Muscadine Grape Skin Extract in Treating Patients With Malignancy That Is Metastatic or Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase I trial studies the side effects and the best dose of muscadine grape skin extract (MGE) in treating patients with malignancy (tumor or cancer) that has spread to other parts of the body or cannot be removed by surgery. MGE is a nutritional supplement containing an extract of the skin of muscadine grape that has shown anti-cancer activity in laboratory studies and may be able to fight or kill malignant cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety and maximum tolerated dose (MTD) of MGE (muscadine grape skin extract) after 4 weeks of administration for patients with metastatic cancer. Secondary Objectives: I. To monitor adverse events/toxicity every 4 weeks while on treatment. II. To evaluate change in phenolic levels (total and component, blood and urine) from baseline to 4 and 8 weeks. III. To evaluate change in serum cytokines and growth factors from baseline to 4 and 8 weeks on MGE. IV. To observe the response rate of MGE in patients with metastatic cancer. V. To assess overall and progression-free survival in patients with metastatic cancer receiving MGE. VI. To assess global quality of life (Functional Assessment of Cancer Therapy-General [FACT-G] and fatigue (Patient Reported Outcomes Measurement Information System [PROMIS]-fatigue Short Form [SF]) in cancer patients taking MGE. VII. To assess adherence to MGE treatment. OUTLINE: This is a dose-escalation study. Patients receive muscadine grape skin extract orally (PO) twice daily (BID). Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing benefit from muscadine grape skin extract may continue treatment in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then every 6 weeks.

Official Title
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Phase I Study of Muscadine Grape Extract (MGE) in Advanced Malignancy

Conditions
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Advanced Malignant Neoplasm, Metastatic Malignant Neoplasm, Unresectable Malignant Neoplasm

Intervention / Treatment
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* Diagnostic Test: Laboratory Biomarker Analysis
* Drug: Muscadine Grape Skin Extract
* Procedure: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed malignancy that is metastatic or unresectable and have failed standard therapies Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Absolute neutrophil count >= 1000/mcL Platelets >= 50,000/mcL Total bilirubin within normal institutional limits Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit or normal Creatinine clearance >= 40 mL/min Stable supplement usage for > 2 weeks prior to starting and agrees not to change while on this study Life expectancy > 3 months Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Patients may not be receiving any other investigational cancer-directed agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to MGE Patients unable to take oral medications or those with history of malabsorption due to bowel resection Patients with uncontrolled diarrhea or persistent nausea/vomiting requiring daily antiemetic therapy for symptom management Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; breastfeeding should be discontinued Patients with primary brain tumors are excluded

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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (muscadine grape skin extract) 1 pill 2 times a day<br>Patients receive muscadine grape skin extract PO BID. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing benefit from muscadine grape skin extract may continue treatment in the absence of disease progression or unacceptable toxicity. | Diagnostic Test: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Muscadine Grape Skin Extract<br>* Given PO<br>* Other names: MSKE;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm 2 (muscadine grape skin extract) 2 pills 2 times a day<br>Patients receive muscadine grape skin extract PO BID. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing benefit from muscadine grape skin extract may continue treatment in the absence of disease progression or unacceptable toxicity. | Diagnostic Test: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Muscadine Grape Skin Extract<br>* Given PO<br>* Other names: MSKE;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm 3 (muscadine grape skin extract) 3 pills 2 times a day<br>Patients receive muscadine grape skin extract PO BID. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing benefit from muscadine grape skin extract may continue treatment in the absence of disease progression or unacceptable toxicity. | Diagnostic Test: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Muscadine Grape Skin Extract<br>* Given PO<br>* Other names: MSKE;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm 4 (muscadine grape skin extract) 4 pills 2 times a day<br>Patients receive muscadine grape skin extract PO BID. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing benefit from muscadine grape skin extract may continue treatment in the absence of disease progression or unacceptable toxicity. | Diagnostic Test: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Muscadine Grape Skin Extract<br>* Given PO<br>* Other names: MSKE;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm 5 muscadine grape skin extract) 5 pills 2 times a day<br>Patients receive muscadine grape skin extract PO BID. Treatment continues for 8 weeks in the absence of disease progression or unacceptable toxicity. Patients experiencing benefit from muscadine grape skin extract may continue treatment in the absence of disease progression or unacceptable toxicity. | Diagnostic Test: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Muscadine Grape Skin Extract<br>* Given PO<br>* Other names: MSKE;Procedure: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicity | Maximum tolerable dose of muscadine grape extract is defined as the dose level immediately below the dose level that induced a dose-limiting toxicity (DLT) in >= 2 patients, as assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0DLT will be assessed by severity of adverse events. | 29 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adherence to MGE Treatment, as Measured by Percent of Pills Taken at the End of Every 4 Week Period | Pill count will be calculated from counting the number of pills returned as well as by summarizing the patient's pill diary. The percent of pills taken will be summarized by dose level using the median and 95% confidence interval. Investigators will summarize the percent of pills taken at the end of every 4 week period i using the formula: Percent of pills taken)i = (Dose Level ×7 ×4)i minus Pill Count divided by Dose Level ×7 ×4)i | Up to 1 year | 
| Best Response | Best response will be characterized using a frequency table. Evaluation of new or enlarging effusions to differentiate between Progressive Disease and Response/Stable Disease. Measurements will be obtained from usual care imaging and assessed by the principal investigators in confirmation with the physician of record. Clinical lesions will only be considered measurable when they are superficial and ≥10 mm in diameter as assessed using calipers. For the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. | At the end of treatment, up to 1 year | 
| Change in Total Phenolic Levels in Blood | A mixed model analysis of variance (ANOVA) model will be fit with phenolic level as the outcome and time (baseline, 4, and 8 weeks) as a fixed effect and subject as a random effect. Contrasts will be used to estimate the changes from baseline to week 4 and week 8. | Baseline to up to 8 weeks | 
| Change in Total Phenolic Levels in Urine | A mixed model analysis of variance (ANOVA) model will be fit with phenolic level as the outcome and time (baseline, 4, and 8 weeks) as a fixed effect and subject as a random effect. Contrasts will be used to estimate the changes from baseline to week 4 and week 8. | Baseline to up to 8 weeks | 
| Change in Quality of Life and Fatigue in Cancer Patients Taking MGE as Measured by FACT-G | A mixed model ANOVA model will be fit with phenolic level as the outcome and time (baseline, every 4 weeks) as a fixed effect and subject as a random effect. Contrasts will be use to estimate changes from baseline to each follow-up time period. Score scales from 0 (not at all) to 4 (very much). Sum of scores range 0-28 for social, functional and physical well being and 0-24 for emotional well being and multiplied by 6. All four scores are totaled with a score range of 0-108. A mean of the combined group scores will be used. A higher score indicates a higher worse outcome of the illness on the participant. | Baseline to up to 1 year | 
| Change in Systemic Cytokine Levels | A mixed model ANOVA model will fit with the outcome of interest (cytokine or growth factor) as the outcome and time (baseline, 4, and 8 weeks) as a fixed effect and subject as a random effect. Contrasts will be used to estimate the changes from baseline to week 4 and week 8. | Baseline to up to 8 weeks | 
| Incidence of Adverse Events (AEs), Assessed Using NCI CTCAE Version 4.0 | AEs/toxicity will be assessed at weeks 4, 8 and every 4 weeks thereafter if patients remain on treatment. Any expected toxicities, any laboratory based toxicities, and any grade 3 or higher gastrointestinal toxicities, and any grade 4 or higher toxicities will be summarized using frequency tables overall and by week. | Up to 1 year | 
| Overall Response Rate of MGE (Complete Response, Partial Response, and Stable Disease) | Response will be characterized using a frequency table. | At 8 weeks | 
| Overall Survival (OS) | OS will summarized using the Kaplan-Meier method. Median survival rates and associated 95% confidence intervals will be calculated. | Up to 4 years | 
| Progression-free Survival (PFS) | PFS will summarized using the Kaplan-Meier method. | Up to 4 years | 
| Change in Component Phenolic Levels in Urine | A mixed model analysis of variance (ANOVA) model will be fit with phenolic level as the outcome and time (baseline, 4, and 8 weeks) as a fixed effect and subject as a random effect. Contrasts will be used to estimate the changes from baseline to week 4 and week 8. | Baseline to up to 8 weeks | 
| Change in Component Phenolic Levels in Blood | A mixed model analysis of variance (ANOVA) model will be fit with phenolic level as the outcome and time (baseline, 4, and 8 weeks) as a fixed effect and subject as a random effect. Contrasts will be used to estimate the changes from baseline to week 4 and week 8. | Baseline to up to 8 weeks | 
| Change in Quality of Life and Fatigue in Cancer Patients Taking MGE as Measured by PROMIS-Fatigue SF | A mixed model ANOVA model will be fit with phenolic level as the outcome and time (baseline, every 4 weeks) as a fixed effect and subject as a random effect. Contrasts will be use to estimate changes from baseline to each follow-up time period. A 6-item questionnaire with T-score responses ranging from a minimum of 33.4 to a maximum of 76.8. Higher scores equals more of the concept being measured. | Baseline to up to 1 year | 
| Change in Systemic Cytokine Levels (Log IL-8) | A mixed model ANOVA model will fit with the outcome of interest (cytokine or growth factor) as the outcome and time (baseline, 4, and 8 weeks) as a fixed effect and subject as a random effect. Contrasts will be used to estimate the changes from baseline to week 4 and week 8. | Baseline to up to 8 weeks | 
| Change in Systemic Cytokine Levels (Log VEGF) | A mixed model ANOVA model will fit with the outcome of interest (cytokine or growth factor) as the outcome and time (baseline, 4, and 8 weeks) as a fixed effect and subject as a random effect. Contrasts will be used to estimate the changes from baseline to week 4 and week 8. | Baseline to up to 8 weeks |