Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies: HOG LUN 07-130

Shadia Jalal, Nasser Hanna, Robin Zon, Gregory A. Masters, Hossein Borghaei, Karuna Koneru, Sunil Badve, Nagendra Prasad, Neeta Somaiah, Jingwei Wu, Zhangsheng Yu, Lawrence Einhorn

Research output: Contribution to journalArticle

Abstract

MATERIALS AND METHODS:: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response.

RESULTS:: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response.

CONCLUSIONS:: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.

OBJECTIVES:: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC.

Original languageEnglish (US)
JournalAmerican Journal of Clinical Oncology: Cancer Clinical Trials
DOIs
StateAccepted/In press - Dec 10 2014

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Small Cell Lung Carcinoma
Cyclophosphamide
Neoplasms
Maximum Tolerated Dose
Anthracyclines
amrubicin
Therapeutics
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies : HOG LUN 07-130. / Jalal, Shadia; Hanna, Nasser; Zon, Robin; Masters, Gregory A.; Borghaei, Hossein; Koneru, Karuna; Badve, Sunil; Prasad, Nagendra; Somaiah, Neeta; Wu, Jingwei; Yu, Zhangsheng; Einhorn, Lawrence.

In: American Journal of Clinical Oncology: Cancer Clinical Trials, 10.12.2014.

Research output: Contribution to journalArticle

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abstract = "MATERIALS AND METHODS:: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response.RESULTS:: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50{\%}). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6{\%} (n=7), 38.2{\%} (n=13), and 41.2{\%} (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8{\%} (n=7), 26.3{\%} (n=5), and 36.8{\%} (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response.CONCLUSIONS:: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.OBJECTIVES:: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC.",
author = "Shadia Jalal and Nasser Hanna and Robin Zon and Masters, {Gregory A.} and Hossein Borghaei and Karuna Koneru and Sunil Badve and Nagendra Prasad and Neeta Somaiah and Jingwei Wu and Zhangsheng Yu and Lawrence Einhorn",
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T1 - Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies

T2 - HOG LUN 07-130

AU - Jalal, Shadia

AU - Hanna, Nasser

AU - Zon, Robin

AU - Masters, Gregory A.

AU - Borghaei, Hossein

AU - Koneru, Karuna

AU - Badve, Sunil

AU - Prasad, Nagendra

AU - Somaiah, Neeta

AU - Wu, Jingwei

AU - Yu, Zhangsheng

AU - Einhorn, Lawrence

PY - 2014/12/10

Y1 - 2014/12/10

N2 - MATERIALS AND METHODS:: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response.RESULTS:: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response.CONCLUSIONS:: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.OBJECTIVES:: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC.

AB - MATERIALS AND METHODS:: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response.RESULTS:: Thirty-six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response.CONCLUSIONS:: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients.OBJECTIVES:: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC.

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