Abstract
Purpose
Preclinical studies have demonstrated a synergistic effect with the angiogenesis inhibitor TNP-470 and several cytotoxic agents. A recent clinical trial with the combination of paclitaxel and TNP-470 has shown promising effects. The present study was designed to determine the toxicity and pharmacokinetics of carboplatin in combination with TNP-470 in comparison with the doublet regimen of paclitaxel and carboplatin in patients with solid tumors.
Experimental design
Enrolled in the study were 17 patients with lung (11), head/neck (3), sarcoma (2) and thymoma (1). The patients received intravenous paclitaxel and carboplatin on day 1 followed by TNP-470 (60 mg/m2 i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday). Each cycle of therapy consisted of 3 weeks. The initial cohort of three patients received carboplatin at AUC 5 mg/ml×min. No dose-limiting toxic effects occurred, thus the subsequent cohort received carboplatin at AUC 6 mg/ml×min. In addition to toxicity, the pharmacokinetics of carboplatin were evaluated, and tumor response and patient survival rates were assessed.
Results
The administered regimen of paclitaxel (225 mg/m2 i.v. over 3 h) and carboplatin (AUC 6 mg/ml×min i.v. over 1 h) on day 1 followed by TNP-470 (60 mg/m2 i.v. over 1 h administered thrice weekly on Monday, Wednesday, and Friday) was defined as both the maximum tolerated and optimal dose. Hematological toxic effects were similar to those expected with the chemotherapy doublet. All neurocognitive impairments were graded as mild to moderate and reversed after discontinuation of TNP-470 administration. No alterations in the pharmacokinetic disposition of carboplatin were noted. Overall, the median survival duration was 297 days. Four patients (24%) had a partial response, and eight (47%) had stable disease.
Conclusions
The combination of TNP-470, paclitaxel, and carboplatin is a reasonably well tolerated regimen. Further randomized studies of TNP-470 with this doublet regimen are now warranted for non-small-cell lung carcinoma and other solid tumors.
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References
Antoine N, Greimers R, De Roanne C, Kusaka M, Heinen E, Simar LJ, Castronovo V (1994) AGM-1470, a potent angiogenesis inhibitor, prevents the entry of normal but not transformed endothelial cells into the G1 phase of the cell cycle. Cancer Res 54:2073–2076
Baidas S, Bhargava P, Isaacs C, Rizvi N, Trocky N, Pipkin T, Hayes D, Marshall J (2000) Phase I study of the combination of TNP-470 and paclitaxel in patients with advanced cancer. Proc Am Soc Clin Oncol (abstract 800)
Bhargava P, Marshall JL, Rizvi N, Dahut W, Yoe J, Figuera M, Philipps K, Ong VS, Kato A, Hawkins MJ (1999) A phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer. Clin Cancer Res 5:1989–1995
Bhargava P, Rizvi N, Baidas S, Figueira M, Malerczyk C, Dordal M, Marshall J, Anton, Wellstein A (2000) Phase I study and assessment of bioactivity of 120-hour infusion of TNP-470 in patients with advanced cancer. Proc Am Soc Clin Oncol (abstract 681)
Bissett D, O’Byrne K, von Pawel J, Mercier R, Price A, Nicolson M, Shepherd F, Mazabel E, Penning C, Zhang MH, Collier MA (2002) Phase III study of the matrix metalloprotease (MMP) inhibitor prinomastat (P) in combination with gemcitabine (G) and cisplatin (C) in non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:296a (abstract 1183)
Blumenschein GR Jr, Fossella FV, Pisters KM, Khuri FR, Lu C, Kies MS, Glisson BS, Zinner R, Crane E, Schaerer R, Dordal M, Goodin T, Hong WK, Herbst RS (2002) A phase I study of TNP-470 continuous infusion alone or in combination with paclitaxel and carboplatin in adult patients with NSCLC and other solid tumors. Proc Am Soc Clin Oncol 21:314a (abstract 1254)
Castronovo V, Belotti D (1996) TNP-470 (AGM-1470): mechanism of action and early clinical development. Eur J Cancer 32A:2520–2527
Fountzilas G, Dimopoulos AM, Papadimitriou C, Kalogera-Fountzila A, Aravantinos G, Bafaloukos D, Athanassiades A, Nicolaides C, Keramopoulos A, Pavlidis N, Kosmidis P, Skarlos D (1998) First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): a phase II study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 9:1031–1034
Gadducci A, Brunetti I, Cosio S, Giannessi PG, Genazzani AR, Conte P (1997) Platinum compounds and paclitaxel in advanced epithelial ovarian cancer. Anticancer Res 17(6D):4703–4708
Herbst RS, Takeuchi H, Teicher BA (1998) Paclitaxel/carboplatin administration along with antiangiogenic therapy in non-small cell lung and breast carcinoma models. Cancer Chemother Pharmacol 41:497–504
Herbst RS, Madden TL, Tran HT, Blumenschein GR Jr, Meyers CA, Seabrooke LF, Khuri FR, Puduvalli VK, Allgood V, Fritsche HA Jr, Hinton L, Newman RA, Crane EA, Fossella FV, Dordal M, Goodin T, Hong WK (2002) 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. J Clin Oncol 20:4440–4447
Herbst RS, Hammond LA, Carbone DP, Tran HT, Holroyd KJ, Desai A, Williams JI, Bekele BN, Hait H, Allgood V, Solomon S, Schiller JH (2003) A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin Cancer Res 9:4108–4115
Ingber D, Fujita T, Kishimoto S, Sudo K, Kanamaru T, Brem H, Folkman J (1990) Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumor growth. Nature 348:555–557
Isobe N, Uozumi T, Kurisu K, Kawamoto K (1996) Experimental studies of the antitumor effect of TNP-470 on malignant brain tumors. Antitumor effects of TNP-470 on a human medulloblastoma xenograft line. Neuropediatrics 27:136–142
Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457–481
Kudelka AP, Levy T, Verschraegen CF, Edwards CL, Piamsomboon S, Termrungruanglert W, Freedman RS, Kaplan AL, Kieback DG, Meyers CA, Jaeckle KA, Loyer E, Steger M, Mante R, Mavligit G, Killian A, Tang RA, Gutterman JU, Kavanagh JJ (1997) A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix. Clin Cancer Res 3:1501–1515
Kudelka AP, Verschraegen CF, Loyer E (1998) Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470. N Engl J Med 338:991–992
Logothetis CJ, Wu KK, Finn LD, Daliani D, Figg W, Ghaddar H, Gutterman JU (2001) Phase I trial of the angiogenesis inhibitor TNP-470 for progressive androgen-independent prostate cancer. Clin Cancer Res 7:1198–1203
Madden T, Sunderland M, Santana VM, Rodman JH (1992) The pharmacokinetics of high-dose carboplatin in pediatric patients with cancer. Clin Pharmacol Ther 51:701–707
Mininberg ED, Herbst RS, Henderson T, Kim E, Hong WK, Mass R, Novotny W, Garcia B, Johnson D, Sandler A (2003) Phase I/II study of the recombinant humanized monoclonal anti-VEGF antibody bevacizumab and the EGFR-TK inhibitor erlotinib in patients with recurrent non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 22:627 (abstract 2521)
Offedile R, Walton T, Lee M, Stiles A, Nguyen M (1999) Regression of metastatic breast cancer in patients treated with the anti-angiogenic drug TNP-470. Tumori 85:51–53
Rigas JR, Denham CA, Rinaldi DA, Moore TD, Smith JW, Winston RD, Sridhar KS, Valera SZB, Humphrey R, Sorensen JM (2003) Randomized placebo-controlled trials of the matrix metalloproteinase inhibitor (MMPI), BAY12-9566 as adjuvant therapy for patients with small cell and non-small cell lung cancer. Proc Am Soc Oncol 22:628 (abstract 2525)
Satchi-Fainaro R, Corfas G, Tran H, Folkman J (2004) Tumor angiogenesis as a novel target for polymer therapeutics. In: Proceedings of the meeting Angiogenesis: Novel Basic Science Insights and Human Therapy. Keystone Symposia, Silverthorne, CO, p 84
Satchi-Fainaro R, Puder M, Davies J, Tran HT, Greene AK, Corfas G, Folkman J (2004) Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat Med 10:255–261
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92–98
Sin M, Meng L, Wang MQ, Wen JJ, Bornmann WG, Crews CM (1997) The antiangiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2. Proc Natl Acad Sci U S A 94:6099–6103
Smylie M, Mercier R, Aboulafia D, Tucker R, Bonomi P, Collier M, Keller MR, Stuart-Smith J, Knowles M, Clendeninn NJ, Shepherd F (2001) Phase III study of the matrix metalloproteinase (MMP) inhibitor prinomastat in patients having advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 20:307a (abstract 1226)
Sridhar SS, Shepherd FA (2003) Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer. Lung Cancer 42:S81–S91
Takamiya Y, Brem H, Ojeifo J, Mineta T, Martuza R (1994) AGM-1470 inhibits growth of human glioblastoma cells in vitro and in vivo. Neurosurgery 34:869–875
Teicher BA, Holden SA, Ara G, Sotomayor EA, Huang ZD, Chen YN, Brem H (1994) Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other antiangiogenic agents. Int J Cancer 57:920–925
Teicher BA, Holden SA, Dupuis NP, Kakeji Y, Ikebe M, Emi Y, Goff D (1995) Potentiation of cytotoxic therapies by TNP-470 and minocycline in mice bearing EMT-6 mammary carcinoma. Breast Cancer Res Treat 36:227–236
Teicher BA, Holden SA, Ara G, Korbut T, Menon K (1996) Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma. Cancer Chemother Pharmacol 38:169–177
Turk BE, Griffith EC, Wolf S, Biemann K, Chang YH, Liu JO (1999) Selective inhibition of amino-terminal methionine processing by TNP-470 and ovalicin in endothelial cells. Chem Biol 6:823–833
Whalen CT, Hanson, Putzer KJ, Mayer MD, Mulford ML (2002) Assay of TNP-470 and its two major metabolites in human plasma by high performance liquid chromatography-mass spectrometry. J Chromatogr Sci 49:214–218
Acknowledgement
This research was supported by a grant from TAP Pharmaceutical Products, Inc., an ASCO Career Development Award, and an M. D. Anderson Cancer Center Physician Scientist Program Award to Dr. Roy S. Herbst.
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Tran, H.T., Blumenschein, G.R., Lu, C. et al. Clinical and pharmacokinetic study of TNP-470, an angiogenesis inhibitor, in combination with paclitaxel and carboplatin in patients with solid tumors. Cancer Chemother Pharmacol 54, 308–314 (2004). https://doi.org/10.1007/s00280-004-0816-z
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DOI: https://doi.org/10.1007/s00280-004-0816-z