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

• ClinicalTrials.gov Identifier: NCT02024607
• Recruitment Status: Completed
• First Posted: December 31, 2013
• Results First Posted: September 20, 2021
• Last Update Posted: April 6, 2022
• Sponsor: Sumitomo Pharma Oncology, Inc.
• Information provided by (Responsible Party): Sumitomo Pharma Oncology, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Gastrointestinal Cancer	Drug: BBI608; Drug: Fluorouracil; Drug: Oxaliplatin; Drug: Leucovorin; Drug: Irinotecan; Drug: Bevacizumab; Drug: Capecitabine; Drug: Regorafenib	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 495 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/II Clinical Study of BBI608 in Combination With Standard Chemotherapies in Adult Patients With Advanced Gastrointestinal Cancer
• Study Start Date: January 2014
• Actual Primary Completion Date: March 2019
• Actual Study Completion Date: November 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: ARM A- BBI608 in combination with FOLFOX6; 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; Other Names: Napabucasin; BB608; BBI-608; Drug: Fluorouracil; Other Names: 5-FU; Carac; Efudex; Fluoroplex; Adrucil; Drug: Oxaliplatin; Other Name: Eloxatin; Drug: Leucovorin; Other Name: Folinic Acid
Experimental: ARM B- BBI608 in combination with FOLFOX6 and Bevacizumab; 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; Other Names: Napabucasin; BB608; BBI-608; Drug: Fluorouracil; Other Names: 5-FU; Carac; Efudex; Fluoroplex; Adrucil; Drug: Oxaliplatin; Other Name: Eloxatin; Drug: Leucovorin; Other Name: Folinic Acid; Drug: Bevacizumab; Other Name: Avastin
Experimental: ARM C- BBI608 in combination with CAPOX; 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; Other Names: Napabucasin; BB608; BBI-608; Drug: Oxaliplatin; Other Name: Eloxatin; Drug: Capecitabine; Other Name: Xeloda
Experimental: ARM D- BBI608 in combination with FOLFIRI; 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; Other Names: Napabucasin; BB608; BBI-608; Drug: Fluorouracil; Other Names: 5-FU; Carac; Efudex; Fluoroplex; Adrucil; Drug: Leucovorin; Other Name: Folinic Acid; Drug: Irinotecan; Other Name: Camptosar
Experimental: ARM E- BBI608 in combination with FOLFIRI and Bevacizumab; 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; Other Names: Napabucasin; BB608; BBI-608; Drug: Fluorouracil; Other Names: 5-FU; Carac; Efudex; Fluoroplex; Adrucil; Drug: Leucovorin; Other Name: Folinic Acid; Drug: Irinotecan; Other Name: Camptosar; Drug: Bevacizumab; Other Name: Avastin
Experimental: ARM F- BBI608 in combination with Regorafenib; 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; Other Names: Napabucasin; BB608; BBI-608; Drug: Regorafenib; Other Name: Stivarga
Experimental: Arm G- BBI608 in combination with Irinotecan; 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; Other Names: Napabucasin; BB608; BBI-608; Drug: Irinotecan; Other Name: Camptosar

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Adverse Events and Serious Adverse Events [ Time Frame: 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. ]
   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
2. The Objective Response Rate of Napabucasin Administered in Combination in FOLFIRI in Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer [ Time Frame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months ]
   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.

Secondary Outcome Measures :

1. Determination of the Maximum Observed Concentration (Cmax) and Area Under the Plasma Concentration vs. Time Curve (AUClast) [ Time Frame: Blood samples drawn on days 1, 2, 15, 16, 21, and 22 of the first study cycle ]
   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.
2. Pharmacodynamics [ Time Frame: Day 1 of cycle 2 ]
   To determine the response (increase or decrease) of biomarkers from biopsied tumors following the administration of napabucasin
3. Disease Control Rate [ Time Frame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months. ]
   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.
4. Disease Control Rate of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer [ Time Frame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months ]
   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.
5. Progression Free Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer [ Time Frame: 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 ]
   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.
6. Overall Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer [ Time Frame: 4 weeks after the patient has been off study treatment, every 3 months thereafter until death, the study closes, up to 36 months. ]
   The effect of napabucasin given in combination with FOLFIRI on Overall Survival (OS) of patients with FOLFIRI/XELIRI-refractory metastatic colorectal cancer.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed written informed consent

2. A histologically confirmed solid tumor of the gastrointestinal tract including

   1. 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.
   2. Hepatocellular carcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator.
   3. Pancreatic adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator.
   4. Cholangiocarcinoma for which treatment with FOLFOX6 or CAPOX would be acceptable as determined by the Investigator.
   5. Gastric, GEJ or esophageal adenocarcinoma for which treatment with FOLFOX6, CAPOX, FOLFIRI, or irinotecan would be acceptable as determined by the Investigator.
3. Patients may be treatment naïve, or may have received standard chemotherapy; including regimens containing a fluoropyrimidine, or oxaliplatin, or irinotecan, or regorafenib, or bevacizumab.
4. ≥18 years of age.
5. Karnofsky performance status score ≥70%.
6. 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.
7. Females of childbearing potential have a negative serum pregnancy test.
8. 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.
9. Hemoglobin ≥10 g/dl.
10. Total bilirubin level ≤1.5 × ULN.
11. 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).
12. Absolute neutrophil count ≥ 1.5 x 10^9/L.
13. Platelets ≥100 x 10^9/L.
14. Life expectancy estimated at ≥3 months.

Exclusion Criteria:

1. Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 days of the first dose of BBI608.
2. Major surgery within 4 weeks prior to first dose.
3. 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.
4. Pregnant or breastfeeding.
5. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent
6. Unable or unwilling to swallow BBI608 capsules daily.
7. Prior treatment with BBI608.
8. Uncontrolled intercurrent illness

9. For patients to be treated with a regimen containing 5-fluorouracil/leucovorin:

   1. Known hypersensitivity to 5-fluorouracil/leucovorin
   2. Known dihydropyrimidine dehydrogenase (DPD) deficiency

10. For patients to be treated with a regimen containing capecitabine:

    1. Known hypersensitivity to capecitabine
    2. Known dihydropyrimidine dehydrogenase (DPD) deficiency
    3. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent

11. For patients to be treated with a regimen containing oxaliplatin:

    1. Neurosensory neuropathy ≥ grade 2 at baseline
    2. Known hypersensitivity to oxaliplatin or other platinum containing compounds

12. For patients to be treated with a regimen containing irinotecan:

    1. Known hypersensitivity to irinotecan
    2. Abnormal glucuronidation of bilirubin

13. For patients to be treated with a regimen containing bevacizumab:

    1. Current uncontrolled hypertension as well as prior history of hypertensive crisis or hypertensive encephalopathy
    2. 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
    3. History of arterial thrombotic or embolic events (within 6 months prior to study entry)
    4. Significant vascular disease
    5. Evidence of bleeding diathesis or clinically significant coagulopathy
    6. 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
    7. Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥ 2+.
    8. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-abdominal abscess within 6 months
    9. Ongoing serious, non-healing wound, ulcer, or bone fracture
    10. Known hypersensitivity to any component of bevacizumab
    11. History of reversible posterior leukoencephalopathy syndrome (RPLS)

14. For patients to be treated with a regimen containing regorafenib:

    1. 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
    2. Current uncontrolled hypertension
    3. Interstitial lung disease with ongoing signs and symptoms at the time of screening
    4. History of HIV infection or chronic hepatitis B or C
    5. Active clinically serious infections
    6. History of arterial or embolic events (within 6 months prior to study entry)
    7. Liver cirrhosis ≥ Child-Pugh class B with uncontrolled ascites
    8. History of RPLS
    9. Ongoing serious, non-healing wound, ulcer, or bone fracture
    10. Evidence of bleeding diathesis or a clinically significant coagulopathy
    11. Renal failure requiring hemo- or peritoneal dialysis
    12. Persistent proteinuria of CTCAE grade 3 (>3.5g/24 hours)
    13. Significant gastrointestinal disorder(s) that would, in the opinion of the Principal Investigator, prevent absorption of an orally available agent
    14. Known hypersensitivity to regorafenib

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Campus in Arizona

Phoenix, Arizona, United States, 85054

United States, Florida

Florida Cancer Specialists

Fort Myers, Florida, United States, 33916

United States, Georgia

Emory University Winship Cancer Institute

Atlanta, Georgia, United States, 30322

United States, Indiana

Parkview Research Center

Fort Wayne, Indiana, United States, 46845

Indiana University Health Goshen Center for Cancer Care

Goshen, Indiana, United States, 46526

Indiana University Simon Cancer Center

Indianapolis, Indiana, United States, 46202

Indiana University Health Arnett Hospital

Lafayette, Indiana, United States, 47905

Indiana University Health Ball Memorial Hospital

Muncie, Indiana, United States, 47303

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55901

United States, Ohio

Oncology Hematology Care, Inc.

Cincinnati, Ohio, United States, 45242

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

Institute for Translational Oncology Research, Greenville Health System

Greenville, South Carolina, United States, 29605

United States, Tennessee

Tennessee Oncology - Chattanooga

Chattanooga, Tennessee, United States, 37404

Tennessee Oncology - Nashville

Nashville, Tennessee, United States, 37203

Canada, Ontario

Ottawa Hospital Cancer Center

Ottawa, Ontario, Canada, K1H 8L6

Sponsors and Collaborators

Sumitomo Pharma Oncology, Inc.

Investigators

• Study Director: Boston Biomedical; Sumitomo Pharma Oncology, Inc.

  Study Documents (Full-Text)

Documents provided by Sumitomo Pharma Oncology, Inc.:

Study Protocol  [PDF] June 23, 2017

Statistical Analysis Plan  [PDF] October 12, 2020

More Information

• Responsible Party: Sumitomo Pharma Oncology, Inc.
• ClinicalTrials.gov Identifier: NCT02024607
• Other Study ID Numbers: BBI608-246
• First Posted: December 31, 2013
• Results First Posted: September 20, 2021
• Last Update Posted: April 6, 2022
• Last Verified: April 2022

Additional relevant MeSH terms:

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Leucovorin; Bevacizumab; Fluorouracil; Capecitabine; Oxaliplatin; Irinotecan; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antidotes; Protective Agents; Vitamin B Complex