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Certain criteria of patient selection are standard, including: |
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1. Histological confirmation of malignancy no longer amenable to established forms of therapy, |
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3. Performance status (ECOG-Zubrod scale) <3, |
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4. Normal hematology (WBC > 4000/mm3 and platelets > 100,000/mm3), |
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5. Life expectancy of more than 12 weeks, and |
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6. Informed consent for entry to the trial. |
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In addition the following are normally excluded: |
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1. Antitumor therapy within the last 4 weeks (6 weeks for nitrosoureas or mitomycin C), |
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2. Pregnancy, or women of child bearing potential not taking adequate contraceptive precautions, |
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3. Patients with intercurrent illness or complications of malignancy (e.g., hypercalcaemia), |
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4. Patients with psychotic disorders or other psychiatric complaints that might inhibit informed consent or follow-up, and |
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5. Patients with major organ dysfunction at a site of likely drug toxicity (e.g., cardiotoxicity). |
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B. Selection of Starting Dose |
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In drugs that produce toxicity in animal species we rely heavily on this information to establish what is hoped will be a safe starting dose. As discussed previously this is conventionally taken as 1/10 of the LD10 (in mg/m2) in the mouse. Prior verification in another species that this dose is safe is usually performed before initiation of patient dosing. This approach has proven to be safe in most instances, but occasionally unusual or unpredictable toxicities such as headache are observed even at the entry dose [10]. Some investigators now feel this starting dose may be too low. In a review of 45 Phase I drugs Penta et al. [11], found that the median range of maximal tolerated dose (MTD) to starting dose for all drugs was 20, with a median number of eight dose-escalation steps to reach the MTD. Even more worrying was the finding that for drugs with nonhaematologic toxicity the median ratio of MTD to starting dose was 30; necessitating a median of 9 dose-escalation steps. |
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Whilst it is morally laudable to pick a safe starting dose, one must also remember that patients enter Phase I trials with some hope of anticancer response. Thus wasteful exploration of doses that are too low for toxicity may deny patients the possibility of response, which is almost always experienced |
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