Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

Docetaxel (Taxotere): an active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck. EORTC Early Clinical Trials Group.

BACKGROUND: Docetaxel (Taxotere) is a new cytotoxic agent acting as a promoter of tubulin polymerisation with broad spectrum antitumor activity in preclinical testing. Phase I clinical trials have shown promising activity of docetaxel in patients with breast, ovarian and lung carcinomas. The objective of this open multicentre phase II study was to determine the efficacy and tolerability of this agent in patients with head and neck cancer. PATIENTS AND METHODS: Patients with proven advanced and/or recurrent squamous cell carcinoma of the head and neck without prior chemotherapy for advanced disease were eligible for this trial. Docetaxel was given at a dose of 100 mg/m2 as a 1 hour infusion every 3 weeks. Dose reductions were performed according to hematological and non-hematological toxicities. No pre-medication was given to prevent hypersensitivity reactions. RESULTS: Fourty-three patients entered this trial: 39 patients were evaluable for toxicity and 37 patients were evaluable for response. Sixty-five percent of the patients had locoregional disease, 28% had metastatic disease, and 7% had both. Twenty-five percent of the patients had previously received neo-adjuvant cisplatin-based chemotherapy. A total of 166 docetaxel courses were administered. The most frequent side-effects associated with docetaxel were alopecia (90% of the patients), asthenia (69% of the patients) and short lasting neutropenia (grade 3-4 neutropenia in 61% of the courses). Fifty-four percent of the patients experienced skin toxicity, 23% experienced hypersensitivity reaction, and 31% developed peripheral edema. Ten partial and 2 complete responses were observed, yielding a response rate of 32% (95% confidence interval 17%-47%). CONCLUSION: Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck.Clinical TrialClinical Trial, Phase IIJournal ArticleMulticenter StudySCOPUS: ar.jinfo:eu-repo/semantics/publishe

Carzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG).

PURPOSE: In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed. PATIENTS AND METHODS: Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered. RESULTS: In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen. CONCLUSIONS: At this dose and schedule carzelesin did not yield activity in the types of tumors studied.Clinical TrialClinical Trial, Phase IIJournal ArticleMulticenter Studyinfo:eu-repo/semantics/publishe

An EORTC-ECSG phase I study of LU 79553 administered every 21 or 42 days in patients with solid tumours.

A single-agent dose-escalating phase I and pharmacokinetic study on the naphthalamide agent, LU 79553, was performed to determine its safety profile, maximum tolerated dose (MTD) and recommended dose for phase II studies. LU 79553 was given intravenously (i.v.) every 3 weeks to patients with advanced solid cancers (an extended cohort of patients also received the drug every 6 weeks). 59 patients were enrolled into the study (50 patients in the 3-weekly schedule and 9 patients in the 6-weekly schedule). Dose levels studied ranged from 10 mg/m(2) to 160 mg/m(2). Neuro-muscular toxicity was identified as the dose-limiting toxicity (DLT). This muscular toxicity was observed after administrating total doses of 160-450 mg/m(2) (median 330 mg/m(2)). Non-DLTs consisted of diarrhoea, nausea and vomiting, fatigue and local venous phlebitis. The major haematological toxicities observed were anaemia and neutropenia (and were mainly observed at the two highest dose levels). The proposed dose for phase II studies using the 3-weekly regimen is 100 mg/m(2)/course (60 min infusion in 500 ml normal saline), but a close clinical follow-up of the patients for neuromuscular toxicity is mandatory. Prolongation of the treatment interval to 6 weeks, based upon the long half-life of the drug in the plasma and tissue, observed during this study, seemed not to be feasible in this heavily pretreated group of patients.Clinical TrialClinical Trial, Phase IJournal Articleinfo:eu-repo/semantics/publishe

Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.Clinical TrialClinical Trial, Phase IJournal Articleinfo:eu-repo/semantics/publishe

Pemetrexed combined with paclitaxel: a dose-finding study evaluating three schedules in solid tumors.

The objectives of this phase I study were to determine the maximum tolerated dose (MTD), recommended phase II dose (RD), antitumor activity, safety, and pharmacokinetics of pemetrexed-paclitaxel combination. Patients (N = 95) with advanced solid tumors were assigned to three schedules (21-day cycles [q21d]). Starting doses for each schedule of pemetrexed and paclitaxel, respectively, were: (S1) 400 and 135 mg/m(2) on d1; (S2) 400 mg/m(2) d1 and 40 mg/m(2) d1 and d8; S3) 400 mg/m(2) d8 and 30 mg/m(2) d1 and d8. MTD was 500/135 mg/m(2) (S1), 400/40 mg/m(2) (S2), and 500/120 mg/m(2) (S3). Most common dose limiting toxicities were febrile neutropenia, fatigue, and neuromotor toxicities. Most common toxicity was grade 3/4 lymphopenia. Four patients had partial response, 43 patients had stable disease. The RD determined was pemetrexed 500 mg/m(2) (d8) and paclitaxel 90 mg/m(2) (d1 and d8), q21d. The combination was well tolerated and showed efficacy in thyroid carcinoma and mesothelioma.Clinical Trial, Phase IJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe