Approximately 1 year after the first dose of RK-582]
• Disease control rate as assessed by RECIST guideline ver. 1.1 [Time frame: Approximately 1 year after the first dose of RK-582]
• Time to response as assessed by RECIST guideline ver. 1.1 [Time frame: Approximately 1 year after the first dose of RK-582]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Japan · 1 center

• Cancer Institute Hospital of JFCR — Koto-ku

Identifiers

NCT: NCT06853496 · RK582CRCPI · jRCT2031240702

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗