Lung Cancer (2005) 50, 83—86
`
`Limited efficacy of imatinib mesylate in malignant
`mesothelioma: A phase II trial
`Alexandre Mathy a,∗, Paul Baas b, Otilia Dalesio a, Nico van Zandwijk b
`
`a Biometrics Department, Netherlands Cancer Institute, Plesmanlaan 121,
`1066 CX Amsterdam, The Netherlands
`b Department of Thoracic Oncology, Netherlands Cancer Institute, Plesmanlaan 121,
`1066 CX Amsterdam, The Netherlands
`
`Received 7 March 2005; received in revised form 26 April 2005; accepted 27 April 2005
`
`KEYWORDS
`Malignant
`mesothelioma;
`Treatment;
`Imatinib;
`PDGF;
`c-Kit;
`Anti-cancer agents
`
`Summary
`Twenty-five patients with histologically proven malignant mesothelioma
`participated in a trial of imatinib mesylate (Glivec) with a starting dose of 400 mg
`per day taken orally, up to a maximal dose of 800 mg. No responses were observed in
`the patient group, while three patients showed prolonged (> 6 months) stabilization
`of disease. The median survival time was 398 days (range 88—840); the median time
`to progression was 63 days (range 29—275). Side effects of the medication were mild
`and included edema, nausea, constipation and diarrhea. We conclude that further
`investigation with monotherapy imatinib in mesothelioma is not warranted.
`© 2005 Elsevier Ireland Ltd. All rights reserved.
`
`1. Introduction
`
`Malignant mesothelioma (MM) is a rare neoplasm of
`the pleura with an extremely poor prognosis [1].
`It is associated with exposure to asbestos fibers,
`particularly of the crocidolite variety. While the
`exact pathogenesis of mesothelioma is still unclear,
`it is thought to arise from the mesenchymal cells of
`the pleura. Abestos fibers are inhaled and subse-
`quently accumulate in the pleura, where years of
`reactive processes around the fibers are thought to
`contribute to the disease [2].
`Despite the recent positive results reported
`with a new multitargeted antifolate, Pemetrexed
`
`∗ Corresponding author. Tel.: +31 20 5122671.
`E-mail address: a.mathy@nki.nl (A. Mathy).
`
`[3], this malignant condition of pleura or peri-
`toneum resists most oncological treatment and
`long-term survival long-term survival is very uncom-
`mon. Therefore, the investigation of new agents,
`especially those with novel working mechanisms,
`merits high priority in mesothelioma research.
`Many patients with MM experience a sharp
`increase in their thrombocyte counts, which is
`thought to be the result of increased platelet
`derived growth factor (PDGF) secretion (angiogenic
`activity) associated with the disease [4]. It has
`not yet been settled whether the PDGF activity is
`autocrine or paracrine in nature, but in any case
`PDGF appears to be an important factor in patho-
`genesis. Another potentially important signaling
`pathway in MM is c-Kit: in a series of MM patients,
`one-third was shown to express this oncogene [5].
`
`0169-5002/$ — see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
`doi:10.1016/j.lungcan.2005.04.010
`
`Ex. 1071-0001
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`84
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`A. Mathy et al.
`
`These findings stress the importance of clinical
`studies with agents inhibiting c-Kit and PDGF recep-
`tor tyrosine kinases.
`Imatinib mesylate (Glivec) is such an agent. It is a
`2-phenylaminopyrimidine tyrosine kinase inhibitor
`known to affect both c-Kit and the PDGF alpha
`and beta receptors. This drug has been shown to
`be effective in treating chronic myeloid leukaemia
`(CML) [6] and gastrointestinal stromal tumors (GIST)
`[7], and is specific. For instance, it does not affect
`Ser/Thr kinases, nor other members of the Type III
`RTK family such as Flt-3 and Fms [8].
`
`2. Patients and methods
`
`Patient selection criteria were: a diagnosis of
`malignant mesothelioma (pleural or peritoneal)
`backed up by histological evidence, at
`least
`one target lesion, no prior non-palliative radi-
`ation therapy given at
`the target
`lesion(s),
`adequate
`organ
`function
`and
`hematologi-
`bilirubin < 1.5× ULN,
`cal
`status
`(total
`SGOT
`SGPT < 2.5× ULN,
`creatinine < 1.5× ULN,
`and
`ANC > 1.5× 109 L−1, platelets > 100× 109 L−1), a
`performance status (ECOG WHO) of less than 3,
`age over 18 years and a signed informed consent
`form. Prior chemotherapy was permitted, but
`patients were non-eligible if they had received
`any investigational agent in the month before
`enrolment.
`The drug was to be administered orally at an ini-
`tial daily dose of 400 mg. Patients were required
`to keep a diary to monitor the side effects and
`adherence to the treatment. In case there was no
`excessive toxicity and the cancer did not respond
`to the medication, the study protocol permit-
`ted escalation of the daily dose to 600 mg 8
`weeks after enrolment and 800 mg 16 weeks after
`enrolment.
`Patients were to be taken off the treatment
`in case of progression, or if they experienced
`high toxicity (grade 2 or higher according to WHO
`criteria).
`The clinical measurements to be performed
`before the start of treatment included hematol-
`ogy lab values (hemoglobin, WBC and platelet
`counts), an ECG, assessment of organ function by
`serum chemistry, and a CT-scan to evaluate the
`status of the disease. Every 2 weeks, the serum
`lab values were to be measured again. On finding
`abnormal lab values (ANC < 1× 109 L−1, or platelet
`count < 50× 109 L−1), the imatinib dose could be
`reduced (from 800 mg to 600 mg, 600 mg to 400 mg),
`or the treatment interrupted until the toxicity
`
`resolved. A CT-scan was scheduled to monitor the
`course of the disease every 8 weeks.
`The study was set up as a single-center phase
`II trial following Fleming’s single stage design.
`Response was to be evaluated using the RECIST [9]
`criteria, while the WHO criteria were adopted to
`assess toxicity.
`
`3. Results
`
`From May 2002 to September 2003, 25 patients were
`included in the trial. Table 1 presents patient and
`disease characteristics at entry. The majority of the
`patients were male, and the main histological sub-
`type was epithelial. All but two of the cases were
`pleural. Two patients had received prior therapy
`(suramin and thalidomide).
`The median treatment duration was 63 days
`(range 8—245). Dose escalation to 600 mg was per-
`formed in seven patients, and subsequently the
`dose was increased to 800 mg in two of these
`patients. Treatment was discontinued in 15 patients
`due to progression of the disease and in the 10
`remaining cases due to side effects.
`Table 2 presents the worst degree of toxicity dur-
`ing treatment. No grade 4 toxicity was observed.
`The main side effects were edema (ankles, face,
`genitals and lungs) sometimes causing exacerbation
`of pleural or abdominal effusions, nausea and vom-
`iting.
`Imatinib produced no objective response in this
`group of patients. The median survival was 398
`days (range 88—840). There was no regression of
`the tumor observed in any of the patients. All of
`the 15 patients that continued treatment for a pro-
`longed period eventually experienced progression
`of their disease. For three patients, there was a
`stabilization of disease for over 6 months during
`treatment. Patients stopping protocol treatment
`
`Table 1
`
`Patient characteristics
`
`Characteristics
`Total
`Male/female
`Median age (years)
`Pleural/peritoneal
`Histological subtype
`Epithelial
`Mesenchymal
`Mixed
`Unknown
`Prior chemotherapy
`
`Number of patients (%)
`25
`20/5 (80/20)
`58 (range 48—74)
`23/2 (92/8)
`
`20 (80)
`1 (4)
`3 (12)
`1 (4)
`2 (8)
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`Limited efficacy of imatinib mesylate in malignant mesothelioma
`
`85
`
`Table 2
`
`Toxicity due to imatinib
`
`Type of toxicity
`
`CTC grade
`(number of patients)
`
`Dose at which
`symptom appears
`
`Number of patients
`stopping treatment
`due to symptom
`
`Edema/increase in
`pleural effusion
`Nausea and/or
`vomiting
`Constipation
`Diarrhea
`Rash
`Lymphopenia
`Hemoglobin
`
`G1
`3
`
`7
`
`3
`1
`
`G2
`2
`
`G3
`2
`
`G4
`
`3
`
`2
`
`1
`1
`
`400 mg, N = 6; 600 mg, N = 1
`
`400 mg, N = 9; 600 mg, N = 1
`
`400 mg, N = 2
`400 mg, N = 2; 600 mg, N = 1
`400 mg, N = 1
`400 mg, N = 1
`400 mg, N = 1
`
`5
`
`2
`
`2
`1
`1
`
`because of side effects were treated as censored
`at the time of dismissal, because they were sub-
`sequently recruited for further trials using other
`investigational agents.
`
`the response to treatment. More research in the
`mechanisms of the disease should hold the key to
`developing effective therapies.
`
`4. Discussion
`
`Despite there being sound biochemical grounds for
`hoping that imatinib could act on mesothelioma
`as it does on GIST and CML, the results of this
`study are negative. While the doses administered
`were sufficient to elicit side effects, no regression
`could be observed. The results of this study are
`broadly in agreement with a comparable study con-
`ducted in Australia by Millward et al. [10], where
`the best overall response was stable disease for
`over 3 months in 4 out of 25 patients with initial
`doses of 600 mg of imatinib. We conclude that fur-
`ther study of imatinib as a single agent therapy in
`mesothelioma is not justified.
`This highlights the pressing need for better
`understanding of the precise biological pathways
`involved in mesothelioma pathogenesis. In GIST,
`imatinib’s inhibiting effect on the c-Kit receptor
`is the crux of the therapy. However, the role and
`importance of c-Kit expression in mesothelioma are
`still disputed [11,12]. Furthermore, there is evi-
`dence pointing towards VEGF as an important factor
`[13], confirming the prominent role of angiogene-
`sis in the pathology. Early clinical experience with
`VEGF inhibitors (such as thalidomide and bevaciz-
`imab) suggests that this may be a fruitful pursuit.
`While imatinib also affects angiogenesis via PDGF,
`this does not seem to be as effective as in CML. It is
`possible that combination therapies with imatinib
`as a component could reveal that synergistically
`targeting the angiogenesis pathways will increase
`
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