Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer

Rebecca Suk Heist, Jerry Fain, Bernard Chinnasami, Waseem Khan, Julian R Molina, Lecia V. Sequist, Jennifer S. Temel, Panos Fidias, Valari Brainerd, Lance Leopold, Thomas J. Lynch

Research output: Contribution to journalArticle

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Abstract

Introduction: AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC. Methods: An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression. Results: Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m2 days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort (n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort (n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort. Conclusions: AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m2. The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.

Original languageEnglish (US)
Pages (from-to)1637-1643
Number of pages7
JournalJournal of Thoracic Oncology
Volume5
Issue number10
DOIs
StatePublished - Oct 2010

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Topotecan
Small Cell Lung Carcinoma
gossypol acetic acid
Platinum
Reaction Time
Drug Therapy

Keywords

  • BCL-2 inhibitor
  • Chemotherapy
  • Small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. / Suk Heist, Rebecca; Fain, Jerry; Chinnasami, Bernard; Khan, Waseem; Molina, Julian R; Sequist, Lecia V.; Temel, Jennifer S.; Fidias, Panos; Brainerd, Valari; Leopold, Lance; Lynch, Thomas J.

In: Journal of Thoracic Oncology, Vol. 5, No. 10, 10.2010, p. 1637-1643.

Research output: Contribution to journalArticle

Suk Heist, R, Fain, J, Chinnasami, B, Khan, W, Molina, JR, Sequist, LV, Temel, JS, Fidias, P, Brainerd, V, Leopold, L & Lynch, TJ 2010, 'Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer', Journal of Thoracic Oncology, vol. 5, no. 10, pp. 1637-1643. https://doi.org/10.1097/JTO.0b013e3181e8f4dc
Suk Heist, Rebecca ; Fain, Jerry ; Chinnasami, Bernard ; Khan, Waseem ; Molina, Julian R ; Sequist, Lecia V. ; Temel, Jennifer S. ; Fidias, Panos ; Brainerd, Valari ; Leopold, Lance ; Lynch, Thomas J. / Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer. In: Journal of Thoracic Oncology. 2010 ; Vol. 5, No. 10. pp. 1637-1643.
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abstract = "Introduction: AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC. Methods: An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression. Results: Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m2 days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort (n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort (n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort. Conclusions: AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m2. The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.",
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T1 - Phase I/II study of AT-101 with topotecan in relapsed and refractory small cell lung cancer

AU - Suk Heist, Rebecca

AU - Fain, Jerry

AU - Chinnasami, Bernard

AU - Khan, Waseem

AU - Molina, Julian R

AU - Sequist, Lecia V.

AU - Temel, Jennifer S.

AU - Fidias, Panos

AU - Brainerd, Valari

AU - Leopold, Lance

AU - Lynch, Thomas J.

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N2 - Introduction: AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC. Methods: An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression. Results: Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m2 days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort (n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort (n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort. Conclusions: AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m2. The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.

AB - Introduction: AT-101 is an oral, pan Bcl-2 family protein inhibitor that has demonstrated activity in small cell lung cancer (SCLC) models. A phase I/II study was conducted combining AT-101 with topotecan in relapsed and refractory SCLC. Methods: An open-labeled multicenter phase I/II study was conducted of oral AT-101 with intravenous topotecan in patients with SCLC who had progressed on prior platinum-containing chemotherapy. The phase II portion was a two-stage design, and two cohorts of patients, sensitive relapsed and refractory, were analyzed. Primary endpoint in the two-stage phase II portion was response rate; secondary endpoints were duration of response and time to progression. Results: Thirty-six patients were enrolled. The most common toxicities were hematologic, as would be expected with topotecan and AT-101. The recommended phase II dose was 40 mg AT-101 days 1 to 5 with topotecan 1.25 mg/m2 days 1 to 5 on a 21-day cycle. In the sensitive-relapsed cohort (n = 18), there were 0 complete response (CR), three partial response (PR), 10 stable disease (SD), and four progressive disease (PD). In the refractory cohort (n = 12), there were 0 CR/PR, five SD, and five PD. The study did not meet its prespecified endpoints to continue enrollment in the second stage of the phase II study. Median time to progression in the sensitive-relapsed cohort was 17.4 weeks and 11.7 weeks in the refractory cohort. Conclusions: AT-101 can be safely combined with topotecan at a reduced dose of 1.25 mg/m2. The response rates observed did not meet the criteria for additional enrollment; however, many patients had a best response of SD and the median time to progression in both cohorts was favorable. Additional trials of AT-101 in SCLC are ongoing.

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KW - Chemotherapy

KW - Small cell lung cancer

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