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

Официальное название

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

Обзор

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.

Вмешательства

• Препарат 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

Первичные конечные точки

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

Вторичные конечные точки (12)

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

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Япония · 1 центр

• Cancer Institute Hospital of JFCR — Koto-ku

Идентификаторы

NCT: NCT06853496 · RK582CRCPI · jRCT2031240702

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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