A phase i study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies

Paul K. Paik, Charles M. Rudin, Andrew Brown, Naiyer A. Rizvi, Naoko Takebe, William Travis, Leonard James, Michelle S. Ginsberg, Rosalyn Juergens, Susan Markus, Leslie Tyson, Sara Subzwari, Mark G. Kris, Lee M. Krug

Research output: Contribution to journalArticle

Abstract

Purpose: To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies. Patients and methods: Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m2 by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m 2 was given concurrently as an IV infusion on days 1-5 of each cycle. Results: Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m2 on day 1, 14 mg/m2 on days 1 and 3, and 20 mg/m2 on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m2; no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m2 on day 1, the level was escalated to 14 mg/m2 on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m2 on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks. Conclusion: Obatoclax mesylate administered at 14 mg/m2 IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m2 IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.

Original languageEnglish (US)
Pages (from-to)1079-1085
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number6
DOIs
StatePublished - Nov 2010

Fingerprint

Topotecan
Mesylates
Toxicity
Tumors
Neoplasms
Nervous System
Small Cell Lung Carcinoma
obatoclax
Intravenous Infusions
Cells
Febrile Neutropenia
Maximum Tolerated Dose
Ataxia

Keywords

  • Apoptosis
  • Obatoclax mesylate
  • Small-cell lung cancer
  • Topotecan

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Paik, P. K., Rudin, C. M., Brown, A., Rizvi, N. A., Takebe, N., Travis, W., ... Krug, L. M. (2010). A phase i study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. Cancer Chemotherapy and Pharmacology, 66(6), 1079-1085. https://doi.org/10.1007/s00280-010-1265-5

A phase i study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. / Paik, Paul K.; Rudin, Charles M.; Brown, Andrew; Rizvi, Naiyer A.; Takebe, Naoko; Travis, William; James, Leonard; Ginsberg, Michelle S.; Juergens, Rosalyn; Markus, Susan; Tyson, Leslie; Subzwari, Sara; Kris, Mark G.; Krug, Lee M.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 6, 11.2010, p. 1079-1085.

Research output: Contribution to journalArticle

Paik, PK, Rudin, CM, Brown, A, Rizvi, NA, Takebe, N, Travis, W, James, L, Ginsberg, MS, Juergens, R, Markus, S, Tyson, L, Subzwari, S, Kris, MG & Krug, LM 2010, 'A phase i study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies', Cancer Chemotherapy and Pharmacology, vol. 66, no. 6, pp. 1079-1085. https://doi.org/10.1007/s00280-010-1265-5
Paik, Paul K. ; Rudin, Charles M. ; Brown, Andrew ; Rizvi, Naiyer A. ; Takebe, Naoko ; Travis, William ; James, Leonard ; Ginsberg, Michelle S. ; Juergens, Rosalyn ; Markus, Susan ; Tyson, Leslie ; Subzwari, Sara ; Kris, Mark G. ; Krug, Lee M. / A phase i study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 66, No. 6. pp. 1079-1085.
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AU - Brown, Andrew

AU - Rizvi, Naiyer A.

AU - Takebe, Naoko

AU - Travis, William

AU - James, Leonard

AU - Ginsberg, Michelle S.

AU - Juergens, Rosalyn

AU - Markus, Susan

AU - Tyson, Leslie

AU - Subzwari, Sara

AU - Kris, Mark G.

AU - Krug, Lee M.

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N2 - Purpose: To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies. Patients and methods: Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m2 by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m 2 was given concurrently as an IV infusion on days 1-5 of each cycle. Results: Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m2 on day 1, 14 mg/m2 on days 1 and 3, and 20 mg/m2 on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m2; no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m2 on day 1, the level was escalated to 14 mg/m2 on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m2 on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks. Conclusion: Obatoclax mesylate administered at 14 mg/m2 IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m2 IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.

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KW - Apoptosis

KW - Obatoclax mesylate

KW - Small-cell lung cancer

KW - Topotecan

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