Early clinical studies exploring new targets in anticancer treatment

Chemotherapy for cancer has always greatly relied upon the use of cytotoxic agents. These agents exert their activity in the process of nuclear DNA and RNA replication, and their activity in sensitive models leads to cell death and subsequent tumor shrinkage. Although a number of human tumor types can nowadays be cured by treatment involving cytotoxic agents, the overall clinical balance of efficacy and toxicity of these agents remains disappointing. In contrast to the situation with cytotoxic agents, where introduction as anticancer agent is usually preceded by large-scale random screening procedures, more recent research has focussed on anticancer agents for which development and design was preceded by the identification of specific tumor-related molecular targets or processes. These targets and processes are located either intracytoplasmic, in the cell membrane, or even completely outside the tumor cell itself. Examples of these molecular targets and processes are the intracytoplasmic polyamine synthesis pathway and farnesyl transferase pathway, the activity of various transmembrane signal transduction pathways, and the enzymatic breakdown of the extracellular matrix and the process of tumor-related angioneogenesis, respectively. Numerous animal studies with these new so-called rationally designed anticancer agents, aiming at one of the above targets, yielded no or only minor toxicity. The predictive value of results of animal studies for the human situation, however, is relatively limited. Nevertheless, in theory, when performing clinical studies with such compounds, toxicity may turn out to be absent or only mild. As a resultant, defining dose limiting toxicity as an endpoint for phase I studies may not be possible, and consequently, defining a recommended dose for additional activity testing might proof to be difficult. Many of these new anticancer agents were shown in preclinical studies to have a cytostatic rather than cytotoxic effect. Although in a limited number of these studies tumor regressions were noted, growth inhibition was the most frequently seen effect. Although, as said, such results cannot easily be extrapolated to the human situation, it may still be anticipated that these agents are not likely to induce tumor regression in clinically detectable tumor masses. Because of this, performing phase II studies might not make too much sense. Taken these considerations together, it is obvious that the design of clinical studies with new cytostatic agents needs a thorough reappraisal. This thesis involves clinical phase I studies performed in this shifting field of anticancer treatment. It outlines several of the problems described above and reports on efforts made to suggest alternative study endpoints

Tivozanib for the treatment of renal cell carcinoma: patient selection and perspectives

Tivozanib is an oral selective vascular endothelial growth factors receptor (VEGFR) tyrosine kinase inhibitor that is recently approved by the European Medicines Agency for the treatment of previously untreated patients with metastatic renal cell carcinoma (mRCC) as well as for those patients with disease progression during or after cytokine therapy. Nowadays, in first-line and second-line treatment of mRCC, there is an abundance of options, mainly consisting of VEGFR-directed tyrosinekinase inhibitors. This review focusses on the role of tivozanib with respect to patient selection and future perspectives in this fast-changing landscape

Matrix metalloproteinase inhibitors: current developments and future perspectives

Malignant tumors are characterized by invasive growth and metastasis. To facilitate this invasive behavior, the enzymatic breakdown of the extracellular matrix (ECM) is a prerequisite. Many human tumors are characterized by locally increased concentrations of matrix metalloproteinases (MMPs), enzymes that are able to degrade this ECM. A vast number of matrix metalloproteinase inhibitors (MMPIs) have been developed in recent years and after extensive preclinical testing, the results of the first clinical studies with several of these compounds have recently been presented. In this review we will describe some of the basic concepts of the degradation of the ECM, with special emphasis on the role of MMPs in the progression of cancer. Furthermore we will review the results of preclinical and clinical studies with MMPIs and discuss their future perspective

Moving molecular targeted drug therapy towards personalized medicine: Issues related to clinical trial design

With the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into account when designing a trial, including those trials that assess combinations of targets

Effect of food on the pharmacokinetics of oral MMI270B (CGS 27023A), a novel matrix metalloproteinase inhibitor

MMI270B is a matrix metalloproteinase inhibitor (MMPI) with in vitro and in vivo activity. To exert optimal target inhibition, MMPI must be given chronically, and therefore, oral bioavailability is important. We analyzed the effect of food intake on AUC0-8 h, Cmax, and Tmax. Seventeen patients were entered into the study. Doses of MMI270B were 150, 400, and 600 mg. The first day, patients ingested the drug in a fasted state and were not allowed to eat for 2 h. The second day, patients ingested the drug 30 min after a light breakfast. Mean AUC0-8 h was not significantly influenced by food intake. Plasma concentrations were well above the IC50 of several MMPs at all doses tested. Mean Cmax was significantly decreased after food intake. Mean Tmax was significantly delayed after food intake. Food intake did not result in a significant change in exposure to MMI270B (AUC0-8 h) but did result in a significant, although not clinically relevant, decrease in peak plasma levels and time to reach peak plasma levels. No specific guidelines concerning the ingestion of MMI270B in either a fed or a fasted state are recommended

A phase I dose-escalation and pharmacokinetic study of a micellar nanoparticle with entrapped docetaxel (CPC634) in patients with advanced solid tumours

Background: CPC634 is docetaxel entrapped in core-cross linked polymeric micelles. In preclinical studies, CPC634 demonstrated enhanced pharmacokinetics and improved therapeutic index. This phase I dose escalation study is the first-in-human study with CPC634. Methods: adult patients with advanced solid tumours received CPC634 intravenously either 3-weekly (Q3W) (part 1, dose range 15–100 mg/m2 ), 2-weekly (Q2W) (part 2, 45 mg/m2 ) or Q3W with dexamethasone premedication (part 3, 60 mg/m2 ). Results: thirty-three patients were enrolled. Skin toxicity was dose limiting (DLT) at ≥60 mg/m2 in part 1 and at 45 mg/m2 in part 2 and was the most common CPC634 related grade ≥ 3 adverse event (24%). With dexamethasone premedication no DLTs were observed at 60 mg/m2 Q3W. CPC634 exhibited a dose-proportional\ud pharmacokinetic profile. At 60 mg/m2 , the plasma area under the curve was 4067.5 ± 2974.0 ng/h/mL and the peak plasma level 217.3 ± 91.9 ng/mL with a half-life of 39.7 ± 9.4 h for released docetaxel. Conclusion: CPC634 could be administered safely upon pretreatment with dexamethasone. Cumulative skin toxicity was the main DLT. The recommended phase 2 dose was determined at 60 mg/m2 Q3W with dexamethasone premedication

The yield of chest computed tomography in patients with locally advanced pancreatic cancer

Objective: To evaluate the incidence of pulmonary metastases on chest computed tomography (CT) in patients with locally advanced pancreatic cancer (LAPC). Methods: All patients diagnosed with LAPC in a single tertiary center (Erasmus MC) between October 2011 and December 2017 were reviewed. The staging chest CT scan and follow-up chest CT scans were evaluated. Pulmonary nodules were divided into three categories: apparent benign, too small to characterize, and apparent malignant. Results: In 124 consecutive patients diagnosed with LAPC, 119 (96%) patients underwent a staging chest CT scan at the initial presentation. In 88 (74%) patients no pulmonary nodules were found; in 16 (13%) patients an apparent benign pulmonary nodule was found, and in 15 (13%) patients a pulmonary nodule too small to characterize was found. Follow-up chest CT scan(s) were performed in 111 (93%) patients. In one patient with either no pulmonary nodule or an apparent benign pulmonary nodule at initial staging, an apparent malignant pulmonary nodule was found on a follow-up chest CT scan. However, a biopsy of the nodule was inconclusive. Of 15 patients in whom a pulmonary nodule too small to characterize was found at staging, 12 (80%) patients underwent a follow-up CT scan; in 4 (33%) of these patients, an apparent malignant pulmonary nodule was found. Conclusion: In patients with LAPC in whom at diagnosis a chest CT scan revealed either no pulmonary nodules or apparent benign pulmonary nodules, routine follow-up chest CT scans is not recommended. Patients with pulmonary nodules too small to characterize are at risk to develop apparent malignant pulmonary nodules during follow-up

A phase I and pharmacokinetic study of weekly paclitaxel and carboplatin in patients with metastatic esophageal cancer

PURPOSE: To determine the maximum-tolerated dose, toxicity profile, and pharmacokinetics of a fixed dose of paclitaxel followed by increasing doses of carboplatin, given weekly to patients with advanced esophageal or gastric junction cancer. EXPERIMENTAL DESIGN: Paclitaxel was administered on day 1 as a 1-h infusion at a fixed dose of 100 mg/m(2) followed by a 1-h infusion of carboplatin targeting an area under the curve (AUC) of 2-5 mg x min/ml, with cycles repeated on days 8, 15, 29, 36, and 43. RESULTS: Forty patients [36 males; median (range) age, 57 (40-74) years] were enrolled. Dose-limiting toxicity was observed at a carboplatin AUC of 5 mg x min/ml and consisted of treatment delay attributable to myelosuppression. No grade 3/4 treatment-related nonhematological toxicity was observed. The highest dose intensity (>95% of the planned dose over time) was achieved with a carboplatin AUC of 4 mg x min/ml. The mean (+/-SD) AUCs of unbound (Cu) and total paclitaxel were 0.662 +/- 0.186 and 7.37 +/- 1.33 micro M x h, respectively. Clearance of Cu was 188 +/- 44.6 liter/h/m(2), which is not significantly different from historical data (P = 0.52). Cremophor EL clearance was 123 +/- 23 ml/h/m(2), similar to previous findings. Of 37 patients evaluable for response, 1 had complete response, 19 had partial response, and 10 had stable disease, accounting for an overall response rate of 54%. CONCLUSIONS: This regimen is very tolerable and effective, and the recommended doses for additional studies are paclitaxel (100 mg/m(2)), with carboplatin targeting an AUC of 4 mg x min/ml

Omineca Herald, May, 23, 1924

Background: LKB1 mutations are the underlying genetic abnormality causing Peutz-Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated. Methods: Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high-risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts. Results: Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49-year-old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52-year-old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse

Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus

BACKGROUND: We have previously reported a favourable response rate in patients with advanced esophageal cancer after treatment with a biweekly regimen of paclitaxel and cisplatin. In this study we investigate the feasibility and efficacy of this regimen in a neo-adjuvant setting. PATIENTS AND METHODS: Patients with resectable squamous cell carcinoma of the esophagus received paclit-axel 180 mg/m(2) and cisplatin 60 mg/m(2) every 2 weeks. Patients received three courses and responding patients received three additional courses; thereafter, patients were referred for surgery. Patient characteristics of 50 eligible patients were as follows: male, 60%; median age, 62 years (range 45-78); median World Health Organization performance status of 1 (range 0-2). RESULTS: Ninety-four per cent of patients received at least three courses of chemotherapy. Haematological toxicity consisted of National Cancer Institute-Common Toxicity Criteria grade 3 or 4 neutropenia in 71% of patients, with neutropenic fever occurring in only two patients (4%). The overall response rate was 59%. Pathological examination showed tumour-free margins in 38 patients. In seven patients no residual tumour was found. The median overall survival was 20 months and the 1- and 3-year survival rates were 68% and 30%, respectively. CONCLUSIONS: This dose-dense schedule of paclitaxel and cisplatin administered biweekly is well tolerated and the observed overall and complete response rates are promising