Phase I dose-escalation study of plitidepsin in combination with sorafenib or gemcitabine in patients with refractory solid tumors or lymphomas

Abstract

This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously). In the G/P arm, patients with solid tumors or lymphoma were treated at four different DLs with a combination of gemcitabine (DL1: 750 mg/m, DL2-DL4: 1000 mg/m) and plitidepsin (DL1-DL2: 1.8 mg/m; DL3: 2.4 mg/m; DL4: 3 mg/m). Both agents were administered intravenously on day 1, day 8, day 15, and, q4wk. Forty-four patients were evaluable for safety and toxicity. The safety of the combination of plitidepsin with sorafenib or gemcitabine was manageable. Most adverse events (AEs) were mild; no grade 4 treatment-related AEs were reported in any of the groups (except for one grade 4 thrombocytopenia in the gemcitabine arm). The most frequently reported study drug-related (or of unknown relationship) AEs were palmar-plantar erythrodysesthesia, erythema, nausea, vomiting, and fatigue in the S/P arm and nausea, fatigue, and vomiting in the G/P arm. In the S/P arm, one dose-limiting toxicity occurred in two out of six patients treated at the maximum dose tested (DL2): palmar-plantar erythrodysesthesia and grade 2 aspartate aminotransferase/alanine aminotransferase increase that resulted in omission of days 8 and 15 plitidepsin infusions. In the G/P arm, one dose-limiting toxicity occurred in two out of six patients at DL4: grade 2 alanine aminotransferase increase resulted in omission of days 8 and 15 plitidepsin infusions and grade 4 thrombocytopenia. The recommended dose for the combination of plitidepsin with sorafenib was not defined because of a sponsor decision (no expansion cohort to confirm) and for plitidepsin with gemcitabine, it was 2.4 mg/m plitidepsin with 1000 mg/m gemcitabine. In the S/P group, objective disease responses were not observed; however, disease stabilization (≥3months) was observed in four patients. In the gemcitabine group, two lymphoma patients showed an objective response (partial response and complete response) and nine patients showed disease stabilization (≥3months). Combining plitidepsin with gemcitabine and sorafenib is feasible for advanced cancer patients; some objective responses were observed in heavily pretreated lymphoma patients.

Marine natural products

“…Trabectedin (ecteinascidin 743) exhibits in vitro and in vivo activity towards clear cell sarcoma cell lines, 689 while phase I trial data for plitidepsin (Aplidin®) in combination with sorafenib or gemcitabine shows them to be manageably safe with some objective responses observed. 690 Pharmacokinetic experiments with 14 C-plitidepsin show that 77.4% is excreted over 20 days, mainly in faeces, and that higher levels were detected in whole blood compared to plasma, indicating that red blood cells are the major distribution compartment. 691…”

Sandensolide Induces Oxidative Stress-Mediated Apoptosis in Oral Cancer Cells and in Zebrafish Xenograft Model

“…The application of natural products for chemoprevention and therapy has been becoming a more and more important issue over the past three decades [ 19 , 20 , 21 ]. Several studies have shown that some marine-derived compounds possess biological activity and pharmacological effect in cancer models with little or no side effects [ 22 , 23 , 24 ]. To the best of our knowledge, this is the first study illustrating the anti-cancer effect of sandensolide on OSCC cells and a zebrafish xenograft model, which also highlights the possible mechanism underlying the cytotoxic effect of sandensolide.…”

Starvation tactics using natural compounds for advanced cancers: pharmacodynamics, clinical efficacy, and predictive biomarkers

“…Overall, the safety profile of plitidepsin was considered manageable and included reversible myalgia with oral carnitine treatment, transaminase elevation, fatigue, vomiting, and nausea. The recommended dose ranged from 1.2 to 5 mg/m 2 (7 mg/m 2 + carnitine) . In phase II trials (summarized in Table ), plitidepsin showed disappointing activities on several advanced malignancies including liposarcoma, melanoma, thyroid carcinoma, lung cancer, renal cell carcinoma, and other refractory hematologic cancers.…”

“…Plitidepsin alone 1-h intravenous infusion of plitidepsin (starting dose of 0.08 mg/m 2 ) given daily for 5 days q3 wk Nausea, vomiting, and diarrhea Myalgia, fatigue, and skin rash 1.2 mg/m 2 dose ranged from 1.2 to 5 mg/m 2 (7 mg/m 2 + carnitine) [165][166][167][168][169][170][171][172]. In phase II trials (summarized in Table 4), plitidepsin showed disappointing activities on several advanced malignancies including liposarcoma, melanoma, thyroid carcinoma, lung cancer, renal cell carcinoma, and other refractory hematologic cancers.…”