A Study of BBI608 in Adult Patients With Advanced Colorectal Cancer

Study Overview
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Brief Summary
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This is an open label, multi-center, Phase 2 study of BBI608 in combination with cetuximab, panitumumab or capecitabine in patients with advanced colorectal cancer.

Detailed Description
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This is an open label, multi-center, Phase 2 study of BBI608 administered in combination with either cetuximab, or panitumumab, or capecitabine. A cycle will consist of daily and continuous oral administration of BBI608 for four weeks in combination with either cetuximab, or panitumumab, or capecitabine.

Official Title
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A Phase II Clinical Study of BBI608 in Adult Patients With Advanced Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: BBI608
* Drug: Panitumumab
* Drug: Capecitabine
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent must be obtained and documented according to International Conference on Harmonization (ICH), Good Clinical Practice(GCP), the local regulatory requirements, and permission to use private health information in accordance with the Health Insurance Portability and Accountability Act (HIPPA) prior to study-specific screening procedures. A histologically or cytologically confirmed colorectal cancer that is metastatic, unresectable, or recurrent. Patients must have received at least 2 regimens containing 5-Fluorouracil,oxaliplatin, or irinotecan. Patients to be enrolled in the Cetuximab or Panitumumab combination arms must have colorectal cancer which is K-Ras wild-type. ≥ 18 years of age. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Karnofsky performance Status ≥ 70% Male or female patients of child-producing potential must agree to use contraception or avoidance of pregnancy measures during the study and for 30 days after the last BBI608 dose. Females of childbearing potential must have a negative serum pregnancy test. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤1.5 × upper limit of normal(ULN), or ≤ 2.5 × ULN with metastatic liver disease. Hemoglobin (Hgb) ≥ 10 g/dl. Total bilirubin ≤ 1.5 × ULN. Creatinine ≤ 1.5 × ULN or creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal. Absolute neutrophil count ≥ 1.5 x 10^9/L. Platelets ≥ 100 x 10^9/L. Life expectancy ≥ 3 months. Exclusion Criteria: Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within four weeks of first dose with the exception for a single dose radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before beginning the administration of BBI608. Surgery within 4 weeks prior to first dose. Any known symptomatic brain metastases requiring steroids. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated. Pregnant or breastfeeding Significant gastrointestinal disorder(s), in the opinion of the Principal Investigator, (e.g., Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection) Unable or unwilling to swallow BBI608 capsules daily. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BBI608 in combination with cetuximab<br> | Drug: BBI608<br>* BBI608 is administered at 500 mg po bid continuously.<br>* Other names: BBI-608;Drug: Cetuximab<br>* Cetuximab will be administered IV on day 5 at 400 mg/m2 intravenous infusion over 120 minutes as the initial dose, then weekly at 250mg/m2 over 60-minutes at subsequent cycles.<br>* Other names: Erbitux;|
| Experimental: BBI608 in combination with panitumumab<br> | Drug: BBI608<br>* BBI608 is administered at 500 mg po bid continuously.<br>* Other names: BBI-608;Drug: Panitumumab<br>* Panitumumab will be administered IV on day 8 and 22 of each 28 day cycle at 6 mg/kg over 60 minutes.<br>* Other names: Vectibix;|
| Experimental: BBI608 in combination with capecitabine<br> | Drug: BBI608<br>* BBI608 is administered at 500 mg po bid continuously.<br>* Other names: BBI-608;Drug: Capecitabine<br>* Capecitabine will be administered orally at 1000 mg/m2 bid daily on days 8-21 every three weeks.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate | Assessment of Disease Control Rate, defined as the proportion of patients with a documented complete response, partial response and stable disease based on RECIST 1.1, in patients with advanced colorectal cancer given napabucasin in combination with cetuximab, panitumumab or capecitabine | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | The effect of napabucasin given in combination with cetuximab, panitumumab or capecitabine on Progression Free Survival (PFS) of patients with advanced colorectal cancer. | The time from the date of first treatment to the date of first documentation of disease progression or death due to any cause, up to 24 months | 
| Overall Survival | The effect of napabucasin given in combination with cetuximab, panitumumab or capecitabine on the Overall Survival of patients with advanced colorectal cancer | 4 weeks after the patient has been off study treatment, every 3 months thereafter until death, up to 60 months. | 
| Determination of the Maximum Observed Concentration (Cmax) of Napabucasin When Administered 480mg, Twice Daily, on Day 5 of the First Study Cycle | To determine the maximum concentration of napabucasin when given at 480mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 5 during the first study cycle | 
| Determination of the Maximum Observed Concentration (Cmax) of Napabucasin When Administered 480mg, Twice Daily, on Day 21 of the First Study Cycle | To determine the maximum concentration of napabucasin when given at 480mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 21 during the first study cycle | 
| Determination of the Maximum Observed Concentration (Cmax) of Napabucasin When Administered 240mg, Twice Daily, on Day 21 of the First Study Cycle | To determine the maximum concentration of napabucasin when given at 240mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 21 during the first study cycle | 
| Determination of the Maximum Observed Concentration (Cmax) of Napabucasin When Administered 500mg, Twice Daily, on Day 5 of the First Study Cycle | To determine the maximum concentration of napabucasin when given at 500mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 5 during the first study cycle | 
| Determination of the Maximum Observed Concentration (Cmax) of Napabucasin When Administered 500mg, Twice Daily, on Day 21 of the First Study Cycle | To determine the maximum concentration of napabucasin when given at 500mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 21 during the first study cycle | 
| Area Under the Plasma Concentration vs. Time Curve (AUClast) of Napabucasin When Administered 480mg, Twice Daily, on Day 5 of the First Study Cycle | To determine the area under the plasma concentration vs. time curve of napabucasin when given at 480mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 5 during the first study cycle | 
| Area Under the Plasma Concentration vs. Time Curve (AUClast) of Napabucasin When Administered 480mg, Twice Daily, on Day 21 of the First Study Cycle | To determine the area under the plasma concentration vs. time curve of napabucasin when given at 480mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 21 during the first study cycle | 
| Area Under the Plasma Concentration vs. Time Curve (AUClast) of Napabucasin When Administered 240mg, Twice Daily, on Day 21 of the First Study Cycle | To determine the area under the plasma concentration vs. time curve of napabucasin when given at 240mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 21 during the first study cycle | 
| Area Under the Plasma Concentration vs. Time Curve (AUClast) of Napabucasin When Administered 500mg, Twice Daily, on Day 5 of the First Study Cycle | To determine the area under the plasma concentration vs. time curve of napabucasin when given at 500mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 5 during the first study cycle | 
| Area Under the Plasma Concentration vs. Time Curve (AUClast) of Napabucasin When Administered 500mg, Twice Daily, on Day 21 of the First Study Cycle | To determine the area under the plasma concentration vs. time curve of napabucasin when given at 500mg, twice daily, in combination with cetuximab, panitumumab, or capecitabine in patients with advanced colorectal cancer. | Blood samples drawn on day 21 during the first study cycle | 
| Pharmacodynamics | To determine the response (increase or decrease) of biomarkers from biopsied tumors following the administration of napabucasin | During the first 28 days of the study cycle | 
| Number of Patients With Adverse Events and Serious Adverse Events | Assessment of safety of napabucasin given in combination with cetuximab, panitumumab or capecitabine to patients with advanced colorectal cancer by reporting of adverse events and serious adverse events | The time from the date of first treatment, while the patient is taking napabucasin, and for 30 days after stopping therapy, an average of 4 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BBI608