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

Eiji Shinozaki

Status and phase

Enrolling

Phase 1

Conditions

Unresectable Colorectal Neoplasm Metastasis

Treatments

Drug: RK-582

Study type

Interventional

Funder types

Other

Identifiers

NCT06853496

jRCT2031240702 (Registry Identifier)

RK582CRCPI

Details and patient eligibility

About

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.

Enrollment

48 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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