Phase I dose-escalation study of plitidepsin in combination with bevacizumab in patients with refractory solid tumors.
This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m, n=3; 3.8 mg/m, n=4; and 4.8 mg/m, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.
aJules Bordet Institute, Brussels, Belgium bGustave Roussy, Paris-Saclay University, Drug Development Department (DITEP), Villejuif, France cPharma Mar, S.A., Avenida de los Reyes, 1, Polígono Industrial La Mina-Norte, 28770 Colmenar Viejo, Madrid, Spain.
Sandrine
S
Aspeslagh
Ahmad
A
Awada
Arturo
A
S Matos-Pita
Philippe
P
Aftimos
Ratislav
R
Bahleda
Andréa
A
Varga
Jean-Charles
JC
Soria
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010456:Peptides, Cyclic; D011446:Prospective Studies; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism
D047630:Depsipeptides; D010456:Peptides, Cyclic; D000068258:Bevacizumab; C098980:plitidepsin