| Ch 14 | Page 14 / 21 | |
| Cancer follow-up |
Phase I studies | |
For cancer chemotherapy, 4 types of trials are generally described.
Their aim is to determine the useful clinical therapeutic dosage by finding the maximal tolerated dose. The initial dosage, the specific examinations and the potential toxicities are generally deducted from animal studies.
Before beginning human studies, an initial dosage is determined. It is calculated from a ratio between weight and body surface or Km. This Km value is 3 for a mouse (which generally weighs around 20g for a body surface of 66cm2) and 37 for an adult man (weighing 60 kg for a body surface of 1.6 m2).
The initial dosage is one tenth of the dose which kills 10% of the mice by toxicity (LD-10) with a correction according to the various Km.
Generally, studies with other animals have been previously conducted in order to detect toxicities which do not exist in mice but may exist among other species. These toxicities are very carefully looked for during initial dosage of phase I.
After a dosage has been explored, a progressive increase is instituted and the absence of toxicity verified.
Patients who participate in Phase I trials are patients having exhausted all usual therapeutic possibilities. The new product is presented as completely new with a small chance of activity for them, but from which other patients will hopefully benefit. This participation in progress for humanity is often of major significance to these patients who are perfectly aware of their gloomy future.
The table below shows an example of such a study for a product with major haematological toxicity in mice. The dose of 1mg/m2 has been chosen because it was one tenth of LD 10. Toxicities are described according to WHO recommendations.
| Dosage |
Number of patients |
Number of cycles |
Observed toxicity |
Therapeutic result |
1 mg/m2
|
3 patients
|
9, 8, 5 |
1 leucopaenia gr. II | No response |
1.5 mg/m2 |
3 patients |
5, 9, 2 |
2 leucopaenia gr. II, 1 leucopaenia gr. III, 1 thrombocytopenia gr. II |
1 partial response |
2.0 mg/m2 |
3 patients |
9, 4, 6 |
3 leucopaenia gr. III | 1 complete response 1 partial response |
2.5 mg/m2 |
3 patients |
4, 5, 1 |
2 leucopaenia gr. IV, 1 leucopaenia gr. III, 1 neurological toxicity gr II |
No response |
3.0 mg/m2 |
2 patients |
2, 1 |
2 leucopaenia gr. IV, 1 neurological toxicity gr III |
No response |
In the fictive example shown above, the therapeutic dosage will be 2 mg/m2 since beyond this dosage major toxicities are observed. Preventive measures may be advocated to prevent major toxicity.
Observing responses has no particular significance except to direct further phase II studies.
Conducting such phase I studies necessitates a very well trained and united team, in order to rapidly stop the experimentation should any major toxicity appear.
Therefore, in France only a few centres perform phase I trials.
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