Abstract
Purpose
Gemcitabine (Gem) with paclitaxel (Pac) is used for patients with metastatic breast cancer who require cytoreduction with manageable toxicities. Nanoparticle albumin-bound (nab)-Pac exhibits better efficacy and reduces the risk of hypersensitivity reactions associated with solvent-based Pac. Therefore, Gem plus nab-Pac (GA) therapy may be effective for metastatic breast cancer. The purpose of this study was to determine the maximum tolerated dose for GA therapy.
Methods
The subjects were patients with metastatic breast cancer with performance status 0 or 1 and normal hepatic, renal and marrow function. Leukopenia, neutropenia or thrombocytopenia of grade 4, neutropenic fever, or non-hematological toxicity of grade 3 or higher during the 1st cycle, and chemotherapy-induced peripheral neurotoxicity of grade 2 or higher at the end of the 1st cycle were defined as dose-limiting toxicities (DLTs). Gem (1250 mg/m2) was administered on days 1 and 8. nab-Pac was administered at a starting dose of 180 mg/m2 (cohort 1) and escalated to 220 mg/m2 (cohort 2) and 260 mg/m2 (cohort 3) on day 1 of the 21-day cycle, using a 3 + 3 design.
Results
Nine patients (n = 3, 3, and 3 in cohorts 1, 2, and 3, respectively) were included in the study (median age 56 years; range 43–75 years). DLTs did not occur in any cohorts.
Conclusions
The initial recommend dose in GA therapy is 1250 mg/m2 Gem and 260 mg/m2 nab-Pac. It is well known that nab-Pac has cumulative toxicities, and thus the efficacy and safety of GA therapy require validation in a phase 2 study.
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References
Aihara T, Toyama T, Takahashi M, Yamamoto Y, Hara F, Akabane H, Fujisawa T, Ishikawa T, Nagai S, Nakamura R, Tsurutani J, Ito Y, Mukai H (2016) The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2015 edition. Breast Cancer 24 [Epub ahead of print]
O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R (2002) Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20:2812–2823
Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC (2003) Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol 21:588–592
Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O’Shaughnessy J (2008) Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 26:3950–3957
van Zuylen L, Gianni L, Verweij J, Mross K, Brouwer E, Loos WJ, Sparreboom A (2000) Inter-relationships of paclitaxel disposition, infusion duration and cremophor EL kinetics in cancer patients. Anticancer Drugs 11:331–337
Mielke S, Sparreboom A, Mross K (2006) Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes. Eur J Cancer 42:24–30
Authier N, Gillet JP, Fialip J, Eschalier A, Coudore F (2000) Description of a short-term taxol-induced nociceptive neuropathy in rats. Brain Res 887:239–249
Desai N, Trieu V, Yao Z, Louie L, Ci S, Yang A, Tao C, De T, Beals B, Dykes D, Noker P, Yao R, Labao E, Hawkins M, Soon-Shiong P (2006) Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res 12:1317–1324
Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O’Shaughnessy J (2005) Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 23:7794–7803
Frese KK, Neesse A, Cook N, Bapiro TE, Lolkema MP, Jodrell DI, Tuveson DA (2012) nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2:260–269
Roy V, LaPlant BR, Gross GG, Bane CL, Palmieri FM, North Central Cancer Treatment Group (2009) Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531). Ann Oncol 20:449–453
Abraxane®I.V. Infusion 100 mg [package insert version 6.0] (2014) Taiho Pharmaceutical Co., Ltd. Dec. (published as Japanese pdf file in http://www.info.pmda.go.jp/downfiles/ph/PDF/400107_4240409D1023_1_08.pdf)
Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691–1703
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Yoshitomi, S., Taira, N., Doihara, H. et al. A phase 1, dose-finding and pharmacokinetic study of gemcitabine with nab-paclitaxel in patients with metastatic breast cancer. Cancer Chemother Pharmacol 78, 289–294 (2016). https://doi.org/10.1007/s00280-016-3091-x
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DOI: https://doi.org/10.1007/s00280-016-3091-x