Unresectable Colorectal Neoplasm Metastasis
Conditions
Keywords
colorectal neoplasm, colorectal cancer, tankyrase inhibitor
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.
Interventions
DRUGRK-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
Sponsors
Japan Agency for Medical Research and Development
Eiji Shinozaki
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| Measure | Time frame |
|---|---|
| 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 |
| Area under the curve (AUC) after single or repeated dosing | 22 days 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 |
| 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 |
| Maximum plasma concentration (Cmax) after single or repeated dosing | 22 days after the first dose of RK-582 |
Countries
Japan
Contacts
Primary ContactEiji Shinozaki
Outcome results
None listed