A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma

A California Cancer Consortium trial

Tianhong Li, Scott D Christensen, Paul H. Frankel, Kim A. Margolin, Sanjiv S. Agarwala, Thehang Luu, Philip Mack, Primo N Lara, David R Gandara

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background: Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods: Patients with advanced melanoma received UCN-01 at 90 mg/m 2 over 3 h on cycle 1, reduced to 45 mg/m 2 over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17+16), single arm phase II design was employed. A true response rate of ≥20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results: Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2-3.0) while median OS was 7.3 months (95% CI, 3.4-18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N=2), fatigue (N=1), and diarrhea (N=1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion: Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.

Original languageEnglish (US)
Pages (from-to)741-748
Number of pages8
JournalInvestigational New Drugs
Volume30
Issue number2
DOIs
StatePublished - Apr 2012

Fingerprint

Melanoma
Cell Cycle
Neoplasms
Disease-Free Survival
Disease Progression
Survival
7-hydroxystaurosporine
Cell Cycle Checkpoints
Hyperglycemia
Antineoplastic Agents
Fatigue
Anemia
Diarrhea
Creatinine
Survival Rate

Keywords

  • 7-hydroxystaurosporine
  • Cell cycle inhibitor
  • Metastatic melanoma
  • Phase II
  • Targeted therapy
  • UCN-01

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Oncology

Cite this

A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma : A California Cancer Consortium trial. / Li, Tianhong; Christensen, Scott D; Frankel, Paul H.; Margolin, Kim A.; Agarwala, Sanjiv S.; Luu, Thehang; Mack, Philip; Lara, Primo N; Gandara, David R.

In: Investigational New Drugs, Vol. 30, No. 2, 04.2012, p. 741-748.

Research output: Contribution to journalArticle

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title = "A phase II study of cell cycle inhibitor UCN-01 in patients with metastatic melanoma: A California Cancer Consortium trial",
abstract = "Background: Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods: Patients with advanced melanoma received UCN-01 at 90 mg/m 2 over 3 h on cycle 1, reduced to 45 mg/m 2 over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17+16), single arm phase II design was employed. A true response rate of ≥20{\%} (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results: Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24{\%}) patients had stable disease, and 12 (71{\%}) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95{\%} CI, 1.2-3.0) while median OS was 7.3 months (95{\%} CI, 3.4-18.4). One-year and two year OS rates were 41{\%} and 12{\%}, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N=2), fatigue (N=1), and diarrhea (N=1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion: Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.",
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AU - Li, Tianhong

AU - Christensen, Scott D

AU - Frankel, Paul H.

AU - Margolin, Kim A.

AU - Agarwala, Sanjiv S.

AU - Luu, Thehang

AU - Mack, Philip

AU - Lara, Primo N

AU - Gandara, David R

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N2 - Background: Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods: Patients with advanced melanoma received UCN-01 at 90 mg/m 2 over 3 h on cycle 1, reduced to 45 mg/m 2 over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17+16), single arm phase II design was employed. A true response rate of ≥20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results: Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2-3.0) while median OS was 7.3 months (95% CI, 3.4-18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N=2), fatigue (N=1), and diarrhea (N=1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion: Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.

AB - Background: Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods: Patients with advanced melanoma received UCN-01 at 90 mg/m 2 over 3 h on cycle 1, reduced to 45 mg/m 2 over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17+16), single arm phase II design was employed. A true response rate of ≥20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results: Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2-3.0) while median OS was 7.3 months (95% CI, 3.4-18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1-18). Grade 3 treatment-related toxicities include hyperglycemia (N=2), fatigue (N=1), and diarrhea (N=1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion: Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.

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