A phase I and pharmacokinetic study of oral 3-aminopyridine-2- carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: A California Cancer Consortium Study

Joseph Chao, Timothy W. Synold, Robert J. Morgan, Charles Kunos, Jeff Longmate, Heinz Josef Lenz, Dean Lim, Stephen Shibata, Vincent Chung, Ronald G. Stoller, Chandra P. Belani, David R. Gandara, Mark McNamara, Barbara J. Gitlitz, Derick H. Lau, Suresh S. Ramalingam, Angela Davies, Igor Espinoza-Delgado, Edward M. Newman, Yun Yen

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. Methods: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. Results: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. Conclusions: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

Original languageEnglish
Pages (from-to)835-843
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume69
Issue number3
DOIs
Publication statusPublished - Mar 1 2012
Externally publishedYes

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Pharmacokinetics
Toxicity
Tumors
Maximum Tolerated Dose
Neoplasms
Biological Availability
Ribonucleotide Reductases
Therapeutics
Molecules
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
Febrile Neutropenia
Appointments and Schedules
Hypertension

Keywords

  • 3-AP
  • Oral triapine
  • Phase I trial
  • Ribonucleotide reductase

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase I and pharmacokinetic study of oral 3-aminopyridine-2- carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers : A California Cancer Consortium Study. / Chao, Joseph; Synold, Timothy W.; Morgan, Robert J.; Kunos, Charles; Longmate, Jeff; Lenz, Heinz Josef; Lim, Dean; Shibata, Stephen; Chung, Vincent; Stoller, Ronald G.; Belani, Chandra P.; Gandara, David R.; McNamara, Mark; Gitlitz, Barbara J.; Lau, Derick H.; Ramalingam, Suresh S.; Davies, Angela; Espinoza-Delgado, Igor; Newman, Edward M.; Yen, Yun.

In: Cancer Chemotherapy and Pharmacology, Vol. 69, No. 3, 01.03.2012, p. 835-843.

Research output: Contribution to journalArticle

Chao, J, Synold, TW, Morgan, RJ, Kunos, C, Longmate, J, Lenz, HJ, Lim, D, Shibata, S, Chung, V, Stoller, RG, Belani, CP, Gandara, DR, McNamara, M, Gitlitz, BJ, Lau, DH, Ramalingam, SS, Davies, A, Espinoza-Delgado, I, Newman, EM & Yen, Y 2012, 'A phase I and pharmacokinetic study of oral 3-aminopyridine-2- carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: A California Cancer Consortium Study', Cancer Chemotherapy and Pharmacology, vol. 69, no. 3, pp. 835-843. https://doi.org/10.1007/s00280-011-1779-5
Chao, Joseph ; Synold, Timothy W. ; Morgan, Robert J. ; Kunos, Charles ; Longmate, Jeff ; Lenz, Heinz Josef ; Lim, Dean ; Shibata, Stephen ; Chung, Vincent ; Stoller, Ronald G. ; Belani, Chandra P. ; Gandara, David R. ; McNamara, Mark ; Gitlitz, Barbara J. ; Lau, Derick H. ; Ramalingam, Suresh S. ; Davies, Angela ; Espinoza-Delgado, Igor ; Newman, Edward M. ; Yen, Yun. / A phase I and pharmacokinetic study of oral 3-aminopyridine-2- carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers : A California Cancer Consortium Study. In: Cancer Chemotherapy and Pharmacology. 2012 ; Vol. 69, No. 3. pp. 835-843.
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abstract = "Background: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. Methods: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. Results: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25{\%}) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29{\%} and was consistent with the finding that the MTD by the oral route was 33{\%} higher than by the intravenous route. Conclusions: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25{\%} in our treated patient population with advanced solid tumors.",
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T1 - A phase I and pharmacokinetic study of oral 3-aminopyridine-2- carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers

T2 - A California Cancer Consortium Study

AU - Chao, Joseph

AU - Synold, Timothy W.

AU - Morgan, Robert J.

AU - Kunos, Charles

AU - Longmate, Jeff

AU - Lenz, Heinz Josef

AU - Lim, Dean

AU - Shibata, Stephen

AU - Chung, Vincent

AU - Stoller, Ronald G.

AU - Belani, Chandra P.

AU - Gandara, David R.

AU - McNamara, Mark

AU - Gitlitz, Barbara J.

AU - Lau, Derick H.

AU - Ramalingam, Suresh S.

AU - Davies, Angela

AU - Espinoza-Delgado, Igor

AU - Newman, Edward M.

AU - Yen, Yun

PY - 2012/3/1

Y1 - 2012/3/1

N2 - Background: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. Methods: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. Results: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. Conclusions: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

AB - Background: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. Methods: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. Results: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. Conclusions: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

KW - 3-AP

KW - Oral triapine

KW - Phase I trial

KW - Ribonucleotide reductase

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