A phase I evaluation of the effect of curcumin on dose‐limiting toxicity and pharmacokinetics of irinotecan in participants with solid tumors

Curcumin inhibits UDP‐glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration. Ten participants with advanced solid tumors received one of four doses (1, 2, 3, and 4 g) of a curcumin phosphatidylcholine complex (PC) orally daily, and 200 mg/m² of i.v. infusion irinotecan on days 1 and 15 of a 28‐day cycle, to determine the maximum tolerated dose (MTD) of PC. Thirteen participants received 4 g of PC (MTD) to assess the effect on the pharmacokinetic (PK) properties of irinotecan and its metabolites, SN‐38 and SN‐38G. Irinotecan, SN‐38, and SN‐38G exposure equivalence with and without curcumin was assessed using area under the plasma concentration‐time curves from 0 to 6 h (AUC_0‐6h). Safety assessments and disease responses were also evaluated. The combination of irinotecan and PC was well‐tolerated. Because there was no dose limiting toxicity, the maximum dose administered (4 g) was defined as the recommended phase II dose of PC. PC did not significantly alter the plasma exposure and other PK properties of irinotecan and its metabolites. There was no apparent increase in the incidence of irinotecan‐associated toxicities. The objective response rate was 3/19 (22%, 95% confidence interval [CI]: 5–39%), median progression free survival and overall survival (n = 23) were 4 months (95% CI: 2.9–8.9 months) and 8.4 months (95% CI: 3.7 – not evaluable [NE]), respectively. Future studies are required to evaluate the efficacy of this combination.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Curcumin can be safely administered with some standard chemotherapy agents like gemcitabine, taxanes, and 5‐fluorouracil.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Both curcumin and irinotecan are metabolized by UGT enzymes and concurrent administration may affect the pharmacokinetics (PKs) and clinical effect of irinotecan. This study sought to assess the effect of curcumin on the PK properties and adverse effect profile of irinotecan.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Up to 4 g of a phosphatidylcholine curcumin (PC) formulation can be safely administered with irinotecan without an impact on the PK and adverse event profile of irinotecan.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Curcumin’s anticancer properties have been documented. Higher doses of PC can be investigated to determine a dose that acts synergistically with irinotecan to improve clinical outcomes.