Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer

X-TRAP: Phase I/II Study of Capecitabine Plus Aflibercept in Metastatic Colorectal Cancer

The Primary Phase I objectives are to determine the recommended phase II dose for the capecitabine and aflibercept doublet combination; and to describe any dose limiting and non-dose limiting toxicities. The Phase II Primary objective is to determine progression free survival associated with this regimen. The Phase II secondary objectives are to determine response rate associated with this regimen; to determine overall survival associated with this regimen; and to explore any correlation of clinical outcome with baseline and on treatment changes in blood-based angiogenesis biomarkers.

This open-label, non-randomized phase I/II trial is designed to assess the safety, tolerability and RPTD of capecitabine plus aflibercept in adult subjects with metastatic colorectal cancer.

Inclusion Criteria:

1. For the phase I portion, patients must have histologically and/or cytologically confirmed malignant solid tumor that is refractory to standard therapies.

   For the phase II portion, patients must have histologically and/or cytologically confirmed metastatic colorectal carcinoma that has progressed on, is intolerant of, or is inappropriate for all standard therapies. Subjects must have been treated with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan and bevacizumab or have contraindication to such treatment. Prior epithelial growth factor receptor (EGFR)-targeting agent (or contraindication to these drugs) is required for subjects with K-Ras wildtype tumors

2. Measurable disease by RECIST 1.1 criteria (see Appendix 1). Previously irradiated sites can be included if there is documented progression of disease in that site.

3. Age 18 years and older.

4. KPS > 70% (see Appendix 2)

5. Life expectancy > 3 months.

6. Adequate organ and marrow function as defined below:

   • Absolute neutrophil count > 1.5 x 109/L
   • Platelet count > 100 x 109/L
   • Hemoglobin > 9 g/dl
   • Total bilirubin < 1.5 x ULN
   • AST (SGOT)/ALT (SGPT) < 2.5 x ULN (or <5 x ULN if liver metastases)
   • Creatinine clearance ≥50 mls/min by Cockcroft-Gault
   • Urine Protein/Creatinine ratio < 1 (or protein < 1+ on urinalysis or 24hour urine protein < 1gram/24 hours)

7. Previous radiotherapy for palliation of recurrent disease is allowed if >4 weeks have elapsed since completion of therapy.

8. Ability to take oral medications.

9. Ability to understand and the willingness to sign a written informed consent document.

10. Women of childbearing potential must have a negative serum pregnancy test within 7 days from day 1 of study drug; both men and women must be willing to use two methods of contraception, one of them being a barrier method during the study and for 6 months after last study drug administration.

11. Signed informed consent

Exclusion Criteria:

1. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks from day 1 of study drug (including investigational agents, chemotherapy, radiation therapy, antibody based therapy, etc.)
2. History of severe hypersensitivity reactions/anaphylaxis attributed to humanized and/or chimeric monoclonal antibodies or other such proteins.
3. History of significant intolerance to capecitabine or 5FU (ie. Grade 4 toxicity related to one of these agents; grade 3-4 toxicity related to other concurrently administered agents is not an exclusion).
4. History of abdominal fistula or gastrointestinal perforation at any point within 6 months prior to day 1 of study drug, unless surgically repaired.
5. Active peptic ulcer disease, inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), diverticular disease or other gastrointestinal conditions with increased risk of perforation or gastrointestinal bleeding.
6. Active bleeding diathesis or history of any major bleeding, CNS bleeding, or significant hemoptysis within 6 months of enrollment.
7. Anticoagulation with warfarin (anticoagulation with low molecular weight heparin is not an exclusion).
8. History of arterial thromboembolic events or symptomatic pulmonary embolism within 6 months of study enrollment.
9. Poorly controlled hypertension [defined as systolic blood pressure (SBP of >150 mmHg or diastolic blood pressure (DBP) of >90 mmHg]
10. Patients who have had a major surgery or significant traumatic injury within 4 weeks from day 1 of study drug.
11. History of active brain metastases or carcinomatous meningitis (treated metastases are permitted, provided the patient is asymptomatic and off steroids for 28 days).
12. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Two acceptable forms of contraceptives must be continued throughout the trial by either sex. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to day 1 of study drug).
13. Any active infection, intercurrent illness, severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.