Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of Marimastat After Response to First-Line Chemotherapy in Patients With Small-Cell Lung Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer

Shepherd, Frances A.; Giaccone, Giuseppe; Seymour, Lesley; Debruyne, Channa; Bezjak, Andrea; Hirsh, Vera; Smylie, Michael; Rubin, Sheldon; Martins, Heidi; Lamont, Alan; Krzakowski, Maciej; Sadura, Anna; Zee, Benny

doi:10.1200/jco.2002.02.108

Cited by 235 publications

(84 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This assumption is supported by the disappointing outcome of several recent clinical studies using such agents (Bramhall et al, 2001;Coussens et al, 2002;Shepherd et al, 2002).…”

Section: Discussionmentioning

confidence: 96%

Serum markers of matrix turnover as predictors for the evolution of colorectal cancer metastasis under chemotherapy

et al. 2003

View full text Add to dashboard Cite

Connective tissue turnover plays a prominent role in tumour growth and metastasis. We followed serum levels of seven connective tissue parameters in 37 patients with colorectal cancer metastatic to the liver prior to and during chemotherapy. Serum samples with episodes of tumour control (n ¼ 112) showed an increase of matrix metalloproteinase-2 (MMP-2) (Pp0.01) and a decrease of tissue inhibitor of MMPs (TIMP-1) levels (Pp0.01), while serum samples with episodes of tumour progression displayed the reverse pattern (Pp0.01 and Pp0.05, resp.). The ratio of circulating MMP-2/TIMP-1 was also significantly higher in episodes of tumour control vs tumour progression and prior to treatment (Pp0.0001). We conclude that serum MMP-2 appears to reflect tumour resorption, while serum TIMP-1 may mirror tumour expansion. Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a central role in benign and malignant matrix remodelling (Kähäri and Saarialho-Kere, 1999;Nagase and Woessner, 1999). MMP-2 and MMP-9 (gelatinases A and B, resp.) degrade basement membrane collagen as well as denatured collagens (gelatin). MMP activity is tightly regulated (1) on the level of transcription, (2) on the level of proteolytic activation of the pro-MMPs, (3) by the tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) and (4) by their strict compartmentalisation in cell membrane domains. Enhanced local expression and activity of MMPs and low levels of inhibitory TIMPs correlate with tumour growth and metastasis (Zeng et al, 1995(Zeng et al, , 1996Murray et al, 1996). However, the findings on circulating MMP-and TIMP levels in patients with metastatic colorectal tumours are unclear (Holten-Andersen et al, 2000;Pellegrini et al, 2000;Ylisirnio et al, 2000).CEA and CA 19-9 have been previously shown to predict tumour growth in patients with liver metastasis treated by chemotherapy (Hanke et al, 2001). However, there exist no follow-up data with serum connective tissue markers to predict treatment response or nonresponse in these patients. Colorectal cancer metastatic to the liver is particularly suited to validate novel markers, since the condition is characterised by a large and defined tumour burden. MATERIALS AND METHODSWe studied 37 consecutive patients (29 men, eight women, age 42 -76 years, mean 62 years) with colorectal carcinoma metastatic to the liver. Primary carcinoma was confirmed histologically. Histological confirmation was also obtained for synchronous liver metastasis. In case of metachronous liver metastasis, histological confirmation was only pursued when imaging techniques (spiral computerised tomography (CT) of the abdomen or MRT of the liver) did not show clear results. Patients received first-line chemotherapy, consisting of a weekly 1 -2 h infusion of folinic acid (500 mg m À2 ) followed by a 24-h infusion of 5-fluorouracil (2600 mg m À2 ). One cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 16 patients received additional biweekly oxaliplatin (85 mg m À2 ) and three patients ad...

show abstract

“…This assumption is supported by the disappointing outcome of several recent clinical studies using such agents (Bramhall et al, 2001;Coussens et al, 2002;Shepherd et al, 2002).…”

Section: Discussionmentioning

confidence: 96%

Serum markers of matrix turnover as predictors for the evolution of colorectal cancer metastasis under chemotherapy

et al. 2003

View full text Add to dashboard Cite

show abstract

“…This dose was chosen based on pharmacokinetic data from a phase 1 trial of marimastat in patients with advanced cancer, which suggested that this dose would generate plasma concentrations in the range required to inhibit the target enzymes, MMP2 and MMP9, while minimising the incidence of musculoskeletal side effects (Wojtowicz-Praga et al, 1998). This dose level has been used in several phase II and III trials of marimastat as a single agent (Bramhall et al, 2002;Miller et al, 2002;Shepherd et al, 2002). Fragmin was administered by a once daily subcutaneous injection at a dose of 200 units kg À1 for 4 weeks, after which the dose was reduced to 5000 units per day for the duration of the study.…”

Section: Methodsmentioning

confidence: 99%

Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

et al. 2004

View full text Add to dashboard Cite

Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg À1 for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.

show abstract

“…One is that the molecular target was not essential for growth, invasion, or metastasis of the tumor, and this hypothesis may explain the negative results for matrix metalloprotease inhibitors 15) and small molecules against vascular endothelial growth factor (VEGF) tyrosine kinase.…”

Section: Reasons For Negative Phase III Trialsmentioning

confidence: 99%

What are the reasons for negative phase III trials of molecular‐target‐based drugs?

Saijo

2004

Cancer Science

View full text Add to dashboard Cite

The results of molecular-biological studies of cancer are changing the way we diagnose and treat cancer. Target n an attempt to modulate specific molecular targets in tumor cells and the tumor environment, the emphasis in anticancer drug discovery has shifted from an empirical approach characterized by random screening of a variety of natural and synthetic compounds by means of cell-based cytotoxicity assays to more rational and mechanistic molecular screening. 1-5)The concept of molecular-target-based therapy is not new, because modern therapy of breast cancer and prostate cancer is in reality target-based therapy. What is new is that we now recognize that tumor cells contain many targets, and drugs specifically directed at such targets have been introduced clinically. [6][7][8][9]

show abstract

Prospective, Randomized, Double-Blind, Placebo-Controlled Trial of Marimastat After Response to First-Line Chemotherapy in Patients With Small-Cell Lung Cancer: A Trial of the National Cancer Institute of Canada-Clinical Trials Group and the European Organization for Research and Treatment of Cancer

Abstract: Treatment with marimastat after induction therapy for SCLC did not result in improved survival and had a negative impact on quality of life.

Cited by 235 publications

References 21 publications

Serum markers of matrix turnover as predictors for the evolution of colorectal cancer metastasis under chemotherapy

Serum markers of matrix turnover as predictors for the evolution of colorectal cancer metastasis under chemotherapy

Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

What are the reasons for negative phase III trials of molecular‐target‐based drugs?

Contact Info

Product

Resources

About