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Phase 1 trial of intraperitoneal AD-32 in gynecologic malignancies
M Markman1, H Homesley, D A Norberts
1The Cleveland Clinic Foundation, Ohio 44195, USA.
Abstract:
AD-32 (N-trifluoroacetyladriamycin-14-valerate), an analogue of doxorubicin, was examined for intraperitoneal (ip) administration in a phase 2 trial involving 25 patients with advanced gynecologic malignancies. At an AD-32 dose of 600 mg/m2, the limiting toxicity was grade 4 neutropenia (64% of patients), while severe abdominal pain was relatively uncommon (12%). Intraperitoneal AD-32 administration was associated with a 200-fold pharmacokinetic advantage for cavity exposure, compared to the systemic compartment. At the 600 mg/m2 dose level, 4 of 9 patients (44%) with ascites experienced control of malignant fluid reaccumulation. Based on the results of this phase 1 trial, further exploration of a possible role for the ip administration of AD-32 in individuals with gynecological malignancies appears indicated, particularly in patients with either small volume residual disease after initial systemic chemotherapy or in those with intractable ascites.
Insights
Intraperitoneal AD-32 (N-trifluoroacetyladriamycin-14-valerate) showed promise in treating advanced gynecologic cancers. This chemotherapy demonstrated a pharmacokinetic advantage and controlled ascites in patients.
Area of Science:
- Oncology
- Pharmacology
- Gynecologic Oncology
Background:
- AD-32 (N-trifluoroacetyladriamycin-14-valerate) is an analogue of doxorubicin.
- Advanced gynecologic malignancies pose significant treatment challenges.
Purpose of the Study:
- To evaluate the safety and efficacy of intraperitoneal (IP) AD-32 in patients with advanced gynecologic malignancies.
- To assess the pharmacokinetic profile of IP AD-32.
Main Methods:
- Phase 2 clinical trial involving 25 patients.
- Intraperitoneal administration of AD-32 at a dose of 600 mg/m2.
- Monitoring for toxicity, pharmacokinetic analysis, and assessment of malignant fluid reaccumulation control.
Main Results:
- The dose-limiting toxicity was grade 4 neutropenia (64% of patients).
- Severe abdominal pain was infrequent (12%).
- A 200-fold pharmacokinetic advantage was observed for cavity exposure compared to the systemic compartment.
- 44% of patients with ascites experienced control of malignant fluid reaccumulation.
Conclusions:
- Intraperitoneal AD-32 demonstrated a favorable pharmacokinetic profile and activity in controlling ascites.
- Further investigation of IP AD-32 is warranted for gynecologic malignancies, especially in patients with residual disease or intractable ascites.