Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer.
OBJECTIVE
Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions.


METHODS
Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity.


RESULTS
The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy.


CONCLUSIONS
The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.
Herbst
Roy S
RS
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. rherbst@mdanderson.org
Madden
Timothy L
TL
Tran
Hai T
HT
Blumenschein
George R
GR
Meyers
Christina A
CA
Seabrooke
Lee F
LF
Khuri
Fadlo R
FR
Puduvalli
Vinay K
VK
Allgood
Victoria
V
Fritsche
Herbert A
HA
Hinton
Leslie
L
Newman
Robert A
RA
Crane
Elizabeth A
EA
Fossella
Frank V
FV
Dordal
Margaret
M
Goodin
Thomas
T
Hong
Waun Ki
WK
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D003510:Cyclohexanes; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D017239:Paclitaxel; D000077609:O-(Chloroacetylcarbamoyl)fumagillol