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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: KD018
* Drug: Irinotecan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically confirmed metastatic colorectal cancer (mCRC), who have received and/or progressed on a prior oxaliplatin-based chemotherapy regimen. Patients must have been off of chemotherapy for at least 4 weeks prior to signing the informed consent/start of screening. Patients with wild-type or mutant KRAS mCRC. At least one measurable lesion by RECIST 1.1. ECOG PS Performance Status 0-2. Must be >/=18 years of age. Expected survival of at least 6 months. 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. Must be able and willing to give written informed consent. Patients must have the following clinical laboratory values: ANC count >/= 1,500/ mm3. Platelets >/= 100,000/ mm3. Hemoglobin >/= 9 gm/dL (may be corrected by transfusion). 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) Serum creatinine </=2 x ULN Serum potassium within institutional limits of normal (may be corrected with potassium repletion). Exclusion Criteria: Continued treatment with bevacizumab with documented evidence of disease progression on a bevacizumab-containing regimen. Uncontrolled or symptomatic brain metastasis. 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. Unwilling or unable to follow protocol requirements or to give informed consent. 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. Known HIV positivity, as safety in this patient population has not been assessed. Presence of metastatic disease that, in the opinion of the investigator, would require palliative treatment within 4 weeks of enrollment. Altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies. Pregnant or breast-feeding women. Men and women of childbearing age and potential, who are not willing to use effective contraception. Major surgery within the previous 4 weeks. Patients taking concurrent medications of any kind which are strong inducers or inhibitors of CYP3A4. Patients previously treated with an irinotecan-containing regimen.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>irinotecan+ KD018 | Drug: KD018<br>* Traditional Chinese Medicine formulation administered orally twice a day for 4 days on days 1-4 every 2 weeks from the second cycle, at a dose of 1,800 mg, twice a day.<br>Drug: Irinotecan<br>* Irinotecan will be administered intravenously once every 2 weeks from the first cycle, at a dose of 215 mg/m².<br>* Other names: CPT-11;|
| Experimental: Arm B<br>irinotecan + placebo | Drug: Irinotecan<br>* Irinotecan will be administered intravenously once every 2 weeks from the first cycle, at a dose of 215 mg/m².<br>* Other names: CPT-11;Drug: Placebo<br>* Placebo capsules will be administered orally twice a day for 4 days on days 1-4 every 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Grade 2-4 Toxicities | The proportion of participants with a toxicity grade greater than or equal to grade 2, per NCI CTCAE 4.0. Toxicity is defined as any adverse event (AE) at least probably related to treatment occurring with 90 days of the beginning of treatment. The worst grade of AE at least probably related to treatment was determined for each participant. | Up to 3 months after start of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response (OR) | Number of participants who experienced a best response of Partial Response (PR) or Stable Disease (SD) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1), PR is >=30% decrease in the sum of the longest diameter of target lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameter. | Up to 36 months | 
| Progression-free Survival (PFS) | Median number of days and after the treatment participants remained alive without worsening disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | Up to 450 days | 
| Overall Survival (OS) | Median number of days from the start of treatment that study participants remained alive. | Up to 900 days | 
| Clinical Response (CR) | Number of patients that experienced Progressed Disease, Stable Disease or Partial Response per RECIST 1.1. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters, and Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy (Diarrhea) FACIT-D Total Score | The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System is a collection of health-related quality of life (HRQOL) questionnaires targeted to the management of chronic illness. The Functional Assessment of Chronic Illness Therapy (Diarrhea), the FACIT-D, contains 11 items which address concerns related to treatment-related diarrhea. Responses are on a Likert scale and range from 0 = Not at all to 4 = Very Much. Thus, total scores can range from 0 to 44. Higher scores relate to better functioning. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy FACIT-D - PWB: Physical Well-Being | The Functional Assessment of Chronic Illness Therapy FACIT-D - PWB: Physical Well-Being is a 7-item subscale score of the total FACIT-D self-assessment that measures a patient's physical well-being. Individual responses are scale and range from 0 = Not at all to 4 = Very Much. The total score ranges from 0-28. Higher scores related to better physical well-being. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy FACIT-D EWB: Emotional Well-Being | The Functional Assessment of Chronic Illness Therapy FACIT-D Emotional Well-Being (EWB) is a 6-item subscale score of the total FACIT-D self-assessment that measures a patient's emotional well-being. Individual responses are scale and range from 0 = Not at all to 4 = Very Much. The total score ranges from 0-24. Higher scores related to better emotional well-being. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy FACIT-D SWB: Social Well-Being | The Functional Assessment of Chronic Illness Therapy FACIT-D Social Well-Being (SWB) is a 7-item subset score of the total FACIT-D self-assessment that measures a patient's social well-being. Individual responses are scale and range from 0 = Not at all to 4 = Very Much. The total score ranges from 0-28. Higher scores related to better social well-being. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy FACIT-D FWB: Functional Well-Being | The Functional Assessment of Chronic Illness Therapy FACIT-D Functional Well-Being (FWB) is a 7-item subscale of the FACIT-D that measures a patient's functional well-being. Individual responses are scale and range from 0 = Not at all to 4 = Very Much. The total score ranges from 0-28. Higher scores related to better family well-being. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy FACIT-D FACTG: FACT-G Total Score (PWB+SWB+EWB+FWB) | The FACIT-D FACTG: FACT-G Total Score is a total of PWB (Physical Well-Being)+SWB (Social Well-Being)+EWB (Emotional Well-Being)+FWB (Functional Well-Being) subset scores. Individual responses are scale and range from 0 = Not at all to 4 = Very Much. The total score ranges from 0-108. Higher scores indicate greater well-being. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy FACIT-Fatigue FS: Fatigue Score | The Functional Assessment of Chronic Illness Therapy FACIT-Fatigue FS: Fatigue Score is a 13 -item self-reporting assessment that measures fatigue related to their illness. Individual responses are scale and range from 0 = Not at all to 4 = Very Much. The total score ranges from 0-52. Higher scores indicate better functioning. | Up to 36 months | 
| The Functional Assessment of Chronic Illness Therapy FACIT-D TOI: Trial Outcome Index | The Functional Assessment of Chronic Illness Therapy FACIT-D TOI: Trial Outcome Index. is the sum of the Physical Well-Being (PWB), Functional Well-Being (FWB), and additional concerns subscales of the FACIT-D. The TOI is an efficient summary index of physical/functional outcomes. The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System is a collection of health-related quality of life (HRQOL) questionnaires targeted to the management of chronic illness. Individual responses are scale and range from 0 = Not at all to 4 = Very Much. The total score can range from 0-100. Higher scores relate to better functioning. | Up to 36 months | 
| Metabolites and Cytokine Scoring for Prediction of Time to Disease Progression | Number of patients with metabolites in their blood samples with a score less than 4.8 and greater than 4.8. A Cox Proportional Hazard Regression Analysis was fitted using survival time, status to the cytokines and metabolites as covariates. The analysis computes beta coefficients (hazard ratios) for each cytokine/metabolite. Scores higher than a threshold value of 4.8 were associated with higher overall survival than patients who scored less than 4.8. | Up to 36 months | 
| Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 Alleles | The number of patients with specific polymorphisms of UGT1A1 using genotype analysis of peripheral blood sample. UGT1A1*1 is the wild-type allele associated with normal enzyme activity. Patients with genotypic status of 7/7 are at an increased risk of neutropenia following intravenous irinotecan therapy. | From 30 minutes prior to irinotecan infusion through to Immediately after irinotecan infusion, up to 8 weeks | 
| Circulating Tumor DNA - Percentage of Patients With DNA Mutations | Percentage of patients with Braf, Kras, Nras, PIK3CA and PTEN mutations associated with tumor detected in the circulating DNA of plasma, before treatment. | Baseline - prior to treatment | 
| Circulating Tumor DNA - Percentage of Patients With DNA Mutations | Percentage of patients with Braf, Kras, Nras, PIK3CA and PTEN mutations associated with tumor detected in the circulating DNA of plasma, before treatment. | End of treatment - up to 8 weeks |