Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors

William C. Zamboni, Laura L. Jung, Merrill J. Egorin, Douglas M. Potter, David M. Friedland, Chandra P. Belani, Sanjiv S. Agarwala, Michael M W Wong, Marwan Fakih, Donald L. Trump, Ruzhi Jin, Sandra Strychor, Michael Vozniak, Monica Troetschel, Ramesk K Ramanathan

Research output: Contribution to journalArticle

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Abstract

Purpose: 9-Nitroeamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m2/day × 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration. Experimental Design: On schedule A, 9NC was administered orally daily × 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily × 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography. Results: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m 2/day, respectively, each providing the same dose intensity (i.e., 24 mg/m2/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of ∼4 to 1. Conclusions: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m2 basis does not reduce pharmacokinetic variability.

Original languageEnglish (US)
Pages (from-to)5058-5064
Number of pages7
JournalClinical Cancer Research
Volume10
Issue number15
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

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Appointments and Schedules
9-aminocamptothecin
Pancreatic Neoplasms
Neoplasms
Stomach Neoplasms
Pharmacokinetics
rubitecan
Camptothecin
Neutropenia
Thrombocytopenia
Diarrhea
Research Design
High Pressure Liquid Chromatography
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors. / Zamboni, William C.; Jung, Laura L.; Egorin, Merrill J.; Potter, Douglas M.; Friedland, David M.; Belani, Chandra P.; Agarwala, Sanjiv S.; Wong, Michael M W; Fakih, Marwan; Trump, Donald L.; Jin, Ruzhi; Strychor, Sandra; Vozniak, Michael; Troetschel, Monica; Ramanathan, Ramesk K.

In: Clinical Cancer Research, Vol. 10, No. 15, 01.08.2004, p. 5058-5064.

Research output: Contribution to journalArticle

Zamboni, WC, Jung, LL, Egorin, MJ, Potter, DM, Friedland, DM, Belani, CP, Agarwala, SS, Wong, MMW, Fakih, M, Trump, DL, Jin, R, Strychor, S, Vozniak, M, Troetschel, M & Ramanathan, RK 2004, 'Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors', Clinical Cancer Research, vol. 10, no. 15, pp. 5058-5064. https://doi.org/10.1158/1078-0432.CCR-03-0288
Zamboni, William C. ; Jung, Laura L. ; Egorin, Merrill J. ; Potter, Douglas M. ; Friedland, David M. ; Belani, Chandra P. ; Agarwala, Sanjiv S. ; Wong, Michael M W ; Fakih, Marwan ; Trump, Donald L. ; Jin, Ruzhi ; Strychor, Sandra ; Vozniak, Michael ; Troetschel, Monica ; Ramanathan, Ramesk K. / Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 15. pp. 5058-5064.
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abstract = "Purpose: 9-Nitroeamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m2/day × 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration. Experimental Design: On schedule A, 9NC was administered orally daily × 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily × 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography. Results: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m 2/day, respectively, each providing the same dose intensity (i.e., 24 mg/m2/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of ∼4 to 1. Conclusions: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m2 basis does not reduce pharmacokinetic variability.",
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T1 - Phase I and pharmacologic study of intermittently administered 9-nitrocamptothecin in patients with advanced solid tumors

AU - Zamboni, William C.

AU - Jung, Laura L.

AU - Egorin, Merrill J.

AU - Potter, Douglas M.

AU - Friedland, David M.

AU - Belani, Chandra P.

AU - Agarwala, Sanjiv S.

AU - Wong, Michael M W

AU - Fakih, Marwan

AU - Trump, Donald L.

AU - Jin, Ruzhi

AU - Strychor, Sandra

AU - Vozniak, Michael

AU - Troetschel, Monica

AU - Ramanathan, Ramesk K

PY - 2004/8/1

Y1 - 2004/8/1

N2 - Purpose: 9-Nitroeamptothecin (9NC) is an oral camptothecin analogue currently administered at 1.5 mg/m2/day × 5 days/week in Phase III studies for pancreatic carcinoma. In an effort to increase the dose administered per day and determine whether the daily dose or number of days of treatment influence toxicity, we performed a Phase I study of 9NC using intermittent schedules of administration. Experimental Design: On schedule A, 9NC was administered orally daily × 5 days for 2 weeks every 4 weeks (one cycle). On schedule B, 9NC was administered orally daily × 14 days every 4 weeks (one cycle). Dose levels were determined by adaptive dose finding. Serial blood samples were obtained on day 1 of each schedule for pharmacokinetic studies of 9NC and its 9-aminocamptothecin (9AC) metabolite, and lactone forms were measured by high-performance liquid chromatography. Results: The recommended Phase II doses for schedules A and B were 2.43 and 1.70 mg/m 2/day, respectively, each providing the same dose intensity (i.e., 24 mg/m2/cycle). The primary toxicities on schedules A and B were neutropenia, thrombocytopenia, and diarrhea. On schedule A, two patients with gastric cancer and two patients with pancreatic cancer had stable disease for more than six cycles. On schedule B, one patient with pancreatic cancer had stable disease for more than six cycles, and a patient with pancreatic cancer had a partial response. There was significant interpatient variability in the disposition of 9NC and 9AC. Most of the drug remained in the 9NC form with a ratio of 9NC to 9AC of ∼4 to 1. Conclusions: These studies suggest that 9NC administered on an intermittent schedule is tolerable and may be an active regimen in patients with gastric or pancreatic cancers. Dosing 9NC on a mg/m2 basis does not reduce pharmacokinetic variability.

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