A Phase II Multicenter, Randomized, Placebo Controlled, Double Blinded Clinical Study of KD018 as a Modulator of Irinotecan Chemotherapy in Patients With Metastatic Colorectal Cancer

The proposed plan will investigate the mechanism and efficacy of Chinese herbal medicine as an adjunct to chemotherapy in treatment of patients with metastatic colorectal cancer. Our rationale for the therapeutic use of KD018 is its potential activity in reducing chemotherapy-induced toxicity, especially diarrhea.

KD018 is an oral form of a spray dried aqueous extract composed of four main herbs, which have been used in the Orient for nearly 2000 years for a variety of GI symptoms including diarrhea and nausea/vomiting. Extensive pre-clinical research has been done with Chinese herbal medicine, and studies have documented significant anticancer activity in combination with various cytotoxic agents including Irinotecan, which is a semi-synthetic derivative of the natural alkaloid camptothecin and belongs to the class of topoisomerase I inhibitors. Irinotecan has been evaluated extensively as a single agent as well as in combination with other cytotoxic agents in several schedules. We recently completed a phase I study of irinotecan using the every-2-week schedule in combination with varying doses of KD018. Based on this phase I study, the dose of irinotecan that will be used in this study is 215 mg/m2.

Eligibility Criteria:
Inclusion Criteria:

1. Patients with histologically confirmed metastatic colorectal cancer (mCRC), who have received and/or progressed on a prior oxaliplatin-based chemotherapy regimen.
2. Patients must have been off of chemotherapy for at least 4 weeks prior to signing the informed consent/start of screening.
3. Patients with wild-type or mutant KRAS mCRC.
4. At least one measurable lesion by RECIST 1.1.
5. ECOG PS Performance Status 0-2.
6. Must be \>/=18 years of age.
7. Expected survival of at least 6 months.
8. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use acceptable contraceptive methods (abstinence, intrauterine device \[IUD\], oral contraceptive or double barrier device), and must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial. Nursing patients are excluded. Sexually active men must also use acceptable contraceptive methods. Pregnant and nursing patients are excluded because the effects of the combination of KD018 and irinotecan on a fetus or nursing child are unknown.
9. Must be able and willing to give written informed consent.
10. Patients must have the following clinical laboratory values:

    1. ANC count \>/= 1,500/ mm3.
    2. Platelets \>/= 100,000/ mm3.
    3. Hemoglobin \>/= 9 gm/dL (may be corrected by transfusion).
11. Evidence of adequate hepatic function, Bilirubin \< 1.5 x upper limit of normal (ULN) AST \</= 2.5 x ULN or ALT \</= 2.5 x ULN (Note, if both AST and ALT are done, both must be \</= 2.5 x ULN) OR AST \</= 5.0 x ULN or ALT \</= 5.0 x ULN is acceptable if liver has tumor involvement. (Note, if both AST and ALT are done, both must be \</= 5.0 x ULN)
12. Serum creatinine \</=2 x ULN
13. Serum potassium within institutional limits of normal (may be corrected with potassium repletion).

Exclusion Criteria:

1. Continued treatment with bevacizumab with documented evidence of disease progression on a bevacizumab-containing regimen.
2. Uncontrolled or symptomatic brain metastasis.
3. Serious concomitant systemic disorders (e.g., active infection) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study.
4. Unwilling or unable to follow protocol requirements or to give informed consent.
5. No treatment with cytotoxic or biologic agents within the 4 weeks prior to beginning treatment on this study (6 weeks for mitomycin or nitrosoureas). At least 4 weeks must have elapsed from any prior surgery, radiation, hormonal or other drug therapy for their cancer.
6. Known HIV positivity, as safety in this patient population has not been assessed.
7. Presence of metastatic disease that, in the opinion of the investigator, would require palliative treatment within 4 weeks of enrollment.
8. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies.
9. Pregnant or breast-feeding women.
10. Men and women of childbearing age and potential, who are not willing to use effective contraception.
11. Major surgery within the previous 4 weeks.
12. Patients taking concurrent medications of any kind which are strong inducers or inhibitors of CYP3A4.
13. Patients previously treated with an irinotecan-containing regimen.