Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer.
OBJECTIVE
Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel-mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting >/= 6 months in patients with relapsed ovarian cancer.


METHODS
Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 microg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting >/= 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured.


RESULTS
Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the >/= 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed.


CONCLUSIONS
CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.
Hussain
Mahrukh M
MM
Medical Oncology Clinical Research Unit, Medical Ovarian Cancer Clinic and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1500, USA.
Kotz
Herbert
H
Minasian
Lori
L
Premkumar
Ahalya
A
Sarosy
Gisele
G
Reed
Eddie
E
Zhai
Suoping
S
Steinberg
Seth M
SM
Raggio
Miranda
M
Oliver
Vyta Kulpa
VK
Figg
William D
WD
Kohn
Elise C
EC
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000378:metabolism; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016879:Salvage Therapy; D015996:Survival Rate; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015415:Biomarkers; D002121:Calcium Channel Blockers; D014230:Triazoles; C062058:carboxyamido-triazole