BACKGROUND: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed. METHODS: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0-2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle. RESULTS: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3-4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0-29.4). CONCLUSIONS: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).
BACKGROUND: Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed. METHODS: This was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0-2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle. RESULTS: Forty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3-4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0-29.4). CONCLUSIONS: The combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).
Authors: Junji Tsurutani; Junya Fukuoka; Hiroko Tsurutani; Joanna H Shih; Stephen M Hewitt; William D Travis; Jin Jen; Phillip A Dennis Journal: J Clin Oncol Date: 2005-12-05 Impact factor: 44.544
Authors: F V Fossella; R DeVore; R N Kerr; J Crawford; R R Natale; F Dunphy; L Kalman; V Miller; J S Lee; M Moore; D Gandara; D Karp; E Vokes; M Kris; Y Kim; F Gamza; L Hammershaimb Journal: J Clin Oncol Date: 2000-06 Impact factor: 44.544
Authors: Paolo Ceppi; Marco Volante; Silvia Saviozzi; Ida Rapa; Silvia Novello; Alberto Cambieri; Marco Lo Iacono; Susanna Cappia; Mauro Papotti; Giorgio V Scagliotti Journal: Cancer Date: 2006-10-01 Impact factor: 6.860
Authors: Nasser Hanna; Frances A Shepherd; Frank V Fossella; Jose R Pereira; Filippo De Marinis; Joachim von Pawel; Ulrich Gatzemeier; Thomas Chang Yao Tsao; Miklos Pless; Thomas Muller; Hong-Liang Lim; Christopher Desch; Klara Szondy; Radj Gervais; Christian Manegold; Sofia Paul; Paolo Paoletti; Lawrence Einhorn; Paul A Bunn Journal: J Clin Oncol Date: 2004-05-01 Impact factor: 44.544
Authors: Giorgio V Scagliotti; Paul Germonpré; Leon Bosquée; Johan Vansteenkiste; R Gervais; David Planchard; Martin Reck; Filippo De Marinis; Jin Soo Lee; Keunchil Park; Bonne Biesma; Steven Gans; R Ramlau; Aleusandra Szczesna; A Makhson; G Manikhas; Bruno Morgan; Y Zhu; Kai C Chan; Joachim von Pawel Journal: Lung Cancer Date: 2009-08-18 Impact factor: 5.705
Authors: Alberto Chiappori; Gerold Bepler; Fabrice Barlesi; Jean-Charles Soria; Martin Reck; Alessandra Bearz; Fernando Barata; Giorgio Scagliotti; Keunchil Park; Asavari Wagle; Astra M Liepa; Yan Daniel Zhao; Nadia Chouaki; Neill Iscoe; Joachim von Pawel Journal: J Thorac Oncol Date: 2010-03 Impact factor: 15.609
Authors: Jennifer Sigmond; Harold H J Backus; Dorine Wouters; Olaf H Temmink; Gerrit Jansen; Godefridus J Peters Journal: Biochem Pharmacol Date: 2003-08-01 Impact factor: 5.858