Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance)

Jesus Vera Aguilera, Ravi D. Rao, Jacob B. Allred, Vera Jean Suman, Harold E. Windschitl, Judith S Kaur, William J. Maples, Val Lowe, Edward T. Creagan, Lori A. Erickson, Svetomir Nenad Markovic

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Abstract

Lessons Learned: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma. Patients treated with 10 mg per day dose were most likely to require dose reductions. Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. Background: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). Methods: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. Results: A total of 53 patients were enrolled in cohort 1 (n=24) and cohort 2 (n=29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. Conclusion: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.

Original languageEnglish (US)
JournalOncologist
DOIs
StateAccepted/In press - Jan 1 2018

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Melanoma
Regulatory T-Lymphocytes
Disease-Free Survival
Medical Futility
Therapeutics
Safety
Everolimus
Mucositis
Survival
Cytostatic Agents
Anorexia
Sirolimus
Hyperglycemia
Vascular Endothelial Growth Factor A
Myocardial Ischemia
Fatigue
Mouth
Anemia
Neoplasms
Confidence Intervals

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance). / Vera Aguilera, Jesus; Rao, Ravi D.; Allred, Jacob B.; Suman, Vera Jean; Windschitl, Harold E.; Kaur, Judith S; Maples, William J.; Lowe, Val; Creagan, Edward T.; Erickson, Lori A.; Markovic, Svetomir Nenad.

In: Oncologist, 01.01.2018.

Research output: Contribution to journalArticle

Vera Aguilera, Jesus ; Rao, Ravi D. ; Allred, Jacob B. ; Suman, Vera Jean ; Windschitl, Harold E. ; Kaur, Judith S ; Maples, William J. ; Lowe, Val ; Creagan, Edward T. ; Erickson, Lori A. ; Markovic, Svetomir Nenad. / Phase II Study of Everolimus in Metastatic Malignant Melanoma (NCCTG-N0377, Alliance). In: Oncologist. 2018.
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abstract = "Lessons Learned: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma. Patients treated with 10 mg per day dose were most likely to require dose reductions. Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. Background: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). Methods: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. Results: A total of 53 patients were enrolled in cohort 1 (n=24) and cohort 2 (n=29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25{\%}; 95{\%} confidence interval, 8.6{\%}-49.1{\%}); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4{\%}); grade 3 fatigue, mucositis, and hyperglycemia (10.3{\%}); and anorexia and anemia (6.9{\%}). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. Conclusion: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.",
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AU - Vera Aguilera, Jesus

AU - Rao, Ravi D.

AU - Allred, Jacob B.

AU - Suman, Vera Jean

AU - Windschitl, Harold E.

AU - Kaur, Judith S

AU - Maples, William J.

AU - Lowe, Val

AU - Creagan, Edward T.

AU - Erickson, Lori A.

AU - Markovic, Svetomir Nenad

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N2 - Lessons Learned: Everolimus does not have sufficient activity to justify its use as single agent in metastatic melanoma. Patients treated with 10 mg per day dose were most likely to require dose reductions. Everolimus appeared to reduce the numbers of regulatory T cells in approximately half of the treated patients; unfortunately, these effects were not correlated with clinical outcomes. Background: Everolimus (RAD-001) is an orally active rapamycin analogue shown in preclinical data to produce cytostatic cell inhibition, which may be potentially beneficial in treating melanoma. We conducted a phase II study to evaluate the efficacy and safety of everolimus in patients with unresectable metastatic melanoma (MM). Methods: This study included two cohorts; cohort 1 received 30 mg of everolimus by mouth (PO) weekly, and cohort 2 was dosed with 10 mg of everolimus PO daily. The endpoints of the study were safety, 16-week progression-free survival (PFS), overall survival (OS), and measures of immunomodulatory/antiangiogenic properties with therapy. Tumor samples before therapy and at week 8 of treatment were analyzed. Peripheral blood plasma or mononuclear cell isolates collected prior to therapy and at weeks 8 and 16 and at time of tumor progression were analyzed for vascular endothelial growth factor and regulatory T-cell (Treg) measurements. Results: A total of 53 patients were enrolled in cohort 1 (n=24) and cohort 2 (n=29). Only 2 patients of the first 20 patients enrolled in cohort 2 had treatment responses (25%; 95% confidence interval, 8.6%-49.1%); this result did not allow full accrual to cohort 2, as the study was terminated for futility. Median OS was 12.2 months for cohort 1 versus 8.1 months in cohort 2; no PFS advantage was seen in either group (2.1 months vs. 1.8 months). Dose-limiting toxicities included grade 4 myocardial ischemia (3.4%); grade 3 fatigue, mucositis, and hyperglycemia (10.3%); and anorexia and anemia (6.9%). Everolimus significantly reduced the number of Tregs in approximately half of the treated patients; however, these effects were not correlated with clinical outcomes. Conclusion: Everolimus does not have sufficient single-agent activity in MM; however, we have identified evidence of biological activity to provide a potential rationale for future combination studies.

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