Clinical trial NCT06853496: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Unresectable Colorectal Neoplasm Metastasis
Keywords: colorectal neoplasm
colorectal cancer
tankyrase inhibitor
Lead sponsor: Japanese Foundation for Cancer Research
Sponsor class: OTHER
Collaborators: name: Japan Agency for Medical Research and Development
First posted: 2025-03-03
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


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

Primary outcomes:
measure: Percentage of dose-limiting toxicity
timeFrame: 35 days after the first dose of RK-582
measure: Number of participants with adverse events as assessed by CTCAE v5.0
timeFrame: Approximately 1 year after the first dose of RK-582
Secondary outcomes:
measure: Area under the curve (AUC) after single or repeated dosing
timeFrame: 22 days after the first dose of RK-582
measure: Maximum plasma concentration (Cmax) after single or repeated dosing
timeFrame: 22 days after the first dose of RK-582
measure: Maximum concentration time (Tmax) after single or repeated dosing
timeFrame: 22 days after the first dose of RK-582
measure: Elimination rate constant (kel) after single or repeated dosing
timeFrame: 22 days after the first dose of RK-582
measure: Elimination half-life (t1/2) after single or repeated dosing
timeFrame: 22 days after the first dose of RK-582
measure: Apparent total body clearance (CLtot/F) after single or repeated dosing
timeFrame: 22 days after the first dose of RK-582
measure: Apparent volume of distribution (Vd/F) after single or repeated dosing
timeFrame: 22 days after the first dose of RK-582
measure: Objective response rate based on investigator's judgment as assessed by RECIST guideline ver. 1.1
timeFrame: Approximately 1 year after the first dose of RK-582
measure: Percentage of subjects who achieved a complete or partial response on the best overall response as assessed by RECIST guideline ver. 1.1
timeFrame: Approximately 1 year after the first dose of RK-582
measure: Duration of response as assessed by RECIST guideline ver. 1.1
timeFrame: Approximately 1 year after the first dose of RK-582
measure: Disease control rate as assessed by RECIST guideline ver. 1.1
timeFrame: Approximately 1 year after the first dose of RK-582
measure: Time to response as assessed by RECIST guideline ver. 1.1
timeFrame: Approximately 1 year after the first dose of RK-582
measure: Progression-free survival as assessed by RECIST guideline ver. 1.1
timeFrame: Approximately 1 year after the first dose of RK-582
measure: Overall survival
timeFrame: Approximately 30 months after the first dose of RK-582
Other outcomes:
Locations:
city: Koto-ku
country: Japan
facility: Cancer Institute Hospital of JFCR
state: Tokyo
Study officials:
affiliation: Cancer Institute Hospital of JFCR
name: Kensei Yamaguchi
role: STUDY_CHAIR
References: