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Prinomastat

Prinomastat is a synthetic hydroxamic acid derivative with potential antineoplastic activity. Prinomastat inhibits matrix metalloproteinases (MMPs) (specifically, MMP-2, 9, 13, and 14), thereby inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis. As a lipophilic agent, prinomastat crosses the blood-brain barrier. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

According to http://www.medscape.com/viewarticle/412097, Pfizer has announced that preliminary results of phase III clinical trials of prinomastat, a matrix metalloprotease inhibitor (MMPI) in advanced hormone refractory prostate cancer and advanced (stage IV) non-small cell lung cancer did not meet primary efficacy objectives. Neither detrimental nor convincing beneficial effect of the combination of prinomastat with standard chemotherapy was observed. Consequently, Pfizer is halting both of these phase III trials. Based on input from the Data Safety Monitoring Board (DSMB), patients having earlier stage (stage IIIB) disease recruited into a second ongoing non-small cell lung cancer trial will continue to be studied. The company intends to continue exploration of prinomastat in other tumor types and most importantly, in earlier stage disease, where oncologists believe inhibition of angiogenesis may have greater utility. Four phase II trials are currently underway, and 2 additional phase II trials will begin shortly.

Prinomastat: clinical trial results

1. Phase II,  prinomastat in patients with esophageal adenocarcinoma.

PATIENTS AND METHODS: Preoperative staging included computed tomography, endoscopic ultrasound, and, when feasible, laparoscopy. Eligible patients were randomized to preoperative prinomastat or placebo, plus continuous infusion 5-FU, cisplatin, paclitaxel, and concurrent radiotherapy. Esophagectomy was performed on day 71. Adjuvant paclitaxel and prinomastat were available to all study patients.  RESULTS: Between August 2000 and June 2001, 15 of a planned 78 patients were randomized into the trial. One patient after randomization withdrew consent. Fourteen patients, 7 in each arm, completed preoperative treatment and surgery. pCR was achieved in 5 patients; 1/ 7 prinomastat and 4/ 7 placebo. Disease improvement was achieved in 7 patients; 5 /7 prinomastat and 2 /7 placebo. At a median follow-up of 28 months, 7 patients (2 prinomastat, 5 placebo) are alive with no evidence of disease. The primary prinomastat related toxicity was moderate to severe musculoskeletal toxicity interfering with daily function. This toxicity was managed with treatment rest, dose reduction, or discontinuation. Five patients (3 prinomastat and 2 placebo) had life-threatening thrombo-embolic events, which led to early evaluation of safety and efficacy, and subsequent termination of the study. CONCLUSIONS: All patients, regardless of treatment arm, were able to successfully undergo neoadjuvant combined modality therapy and esophagectomy. However, early closure of the study due to unexpected thrombo-embolic events precluded any conclusions regarding clinical activity of prinomastat in locally advanced esophageal cancer patients. [source: Heath EI, Burtness BA, Kleinberg L, Salem RR, Yang SC, Heitmiller RF, Canto MI, Knisely JP, Topazian M, Montgomery E, Tsottles N, Pithavala Y, Rohmiller B, Collier M, Forastiere AA. Invest New Drugs. 2006 Mar;24(2):135-40.]

2. Phase III study of  prinomastat in non-small-cell lung cancer.

PATIENTS AND METHODS: Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. RESULTS: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients.
CONCLUSION: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC. [source: Bissett D, O'Byrne KJ, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang MH, Collier MA, Shepherd FA. J Clin Oncol. 2005 Feb 1;23(4):842-9.]

Current developer:   Pfizer, Inc.

 1: Younis HS, Jessen BA, Wu EY, Stevens GJ. Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats. Birth Defects Res B Dev Reprod Toxicol. 2006 Apr;77(2):95-103. PubMed PMID: 16607633.

2: Heath EI, Burtness BA, Kleinberg L, Salem RR, Yang SC, Heitmiller RF, Canto MI, Knisely JP, Topazian M, Montgomery E, Tsottles N, Pithavala Y, Rohmiller B, Collier M, Forastiere AA. Phase II, parallel-design study of preoperative combined modality therapy and the matrix metalloprotease (mmp) inhibitor prinomastat in patients with esophageal adenocarcinoma. Invest New Drugs. 2006 Mar;24(2):135-40. PubMed PMID: 16502351.

3: Bissett D, O'Byrne KJ, von Pawel J, Gatzemeier U, Price A, Nicolson M, Mercier R, Mazabel E, Penning C, Zhang MH, Collier MA, Shepherd FA. Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer. J Clin Oncol. 2005 Feb 1;23(4):842-9. PubMed PMID: 15681529.

4: El-Bradey MH, Cheng L, Bartsch DU, Niessman M, El-Musharaf A, Freeman WR. The effect of prinomastat (AG3340), a potent inhibitor of matrix metalloproteinase, on a new animal model of epiretinal membrane. Retina. 2004 Oct;24(5):783-9. PubMed PMID: 15492635.

5: Wiart M, Fournier LS, Novikov VY, Shames DM, Roberts TP, Fu Y, Shalinsky DR, Brasch RC. Magnetic resonance imaging detects early changes in microvascular permeability in xenograft tumors after treatment with the matrix metalloprotease inhibitor Prinomastat. Technol Cancer Res Treat. 2004 Aug;3(4):377-82. PubMed PMID: 15270589.

6: Ferrario A, Chantrain CF, von Tiehl K, Buckley S, Rucker N, Shalinsky DR, Shimada H, DeClerck YA, Gomer CJ. The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model. Cancer Res. 2004 Apr 1;64(7):2328-32. PubMed PMID: 15059880.

7: Hande KR, Collier M, Paradiso L, Stuart-Smith J, Dixon M, Clendeninn N, Yeun G, Alberti D, Binger K, Wilding G. Phase I and pharmacokinetic study of prinomastat, a matrix metalloprotease inhibitor. Clin Cancer Res. 2004 Feb 1;10(3):909-15. PubMed PMID: 14871966.

8: Liu J, Tsao MS, Pagura M, Shalinsky DR, Khoka R, Fata J, Johnston MR. Early combined treatment with carboplatin and the MMP inhibitor, prinomastat, prolongs survival and reduces systemic metastasis in an aggressive orthotopic lung cancer model. Lung Cancer. 2003 Dec;42(3):335-44. PubMed PMID: 14644522.

9: Behrendt CE, Ruiz RB. Venous thromboembolism among patients with advanced lung cancer randomized to prinomastat or placebo, plus chemotherapy. Thromb Haemost. 2003 Oct;90(4):734-7. PubMed PMID: 14515196.

10: Deryugina EI, Ratnikov BI, Strongin AY. Prinomastat, a hydroxamate inhibitor of matrix metalloproteinases, has a complex effect on migration of breast carcinoma cells. Int J Cancer. 2003 May 1;104(5):533-41. PubMed PMID: 12594807.

11: Garcia C, Bartsch DU, Rivero ME, Hagedorn M, McDermott CD, Bergeron-Lynn G, Cheng L, Appelt K, Freeman WR. Efficacy of Prinomastat) (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization. Curr Eye Res. 2002 Jan;24(1):33-8. PubMed PMID: 12187492.

12: Ozerdem U, Mach-Hofacre B, Varki N, Folberg R, Mueller AJ, Ochabski R, Pham T, Appelt K, Freeman WR. The effect of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinases, on uveal melanoma rabbit model. Curr Eye Res. 2002 Feb;24(2):86-91. PubMed PMID: 12187478.

13: Foda HD, Rollo EE, Drews M, Conner C, Appelt K, Shalinsky DR, Zucker S. Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340). Am J Respir Cell Mol Biol. 2001 Dec;25(6):717-24. PubMed PMID: 11726397.

14: Cheng L, Rivero ME, Garcia CR, McDermott CD, Keefe KS, Wiley CA, Soules KA, Bergeron-Lynn G, Vekich S, Zhang K, Appelt K, Freeman WR. Evaluation of intraocular pharmacokinetics and toxicity of prinomastat (AG3340) in the rabbit. J Ocul Pharmacol Ther. 2001 Jun;17(3):295-304. PubMed PMID: 11436949.

15: Ozerdem U, Mach-Hofacre B, Keefe K, Pham T, Soules K, Appelt K, Freeman WR. The effect of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinases, on posttraumatic proliferative vitreoretinopathy. Ophthalmic Res. 2001 Jan-Feb;33(1):20-3. PubMed PMID: 11114600.

16: Scatena R. Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor. A novel pharmacological approach for tissue remodelling-related diseases. Expert Opin Investig Drugs. 2000 Sep;9(9):2159-65. Review. PubMed PMID: 11060800.

17: Ozerdem U, Mach-Hofacre B, Cheng L, Chaidhawangul S, Keefe K, McDermott CD, Bergeron-Lynn G, Appelt K, Freeman WR. The effect of prinomastat (AG3340), a potent inhibitor of matrix metalloproteinases, on a subacute model of proliferative vitreoretinopathy. Curr Eye Res. 2000 Jun;20(6):447-53. PubMed PMID: 10980656.