Irinotecan Plus Brivanib in Metastatic Colorectal Cancer (CRC) Enriched for Elevated Levels of Plasma FGF
Condition: Colorectal Cancer; Colorectal Adenocarcinoma
MeSH terms: Colorectal Neoplasms; Adenocarcinoma
Intervention: Brivanib; Irinotecan
Intervention description: 800 mg (4 x 200 mg tablets) self-administered orally at approximate same time each day on a continuous daily schedule Days 1-14 of 14 day cycle.; 180 mg/m^2 by vein on Day 1 of a 14 day cycle.
Intervention MeSH terms: Irinotecan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: colon; Colorectum; Colorectal Cancer; Plasma FGF; Colorectal adenocarcinoma; Bevacizumab; Brivanib; BMS-582664; Irinotecan; CPT-11; Camptosar; Fibroblast Growth Factor; bFGF; tyrosine kinase receptors; vascular endothelial growth factor receptors; VEGFR; fibroblast growth factor receptors; FGFR

Summary:

      The goal of this clinical research study is to learn if adding brivanib to irinotecan can
      help control the disease in patients with colorectal cancer that has spread. The safety of
      this drug combination will also be studied.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed written Informed Consent.

          2. Patient must have progressed on front-line chemotherapy treatment containing
             bevacizumab for histologically confirmed colorectal adenocarcinoma that is
             unresectable or metastatic. Progression is defined as either radiographic or clinical
             progression.

          3. Patient must have measurable lesions as defined by RECIST version 1.1 criteria.

          4. ECOG performance status 0-2.

          5. Known bFGF level performed by a CLIA-certified laboratory performed during or within
             12 weeks of last bevacizumab treatment

          6. Enrollment in the "Assessment of Targeted Therapies Against Colorectal Cancer"
             (ATTACC) protocol 2009-0091.

          7. LVEF > 50% measured by 2-D echocardiogram

          8. Bone marrow function defined as the following: An absolute neutrophil count (ANC)
             =/>1,500/mcl; Platelets =/>100,000/mcl; Hemoglobin =/> 8.5 g/dl.

          9. Renal function defined as the following: Serum creatinine less than or equal to 1.5 x
             institutional upper limit normal (ULN).

         10. Hepatic function defined as the following: Serum total bilirubin < 1.5 x ULN; AST
             (SGOT), ALT (SGPT) and alkaline phosphatase =/< 2.5 x ULN; Serum albumin =/> 2.5 g/dl;
             If liver involvement, AST, ALT, and alkaline phosphatase =/< 5.0 x ULN.

         11. International normalized ratio (INR) =/< 2.3 or Prothrombin Time (PT) =/< 6 seconds
             above control unless patient is currently receiving warfarin therapy for the treatment
             or prevention of venous thrombosis.

         12. Men and women, age =/> 18 years.

         13. A male subject of fathering potential must use an adequate method of contraception to
             avoid conception throughout the study [and for up to 12 weeks after the last dose of
             study drug] to minimize the risk of pregnancy. If the partner is pregnant or
             breastfeeding, the subject must use a condom.

         14. Women of childbearing potential (WOCBP) must be using an adequate method of
             contraception to avoid pregnancy throughout the study and for up to 12 weeks after the
             last dose of study drug to minimize the risk of pregnancy. WOCBP must have a negative
             serum or urine pregnancy test within 72 hours before the start of the investigational
             product.

        Exclusion Criteria:

          1. Women who are pregnant or breastfeeding.

          2. Patients with brain metastases.

          3. Patients with resectable colorectal cancer or non-adenocarcinoma cancer of the colon
             or rectum.

          4. Patients who have had prior therapy with brivanib, anti-PDGFR (platelet-derived growth
             factor receptor) or anti-FGFR (fibroblast growth factor receptor) therapy.

          5. Recent (within 4 weeks of the first study drug administration), or planned
             participation in another experimental therapeutic drug study.

          6. Recent (within 4 weeks of the first study drug administration) infusion of bevacizumab
             therapy.

          7. Prior irinotecan chemotherapy.

          8. Prior full field radiotherapy =/<4 weeks or limited field radiotherapy =/<2 weeks
             prior to first study drug administration.

          9. Recent use (within 4 weeks of first study drug administration) of St. John's Wort.

         10. Patients with a history of thrombotic or embolic events within the last six months
             such as a cerebrovascular accident (including transient ischemic attacks), pulmonary
             embolism.

         11. Patients with gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE
             (version 4.0) Grade 4 within 30 days prior to first study drug administration

         12. Patients with uncontrolled or significant cardiovascular disease including: i) Active
             coronary artery disease, unstable or newly diagnosed angina or myocardial infarction <
             12 months prior to first study drug administration. ii) Class III-IV New York Heart
             Association (NYHA) congestive heart failure. iii) Uncontrolled hypertension (Systolic
             blood pressure [BP] > 150 mmHg and diastolic BP > 90 mmHg for 24 hours) despite
             optimal medical management. Blood pressure must be below 140/90 mmHg at screening.
             Subjects with a history of hypertension who are receiving treatment with calcium
             channel blockers that are CYP3A4 substrates should be changed to an alternative
             antihypertensive medication prior to first study drug administration. iv) Cardiac
             arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin. v)
             QTc (Fridericia) prolongation >450 msec. vi) Subjects with valvular heart disease =/>
             CTCAE (Ver. 4.0) Gr 2. vii) Left ventricular ejection fraction (LVEF) < 50%.

         13. Active infection, less than 7 days after completing systemic antibiotic therapy.

         14. History of non-healing wounds or ulcers, or bone fractures within 3 months prior to
             first study drug administration.

         15. Major surgical procedure, open biopsy, or significant traumatic injury less than 3
             weeks or those who receive minor surgical procedures (e.g. core biopsy or fine needle
             aspiration) within 1 week from first dose of first study drug administration.

         16. Inability to swallow tablets or untreated malabsorption syndrome.

         17. Pre-existing thyroid abnormality with thyroid function that can not be maintained in
             the normal range with medication.

         18. History of human immunodeficiency virus (HIV).

         19. Patients with centrally cavitating lung lesions.

         20. Known bleeding diathesis.

         21. Inability to comply with study and/or follow-up procedures.

         22. Patients with known glomerular nephritis.

         23. Patients with known polycythemia.

         24. Patients with known Gilbert's syndrome.

         25. Women with a positive pregnancy test.

         26. Patients with hyponatremia (sodium < 130 mmol/L).

         27. Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to
             restore the serum potassium above this level prior to study entry).

         28. Baseline serum calcium < 8.4 mg/dL (calcium supplementation may be given to restore
             the serum calcium above this level prior to study entry).

         29. Baseline serum magnesium < 1.5 mg/dL (magnesium supplementation may be given to
             restore the serum magnesium above this level prior to study entry).

         30. Known or suspected history of allergy to brivanib or any agents given in association
             with this study.

         31. Prisoners or subjects who are involuntarily incarcerated. Patients who are
             compulsorily detained for treatment of either a psychiatric or physical (eg,
             infectious disease) illness.