Phase I/IIa Study of Pharmacokinetics and Safety of Epidiferphane™ and Taxanes in Breast Cancer Patients

Study Overview
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Brief Summary
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Patients with breast cancer are commonly treated with taxane chemotherapy. Some very common side effects of taxanes, such as anemia and peripheral neuropathy, are often as not well addressed during treatment, resulting in dose reductions, dose delays and early discontinuation (collectively called relative dose intensity) of these chemotherapy agents in 15-80 % of patients on these drugs. This reduction in relative dose intensity (RDI) results in worse clinical outcomes such as progression free and overall survival. Pre-clinical studies in mouse models subjected to standardized chemotherapy regimens containing paclitaxel or oxaliplatin have shown that the nutritional supplement Epidiferphane™ reduces both neuropathy and anemia. This study will investigate whether the use of Epidiferphane™ in patients with breast cancer receiving taxane chemotherapy results in an attenuation of the side effects experienced, as well as an improvement in tumor response rate. The safety and maximum tolerated dose of Epidiferphane™ in this patient population will also be determined in this study.

Official Title
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Study of Pharmacokinetics and Safety of Epidiferphane™ and Taxanes in Breast Cancer Patients

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Epidiferphane
* Drug: Taxane Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be at least 18 years of age Subjects on the phase I portion must have a clinical diagnosis of metastatic breast cancer. Subjects on the phase IIa portion must have a clinical diagnosis of breast cancer of any stage and histology. Must be about to start a new chemotherapy treatment regimen containing either paclitaxel given weekly or docetaxel given every 3 weeks at UF Health Must continue cancer therapy at UF Health for at least the next three months A functioning digestive tract with no obstruction Subjects must be willing to avoid regular consumption of green tea for the duration of trial participation. Written informed consent obtained from the subject or the subject's legal representative and the ability for the subject to comply with all the study-related procedures. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study. Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study. Exclusion Criteria: Must not be receiving any other investigational agents Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and following completion of taxane therapy for an additional 6 months for women of child bearing potential and 3 months for men with partners of child bearing potential. Females who are pregnant or breastfeeding Active systemic infection considered to be opportunistic, life threatening or clinically significant at the time of treatment. Psychiatric illness or social situation that would limit compliance with trial requirements. Known allergy to turmeric, broccoli, or green tea. Subjects must not be on treatment with verapamil or tacrolimus during the trial. History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding (e.g. hemoglobin < 10 mg/dL, CTCAE v 5.0 grade 3 or higher neutropenia or thrombocytopenia) giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician. Prisoners or subjects who are involuntarily incarcerated. Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness. Subjects demonstrating an inability to comply with the study and/or follow-up procedures. CTCAE v 5.0 grade 2 or higher peripheral sensory or motor neuropathy CTCAE v 5.0 grade 1 or higher paresthesia Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) >2.5 × the upper limit of normal (ULN) Total bilirubin (TBL) >1.5 × ULN or >3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia) Glomerular filtration rate (GFR) <50 mL/min

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Epidiferphane + taxane chemotherapy<br> | Drug: Epidiferphane<br>* During the phase I portion of the study, subjects will be assigned to take either two (half target dose) or four (full target dose) Epidiferphane tablets orally three times daily following a 3 + 3 design. Three subjects will be sequentially enrolled at each of the 2 dose levels (beginning with the half target dose) until at least one dose-limiting toxicity (DLT) occurs. Dosing escalation will be stopped if two or more DLTs occur at either dose level. The maximum tolerated dose will be one dose level lower than the dose level at which 2 or more DLTs occur. Dose escalation will occur separately for each of the two taxane regimens (weekly paclitaxel or docetaxel every 3 weeks). All subjects in the phase IIa portion of the study will receive the maximum tolerated dose determined in the phase I portion of the study for their taxane regimen. Subjects in both portions of the study will receive treatment with Epidiferphane for a maximum of three months.<br>Drug: Taxane Chemotherapy<br>* All subjects on both phases of the study will be concurrently treated with a taxane regimen containing either paclitaxel given weekly or docetaxel given every 3 weeks. The choice of taxane regimen will be determined by the treating physician prior to consenting to participate in this trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of Epidiferphane's components | The Cmax of each of Epidiferphane's components will be based on blood concentration measured prior to taxane chemotherapy administration, as well as at 1, 2 and 24 hours after taxane chemotherapy administration. | 24 hours | 
| Rate of occurrence of DLTs by dose level in patients with breast cancer who are being treated with taxanes | This will be assessed by the rate of occurrence of DLTs by Epidiferphane dose level | 4 months | 
| Maximum tolerated dose of Epidiferphane in patients with breast cancer who are being treated with taxanes |  | 3 months | 
| Cmax of taxanes | The Cmax of the taxane chemotherapy agents given will be based on blood concentrations measured prior to taxane chemotherapy administration, as well as at 1, 2 and 24 hours after taxane chemotherapy administration. | 3 weeks | 
| Number of adverse events (graded according to CTCAE v5.0 criteria) by epidiferphane dose level |  | 4 months | 
| Concentration at 24 hours (C24 hours) of Epidiferphane's components | The C24 hours of each of Epidiferphane's components will be based on blood concentration measured 24 hours after taxane chemotherapy administration. | 24 hours | 
| Concentration at 24 hours (C24 hours) of taxanes | The C24 hours of the taxanes given will be based on blood concentration measured 24 hours after taxane chemotherapy administration. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CTCAE grade 2 or higher neuropathy and anemia, as compared to historically reported rates for the occurrence of each of these events |  | 4 months | 
| Effect of Epidiferphane on tumor response rate, as measured by RECIST 1.1 criteria and pathologic tumor response at surgery |  | 3 months | 
| Effect of Epidiferphane on the neuropathy marker NF-kB, as measured by multiplex cytokine bead analysis |  | 3 weeks | 
| Effect of Epidiferphane on the neuropathy marker VEGFA, as measured by multiplex cytokine bead analysis |  | 3 weeks | 
| Effect of Epidiferphane on the neuropathy marker Nrf2, as measured by multiplex cytokine bead analysis |  | 3 weeks | 
| Effect of Epidiferphane on the neuropathy marker IL18, as measured by multiplex cytokine bead analysis |  | 3 weeks | 
| Effect of Epidiferphane on quality of life, as measured by the EORTC QLQ-C30 scale | The EORTC QLQ-C30 measures ability to perform everyday activities and whether the subject has experienced select physical symptoms on a scale of 1-4 (with 1 meaning Not at all and 4 meaning Very much), as well as overall quality of life and overall healt over the past week on a scale from 1-7 (with 1 meaning Very Poor and 7 meaning Excellent). | 3 months | 
| Effect of Epidiferphane on quality of life, as measured by the FACT-Taxane scale | The FACT-Taxane measures various aspects of physical, social, emotional, and functional well-being, as well as whether the subject has experienced select physical symptoms over the past 7 days, on a scale of 0-4 (with 0 meaning Not at all and 4 meaning Very much). | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, Epidiferphane, taxane