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


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/m(2) 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/m(2) on day 1, 14 mg/m(2) on days 1 and 3, and 20 mg/m(2) 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/m(2); 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/m(2) on day 1, the level was escalated to 14 mg/m(2) on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m(2) 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.


CONCLUSIONS
Obatoclax mesylate administered at 14 mg/m(2) IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m(2) 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.
Paik
Paul K
PK
Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Rudin
Charles M
CM
Brown
Andrew
A
Rizvi
Naiyer A
NA
Takebe
Naoko
N
Travis
William
W
James
Leonard
L
Ginsberg
Michelle S
MS
Juergens
Rosalyn
R
Markus
Susan
S
Tyson
Leslie
L
Subzwari
Sara
S
Kris
Mark G
MG
Krug
Lee M
LM
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008698:Mesylates / Q000008:administration & dosage; D008875:Middle Aged; D018579:Patient Selection; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D019772:Topotecan / Q000008:administration & dosage
D007211:Indoles; D008698:Mesylates; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D019772:Topotecan; C520962:obatoclax