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 language | English (US) |
|---|---|
| Pages (from-to) | 1079-1085 |
| Number of pages | 7 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 66 |
| Issue number | 6 |
| DOIs | |
| State | Published - Nov 2010 |
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Keywords
- Apoptosis
- Obatoclax mesylate
- Small-cell lung cancer
- Topotecan
ASJC Scopus subject areas
- Cancer Research
- Oncology
- Pharmacology
- Pharmacology (medical)
- Toxicology
Cite this
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 journal › Article
}
TY - JOUR
T1 - A phase i study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies
AU - Paik, Paul K.
AU - Rudin, Charles M.
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.
PY - 2010/11
Y1 - 2010/11
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.
AB - 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.
KW - Apoptosis
KW - Obatoclax mesylate
KW - Small-cell lung cancer
KW - Topotecan
UR - http://www.scopus.com/inward/record.url?scp=78149410044&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78149410044&partnerID=8YFLogxK
U2 - 10.1007/s00280-010-1265-5
DO - 10.1007/s00280-010-1265-5
M3 - Article
C2 - 20165849
AN - SCOPUS:78149410044
VL - 66
SP - 1079
EP - 1085
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 6
ER -