A phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors

Nilofer Azad, Alyssa Perroy, Erin Gardner, Chiyo Imamura, Cynthia Graves, Gisele A. Sarosy, Lori Minasian, Herbert Kotz, Miranda Raggio, William D. Figg, Elise C. Kohn

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active. Results: Twenty-nine heavily pretreated patients [median 3 (0-7)] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m2 q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). a trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4-67 cycles, median 10); two patients had minor responses. Patients and methods: Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m2), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. patients were assessed for toxicity, pharmacokinetics and disease outcome. Conclusions: The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m2 q3weeks, respectively. The combination is tolerable and has potential antitumor activity.

Original languageEnglish
Pages (from-to)1800-1805
Number of pages6
JournalCancer Biology and Therapy
Volume8
Issue number19
DOIs
Publication statusPublished - 2009 Oct 10
Externally publishedYes

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carboxyamido-triazole
Paclitaxel
Neoplasms
Maximum Tolerated Dose
Pharmacokinetics
Neutropenia

Keywords

  • Carboxyamidotriazole
  • Clinical trial
  • Ovarian cancer
  • Paclitaxel
  • Pharmacokinetics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Azad, N., Perroy, A., Gardner, E., Imamura, C., Graves, C., Sarosy, G. A., ... Kohn, E. C. (2009). A phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors. Cancer Biology and Therapy, 8(19), 1800-1805. https://doi.org/10.4161/cbt.8.19.9593

A phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors. / Azad, Nilofer; Perroy, Alyssa; Gardner, Erin; Imamura, Chiyo; Graves, Cynthia; Sarosy, Gisele A.; Minasian, Lori; Kotz, Herbert; Raggio, Miranda; Figg, William D.; Kohn, Elise C.

In: Cancer Biology and Therapy, Vol. 8, No. 19, 10.10.2009, p. 1800-1805.

Research output: Contribution to journalArticle

Azad, N, Perroy, A, Gardner, E, Imamura, C, Graves, C, Sarosy, GA, Minasian, L, Kotz, H, Raggio, M, Figg, WD & Kohn, EC 2009, 'A phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors', Cancer Biology and Therapy, vol. 8, no. 19, pp. 1800-1805. https://doi.org/10.4161/cbt.8.19.9593
Azad, Nilofer ; Perroy, Alyssa ; Gardner, Erin ; Imamura, Chiyo ; Graves, Cynthia ; Sarosy, Gisele A. ; Minasian, Lori ; Kotz, Herbert ; Raggio, Miranda ; Figg, William D. ; Kohn, Elise C. / A phase I study of paclitaxel and continuous daily CAI in patients with refractory solid tumors. In: Cancer Biology and Therapy. 2009 ; Vol. 8, No. 19. pp. 1800-1805.
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abstract = "Background: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active. Results: Twenty-nine heavily pretreated patients [median 3 (0-7)] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79{\%} of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m2 q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100{\%} (p < 0.0001). a trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24{\%}; 4-67 cycles, median 10); two patients had minor responses. Patients and methods: Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m2), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. patients were assessed for toxicity, pharmacokinetics and disease outcome. Conclusions: The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m2 q3weeks, respectively. The combination is tolerable and has potential antitumor activity.",
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AU - Azad, Nilofer

AU - Perroy, Alyssa

AU - Gardner, Erin

AU - Imamura, Chiyo

AU - Graves, Cynthia

AU - Sarosy, Gisele A.

AU - Minasian, Lori

AU - Kotz, Herbert

AU - Raggio, Miranda

AU - Figg, William D.

AU - Kohn, Elise C.

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N2 - Background: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active. Results: Twenty-nine heavily pretreated patients [median 3 (0-7)] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m2 q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). a trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4-67 cycles, median 10); two patients had minor responses. Patients and methods: Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m2), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. patients were assessed for toxicity, pharmacokinetics and disease outcome. Conclusions: The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m2 q3weeks, respectively. The combination is tolerable and has potential antitumor activity.

AB - Background: Carboxyamido-triazole (CAI) is a calcium influx inhibitor with anti-angiogenic and anti-invasive properties and stabilizes tumor progression in patients. We hypothesized daily oral micronized CAI with q3 week paclitaxel would be well-tolerated and active. Results: Twenty-nine heavily pretreated patients [median 3 (0-7)] were enrolled on five dose levels. No additive or cumulative toxicity was observed, and grade III nonhematological toxicity was rare. Neutropenia was the most common hematologic toxicity, seen in 79% of patients, with a trend towards increasing grade with higher paclitaxel doses. The recommended phase II dose defined by the maximum tolerated dose (MTD) was CAI 250 mg daily and paclitaxel 200 mg/m2 q3weeks. Pharmacokinetic analysis revealed paclitaxel increases CAI trough concentration at all dose levels by over 100% (p < 0.0001). a trend towards higher steady-state CAI trough concentrations was found in patients with a partial response (PR; p = 0.09). Six patients had confirmed PR (24%; 4-67 cycles, median 10); two patients had minor responses. Patients and methods: Eligible patients with solid tumors received micronized CAI daily (150-250 mg PO) and paclitaxel intravenously q3weeks (175-250 mg/m2), sequentially escalating each drug. CAI preceded paclitaxel by one week to permit pharmacokinetic analysis. patients were assessed for toxicity, pharmacokinetics and disease outcome. Conclusions: The MTD of the combination of CAI and paclitaxel is 250 mg daily and 200 mg/m2 q3weeks, respectively. The combination is tolerable and has potential antitumor activity.

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