Dose limiting toxicity determination

Determination of appropriate doses delivered based upon preliminary activity obtained from both in vitro and in vivo studies (i.e., finding a dose likely to be effective yet not dangerous, no observed adverse effect level, and a dose causing dose-limiting toxicity). 

Limonene and perillic acid remarkably reduced the lung metatastatic tumour nodule formation by 65 and 67%, respectively however, perillyl alcohol was considerably more potent than limonene against breast cancer [284, 302], rat mammary cancer and pancreatic tumours [288]. Phase 1 studies of d-limo-nene [303, 304] and phase I and phase II [305-311] studies of perillyl alcohol revealed dose-limiting toxicities nausea, vomiting, anorexia, unpleasant taste and eructation, and thus a maximum tolerated dose for perillyl alcohol was determined [305]. 

Dose-limiting toxicity and cause of death determination... 

Investigations in a phase I trial determined the MTD with 2.5 mg/m and neutropenia, peripheral oedema as well as liver function test abnormalities as dose-limiting toxicities [89]. Phase II trails in patients with malignant melanoma noted only a small percentage of responders, but significant duration of response in patients with liver metastases [90]. Only a few data are published on ILX-651 developed by Ilex Oncology. Data from a phase I study have been reported showing reasonable tolerability but short plasma half-life [91]. ILX 651 is currently in multicentric phase II studies in advanced melanoma or NSCLC patients with additional trials scheduled. 

The widespread use of bevacizumab in multimodal attempts to treat different tumor entities logically demands an extension to address the advantages of bevacizumab in combination with radiation with or without chemotherapy. To date, no phase III studies have been completed, so that the extent of the benefit that bevacizumab seems to have remains to be determined. In patients with rectal carcinoma, Willet and colleagues (2007) demonstrated in a continuation of a dose-escalation phase I trial in addition to the dose limiting toxicity... 

Phase I of clinical trials of taxol began in 1983 and was aimed at determining the maximum tolerated dose in humans and any dose-limiting toxicities. At first, the drug caused some serious hypersensitivity reactions, but decreasing the rate of infusion or premedicating patients with antihistamines and steroids avoided such reactions. Studies in this phase showed efficacy of taxol against ovarian cancer. 

In Phase I trials in the UK, HPMA copolymer doxombicin (PKl) given once every three weeks, had significantly reduced toxicity when compared to free doxombicin. The maximum tolerated dose, toxicity profile, and pharmacokinetics of PKl as an i.v. infusion every 3 weeks to patients with refractory or resistant cancers was determined. In the most recent report, 100 cycles were administered (range, 20-320 mg/m [free dmg equivalent]) to 36 patients (20 males and 16 females) with a mean age of 58.3 years (age range, 34-72 years). The maximum tolerated dose was 320 mg/m, and the dose-limiting toxicities were febrile neutropenia and mucositis. This maximum tolerated dose was a 4-5 fold increase over the usual clinical doses (60-80 mg/m ). No congestive cardiac failure was seen despite individual cumulative doses up to 1680 mg/m. Other anthracycline-like toxicities were attenuated. Pharmacokinefically, PKl had a distribution t(l/2) of 1.8 h and... 

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