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A phase I study of 17-allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid
Suresh S Ramalingam1, Merrill J Egorin, Ramesh K Ramanathan
1Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. suresh.ramalingam@emory.edu
Background:
17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits heat shock protein 90, promotes degradation of oncoproteins, and exhibits synergy with paclitaxel in vitro. We conducted a phase I study in patients with advanced malignancies to determine the recommended phase II dose of the combination of 17-AAG and paclitaxel.
Methods:
Patients with advanced solid malignancies that were refractory to proven therapy or without any standard treatment were included. 17-AAG (80-225 mg/m2) was given on days 1, 4, 8, 11, 15, and 18 of each 4-week cycle to sequential cohorts of patients. Paclitaxel (80-100 mg/m2) was administered on days 1, 8, and 15. Pharmacokinetic studies were conducted during cycle 1.
Results:
Twenty-five patients were accrued to five dose levels. The median number of cycles was 2. Chest pain (grade 3), myalgia (grade 3), and fatigue (grade 3) were dose-limiting toxicities at dose level 4 (225 mg/m2 17-AAG and 80 mg/m2 paclitaxel). None of the six patients treated at dose level 3 with 17-AAG (175 mg/m2) and paclitaxel (80 mg/m2) experienced dose-limiting toxicity. Disease stabilization was noted in six patients, but there were no partial or complete responses. The ratio of paclitaxel area under the concentration to time curve when given alone versus in combination with 17-AAG was 0.97 +/- 0.20. The ratio of end-of-infusion concentration of 17-AAG (alone versus in combination with paclitaxel) was 1.14 +/- 0.51.
Conclusions:
The recommended phase II dose of twice-weekly 17-AAG (175 mg/m2) and weekly paclitaxel (80 mg/m2/wk) was tolerated well. There was no evidence of drug-drug pharmacokinetic interactions.
Insights
The combination of 17-allylamino-17-demethoxygeldanamycin (17-AAG) and paclitaxel is safe for advanced cancers. The recommended Phase II dose is 175 mg/m2 of 17-AAG and 80 mg/m2 of paclitaxel weekly.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- 17-Allylamino-17-demethoxygeldanamycin (17-AAG) targets heat shock protein 90 and oncoproteins.
- Preclinical studies indicated synergy between 17-AAG and paclitaxel.
Purpose of the Study:
- Determine the recommended Phase II dose for the combination of 17-AAG and paclitaxel.
- Evaluate the safety and tolerability of this combination in patients with advanced malignancies.
Main Methods:
- Phase I clinical trial involving patients with advanced solid malignancies.
- Dose escalation of 17-AAG (80-225 mg/m2) and paclitaxel (80-100 mg/m2).
- Pharmacokinetic studies were performed during cycle 1.
Main Results:
- Twenty-five patients were enrolled across five dose levels.
- Dose-limiting toxicities (chest pain, myalgia, fatigue) observed at 225 mg/m2 17-AAG and 80 mg/m2 paclitaxel.
- Recommended Phase II dose established at 175 mg/m2 17-AAG and 80 mg/m2 paclitaxel, with no dose-limiting toxicities observed.
Conclusions:
- The combination of 17-AAG and paclitaxel at the recommended Phase II dose is well-tolerated.
- No significant pharmacokinetic drug-drug interactions were identified between 17-AAG and paclitaxel.
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