title: The tumor-targeting immunocytokine F16-IL2 in combination with doxorubicin: dose escalation in patients with advanced solid tumors and expansion into patients with metastatic breast cancer.
abstract: A phase Ib/II trial was performed to evaluate safety, tolerability, recommended dose (RD) and efficacy of F16-IL2, a recombinant antibody-cytokine fusion protein, in combination with doxorubicin in patients with solid tumors (phase Ib) and metastatic breast cancer (phase II). Six patient cohorts with progressive solid tumors (n = 19) received escalating doses of F16-IL2 [5-25 Million International Units (MIU) of IL2 equivalent dose] in combination with escalating doses of doxorubicin (0-25 mg/m(2)) on day 1, 8 and 15 every 4 weeks. Subsequently, patients with metastatic breast cancer (n = 10) received the drug combination at the RD. Clinical data and laboratory findings were analyzed for safety, tolerability, and activity. F16-IL2 could be administered up to 25 MIU, in combination with the RD of doxorubicin (25 mg/m(2)). No human anti-fusion protein antibodies (HAFA) response was detected. Pharmacokinetics of F16-IL2 was dose-dependent over the tested range, with half-lives of ca. 13 and ca. 8 hours for cohorts dosed at lower and higher levels, respectively. Toxicities were controllable and reversible, with no combination treatment-related death. After 8 weeks, 57% and 67% disease control rates were observed for Phase I and II, respectively (decreasing to 43% and 33% after 12 weeks), considering 14 and 9 patients evaluable for efficacy. One patient experienced a long lasting partial response (45 weeks), still on-going at exit of study. F16-IL2 can be safely and repeatedly administered at the RD of 25 MIU in combination with 25 mg/m(2) doxorubicin; its safety and activity are currently being investigated in combination with other chemotherapeutics, in order to establish optimal therapy settings.
authors.affiliation: a Clinical Pharmacology and New Drugs Development Unit; European Institute of Oncology; Milan , Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Catania
authors.forename: Michela
authors.initials: M
authors.lastname: Maur
authors.forename: Rossana
authors.initials: R
authors.lastname: Berardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Rocca
authors.forename: Anna Maria Di
authors.initials: AM
authors.lastname: Giacomo
authors.forename: Gianluca
authors.initials: G
authors.lastname: Spitaleri
authors.forename: Cristina
authors.initials: C
authors.lastname: Masini
authors.forename: Chiara
authors.initials: C
authors.lastname: Pierantoni
authors.forename: Reinerio
authors.initials: R
authors.lastname: González-Iglesias
authors.forename: Giulia
authors.initials: G
authors.lastname: Zigon
authors.forename: Annaelisa
authors.initials: A
authors.lastname: Tasciotti
authors.forename: Leonardo
authors.initials: L
authors.lastname: Giovannoni
authors.forename: Valeria
authors.initials: V
authors.lastname: Lovato
authors.forename: Giuliano
authors.initials: G
authors.lastname: Elia
authors.forename: Hans D
authors.initials: HD
authors.lastname: Menssen
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.forename: Stefano
authors.initials: S
authors.lastname: Cascinu
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Conte
authors.forename: Filippo de
authors.initials: Fd
authors.lastname: Braud
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; C508594:IL2 protein, human; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin
keywords: antibody; breast neoplasms; clinical trial phase I; immunocytokines; interleukin-2