Phase I study of muscadine grape extract in advanced malignancy

Background: Preclinical studies with muscadine grape extract (MGE) show anti-tumor activity and decreased systemic inflammation. This phase I study (NCT02583269) assessed safety and tolerability of a proprietary MGE in patients (pts) with advanced solid tumors. Methods: Adult pts with metastatic or unresectable malignancy progressing on standard therapies were assigned to MGE (∼160 mg total phenolics/capsule, Piedmont R&D) in a standard 3 + 3 design. Five dose levels were tested (320 to 1600 mg total phenolics/day). Safety and maximum tolerated dose (MTD) were assessed after 4 weeks. Pts were evaluated for response at 8 weeks and continued on MGE if clinically stable. Secondary outcomes were adherence, quality of life (QOL) by Functional Assessment of Cancer Therapy-General [FACT-G] and PROMIS-fatigue, and overall survival (OS). Median time on therapy and OS were estimated using the Kaplan-Meier method. Change in QOL outcomes were compared to zero using a one-sample t-test, and correlated with dose using Pearson correlation. Results: 23 pts (lung n = 7 ; gastrointestinal n = 7; genitourinary n = 6; other n = 3) received MGE in 5 dose levels: 1 (n = 3), 2 (n = 7), 3 (n = 3), 4 (n = 4), 5 (maximum administered dose, n = 6) capsules by mouth twice daily. Two pts were inevaluable at 4 weeks (1 withdrew, 1 noncompliant). The evaluable cohort (median age 72 y [range 43- 86], 48% female, 95% white) was heavily pre-treated. After 4 weeks on MGE, possibly-attributable grade 2-3 adverse events (AEs) were decreased lymphocytes (4.7%), fatigue (4.7%), and constipation (9.5%), including one dose limiting toxicity for grade 3 constipation requiring hospitalization. Dose level 2 was expanded accordingly. There were no > grade 3 AEs. MTD was not reached. 93% of pts took ≥ 80% of pills prescribed. Median time on therapy was 8.1 weeks (95% CI 7.7, 20.3) with a 7.1 month median OS (95% CI 4.3, 12.2). QOL and fatigue levels were stable from baseline to 4 and 8 weeks (p values > 0.2). Higher MGE dose was correlated with improvement in self-reported physical function at 8 weeks (r = 0.56, p = 0.04). Conclusions: MGE is safe and well-tolerated in heavily pretreated and elderly cancer pts. The relationship between MGE and improved physical function warrants further study.