Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer

Kohei Otsubo, Kaname Nosaki, Chiyo K. Imamura, Hiroaki Ogata, Akitaka Fujita, Shinya Sakata, Fumihiko Hirai, Gouji Toyokawa, Eiji Iwama, Taishi Harada, Takashi Seto, Mitsuhiro Takenoyama, Takeshi Ozeki, Taisei Mushiroda, Mieko Inada, Junji Kishimoto, Kenji Tsuchihashi, Kentaro Suina, Osamu Nagano, Hideyuki SayaYoichi Nakanishi, Isamu Okamoto

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(–) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin–pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.

Original languageEnglish
Pages (from-to)1843-1849
Number of pages7
JournalCancer Science
Volume108
Issue number9
DOIs
Publication statusPublished - Sep 2017

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Pemetrexed
Sulfasalazine
Non-Small Cell Lung Carcinoma
Cisplatin
Neoplastic Stem Cells
Disease-Free Survival
Maximum Tolerated Dose
Anorexia
Aspartate Aminotransferases
Alanine Transaminase
Hypotension
Glutathione
Registries
Neoplasms
Pneumonia
Protein Isoforms
Antioxidants
Genotype
Clinical Trials
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer. / Otsubo, Kohei; Nosaki, Kaname; Imamura, Chiyo K.; Ogata, Hiroaki; Fujita, Akitaka; Sakata, Shinya; Hirai, Fumihiko; Toyokawa, Gouji; Iwama, Eiji; Harada, Taishi; Seto, Takashi; Takenoyama, Mitsuhiro; Ozeki, Takeshi; Mushiroda, Taisei; Inada, Mieko; Kishimoto, Junji; Tsuchihashi, Kenji; Suina, Kentaro; Nagano, Osamu; Saya, Hideyuki; Nakanishi, Yoichi; Okamoto, Isamu.

In: Cancer Science, Vol. 108, No. 9, 09.2017, p. 1843-1849.

Research output: Contribution to journalArticle

Otsubo, K, Nosaki, K, Imamura, CK, Ogata, H, Fujita, A, Sakata, S, Hirai, F, Toyokawa, G, Iwama, E, Harada, T, Seto, T, Takenoyama, M, Ozeki, T, Mushiroda, T, Inada, M, Kishimoto, J, Tsuchihashi, K, Suina, K, Nagano, O, Saya, H, Nakanishi, Y & Okamoto, I 2017, 'Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer', Cancer Science, vol. 108, no. 9, pp. 1843-1849. https://doi.org/10.1111/cas.13309
Otsubo, Kohei ; Nosaki, Kaname ; Imamura, Chiyo K. ; Ogata, Hiroaki ; Fujita, Akitaka ; Sakata, Shinya ; Hirai, Fumihiko ; Toyokawa, Gouji ; Iwama, Eiji ; Harada, Taishi ; Seto, Takashi ; Takenoyama, Mitsuhiro ; Ozeki, Takeshi ; Mushiroda, Taisei ; Inada, Mieko ; Kishimoto, Junji ; Tsuchihashi, Kenji ; Suina, Kentaro ; Nagano, Osamu ; Saya, Hideyuki ; Nakanishi, Yoichi ; Okamoto, Isamu. / Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer. In: Cancer Science. 2017 ; Vol. 108, No. 9. pp. 1843-1849.
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AU - Nosaki, Kaname

AU - Imamura, Chiyo K.

AU - Ogata, Hiroaki

AU - Fujita, Akitaka

AU - Sakata, Shinya

AU - Hirai, Fumihiko

AU - Toyokawa, Gouji

AU - Iwama, Eiji

AU - Harada, Taishi

AU - Seto, Takashi

AU - Takenoyama, Mitsuhiro

AU - Ozeki, Takeshi

AU - Mushiroda, Taisei

AU - Inada, Mieko

AU - Kishimoto, Junji

AU - Tsuchihashi, Kenji

AU - Suina, Kentaro

AU - Nagano, Osamu

AU - Saya, Hideyuki

AU - Nakanishi, Yoichi

AU - Okamoto, Isamu

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N2 - Spliced variant isoforms of CD44 (CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(–) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine (SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin–pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin–pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854.

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