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

• ClinicalTrials.gov Identifier: NCT00730158
• Recruitment Status: Completed
• First Posted: August 8, 2008
• Results First Posted: May 22, 2019
• Last Update Posted: May 22, 2019
• Sponsor: Edward Chu, MD
• Collaborator: Kadmon Corporation, LLC
• Information provided by (Responsible Party): Edward Chu, MD, University of Pittsburgh

Tracking Information

• First Submitted Date: August 4, 2008
• First Posted Date: August 8, 2008
• Results First Submitted Date: August 15, 2018
• Results First Posted Date: May 22, 2019
• Last Update Posted Date: May 22, 2019
• Study Start Date: December 2008
• Actual Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 29, 2019)

Proportion of Participants With Grade 2-4 Toxicities [ Time Frame: Up to 3 months after start of study treatment ]

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.

• Original Primary Outcome Measures (submitted: August 4, 2008): To determine maximum tolerated dose of PHY906 when combined with a standard dose of CPT-11 and to determine response rate in patients with metastatic colorectal cancer [ Time Frame: Maximum tolerated dose will be available at end of Phase I while response rate will be available upon completion of study. ]

Current Secondary Outcome Measures (submitted: April 29, 2019)

• Overall Response (OR) [ Time Frame: Up to 36 months ]
  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.
• Progression-free Survival (PFS) [ Time Frame: Up to 450 days ]
  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).
• Overall Survival (OS) [ Time Frame: Up to 900 days ]
  Median number of days from the start of treatment that study participants remained alive.
• Clinical Response (CR) [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy (Diarrhea) FACIT-D Total Score [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy FACIT-D - PWB: Physical Well-Being [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy FACIT-D EWB: Emotional Well-Being [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy FACIT-D SWB: Social Well-Being [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy FACIT-D FWB: Functional Well-Being [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy FACIT-D FACTG: FACT-G Total Score (PWB+SWB+EWB+FWB) [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy FACIT-Fatigue FS: Fatigue Score [ Time Frame: Up to 36 months ]
  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.
• The Functional Assessment of Chronic Illness Therapy FACIT-D TOI: Trial Outcome Index [ Time Frame: Up to 36 months ]
  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.
• Metabolites and Cytokine Scoring for Prediction of Time to Disease Progression [ Time Frame: Up to 36 months ]
  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.
• Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 Alleles [ Time Frame: From 30 minutes prior to irinotecan infusion through to Immediately after irinotecan infusion, up to 8 weeks ]
  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.
• Circulating Tumor DNA - Percentage of Patients With DNA Mutations [ Time Frame: Baseline - prior to treatment ]
  Percentage of patients with Braf, Kras, Nras, PIK3CA and PTEN mutations associated with tumor detected in the circulating DNA of plasma, before treatment.
• Circulating Tumor DNA - Percentage of Patients With DNA Mutations [ Time Frame: End of treatment - up to 8 weeks ]
  Percentage of patients with Braf, Kras, Nras, PIK3CA and PTEN mutations associated with tumor detected in the circulating DNA of plasma, before treatment.

• Original Secondary Outcome Measures (submitted: August 4, 2008): To determine progression-free survival and overall survival [ Time Frame: upon completion of study ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Colorectal Neoplasms

Intervention

• Drug: KD018
  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.
• Drug: Irinotecan
  Irinotecan will be administered intravenously once every 2 weeks from the first cycle, at a dose of 215 mg/m².
  Other Names:

  • Camptosar
  • CPT-11
• Drug: Placebo
  Placebo capsules will be administered orally twice a day for 4 days on days 1-4 every 2 weeks.

Study Arms

• Experimental: Arm A
  irinotecan+ KD018
  Interventions:

  • Drug: KD018
  • Drug: Irinotecan
• Experimental: Arm B
  irinotecan + placebo
  Interventions:

  • Drug: Irinotecan
  • Drug: Placebo

• Publications *: Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, Liu SH, Cheng YC. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. Sci Transl Med. 2010 Aug 18;2(45):45ra59. doi: 10.1126/scitranslmed.3001270.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 29, 2019): 33
• Original Estimated Enrollment (submitted: August 4, 2008): 54
• Actual Study Completion Date: June 2018
• Actual Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00730158
• Other Study ID Numbers: 12-005; ACS IRG 58-012-49
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Edward Chu, MD, University of Pittsburgh
• Original Responsible Party: James Lee, M.D., Ph.D., Principal Investigator, Yale University School of Medicine
• Current Study Sponsor: Edward Chu, MD
• Original Study Sponsor: Yale University
• Collaborators: Kadmon Corporation, LLC

Investigators

• Principal Investigator: Edward Chu, MD; Hillman Cancer Center

• PRS Account: University of Pittsburgh
• Verification Date: April 2019