Genomically matched therapy in refractory colorectal cancer according to ESMO Scale for Clinical Actionability of Molecular Targets: experience of a comprehensive cancer centre network.

Efficiency of expanded genomic profiling (EGP) programmes in terms of final inclusion of patients in genomically matched therapies is still unknown. Fit patients with advanced and refractory colorectal cancer (CRC) were selected for an EGP programme. Next-generation sequencing (NGS) analysis from formalin-fixed paraffin-embedded tumour samples was performed. The purpose was to describe the prevalence of genomic alterations defined by the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), as well as the percentage of patients finally included in genomically guided clinical trials. In total, 187 patients were recruited. Mutational profile was obtained in 177 patients (10 patients were failure due to insufficient tumour sample), copy number alterations in 41 patients and fusions in 31 patients. ESCAT-defined alterations were detected in 28.8% of the intention-to-analyse population. BRAF V600E was clustered in ESCAT I, with a prevalence of 3.7%, KRAS G12C and ERBB2 amplification were clustered in ESCAT II, whose prevalence was 4.2% and 1.6%, respectively. Most alterations were classified in ESCAT III (mutations in ERBB2, PIK3CA or FGFR genes and MET amplification) and IV (mutations in BRAF non-V600E, ERBB3, FBXW7, NOTCH, RNF43), with a single prevalence under 5%, except for PIK3CA mutation (9%). The final rate of inclusion into genomically guided clinical trials was 2.7%, including therapies targeting BRAF V600E or RNF43 mutations in two patients each, and ERBB2 mutation in one patient. In conclusion, EGP programmes in patients with advanced CRC are feasible and identify a subset of patients with potentially druggable genomic alterations. However, further efforts must be made to increase the rate of patients treated with genomically guided therapies.

A Phase 1 Trial of Oncolytic Adenovirus ICOVIR-5 Administered Intravenously to Cutaneous and Uveal Melanoma Patients.

Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic, and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in the United States and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically. Among different viruses, adenovirus has been extensively used in clinical trials but with few evidences of activity upon systemic administration. Preclinical efficacy of a single intravenous administration of our oncolytic adenovirus ICOVIR5, an adenovirus type 5 responsive to the retinoblastoma pathway commonly deregulated in tumors, led us to use this virus in a dose-escalation phase 1 trial in metastatic melanoma patients. The results in 12 patients treated with a single infusion of a dose up to 1 × 1013 viral particles show that ICOVIR5 can reach melanoma metastases upon a single intravenous administration but fails to induce tumor regressions. These results support the systemic administration of armed oncolytic viruses to treat disseminated cancer.

Complete and sustained objective response per RECIST to Irvalec (PM02734) in undifferentiated large cell esophageal adenocarcinoma: A case report and a review of the literature.

Undifferentiated large cell carcinoma is a rare entity in esophageal cancer and very few data are available in the literature on this uncommon histological subtype. We report a case of a 58-year-old Caucasian male previously treated with cisplatin/5-fluorouracil, docetaxel and carboplatin/plitidepsin who received treatment with a novel antitumor agent, Irvalec (PM02734), as fourth line. The patient received treatment from July 2006 to July 2009, a total of 49 cycles, at a dose of 2.4 mg/m(2) as a 24-hour infusion every 3 weeks. He did not present severe complications or unplanned or cumulative toxicities. Complete and durable response according to RECIST was reported. He was alive at the last follow-up on March 2012.

Phase I and pharmacokinetic study of trabectedin 3-hour infusion every three weeks in patients with advanced cancer and alteration of hepatic function.

Maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics (PK) were evaluated for trabectedin 3-h every-3-weeks schedule in 33 cancer patients stratified according to liver dysfunction degree as per baseline alkaline phosphatase (AP). Stratification was as follows: stratum I [upper limit of normal (ULN) < AP ≤ 1.5 × ULN; n = 16], stratum II [1.5 × ULN < AP ≤ 2.5 × ULN; n = 12], and stratum III [AP >2.5 × ULN; n = 5] (bilirubin <2.5 × ULN for all 3 strata). In each stratum, patients were treated in sequential cohorts at escalating doses. Dose-limiting toxicities (DLTs) were grade 3 transaminase increases not recovering baseline values on day 21, febrile neutropenia/grade 4 neutropenia lasting >5 days and AP increase more than twice over baseline. The MTD and RD for stratum I (mild baseline AP) was 1.3 mg/m(2). Recruitment was stopped early in strata II/III (moderate/severe baseline AP) without reaching the MTD due to slow accrual and difficulty in finding patients. Biochemical parameters other than AP (bilirubin, AST or ALT) were similar between strata. No relevant PK differences were found between strata. In conclusion, the MTD and RD (1.3 mg/m(2)) were confirmed only for stratum I. Stratification criteria based on baseline AP apparently did not segregate the patients according to their liver dysfunction degree. Antitumor activity was found in patients with pretreated ovarian cancer.

A phase I clinical and pharmacokinetic study (LIPOTEC - GP PHARM/DOXO 01) of a new liposomal doxorubicin given as 3-week schedule in patients with solid tumors.

As a dose-finding phase I study of a new liposomal formulation of doxorubicin (LipD), patients (n = 39; median age: 60 years; range, 41-75; median ECOG performance status, 1; range, 0-2) with refractory cancer had a starting dose of LipD administered at 30 mg/m(2) as a 1-hour intravenous infusion. Cycle duration was 21 days. At the recommended dose (RD), patients received a first cycle of nonliposomal doxorubicin (non-LipD) to evaluate intrapatient pharmacokinetic differences between non-LipD and LipD. The most frequent diagnosis was head and neck tumor (7 patients). Tolerance and safety of dose levels of 30, 40, 50, 60, 70, 80, and 90 mg/m(2) were evaluated. A total of 131 cycles were administered (median per patient, 3; range, 1-6). Of the 39 patients, 8 completed the planned six cycles. Febrile neutropenia was dose limiting and defined the toxic dose of LipD as 70 mg/m(2). Other significant toxicities included asthenia (G2: 31%; G3: 8%), neutropenia (G3: 35%; G4: 29%), thrombopenia (G3: 15%; G4: 2%), anemia (G1-G2: 67%; G3-G4: 5%), mucositis (G1-G2: 32%, G3: 4%), and acute allergic reactions (G1-G2: 36%). Comparison of pharmacokinetic profiles of non-LipD and LipD showed that higher exposure was achieved with LipD. Stable disease was observed in 14 patients. We conclude that the LipD regimen, given as a 1-hour infusion every 3 weeks, is well tolerated and has a favorable pharmacokinetic profile. The recommended dose is 70 mg/m(2) with prophylactic antihistamines and corticoids to preempt allergic reaction.