Clinical trial NCT02024607: A Study of BBI608 in Combination With Standard Chemotherapies in Adult Patients With Advanced Gastrointestinal Cancer
Official title: A Phase Ib/II Clinical Study of BBI608 in Combination With Standard Chemotherapies in Adult Patients With Advanced Gastrointestinal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Gastrointestinal Cancer
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2013-12-31
Enrollment: 495
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants With Adverse Events and Serious Adverse Events
timeFrame: 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.
measure: The Objective Response Rate of Napabucasin Administered in Combination in FOLFIRI in Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer
timeFrame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months
Secondary outcomes:
measure: Determination of the Maximum Observed Concentration (Cmax) and Area Under the Plasma Concentration vs. Time Curve (AUClast)
timeFrame: Blood samples drawn on days 1, 2, 15, 16, 21, and 22 of the first study cycle
measure: Pharmacodynamics
timeFrame: Day 1 of cycle 2
measure: Disease Control Rate
timeFrame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months.
measure: Disease Control Rate of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer
timeFrame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 24 months
measure: Progression Free Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer
timeFrame: 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
measure: Overall Survival of Patients With FOLFIRI/XELIRI-refractory Metastatic Colorectal Cancer
timeFrame: 4 weeks after the patient has been off study treatment, every 3 months thereafter until death, the study closes, up to 36 months.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Campus in Arizona
state: Arizona
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institute
state: Georgia
city: Fort Wayne
country: United States
facility: Parkview Research Center
state: Indiana
city: Goshen
country: United States
facility: Indiana University Health Goshen Center for Cancer Care
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Lafayette
country: United States
facility: Indiana University Health Arnett Hospital
state: Indiana
city: Muncie
country: United States
facility: Indiana University Health Ball Memorial Hospital
state: Indiana
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Cincinnati
country: United States
facility: Oncology Hematology Care, Inc.
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Institute for Translational Oncology Research, Greenville Health System
state: South Carolina
city: Chattanooga
country: United States
facility: Tennessee Oncology - Chattanooga
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology - Nashville
state: Tennessee
city: Ottawa
country: Canada
facility: Ottawa Hospital Cancer Center
state: Ontario
Study officials:
affiliation: Sumitomo Pharma America, Inc.
name: Boston Biomedical
role: STUDY_DIRECTOR
References: