Clinical activity of a htert (vx-001) cancer vaccine as post-chemotherapy maintenance immunotherapy in patients with stage IV non-small cell lung cancer: final results of a randomised phase 2 clinical trial.

BACKGROUND: The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT572 CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC). METHODS: A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS. RESULTS: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004). CONCLUSION: Vx-001 could induce specific CD8+ immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001. CLINICAL TRIAL REGISTRATION: NCT01935154.

Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study.

BACKGROUND: Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer. METHODS: Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or maximum 24 months. Primary endpoint was time-to-treatment failure (TTF) and secondary were progression-free survival (PFS), toxicity, changes in blood concentrations of angiogenesis-associated biomarkers and pharmacokinetics. RESULTS: Seventy-three patients were enrolled. Four-month TTF rate did not differ between the three arms: 25.9% (11.1%-46.2% 95% Confidence Interval), 33.3% (15.6%-55.3%) and 18.2% (5.2%-40.3%) for the 30 mg, 40 mg and 50 mg arms (p-value = 0.56). Objective response was seen in 2 patients with NSCLC (treated at 30 and 50 mg respectively), one with BC (at 40 m g) and one with PC (at 50 mg) and lasted from 4 to 100 weeks, with maximum response duration achieved at 50 mg. Adverse events were mild and negligible and did not differ between the three arms. Blood levels of vinorelbine reached steady state from the second week of treatment and mean values for the 30, 40 and 50 mg were respectively 1.8 ng/ml (SD 1.10), 2.2 ng/ml (SD 1.87) and 2.6 ng/ml (SD 0.69). Low pre-treatment blood concentrations of FGF2 and IL8 predicted favorable response to therapy (p values 0.02 and 0.006, respectively), while high levels of TEK gene transcript predicted treatment resistance. CONCLUSIONS: Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, we suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine. Further investigation of metronomic oral vinorelbine (MOVIN) at this dose is warranted in combination with conventional chemotherapy regimens and targeted therapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT00278070.

Hypersensitivity reactions associated with oxaliplatin and their clinical management.

INTRODUCTION: Oxaliplatin , has become an integral part of the medical treatment of colorectal cancer and other malignancies. Increased use of the drug during the last decade, has led to increased occurrence of oxaliplatin-induced hypersensitivity reactions (HSRs), posing a significant challenge for clinicians. This article aims to review the existing literature regarding the incidence, clinical presentation, pathophysiology, risk factors and current management of oxaliplatin-induced HSRs. AREAS COVERED: A systematic review of the English literature published in PubMed and Medline was undertaken. The clinical manifestations of HSRs were found to be variable and unpredictable. These reactions should be an important concern, as their potential life-threatening risks can force doctors to stop treatment and seek alternatives, which may be less effective, not as well tolerated and/or more expensive. There are a few strategies to prevent these reactions so that patients can still benefit from oxaliplatin. Such strategies include the use of premedication (steroid and antagonists of type I and II histamine receptors), prolonged infusion time and desensitization. EXPERT OPINION: The presented management strategies as well as novel diagnostic tools including skin/intradermal tests and specific IgE have shown promising results. However, future research and validation are warranted in bigger clinical trials.

Prognostic significance of bone markers in patients with lung cancer metastatic to the skeleton: a review of published data.

The presence of bone metastases significantly affects clinical outcome and quality of life parameters in patients with lung cancer. In this review, we aimed to evaluate the predictive value of markers of bone turnover in skeletal morbidity and clinical parameters, including disease-free survival (DFS) and overall survival (OS), in patients with lung cancer metastatic to the skeleton who were receiving bisphosphonate treatment. A comprehensive overview of all articles published from 1995 to date in 3 medical databases (PubMed, Scopus, and Cochrane) was performed using the keywords bone markers and lung cancer. Most bone formation markers (including bone alkaline phosphatase [bALP], osteocalcin [OC], and osteoprotegerin [OPG]), most bone absorption markers (including urinary calcium, osteopontin [OPN], receptor activator of nuclear factor κ-B ligand [RANKL], tartrate-resistant acid phosphatase isoform-5b [TRACP 5b]), and the metabolites of type I collagen had elevated concentrations in patients with lung cancer and bone metastases compared with patients without skeletal involvement. Two large studies showed that urinary N-terminal telopeptide (NTX) levels are a valid diagnostic method for early detection of bone metastases and a more consistent prognosticator than bALP. Treatment with zoledronic acid reduces NTX, TRACP-5b, RANKL, and OPG levels. Furthermore posttherapeutic reduction of urinary NTX levels seems to correlate with lower risk of skeletal-related events (SREs). Levels of markers of bone remodeling reflect the presence of bone metastases and may contribute to early detection of occult skeletal disease or monitor the effect of bisphosphonate treatment. However their ability to predict SREs, as well as DFS and OS, remains debatable.

Anaphylactic reaction associated with intravenous administration of folinic acid in a patient with colon cancer.

It is known that in colon cancer patients, folinic acid (FA) given intravenously (i.v.) with 5-fluorouracil (5-FU) enhances the cytotoxic effects of chemotherapy. Adverse events regarding administration of FA have rarely been reported in the medical literature. A review of the existing data revealed just one case report of a colon cancer patient, who developed allergic reaction secondary to FA administration. Here, we report a second case of anaphylactic shock of an adult female patient with colon cancer at the end of i.v. FA administration. Finally the patient recovered and the reaction resolved, after she received i.v. epinephrine. Although the patient received combination chemotherapy with multiple targeted agents, which are believed to mainly cause allergic events during their iv administration, symptoms of an allergic event were shown just after FA was given; the etiology of this adverse reaction remains unclear for the time being and a challenging future field for oncologists to investigate.