Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child-Pugh B; CPB) in a phase I/II clinical study. ...This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg;
= 50) or placebo (
= 28). The primary endpoint (overall survival OS) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio HR, 0.82; 95% confidence interval CI 0.49-1.38;
= 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45-1.43,
= 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51-1.55,
= 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%,
= 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB.
Background/Aims: To evaluate the side effects of two antiplatelet agents--ticagrelor and eptifibatide - in mice with experimentally-induced inflammatory bowel disease. Materials and Methods: This ...study was designed as a controlled, animal, drug safety investigation. C57Bl/6 mice were used to establish the ulcerative colitis model by exposure to dextran sulfate sodium (DSS) and divided into three experimental groups: eptifibatide treated (150 microg/day intraperitoneally; n=10), ticagrelor treated (1 mg/day via gastric tube; n=10), and DSS control (plain drinking water; n=10). An unmodeled non-DSS group served as the experimental control. Complete blood count was taken for all mice at baseline (day 0, treatment initiation) and after four days of treatment. On day 4, all animals were sacrificed for autopsy. The primary outcome measure was bleeding, and the secondary outcomes were changes in platelet count, hemoglobin level, and hematocrit level. Results: Neither ticagrelor nor eptifibatide treatment produced a significant effect on DSS colitis mice for the safety parameters measured. Platelet count and hemoglobin and hematocrit levels were statistically similar between the three DSS groups and the non-DSS control group (p>0.05). Autopsy found no evidence of recent bleeding in liver, spleen, central nervous system, or serous cavities. Conclusion: The antiplatelet agents, ticagrelor and eptifibatide, were safe in DSS colitis mice, suggesting their potential in humans suffering from ulcerative colitis and supporting future safety studies. Keywords: Dextran sulfate, colitis, ticagrelor, eptifibatide, mice, adverse effects
Pancreatic ductal adenocarcinoma (PDAC), which is notorious for its aggressiveness and poor prognosis, remains an area of great unmet medical need, with a 5-year survival rate of 10% - the lowest of ...all solid tumours. At diagnosis, only 20% of patients have resectable pancreatic cancer (RPC) or borderline RPC (BRPC) disease, while 80% of patients have unresectable tumours that are locally advanced pancreatic cancer (LAPC) or have distant metastases. Nearly 60% of patients who undergo upfront surgery for RPC are unable to receive adequate adjuvant chemotherapy (CHT) because of postoperative complications and early cancer recurrence. An important paradigm shift to achieve better outcomes has been the sequence of therapy, with neoadjuvant CHT preceding surgery. Three surgical stages have emerged for the preoperative assessment of nonmetastatic pancreatic cancers: RPC, BRPC, and LAPC. The main goal of neoadjuvant treatment (NAT) is to improve postoperative outcomes through enhanced selection of candidates for curative-intent surgery by identifying patients with aggressive or metastatic disease during initial CHT, reducing tumour volume before surgery to improve the rate of margin-negative resection (R0 resection, a microscopic margin-negative resection), reducing the rate of positive lymph node occurrence at surgery, providing early treatment of occult micrometastatic disease, and assessing tumour chemosensitivity and tolerance to treatment as potential surgical criteria. In this editorial, we summarize evidence concerning NAT of PDAC, providing insights into future practice and study design. Future research is needed to establish predictive biomarkers, measures of therapeutic response, and multidisciplinary strategies to improve patient-centered outcomes.
The selective MEK1/2 inhibitor pimasertib has shown anti‐tumour activity in a pancreatic tumour model. This phase I/II, two‐part trial was conducted in patients with metastatic pancreatic ...adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2) in 28‐day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression‐free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58–1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first‐line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.
What's new?
Pimasertib is an orally bioavailable small molecule inhibitor of the mitogen‐activated protein kinase kinase 1/2 (MEK1/2) with promise in cancer therapy. Here the authors designed a two‐part clinical trial testing pimasertib combined with the standard of care drug gemcitabine in patients with metastatic pancreatic cancer. No evidence of clinical benefit was observed in the phase II part despite efficacy having been observed in the phase I part, underscoring the need to confirm phase I data in randomized phase II trials.
Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby ...protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC).
mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m
, 5-fluorouracil bolus 400 mg/m
, oxaliplatin 85 mg/m
and 5-fluorouracil 2400 mg/m
continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale.
Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1-8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups.
Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.
The roles of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9) in monitoring the patient response to chemotherapy for metastatic colorectal cancer (mCRC) are not clearly defined, and ...inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII), have been sparsely investigated for this purpose.
To aim of this study was to evaluate the relationship between the kinetics of CEA, CA19-9, NLR, LMR, PLR and SII in serum and patient response to chemotherapy estimated by computed tomography (CT) in patients with unresectable mCRC.
Patients with mCRC treated with a 1
-line and 2
-line chemotherapy underwent at least 3 whole-body spiral CT scans during response monitoring according to the Response Evaluation Criteria in Solid Tumour 1.1 (RECIST 1.1), and simultaneous determination of CEA, CA19-9, neutrophil, lymphocyte, platelet and monocyte levels was performed. The kinetics of changes in the tumour markers and inflammatory indices were calculated as the percentage change from baseline or nadir, while receiver operating characteristic curves were drawn to select the thresholds to define patients with progressive or responsive disease with the highest sensitivity (Se) and specificity (Sp). The correlation of tumour marker kinetics with inflammatory index changes and RECIST response was determined by univariate and multivariate logistic regression analysis and the clinical utility index (CUI).
A total of 102 patients with mCRC treated with chemotherapy were included. Progressive disease (PD), defined as a CEA increase of 25.52%, resulted in an Se of 80.3%, an Sp of 84%, a good CUI negative CUI (Ve-) value of 0.75 and a good fraction correct (FC) value of 81.2; at a CEA cut-off of -60.85% with an Se of 100% and an Sp of 35.7% for PD, CT could be avoided in 25.49% of patients. The 21.49% CA19-9 cut-off for PD had an Se of 66.5%, an Sp of 87.4%, an acceptable CUI (Ve-) value of 0.65 and an acceptable FC value of 75. An NLR increase of 11.5% for PD had an Se of 67% and an Sp of 66%; a PLR increase of 5.9% had an Se of 53% and an Sp of 69%; an SII increase above -6.04% had an Se of 72% and an Sp of 63%; and all had acceptable CUI (Ve-) values at 0.55. In the univariate logistic regression analysis, CEA (
< 0.001), CA19-9 (
< 0.05), NLR (
< 0.05), PLR (
< 0.05) and SII (
< 0.05) were important predictors of tumour progression, but in the multivariate logistic regression analysis, CEA was the only independent predictor of PD (
< 0.05).
CEA is a useful marker for monitoring the chemotherapy response of patients with unresectable mCRC and could replace a quarter of CT examinations. CA19-9 has poorer diagnostic characteristics than CEA but could be useful in some clinical circumstances, particularly when CEA is not increased. Dynamic changes in the inflammatory indices NLR, PLR and SII could be promising for further investigation as markers of the chemotherapy response.
We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer ...(mCRC) and report the first prospective extended RAS analysis in a phase 3 trial.
Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg
Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint.
Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57-0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53-0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49-2.00). No new safety signals were observed.
Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.
Introduction. Patients with colorectal cancer with metastases in the liver
parenchyma may benefit from perioperative chemotherapy with biological
agents and operative liver resection. Material and ...Methods. This
prospective, multicenter, non-interventional study included 191 previously
untreated patients with metastatic colorectal cancer and potentially
resectable or initially unresectable liver metastases who received
bevacizumab plus chemotherapy. The safety profile, as well as
progression-free-survival, response rate and conversion rate of initially
unresectable metastases to resectable were assessed. Results. A total of 40
adverse events were reported in 29/191 patients (15.2%), of which 31 were
serious adverse events. Among the serious adverse events, 14 were related to
the use of bevacizumab therapy, of which 4 were fatal due to serious adverse
events, but only one could be related to bevacizumab therapy. The median
progression-free period was 9 months (1 - 28). A high rate of response to
the applied therapy, 34.5% and 49%, was recorded in both groups of patients:
with initially unresectable and potentially resectable metastases in the
liver parenchyma. A significant part of patients with metastatic colorectal
cancer and metastases only in the liver parenchyma had a clinical benefit
from intensive chemotherapy with bevacizumab (disease control rate of 70%).
Conclusion. This study confirmed a favourable safety profile and
tolerability in terms of the incidence and severity of adverse and serious
adverse events. High rates of resectability in both groups of patients,
initially unresectable and potentially resectable, reflect the heterogeneity
of criteria in decision making about liver resection and emphasize the need
for establishing multisciplinary oncology teams and following the generally
accepted criteria.
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