Clinical studies, phase dose escalation

Concerns about safety of the study drug may characterise the Japanese clinical trial, in a Phase 1 study, the dose escalation stops at the level of expected therapeutic dose or double dose of it, and is never escalated to identify any toxicity (except for anticancer drugs), if toxicity is observed in a Phase I study, even if it is at the highest dose or under experimental conditions, further study will be difficult. Everybody in the clinical trial is used to handle study drugs with no safety problems and there is the general concept that the drug must be safe. ... 

Type I markers are most often validated in Phase 1 or 2 clinical trials, where it is often demonstrated that the therapeutic intervention favorably changes the marker. Here, often dose-related effects can be established in studies where dose escalation is executed. The best place to establish a Type I marker is in Phase 1, especially when there is a placebo control group so that the natural history of the marker can be followed in the placebo group. 

The Kentucky group reported the results of their phase I/II dose escalation study. Gemcitabine was delivered at a dose of 50 mg/m2 over 24 h with radiation. The dose was increased in 50 mg/m2 increments. The radiation dose was 40 Gy plus a boost at 1.8 Gy fractions. The clinical tumor response was evaluable in 12 unresectable patients. Five patients had a cCR of (42%), four patients (33%) had cPR after being treated with gemcitabine and radiation concurrently (59). Other ongoing phase I studies also found the concomitant delivery of GEM and radiation to be feasible (60-63). 

Ad.TNF gene therapy is presently in clinical trials in patients receiving radiotherapy. An open-label, phase I, dose-escalation study of tumor necrosis factor-alpha (TNFerade) gene transfer with radiation therapy for locally advanced, recurrent, or metastatic solid tumors is currently accruing patients and has several endpoints (82), including toxicity and tolerable dose. Pharmacokinetics will be evaluated and biological correlates will determine the histologic response to therapy. 

Following the successful outcomes of the studies of murine A/342 immunization in several laboratories, clinical trials were initiated. The immunogen used in these studies, AN-1792 (Elan Pharmaceuticals/Wyeth), contained synthetic A/342 in combination with an adjuvant (QS-21). Two Phase I studies were undertaken to evaluate the safety and tolerability of AN-1792 in patients with AD. The first was a single-dose study with three escalating A/342 dosage levels, but with a fixed adjuvant concentration. There were eight patients per dose level and a six-week period between escalations. The second Phase I study was a multi-dose (for both A/342 and QS-21 adjuvant), dose-escalation study, with a two to three month interval between each dose level. 

Phase I studies involve some combination of the evaluation of initial safety and tolerability, pharmacokinetics, pharmacodynamics, and an early measurement of drug activity. The initial clinical study is typically a single dose study conducted in normal healthy volunteers. The initial dose in the study is estimated from the nonclinical data and this dose is escalated until adverse events are seen. This study results in the determination of the maximally tolerated dose of the drug. Analysis of pharmacokinetic parameters and relation of blood levels to adverse events gives great insight for future studies. 

Rasmussen H, Chu K, Campochiaro P, et al. Clinical protocol. An open-label, phase I, single administration, dose-escalation study of ADGVPEDF. 11D (ADPEDF) in neo-vascular age-related macular degeneration (AMD). Hum Gene Ther 2001 12 2029-2032. 

These results suggest that concurrent use of 06-BG and BCNU polymers may serve as an important addition to the treatment of malignant brain tumors. To this end, recently completed NIH-funded phase I clinical trials investigated 06-BG as an adjuvant to BCNU treatment. Ongoing efforts center on the method of 06-BG delivery. Incorporation of 06-BG within polymers for local delivery and dose-escalation studies for systemic and local-delivered 06-BG represent active areas of development. 

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