Special Combination of BBI608 and Pembrolizumab

Study Overview
=================
Brief Summary
-----------------
the efficacy and safety of BBI608 in combination with pembrolizumab

Detailed Description
-----------------
This is a multicenter, open-label Phase Ib/II study to exploratively evaluate the efficacy and safety of BBI608 in combination with pembrolizumab in patients with metastatic colorectal cancer (CRC) not responded to or intolerant of standard chemotherapy.The same analysis will be performed for the additional cohort to the Phase II part, consisting of patients with metastatic CMS 1 or 4, MMS, CRC not responsive to or intolerant of standard chemotherapy.

Official Title
-----------------
A Phase Ib/II Study of BBI608 in Combination With Pembrolizumab in Patients With Metastatic Colorectal Cancer

Conditions
-----------------
Metastatic Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: Napabucasin
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
For the additional cohort to the Phase II part, screening tests will be performed to identify CMS 1 or 4 and MSS before obtaining informed consent. Patients, who meet all of the following inclusion criteria and none of the exclusion criteria, are eligible for enrollment in the study. Inclusion Criteria Patients who personally provided written consent to be the subjects of the study Age of 20 years or older on the day of informed consent [Phase Ib] Histologically confirmed gastrointestinal cancer [Phase II] Histologically confirmed colon or rectal cancer that is adenocarcinoma , and identification of at least the KRAS codon 12 and 13 mutation status determined by RAS gene testing. Confirmation of the microsatellite instability (MSI) status. [Additional cohort to the Phase II part] Histologically confirmed colon or rectal cancer that is adenocarcinoma, and identification of RAS mutation status. Identification of CMS 1 or 4 and MSS by screening tests. [Phase Ib] Gastrointestinal cancer not responded to or intolerant of standard chemotherapy [Phase II]A history of treatment with one or more regimens of the following standard chemotherapies for metastatic CRC, and being not responded to or tolerated the chemotherapies [Additional cohort to the Phase II part] In accordance with Cohort B in the Phase II part. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 Patients with evaluable lesions (Cohort A in Phase II and Phase Ib) or measurable lesions (Cohort B in Phase II and the additional cohort to the Phase II part) specified in the RECIST version 1.1 Patients with adequate organ function based on the following laboratory values measured within 7 days before enrollment Women of childbearing potential who are negative in a pregnancy test within 7 days before enrollment. Both male and female patients who consent to practice appropriate contraception during the study and for 4 months after the discontinuation of the protocol treatment Patients with an expected survival of at least 3 months Exclusion criteria Patients who received chemotherapy, molecular-targeted agents and/or palliative radiotherapy within 2 weeks before the start of the protocol treatment or have not recovered from toxicity caused by previous treatment Patients who underwent general anesthesia, surgery requiring hospitalization and extensive radiotherapy within 4 weeks before the start of the protocol treatment or minor surgery such as implantation of a central venous access device within two weeks before the start of the protocol treatment Patients with active central nervous system metastases or carcinomatous meningitis. Pregnant or lactating women Patients who are unable or not willing to take BBI608 capsules every day Patients with gastrointestinal disease markedly interfering with the absorption of oral formulations as judged by the investigator Patients with active autoimmune disease requiring systemic treatment within 2 years before the start of the protocol treatment. Patients with a history or signs of interstitial lung disease or active non-infectious pneumonitis Patients who underwent organ or bone marrow transplantation Patients who received a live vaccine within 30 days before the start of the protocol treatment Patients who participated in another clinical study within 4 weeks before the start of the protocol treatment and used or using an investigational drug or device Patients who previously received immunotherapy with drugs targeting PD-1, PD-L1 and/or PD-L2 or BBI608 therapy, or took part in a clinical study of pembrolizumab or BBI608 Patients with uncontrollable complications Patients with a history of other malignancies within 3 years before the start of the protocol treatment. Patients with clinically significant Electrocardiogram (ECG) abnormalities Patients with a history of Human Immunodeficiency Virus (HIV) Patients with active hepatitis B or C

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: [Phase Ib] 6 to 9 patients [Phase II] Cohort A (MSI-H): 10 patients Cohort B (MSS): 40 patients Including patients with metastatic CRC treated at the recommended dose (RD) level in the Phase Ib part who meet criteria for the full analysis set (FAS) [Additional cohort to the Phase II part] st stage: CMS 1 or 4, MSS right-side colon cancers*: 10 patients nd stage: : If no patient shows a partial or complete response in the 1st stage, the study will be prematurely terminated. : If 1 or 2 patients show a partial or complete response in the 1st stage, 19 patients with CMS 1 or 4, MSS right-side colon cancers will be enrolled additionally. : If 3 or more patients show a partial or complete response in the 1st stage, 19 patients with CMS 1 or 4, MSS right-side colon cancers and 10 patients with CMS 1 or 4, MSS left-side colon cancers* will be enrolled additionally.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BBI608 + Pembrolizumab<br>BBI608 and Pembrolizumab | Drug: Napabucasin<br>* 1 cycle is 21days. BBI608: Oral administration at a dose of 240mg or 480 mg twice daily (BID), every day. [Additional cohort to the Phase II part] Oral administration at a dose of 240mg mg BID, every day The therapy will be repeated until meeting the discontinuation criteria.<br>Drug: Pembrolizumab<br>* 1 cycle is 21days. Pembrolizumab: Administration at a dose of 200 mg/body on Day 1 of each cycle [Additional cohort to the Phase II part] Administration at a dose of 200 mg/body on Day 1 of each cycle. The therapy will be repeated until meeting the discontinuation criteria.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| irORR | Immune-related objective response rate determined by their Response Evaluation Criteria In Solid Tumors (RESIST): for the Phase II part | 2 years | 
| ORR | Objective response rate determined by RECIST version 1.1: for additional cohort to the Phase II part | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| irPFS | Immune-related progression free survival rate at week 12 determined by the irRECIST | 12 weeks | 
| ORR | Objective response rate determined by RECIST version 1.1: for the Phase II part | 2 years | 
| irORR | Immune-related objective response rate determined by their Response Evaluation Criteria In Solid Tumors (RESIST): for additional cohort to the Phase II part | 1 year | 
| Progression free survival rate at week 12 determined by the RECIST version 1.1 | PFS | 12 weeks | 
| PFS | Progression free survival | 3 years | 
| OS | Overall survival | 4 years | 
| DCR | Disease Control rate | 2 years | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Incidence of adverse events | 4 years | 
| Pharmacokinetic | Area under the blood concentration-time curve (AUC) | 2 months | 
| Pharmacokinetic | CmaxPeak Plasma Concentration (Cmax) | 2 months |