title: Phase Ib study of poly-epitope peptide vaccination to thymidylate synthase (TSPP) and GOLFIG chemo-immunotherapy for treatment of metastatic colorectal cancer patients.
abstract: Thymidylate synthase (TS) is a tumor-associated enzyme critical for DNA replication and main 5'-fluorouracil (5'-FU) target. TSPP/VAC1 is a multi-arm trial phase-Ib trial program aimed to investigate the toxicity and biomodulatory activity of a poly-epitope-peptide vaccine to TS (TSPP) in cancer patients (pts). Here, we present the results of the TSPP/VAC1/arm C trial aimed to evaluate TSPP in combination with chemo-immunotherapy in pretreated metastatic colo-rectal cancer (mCRC) pts. Twenty-nine pts, 14 males and 15 females, received poly-chemotherapy with gemcitabine [GEM; 1,000 mg/sqm, day-1], oxaliplatin [OX; 80 mg/sqm, day-2], levofolinate [100 mg/sqm, days 1-2], bolus/infusional 5'-FU [400 mg/800 mg/sqm, days 1-2], sargramostim [50 μg, days 3-7/q30], and interleukin-2 [sc. 0.5 MIU twice a day, days 8-14/18-30] [GOLFIG-regimen]. Seventeen pts received sc. TSPP injections at escalating dosage [3 pts, 100 µg (DL-1); 3 pts, 200 µg (DL-2) and 11pts, 300 µg (DL-3)] one week after each chemotherapy cycle (concomitant module), while 10 out 12 pts received TSPP (300 µg) after 12 GOLFIG courses [dose level (DL)-0] (sequential module). TSPP MTD was not achieved. Adverse events consisted in swelling/erythema at injection sites (17 cases), G1-2 haematological (16 cases) and gastro-enteric events (12), fever, rhinitis, conjunctivitis, and poly-arthralgia and rise in auto-antibodies [ANA, ENA, c-ANCA, p-ANCA in the DL1-3 pts]. Both treatment-modules showed immunomodulating and antitumor activity (disease-control-rate, DL1-3 and DL0 were 70.6% and 83.3%, respectively) with a better survival recorded in the second group [median OS DL1-3 vs. DL0 = 8 vs. 16 mo,p= 0.049]. The promising long-term survival produced by the sequential treatment module deserves further phase II evaluation.
authors.affiliation: Unit of Radiotherapy, Department of Oncology, University of Siena , Italy.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Correale
authors.affiliation: Medical Oncology Unit, Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro , Italy.
authors.forename: Cirino
authors.initials: C
authors.lastname: Botta
authors.affiliation: Unit of Radiotherapy, Department of Oncology, University of Siena , Italy.
authors.forename: Elodia Claudio
authors.initials: EC
authors.lastname: Martino
authors.affiliation: Department of Science of Life, University of Siena , Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ulivieri
authors.affiliation: Unit of Radiotherapy, Department of Oncology, University of Siena , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: Unit of Radiotherapy, Department of Oncology, University of Siena , Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Carfagno
authors.affiliation: Unit of Pharmacy, Siena University Hospital , Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Rossetti
authors.affiliation: Unit of Rheumatology, Department of Clinical Medicine and Immunologic Sciences, University of Siena , Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Fioravanti
authors.affiliation: Unit of Rheumatology, Department of Clinical Medicine and Immunologic Sciences, University of Siena , Italy.
authors.forename: Giacomo Maria
authors.initials: GM
authors.lastname: Guidelli
authors.affiliation: Unit of Rheumatology, Department of Clinical Medicine and Immunologic Sciences, University of Siena , Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cheleschi
authors.affiliation: Microbiology and Virology Unit, Department of Medical Biotechnology, University of Siena , Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gandolfo
authors.affiliation: Unit of Radiology, Department of Oncology, University of Siena , Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Carbone
authors.affiliation: Department of Science of Life, University of Siena , Italy.
authors.forename: Tatiana Cosima
authors.initials: TC
authors.lastname: Baldari
authors.affiliation: Medical Oncology Unit, Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro , Italy.
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Medical Oncology Unit, Department of Experimental and Clinical Medicine, "Magna Graecia" University of Catanzaro , Italy.
authors.forename: Pierosandro
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Unit of Radiotherapy, Department of Oncology, University of Siena , Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Pirtoli
authors.affiliation: Microbiology and Virology Unit, Department of Medical Biotechnology, University of Siena , Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cusi
keywords: CTLs; Colon cancer; GOLFIG chemo-immunotherapy; epitope peptides; peptide vaccine; thymidylate synthase