A phase I study of 17-Allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies

Suresh S. Ramalingam, Merrill J. Egorin, Ramesh K. Ramanathan, Scot C. Remick, Rachel P. Sikorski, Theodore F. Lagattuta, Gurkamal S. Chatta, David M. Friedland, Ronald G. Stoller, Douglas M. Potter, S. Percy Ivy, Chandra P. Belani

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3456-3461
Number of pages6
JournalClinical Cancer Research
Volume14
Issue number11
DOIs
StatePublished - Jun 1 2008

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tanespimycin
Paclitaxel
Neoplasms
Pharmacokinetics
HSP90 Heat-Shock Proteins
Oncogene Proteins
Myalgia
Chest Pain
Drug Interactions
Fatigue

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ramalingam, Suresh S. ; Egorin, Merrill J. ; Ramanathan, Ramesh K. ; Remick, Scot C. ; Sikorski, Rachel P. ; Lagattuta, Theodore F. ; Chatta, Gurkamal S. ; Friedland, David M. ; Stoller, Ronald G. ; Potter, Douglas M. ; Ivy, S. Percy ; Belani, Chandra P. / A phase I study of 17-Allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 11. pp. 3456-3461.
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title = "A phase I study of 17-Allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies",
abstract = "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.",
author = "Ramalingam, {Suresh S.} and Egorin, {Merrill J.} and Ramanathan, {Ramesh K.} and Remick, {Scot C.} and Sikorski, {Rachel P.} and Lagattuta, {Theodore F.} and Chatta, {Gurkamal S.} and Friedland, {David M.} and Stoller, {Ronald G.} and Potter, {Douglas M.} and Ivy, {S. Percy} and Belani, {Chandra P.}",
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Ramalingam, SS, Egorin, MJ, Ramanathan, RK, Remick, SC, Sikorski, RP, Lagattuta, TF, Chatta, GS, Friedland, DM, Stoller, RG, Potter, DM, Ivy, SP & Belani, CP 2008, 'A phase I study of 17-Allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies', Clinical Cancer Research, vol. 14, no. 11, pp. 3456-3461. https://doi.org/10.1158/1078-0432.CCR-07-5088

A phase I study of 17-Allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies. / Ramalingam, Suresh S.; Egorin, Merrill J.; Ramanathan, Ramesh K.; Remick, Scot C.; Sikorski, Rachel P.; Lagattuta, Theodore F.; Chatta, Gurkamal S.; Friedland, David M.; Stoller, Ronald G.; Potter, Douglas M.; Ivy, S. Percy; Belani, Chandra P.

In: Clinical Cancer Research, Vol. 14, No. 11, 01.06.2008, p. 3456-3461.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A phase I study of 17-Allylamino-17-demethoxygeldanamycin combined with paclitaxel in patients with advanced solid malignancies

AU - Ramalingam, Suresh S.

AU - Egorin, Merrill J.

AU - Ramanathan, Ramesh K.

AU - Remick, Scot C.

AU - Sikorski, Rachel P.

AU - Lagattuta, Theodore F.

AU - Chatta, Gurkamal S.

AU - Friedland, David M.

AU - Stoller, Ronald G.

AU - Potter, Douglas M.

AU - Ivy, S. Percy

AU - Belani, Chandra P.

PY - 2008/6/1

Y1 - 2008/6/1

N2 - 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.

AB - 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.

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