Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma.
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-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα 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.


CONCLUSIONS
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 PDGFRα inhibitors, is warranted.
Department of Thoracic, Head, and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: astsao@mdanderson.org.
Anne S
AS
Tsao
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
Nusrat
N
Harun
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX.
J Jack
JJ
Lee
Department of Thoracic, Head, and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
John
J
Heymach
Department of Thoracic, Head, and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Katherine
K
Pisters
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
Waun Ki
WK
Hong
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Junya
J
Fujimoto
Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX.
Ignacio
I
Wistuba
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D000068437:Pemetrexed; D010879:Piperazines / Q000008:administration & dosage; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D011743:Pyrimidines / Q000008:administration & dosage; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D015996:Survival Rate; D016896:Treatment Outcome
D001549:Benzamides; D005971:Glutamates; D010879:Piperazines; D011743:Pyrimidines; D000068437:Pemetrexed; D006147:Guanine; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor; D002945:Cisplatin
Cisplatin; Imatinib mesylate; Mesothelioma; PDGFR; Pemetrexed