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

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ClinicalTrials.gov Identifier: NCT02024607
Recruitment Status : Active, not recruiting
First Posted : December 31, 2013
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
Boston Biomedical, Inc

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 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
Estimated Primary Completion Date : December 2019

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




Primary Outcome Measures :
  1. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Adverse events will be assessed at baseline, while the participant is taking BBI608, and for 30 days after stopping therapy. The average length of this duration is expected to be approximately 4 months. ]
    Assessment of safety of BBI608 administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan to patients with advanced gastrointestinal malignancies by reporting of adverse events and serious adverse events

  2. To assess the objective response rate (ORR) of BBI608 administered in combination with FOLFIRI in patients with FOLFIRI-refractory metastatic colorectal cancer (mCRC) [ Time Frame: Anti-tumor activity, including ORR, is assessed every 8 weeks, from the first dose of BBI608 to 30 days after the last dose of BBI608. ]

Secondary Outcome Measures :
  1. Pharmacokinetic profile of BBI608 assessed by maximum plasma concentration and area under the curve [ Time Frame: During the first 28 days of treatment ]
    Blood sampling to assess the pharmacokinetic profile of BBI608 administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib.

  2. Pharmacodynamic activity assessed by tumor biopsy [ Time Frame: During the first 28 days of treatment ]
    Tumor Biopsy(s) to provide information on analysis of the targets and downstream genes/ effect of BBI608 on cancer stem cells through immunohistochemistry.

  3. Anti-tumor activity by performing tumor assessments every 8 weeks [ Time Frame: Anti-tumor activity is assessed every 8 weeks, from the first dose of BBI608 to 30 days after the last dose of BBI608, an expected average of 5 months ]
    To assess the preliminary anti-tumor activity of napabucasin administered in combination with either FOLFOX6 with and without bevacizumab, or CAPOX, or FOLFIRI with and without bevacizumab, or regorafenib, or irinotecan.

  4. To assess the disease control rate (DCR), progression free survival (PFS) and overall survival (OS) of BBI608 administered in combination with FOLFIRI in patients with FOLFIRI-refractory mCRC [ Time Frame: Anti-tumor activity, including DCR and PFS, is assessed every 8 weeks, from the first dose of BBI608 to 30 days after the last dose of BBI608. Patients are followed for OS until death or withdrawal of consent to OS follow-up. ]


Information from the National Library of Medicine

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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-refractory patients with CRC enrolling on the FOLFIRI study arm must have failed treatment with one FOLFIRI 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02024607


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
Boston Biomedical, Inc
Investigators
Study Director: Boston Biomedical Boston Biomedical, Inc

Responsible Party: Boston Biomedical, Inc
ClinicalTrials.gov Identifier: NCT02024607     History of Changes
Other Study ID Numbers: BBI608-246
First Posted: December 31, 2013    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018

Additional relevant MeSH terms:
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Bevacizumab
Oxaliplatin
Irinotecan
Capecitabine
Camptothecin
Fluorouracil
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors