PMID- 24492162 OWN - NLM STAT- MEDLINE DCOM- 20141201 LR - 20211021 IS - 1938-0690 (Electronic) IS - 1525-7304 (Print) IS - 1525-7304 (Linking) VI - 15 IP - 3 DP - 2014 May TI - Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma. PG - 197-201 LID - S1525-7304(13)00265-9 [pii] LID - 10.1016/j.cllc.2013.12.008 [doi] AB - BACKGROUND: We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM). METHODS: A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels. RESULTS: Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRalpha IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRalpha in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of >/= 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done. CONCLUSION: The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRalpha inhibitors, is warranted. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Tsao, Anne S AU - Tsao AS AD - Department of Thoracic, Head, and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: astsao@mdanderson.org. FAU - Harun, Nusrat AU - Harun N AD - Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Lee, J Jack AU - Lee JJ AD - Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Heymach, John AU - Heymach J AD - Department of Thoracic, Head, and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Pisters, Katherine AU - Pisters K AD - Department of Thoracic, Head, and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Hong, Waun Ki AU - Hong WK AD - Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Fujimoto, Junya AU - Fujimoto J AD - Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Wistuba, Ignacio AU - Wistuba I AD - Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. LA - eng GR - UG1 CA233329/CA/NCI NIH HHS/United States GR - K12 CA088084/CA/NCI NIH HHS/United States GR - L30 CA103708/CA/NCI NIH HHS/United States GR - 5 K12 CA08808405(PP-9)/CA/NCI NIH HHS/United States GR - P30 CA016672/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131227 PL - United States TA - Clin Lung Cancer JT - Clinical lung cancer JID - 100893225 RN - 0 (Benzamides) RN - 0 (Glutamates) RN - 0 (Piperazines) RN - 0 (Pyrimidines) RN - 04Q9AIZ7NO (Pemetrexed) RN - 5Z93L87A1R (Guanine) RN - 8A1O1M485B (Imatinib Mesylate) RN - EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/adverse effects/*therapeutic use MH - Benzamides/administration & dosage MH - Cisplatin/administration & dosage MH - Disease-Free Survival MH - Female MH - Glutamates/administration & dosage MH - Guanine/administration & dosage/analogs & derivatives MH - Humans MH - Imatinib Mesylate MH - In Situ Hybridization, Fluorescence MH - Lung Neoplasms/*drug therapy/pathology MH - Male MH - Maximum Tolerated Dose MH - Mesothelioma/*drug therapy/pathology MH - Mesothelioma, Malignant MH - Middle Aged MH - Pemetrexed MH - Piperazines/administration & dosage MH - Pleural Neoplasms/*drug therapy/pathology MH - Prognosis MH - Pyrimidines/administration & dosage MH - Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors MH - Survival Rate MH - Treatment Outcome PMC - PMC5080907 MID - NIHMS815993 OTO - NOTNLM OT - Cisplatin OT - Imatinib mesylate OT - Mesothelioma OT - PDGFR OT - Pemetrexed EDAT- 2014/02/05 06:00 MHDA- 2014/12/15 06:00 PMCR- 2016/10/26 CRDT- 2014/02/05 06:00 PHST- 2013/10/22 00:00 [received] PHST- 2013/12/20 00:00 [revised] PHST- 2013/12/23 00:00 [accepted] PHST- 2014/02/05 06:00 [entrez] PHST- 2014/02/05 06:00 [pubmed] PHST- 2014/12/15 06:00 [medline] PHST- 2016/10/26 00:00 [pmc-release] AID - S1525-7304(13)00265-9 [pii] AID - 10.1016/j.cllc.2013.12.008 [doi] PST - ppublish SO - Clin Lung Cancer. 2014 May;15(3):197-201. doi: 10.1016/j.cllc.2013.12.008. Epub 2013 Dec 27.