PURPOSE: Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. PATIENTS AND METHODS: Patients were treated every 28 days with TMZ at 150-200 mg/m2 once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. RESULTS: Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46=7%, 95% confidence interval (CI)=1, 18). Median time to progression was 24 weeks (95% CI=16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI=35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. CONCLUSIONS: Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.
PURPOSE: Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes. PATIENTS AND METHODS: Patients were treated every 28 days with TMZ at 150-200 mg/m2 once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic gliomapatients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out. RESULTS: Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46=7%, 95% confidence interval (CI)=1, 18). Median time to progression was 24 weeks (95% CI=16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI=35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants. CONCLUSIONS: Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.
Authors: J S Rao; M Yamamoto; S Mohaman; Z L Gokaslan; G N Fuller; W G Stetler-Stevenson; V H Rao; L A Liotta; G L Nicolson; R E Sawaya Journal: Clin Exp Metastasis Date: 1996-01 Impact factor: 5.150
Authors: R E Sawaya; M Yamamoto; Z L Gokaslan; S W Wang; S Mohanam; G N Fuller; I E McCutcheon; W G Stetler-Stevenson; G L Nicolson; J S Rao Journal: Clin Exp Metastasis Date: 1996-01 Impact factor: 5.150
Authors: M Yamamoto; S Mohanam; R Sawaya; G N Fuller; M Seiki; H Sato; Z L Gokaslan; L A Liotta; G L Nicolson; J S Rao Journal: Cancer Res Date: 1996-01-15 Impact factor: 12.701
Authors: P A Forsyth; H Wong; T D Laing; N B Rewcastle; D G Morris; H Muzik; K J Leco; R N Johnston; P M Brasher; G Sutherland; D R Edwards Journal: Br J Cancer Date: 1999-04 Impact factor: 7.640
Authors: Francois Fay; Line Hansen; Stefanie J C G Hectors; Brenda L Sanchez-Gaytan; Yiming Zhao; Jun Tang; Jazz Munitz; Amr Alaarg; Mounia S Braza; Anita Gianella; Stuart A Aaronson; Thomas Reiner; Jørgen Kjems; Robert Langer; Freek J M Hoeben; Henk M Janssen; Claudia Calcagno; Gustav J Strijkers; Zahi A Fayad; Carlos Pérez-Medina; Willem J M Mulder Journal: Bioconjug Chem Date: 2017-05-05 Impact factor: 4.774
Authors: Fangyong Dong; Michael Eibach; Jörg W Bartsch; Amalia M Dolga; Uwe Schlomann; Catharina Conrad; Susanne Schieber; Oliver Schilling; Martin L Biniossek; Carsten Culmsee; Herwig Strik; Garrit Koller; Barbara Carl; Christopher Nimsky Journal: Neuro Oncol Date: 2015-03-29 Impact factor: 12.300
Authors: Mohan S Nandhu; Prajna Behera; Vivek Bhaskaran; Sharon L Longo; Lina M Barrera-Arenas; Sadhak Sengupta; Diego J Rodriguez-Gil; E Antonio Chiocca; Mariano S Viapiano Journal: Clin Cancer Res Date: 2017-11-16 Impact factor: 12.531
Authors: Michelle A Rudek; Pamela New; Tom Mikkelsen; Surasak Phuphanich; Jane B Alavi; Louis B Nabors; Steven Piantadosi; Joy D Fisher; Stuart A Grossman Journal: J Neurooncol Date: 2011-05-06 Impact factor: 4.130
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