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: Pierpaolo Correale, Cirino Botta, Elodia Claudio Martino, Cristina Ulivieri, Giuseppe Battaglia, Tommaso Carfagno, Maria Grazia Rossetti, Antonella Fioravanti, Giacomo Maria Guidelli, Sara Cheleschi, Claudia Gandolfo, Francesco Carbone, Tatiana Cosima Baldari, Pierfrancesco Tassone, Pierosandro Tagliaferri, Luigi Pirtoli, Maria Grazia Cusi
• Journal: Oncoimmunology (Oncoimmunology) Vol. 5 Issue 4 Pg. e1101205 (Apr 2016) ISSN: 2162-4011 [Print] United States
• PMID: 27141384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)