A Study of BBI608 in Combination With Standard Chemotherapies in Adult Patients With Advanced Gastrointestinal Cancer

Study Overview
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Brief Summary
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This is an open label, multi-center, Phase 1/2 dose escalation study of BBI608 administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan.

Detailed Description
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This is an open label, multi-center, Phase 1/2 dose escalation study of BBI608 administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan. A study cycle will consist of daily and continuous oral administration of BBI608 for four weeks (28 days) in combination with FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan.

Official Title
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A Phase Ib/II Clinical Study of BBI608 in Combination With Standard Chemotherapies in Adult Patients With Advanced Gastrointestinal Cancer

Conditions
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Advanced Gastrointestinal Cancer

Intervention / Treatment
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* Drug: BBI608
* Drug: Fluorouracil
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Irinotecan
* Drug: Bevacizumab
* Drug: Capecitabine
* Drug: Regorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent A histologically confirmed solid tumor of the gastrointestinal tract including Advanced unresectable, metastatic or recurrent colorectal carcinoma (CRC) for which treatment with FOLFOX6 with or without bevacizumab, FOLFIRI with or without bevacizumab, CAPOX, or regorafenib would be acceptable as determined by the Investigator. FOLFIRI/XELIRI-refractory patients with CRC enrolling on the FOLFIRI study arm must have failed treatment with one FOLFIRI pr XELIRI with or without bevacizumab regimen for unresectable or metastatic disease. Treatment failure is defined as progression of disease (clinical or radiologic) during treatment with FOLFIRI with or without bevacizumab or < 3 months after the last dose of treatment with FOLFIRI with or without bevacizumab. Patients with CRC enrolling on the regorafenib arm of this study will have previously received at least two previous lines of therapy for advanced colorectal cancer, and will have previously received treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Patients with K-ras wild type tumors enrolling on the regorafenib arm will also have previously received either cetuximab or panitumumab. Hepatocellular carcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator. Pancreatic adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator. Cholangiocarcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator. Gastric, GEJ or esophageal adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator. Patients may be treatment naïve, or may have received standard chemotherapy; including regimens containing a fluoropyrimidine, or oxaliplatin, or irinotecan, or regorafenib, or bevacizumab. ≥18 years of age. Karnofsky performance status score ≥70%. Male or female patients of child-producing potential 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 have a negative serum pregnancy test. AST level ≤2.5 x ULN and ALT ≤ 2.5 × ULN. For patients with liver metastases, AST ≤3.5 x ULN, and AST ≤3.5 x ULN may be enrolled if agreed upon by the investigator and medical monitor for the sponsor. Hemoglobin ≥10 g/dl. Total bilirubin level ≤1.5 × ULN. Creatinine ≤1.5 x ULN or creatinine clearance >60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (as determined by Cockcroft-Gault equation). Absolute neutrophil count ≥ 1.5 x 10^9/L. Platelets ≥100 x 10^9/L. Life expectancy estimated at ≥3 months. Exclusion Criteria: Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 days of the first dose of BBI608. Major surgery within 4 weeks prior to first dose. Any known untreated brain metastases. Treated subjects 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) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent Unable or unwilling to swallow BBI608 capsules daily. Prior treatment with BBI608. Uncontrolled intercurrent illness For patients to be treated with a regimen containing 5-fluorouracil/leucovorin: Known hypersensitivity to 5-fluorouracil/leucovorin Known dihydropyrimidine dehydrogenase (DPD) deficiency For patients to be treated with a regimen containing capecitabine: Known hypersensitivity to capecitabine Known dihydropyrimidine dehydrogenase (DPD) deficiency Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent For patients to be treated with a regimen containing oxaliplatin: Neurosensory neuropathy ≥ grade 2 at baseline Known hypersensitivity to oxaliplatin or other platinum containing compounds For patients to be treated with a regimen containing irinotecan: Known hypersensitivity to irinotecan Abnormal glucuronidation of bilirubin For patients to be treated with a regimen containing bevacizumab: Current uncontrolled hypertension as well as prior history of hypertensive crisis or hypertensive encephalopathy History of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapy History of arterial thrombotic or embolic events (within 6 months prior to study entry) Significant vascular disease Evidence of bleeding diathesis or clinically significant coagulopathy Major surgical procedure within 28 days, or anticipation of the need for major surgical procedure during the course of the study as well as minor surgical procedure within 7 days prior to study enrollment Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months Ongoing serious, non-healing wound, ulcer, or bone fracture Known hypersensitivity to any component of bevacizumab History of reversible posterior leukoencephalopathy syndrome (RPLS) For patients to be treated with a regimen containing regorafenib: History of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; unevaluated new onset angina within 3 months or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapy Current uncontrolled hypertension Interstitial lung disease with ongoing signs and symptoms at the time of screening History of HIV infection or chronic hepatitis B or C Active clinically serious infections History of arterial or embolic events (within 6 months prior to study entry) Liver cirrhosis ≥ Child-Pugh class B with uncontrolled ascites History of RPLS Ongoing serious, non-healing wound, ulcer, or bone fracture Evidence of bleeding diathesis or a clinically significant coagulopathy Renal failure requiring hemo- or peritoneal dialysis Persistent proteinuria of CTCAE grade 3 (>3.5g/24 hours) Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent Known hypersensitivity to regorafenib

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM A- BBI608 in combination with FOLFOX6<br>BBI608 is administered orally twice daily, continuously. Oxaliplatin 85 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2 over 46-48 hours) continuous intravenous infusion. This regimen will be repeated every 14 days thereafter. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Fluorouracil<br> <br> * Other names: Adrucil;Drug: Oxaliplatin<br> <br> * Other names: Eloxatin;Drug: Leucovorin<br> <br> * Other names: Folinic Acid;|
| Experimental: ARM B- BBI608 in combination with FOLFOX6 and Bevacizumab<br>BBI608 is administered orally twice daily, continuously. Oxaliplatin 85 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following oxaliplatin/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2 over 46-48 hours) continuous intravenous infusion. Bevacizumab 5 mg/kg will be administered intravenously following oxaliplatin/leucovorin infusion. This regimen will be repeated every 14 days thereafter. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Fluorouracil<br> <br> * Other names: Adrucil;Drug: Oxaliplatin<br> <br> * Other names: Eloxatin;Drug: Leucovorin<br> <br> * Other names: Folinic Acid;Drug: Bevacizumab<br> <br> * Other names: Avastin;|
| Experimental: ARM C- BBI608 in combination with CAPOX<br>BBI608 is administered orally twice daily, continuously. CAPOX regimen will be administered orally (capecitabine) and IV (oxaliplatin). Capecitabine 850 mg/m^2 will be administered orally twice-daily for 14 consecutive days and be repeated every 21 days. Oxaliplatin will be administered IV and be repeated every 21 days thereafter. If capecitabine is tolerated at the 850 mg/m^2 twice daily dose, dosage may be increased to 1000 mg/m^2 twice daily as tolerated after the first cycle. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Oxaliplatin<br> <br> * Other names: Eloxatin;Drug: Capecitabine<br> <br> * Other names: Xeloda;|
| Experimental: ARM D- BBI608 in combination with FOLFIRI<br>BBI608 is administered orally twice daily, continuously. Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously. 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. This regimen will be repeated every 14 days thereafter. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Fluorouracil<br> <br> * Other names: Adrucil;Drug: Leucovorin<br> <br> * Other names: Folinic Acid;Drug: Irinotecan<br> <br> * Other names: Camptosar;|
| Experimental: ARM E- BBI608 in combination with FOLFIRI and Bevacizumab<br>BBI608 is administered orally twice daily, continuously. Irinotecan 180 mg/m^2 together with leucovorin 400 mg/m^2 will be administered intravenously 5-FU 400 mg/m^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m^2/day (total 2400 mg/m^2) continuous infusion. Bevacizumab 5 mg/kg will be administered intravenously following oxaliplatin/leucovorin infusion. This regimen will be repeated every 14 days thereafter. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Fluorouracil<br> <br> * Other names: Adrucil;Drug: Leucovorin<br> <br> * Other names: Folinic Acid;Drug: Irinotecan<br> <br> * Other names: Camptosar;Drug: Bevacizumab<br> <br> * Other names: Avastin;|
| Experimental: ARM F- BBI608 in combination with Regorafenib<br>BBI608 is administered orally twice daily, continuously. Regorafenib 120 mg will be administered orally once daily, with a low-fat meal and be continued for 21 consecutive days of every 28 days thereafter. If regorafenib is tolerated in the first cycle, dosage may be increased to 160 mg once daily as tolerated after the first cycle. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Regorafenib<br> <br> * Other names: Stivarga;|
| Experimental: Arm G- BBI608 in combination with Irinotecan<br>BBI608 is administered orally twice daily, continuously. Irinotecan 180 mg/m^2 will be administered intravenously. This regimen will be repeated every 14 days thereafter. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Irinotecan<br> <br> * Other names: Camptosar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events and Serious Adverse Events | Assessment of safety of napabucasin administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan in participants with advanced gastrointestinal malignancies 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. | 
| The Objective Response Rate of Napabucasin Administered in Combination in FOLFIRI in Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer | Assessment of the objective response rate (ORR) of napabucasin administered in combination with FOLFIRI in patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. The Objective Response Rate (ORR) is the proportion of participants with a complete response or partial response who have measurable disease at baseline imaging. | 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 |
| --- | --- | --- |
| Determination of the Maximum Observed Concentration (Cmax) and Area Under the Plasma Concentration vs. Time Curve (AUClast) | To determine the maximum concentration of napabucasin and the area under the plasma concentration vs. time curve of napabucasin when administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib. | Blood samples drawn on days 1, 2, 15, 16, 21, and 22 of the first study cycle | 
| Pharmacodynamics | To determine the response (increase or decrease) of biomarkers from biopsied tumors following the administration of napabucasin | Day 1 of cycle 2 | 
| Disease Control Rate | To determine the anti-tumor activity (specifically the disease control rate) of napabucasin administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan. Percentage of participants with a documented complete response, partial response and stable disease based on RECIST 1.1. | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months. | 
| Disease Control Rate of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer | To determine the disease control rate of napabucasin administered in combination with FOLFIRI in patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. Percentage of participants with a documented complete response, partial response and stable disease based on RECIST 1.1. | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months | 
| Progression Free Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer | The effect of napabucasin given in combination with FOLFIRI on Progression Free Survival (PFS) of patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. PFS of patients with FOLFIRI/XELIRI-refractory metastatic 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 thirty six months | 
| Overall Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer | The effect of napabucasin given in combination with FOLFIRI on Overall Survival (OS) of patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer. | 4 weeks after the patient has been off study treatment, every 3 months thereafter until death, the study closes, up to 36 months. |