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A phase 1 study of tazarotene in adults with advanced cancer.

Jones PH, Burnett RD, Fainaru I, Nadolny P, Walker P, Yu Z, Tang-Liu D, Ganesan TS, Talbot DC, Harris AL, Rustin GJ - Br. J. Cancer (2003)

Bottom Line: Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly.No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)).We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy.

View Article: PubMed Central - PubMed

Affiliation: MRC Cancer Cell Unit and Cancer Research UK Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 2XZ, UK. phj20@cam.ac.uk

ABSTRACT
Tazarotene is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors RARbeta and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy.

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(A) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (B) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (C) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (D) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (E) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients at week 4. (F) Dose-normalized (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in five cancer patients at week 4.
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fig1: (A) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (B) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (C) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (D) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (E) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients at week 4. (F) Dose-normalized (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in five cancer patients at week 4.

Mentions: Samples were analysed for concentrations of tazarotene and its active metabolite tazarotenic acid. Plasma tazarotene concentrations were not quantifiable in most (79%, 670 out of 848 samples) samples. The single highest plasma tazarotene concentration throughout the study was 24.0 ng ml−1. Peak plasma tazarotenic acid concentration was reached rapidly within 1–3 h of dosing and thereafter declined quickly. Representative concentration–time curves are shown in Figure 1A–FFigure 1


A phase 1 study of tazarotene in adults with advanced cancer.

Jones PH, Burnett RD, Fainaru I, Nadolny P, Walker P, Yu Z, Tang-Liu D, Ganesan TS, Talbot DC, Harris AL, Rustin GJ - Br. J. Cancer (2003)

(A) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (B) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (C) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (D) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (E) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients at week 4. (F) Dose-normalized (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in five cancer patients at week 4.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2394470&req=5

fig1: (A) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (B) Plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (C) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients on day 0. (D) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in seven cancer patients on day 0. (E) Dose-normalised (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 1.4 mg tazarotene in six cancer patients at week 4. (F) Dose-normalized (1 mg) plasma concentrations (mean±s.e.m.) of tazarotenic acid following oral administration of 25.2 mg tazarotene in five cancer patients at week 4.
Mentions: Samples were analysed for concentrations of tazarotene and its active metabolite tazarotenic acid. Plasma tazarotene concentrations were not quantifiable in most (79%, 670 out of 848 samples) samples. The single highest plasma tazarotene concentration throughout the study was 24.0 ng ml−1. Peak plasma tazarotenic acid concentration was reached rapidly within 1–3 h of dosing and thereafter declined quickly. Representative concentration–time curves are shown in Figure 1A–FFigure 1

Bottom Line: Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly.No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)).We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy.

View Article: PubMed Central - PubMed

Affiliation: MRC Cancer Cell Unit and Cancer Research UK Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge CB2 2XZ, UK. phj20@cam.ac.uk

ABSTRACT
Tazarotene is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors RARbeta and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy.

Show MeSH
Related in: MedlinePlus