Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung Cancer

Bissett, Donald; O’Byrne, K.J.; Pawel, Joachim von; Gatzemeier, U.; Price, Allan; Nicolson, Marianne; Mercier, Richard J.; Mazabel, Elva; Penning, C A; Zhang, Min H.; Collier, Mary; Shepherd, Frances A.

doi:10.1200/jco.2005.03.170

Cited by 196 publications

(105 citation statements)

References 17 publications

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“…No survival benefit has been noted when 5 or 15 mg bid prinomastat has been added to standard chemotherapy such as paclitaxel plus carboplatin (20) or gemcitabine plus cisplatin in these studies (21). One explanation for lack of tumor response in these studies could be that the doses of prinomastat were inadequate.…”

Section: Discussionmentioning

confidence: 79%

Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor

Hande

Collier

Paradiso

et al. 2004

Clinical Cancer Research

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Purpose: Prinomastat is a matrix metalloprotease (MMP) inhibitor with selectivity for MMPs 2, 3, 9, 13, and 14. Inhibition of these MMPs has been postulated to block tumor invasion and metastasis. This Phase I, dose-escalation study was designed to evaluate the acute and chronic toxicities of various doses of prinomastat and to determine prinomastat pharmacokinetics.Experimental Design: Seventy-five patients with advanced cancer were given 1, 2, 5, 10, 25, 50, or 100 mg prinomastat orally twice daily until tumor progression or development of significant toxicities. Prinomastat pharmacokinetics were measured on day 29 of therapy.Results: The primary toxicities identified were joint and muscle-related pain, which were generally reversible with treatment rest and/or dose reduction. No dose-limiting toxicities were noted within the first 4 weeks of treatment, but grade 2-3 arthralgias and myalgias were noted 2-3 months after initiation of therapy in >25% of patients at doses >25 mg twice a day. The frequency and severity of symptoms were dose related. Plasma prinomastat concentrations greater than the K i for MMPs 2 and 9 were achieved at all of the dose levels.Conclusions: Doses of 5-10 mg bid were recommended for additional trials, because this dose range was well tolerated for a treatment duration of at least 3 months and achieves trough plasma concentrations 10 -100-fold greater than the K i (in vitro inhibition constant) for the targeted MMPs (2 and 9).

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Section: Discussionmentioning

confidence: 79%

Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor

Hande

Collier

Paradiso

et al. 2004

Clinical Cancer Research

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“…The MMPI, marimastat, that has selective affinity for MMP-2/-9, was evaluated in a phase III trial enrolling patients with platinum resistant, recurrent OvCa. Although the trial was not formally published, abstracts and reviews (11) reported that treatment with marimastat did not block tumor growth or improve survival, a result that is in line with other unsuccessful trials of MMPI in cancer (8,10). The data presented here, demonstrating that MMP-2 is important for adhesion and early metastasis, explain at least partially, why marimastat failed in the treatment of OvCa - patients treated with marimastat had widely metastatic tumors that are less dependant on MMPs for continued growth and survival.…”

Section: Figurementioning

confidence: 77%

“…In spite of these revelations, no MMPs have been identified as being absolutely required for neoplastic cell migration/invasion into ectopic tissue compartments in vivo. Based upon their perceived importance as mediators of ECM remodeling, clinical trials assessing efficacy of broad spectrum MMP inhibitors (MMPI) in patients with solid tumors, including non-small cell lung (8), pancreatic (9), gastric (10), and OvCas (11), were undertaken in patients with recurrent, metastatic, chemotherapy-resistant tumors. Unfortunately, none of the MMPI evaluated improved patient survival (12).…”

Section: Introductionmentioning

confidence: 99%

The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin

Kenny¹,

Kaur²,

Coussens³

et al. 2008

J. Clin. Invest.

331

321

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IntroductionOvarian cancer (OvCa) has the highest mortality rate of all gynecologic tumors and is the fifth leading cause of cancer death among US women (1). It is predominantly confined within the abdominal cavity and, unlike breast, colon, or lung cancer, rarely metastasizes hematogenously. Once an ovarian epithelial cell undergoes neoplastic transformation, it freely disseminates throughout the peritoneal cavity, carried by peritoneal fluid that facilitates attachment to peritoneum and omentum. The omentum is a large fat pad (approximately 12 × 12 cm) located inferior to the stomach and draped over the small bowel. It is the most common metastatic site (80%) for OvCa cells (2) followed by implants on the abdominal peritoneum. Identification of cofactors regulating OvCa cell attachment to omentum and/or peritoneum would have tremendous clinical utility, by enabling identification of cellular or molecular targets that could be pursued therapeutically and thus, enabling blockade of a critical step necessary for OvCa metastasis within the peritoneal cavity.A role for MMPs in OvCa development has been postulated based upon the observation that several members of the MMP family are upregulated during OvCa neoplastic progression (3). When MMPs were first characterized (4), it was hypothesized that their major contribution to cancer development was merely to

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“…2 Additionally, the clinical trials in small-cell lung carcinomas had to be terminated prematurely. 3 This failure led to the early cessation of ongoing trials, and to reconsideration of the merit of a variety of MMPIs in clinical development by a number of pharmaceutical companies. 4 --6 The molecular mechanism behind this disappointing outcome of MMP inhibition is still unclear, given the demonstrable efficacy of MMPI in pre-clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

Shchors

Nozawa

et al. 2012

Oncogene

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Despite their apparent success in pre-clinical trials, metalloproteinase (MMP) inhibitors proved to be inefficacious in clinical settings. In an effort to understand the underlying causes of this unanticipated outcome, we modeled the consequences of long-term MMP inhibition by removing one of the major players in tumorigenesis, MMP9, in two complimentary mouse models of pancreatic neuroendocrine carcinogenesis: Myc;BclXl and RIP1-Tag2. By employing gel zymography and a fluoregenic solution assay, we first established that MMP9 is expressed and activated in Myc;BclXl tumors in an interleukin-1b-dependent manner. The genetic deletion of MMP9 in Myc;BclXl mice impairs tumor angiogenesis and growth analogous to its absence in the RIP1-Tag2 model. Notably, tumors that developed in the context of MMP9-deficient backgrounds in both models were markedly more invasive than their typical wild-type counterparts, and expressed elevated levels of pro-invasive cysteine cathepsin B. The increased invasion of MMP9-deficient tumors was associated with a switch in the spectrum of inflammatory cells at the tumor margins, involving homing of previously undetected, cathepsin-B expressing CD11b;Gr1-positive cells to the invasive fronts. Thus, plasticity in the tumor inflammatory compartment is partially responsible for changes in the expression pattern of tumorassociated proteases, and may contribute to the compensatory effects observed on MMP inhibition, hence accounting for the heightened tumor progression described in late stage clinical trials.Oncogene advance online publication, 5 March 2012; doi:10.1038/onc.2012.60Keywords: tumor; metalloproteinase; invasion; cathepsin; Myc; interleukin-1b INTRODUCTIONMatrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that contribute to development and tissue homeostasis, and modulate cancer progression by digesting a variety of substrates. Owing to the role of MMP in extracellular matrix (ECM) re-arrangement (also referred to as remodeling or degradation), and in the promotion of neoangiogenesis, it was anticipated that MMP inhibition in vivo would have an anti-tumorigenic effect. However, phase III clinical trials with an MMP inhibitor (MMPI), combined with standard-of-care chemotherapy, failed to demonstrate clinical benefit for late stage cancer patients and, remarkably, was in some cases worse than the chemotherapyonly control arm. For instance, the use of Bay 12-9566 in treating patients with pancreatic cancer reduced both median progressionfree survival and quality-of-life when compared with standard care gemcitabine.1 In another case, treatment of glioblastoma patients rendered no statistically significant survival benefits.2 Additionally, the clinical trials in small-cell lung carcinomas had to be terminated prematurely.3 This failure led to the early cessation of ongoing trials, and to reconsideration of the merit of a variety of MMPIs in clinical development by a number of pharmaceutical companies. 4 --6 The molecular mechanism behind this disappointing outc...

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Phase III Study of Matrix Metalloproteinase Inhibitor Prinomastat in Non–Small-Cell Lung Cancer

Abstract: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC.

Cited by 196 publications

References 17 publications

Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor

Phase I and Pharmacokinetic Study of Prinomastat, a Matrix Metalloprotease Inhibitor

The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin

Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesis

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