European Journal of Cancer 39 (2003) 2006–2011
`
`www.ejconline.com
`
`Imatinib mesylate (STI-571 Glivec1, GleevecTM) is an active agent
`for gastrointestinal stromal tumours, but does not yield responses in
`other soft-tissue sarcomas that are unselected for a molecular target:
`Results from an EORTC Soft Tissue and Bone Sarcoma Group
`phase II study
`
`J. Verweija,*, A. van Oosteromb, J.-Y. Blayc, I. Judsond, S. Rodenhuise,
`W. van der Graaff, J. Radfordg, A. Le Cesneh, P.C.W. Hogendoorni, E.D. di Paolaj,
`M. Brownj, O.S. Nielsenk
`aDepartment of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
`bDepartment of Clinical Oncology, University Hospital Gasthuisberg, Leuven, Belgium
`cDepartment of Medical Oncology, Hospital E.Herriot and INSERM U453, Centre Leon Berard, Lyon, France
`dSarcoma Unit, Royal Marsden Hospital, London, UK
`eDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
`fDepartment of Medical Oncology, University Hospital Groningen, Groningen, The Netherlands
`gDepartment of Medical Oncology, Christie Hospital, Manchester, UK
`hDepartment of Medical Oncology, Institute Gustave Roussy, Villejuif, France
`iDepartment of Pathology, Leiden University Medical Center, Leiden, The Netherlands
`jEORTC Data Center, Brussels, Belgium
`kDepartment of Oncology, Aarhus Kommune Hospital, Aarhus, Denmark
`
`Received 21 October 2002; accepted 24 October 2002
`
`Abstract
`
`The aim of this study was to assess the antitumour response and time to progression (TTP) of patients treated with imatinib
`mesylate (Glivec1, GleevecTM, formerly STI-571) who had advanced and/or metastatic gastrointestinal stroma tumours (GIST) or
`other soft tissue sarcomas (STS). Patients with measurable lesions and adequate organ function were entered. They were treated
`with imatinib mesylate at the dose of 400 mg twice daily (bid). All tumours were subject to a stringent pathological review by an
`expert panel. Immunohistochemical expression of KIT expression was evaluated. A total of 51 patients (27 GIST, 24 other STS),
`median age 53 years, median World Health Organization (WHO) performance score 1, were entered. 71% of the patients had
`received prior chemotherapy. The most frequent side-effects were anaemia (92%), periorbital oedema (84%), skin rash (69%),
`fatigue (76%), nausea (57%), granulocytopenia (47%) and diarrhoea (47%). Most of these side-effects were mild to moderate and
`no patient was taken off study due to side-effects. Skin rash and periorbital oedema frequently seem to be self limiting, despite
`continued treatment. In GIST patients, the current response rates (RRs) are 4% complete remission (CR), 67% partial remission
`(PR), 18% stable disease (SD) and 11% progression (PD). 73% of GIST patients are free from progression at 1 year. In the other
`STS group, there were no objective responses. The median time to progression in this subgroup was only 58 days. Imatinib mesylate
`is well tolerated at a dose of 400 mg bid. This dose is active in patients with KIT-positive GIST, but patients with other STS sub-
`types unselected for a molecular target are unlikely to benefit.
`# 2003 Elsevier Ltd. All rights reserved.
`
`Keywords: Gastrointestinal stroma tumours; Sarcoma; Imatinib mesylate
`
`* Corresponding author. Tel.: +31-10-439-1338; fax: +31-10-439-1003.
`E-mail address: verweij@onch.azr.nl (J. Verweij).
`
`0959-8049/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
`doi:10.1016/S0959-8049(02)00836-5
`
`Ex. 1073-0001
`
`

`

`J. Verweij et al. / European Journal of Cancer 39 (2003) 2006–2011
`
`2007
`
`1. Introduction
`
`Soft-tissue sarcomas (STS) represent 1% of all adult
`malignancies and are a heterogeneous group of neo-
`plasms whose only common denominator is their deri-
`vation from mesenchymal tissue. Surgery to obtain wide
`margins is usually the first-line of treatment for STS. In
`the case of lesions of the extremities, the standard of
`radical, or limb-sparing surgery leaving wide-margins
`plus radiotherapy has dramatically improved the local
`control of the disease [1–4]. Radiation therapy as a sin-
`gle primary modality is only used in patients with
`lesions that are not amenable to surgery because of their
`tumour size, or the relationship of their tumour to vital
`anatomical
`structures
`[5]. Nevertheless,
`despite
`improved rates of local control, many patients still die
`from metastatic disease.
`Chemotherapy is currently used for the treatment of
`advanced and/or metastatic STS, but only a few cyto-
`toxic drugs have demonstrated activity in this disease.
`Doxorubicin is the most active single agent, with an
`associated response rate of approximately 20–25% [6].
`Ifosfamide and dacarbazine have also demonstrated
`activity [6,7]. Although some studies suggested that
`combination chemotherapy has higher response rates
`than single-agent doxorubicin therapy [8,9], the lar-
`gest such study performed by the European Organi-
`zation for Research and Treatment of Cancer
`(EORTC) Soft Tissue and Bone Sarcoma Group and
`accruing more than 700 patients, showed that there
`was
`significantly more myelosuppression with the
`combinations of doxorubicin and ifosfamide and of
`cyclophosphamide, vincristine, doxorubicin and dacar-
`bazine, but the response rates were not significantly dif-
`ferent [10]. In all of the studies, there was no benefit in
`terms of survival for patients receiving combination
`chemotherapy. Therefore,
`conventional-dose
`single-
`agent chemotherapy can still be considered standard
`treatment for metastatic STS. Gastrointestinal Stroma
`Tumours (GIST) are a relatively recently described STS
`subtype, that were previously included with other sar-
`coma subtypes. GIST have a specific natural history [11]
`and a high rate of resistance to standard conventional
`chemotherapy agents (EORTC, data on file).
`Imatinib mesylate (Glivec, Gleevec, STI-571) is a
`small molecule tyrosine kinase inhibitor designed to
`target c-ABL and BCR-ABL, but is also able to target
`KIT and the platelet-derived growth factor receptor
`(PDGFR). KIT is extensively expressed in GIST [11],
`and KIT proto-oncogene is often mutated resulting in
`activation of the kinase. PDGFR is widely expressed in
`mesenchymal tissues and the majority of other STS
`subtypes. A previous EORTC phase I study [12] identi-
`fied the highest feasible dose of imatinib mesylate to be
`400 mg twice daily (bid) in solid tumours, and this dose
`had extensive activity in GIST. A randomised phase II
`
`study exploring lower doses also confirmed activity in
`GIST [13].
`To assess the activity of imatinib mesylate in GIST at
`the highest feasible dose of 400 mg bid, and to explore
`potential activity in other subtypes of STS, we per-
`formed a phase II study in these patient groups.
`
`2. Patients and methods
`
`2.1. Eligibility criteria
`
`included histologically-proven
`criteria
`Eligibility
`advanced and/or metastatic GIST characterised by KIT
`expression, or any other subtype of STS, not necessarily
`selected by KIT expression, graded according to the
`Trojani system and incurable by surgery or radio-
`therapy, excluding malignant mesothelioma, chon-
`drosarcoma, neuroblastoma, osteosarcoma, Ewing’s
`sarcoma and embryonal rhabdomyosarcoma.
`The immunohistochemical expression of KIT was
`assessed by standard immunohistochemistry without
`antigen retrieval using antibodies obtained from DAKO
`(Dakopatts, Glostrup, Denmark). Mast cells served as
`an internal positive control in tumour-negative cases; in
`other STS cases staining in parallel was performed on a
`GIST with a known expression as an external positive
`control.
`Patients had to have at least one measurable target
`lesion with a minimum size of at least one diameter
`52 cm, or 51 cm if measured on spiral computed
`tomography (CT) scan, with evidence of progression
`within 6 weeks prior to study entry: No more than
`one line of previous combination chemotherapy or
`two single-agent regimens were allowed. The chemo-
`therapy should have been discontinued for more than
`4 weeks; for GIST, patients who had not been pre-
`viously treated were also eligible: Patients had to
`have had no previous radiation therapy to the sole
`index lesion used to assess response and be aged greater
`than 15 years with a World Health Organization
`(WHO) performance status < 2; an absolute neutrophil
`than 1.5109/l; platelet
`count more
`count more
`than 100109/l; serum creatinine 4120 micromol/l
`or
`calculated
`creatinine
`clearance
`(Cockcroft
`method) > 1.1 ml/s; total bilirubin 430 micromol/l;
`no co-medication with warfarin was allowed. All
`patients gave their written informed consent. His-
`tology was centrally reviewed and the expression of
`KIT was assessed by immunohistochemistry at one of
`the reference centres.
`
`2.2. Prestudy and follow-up investigations
`
`Before the first and all subsequent treatment courses,
`a physical
`examination was performed. Electro-
`
`Ex. 1073-0002
`
`

`

`2008
`
`J. Verweij et al. / European Journal of Cancer 39 (2003) 2006–2011
`
`cardiography and chest radiography were performed at
`baseline and repeated every 8 weeks.
`Before the study and every 4 weeks thereafter, total
`bilirubin. alkaline phosphatase, aspartate aminotransfer-
`ase, alanine aminotransferase,
`lactate dehydrogenase,
`sodium, potassium, calcium, glucose, creatinine, and
`albumin levels were measured. White Blood Cells (WBC),
`neutrophil, and platelet counts and haemoglobin levels
`were performed weekly. Tumour assessments were per-
`formed every 8 weeks until month 6, and every 3
`months thereafter until the end of treatment. Standard
`Response Evaluation Criteria in Solid Tumours
`(RECIST)
`criteria [14] were used for
`evaluating
`response and all responses were subject to independent
`review. The duration of partial
`response or no
`change was calculated from the date of registration
`to the date of documented progression, and the
`duration of complete response noted to the docu-
`mented time of progression. Time to progression
`(TTP) was calculated from the date of registration to
`progression or last contact. Duration of survival was
`calculated from the date of registration to the date of
`death.
`Toxicity was graded using National Cancer Institute
`Common Toxicity Criteria (NCI-CTC) version 2.0.
`
`2.3. Treatment and dose modifications
`
`Imatinib mesylate (Novartis, Basle, Switzerland) was
`supplied as 100 mg yellow hard gelatine capsules pack-
`aged in polystyrene bottles, and administered orally at a
`dose of 400 mg bid, continuously. Imatinib mesylate
`was to be taken directly after a meal. There was no
`prophylactic co-medication. All patients were scheduled
`to continue treatment until disease progression, or
`unacceptable toxicity.
`If the neutrophil count became less than 1.0109/l or
`the platelet count was less than 50109/l, treatment was
`withheld until recovery to grade 1 and then restarted at
`a daily total dose of 600 mg. If similar toxicity recurred,
`a further dose reduction to 400 mg daily was permitted.
`For any grade 52 non-haematological toxicity, the
`drug was to be withheld until recovery to grade 1. It
`could than be resumed at the same daily dose. If grade
`52 non-haematological
`toxicity recurred,
`imatinib
`mesylate was again withheld and upon recovery the
`dose was reduced to 600 mg daily, or (if necessary) fur-
`ther reduced to 400 mg daily.
`
`2.4. Statistical analysis
`
`The study was designed as a two strata phase II study
`evaluating response, using a Fleming one-stage design
`testing procedure, with P0 taken as 10%, P1 as 30%, a
`as 0.1 and b as 0.1. Under these hypotheses, 24 evalu-
`able patients per stratum were required.
`
`3. Results
`
`3.1. Patient characteristics
`
`A total of 51 patients (27 GIST, 24 other STS) were
`entered onto the study by 13 centres over a 2-month
`period. Patients’ characteristics and pathological diag-
`nosis following external review are listed in Table 1.
`Diagnostic criteria used are detailed elsewhere [15].
`All GIST were shown to express membranous KIT.
`In the other STS group, none of the tumours was
`KIT-positive.
`2 patients in the other STS group were formally ineli-
`gible, because they had not received any prior chemo-
`therapy. All analyses were performed on an intent-to-
`treat basis.
`The median time on treatment was 13+ months for
`the GIST patients and 2 months for the other STS
`patients.
`
`3.2. Toxicity
`
`No patient discontinued therapy because of toxicity.
`The side-effects are listed in Table 2. The most frequent
`side-effects were anaemia (92%), oedema (particularly
`periorbital oedema) (84%), skin rash (69%), fatigue
`(76%), nausea (57%), granulocytopenia and diarrhoea
`(47%). Most of these side-effects were mild to moderate
`and tended to occur in the first 8 weeks of treatment.
`Although the numbers are small, the decrease of side-
`effects did not seem to be related to dose reductions
`(data not shown). Periorbital oedema showed as puffy
`
`Table 1
`Patients’ characteristics
`
`No. of patients entered
`Gender
`Male/female
`
`Age (years)
`Median (range)
`
`WHO performance score
`Median (range)
`
`Prior treatment
`Surgery
`Radiotherapy
`Chemotherapy
`
`Histology
`GIST
`Liposarcoma
`Leimyosarcoma
`Fibrosarcoma
`Synovial sarcoma
`Unclassified
`Miscellaneous
`
`51
`
`67%/33%
`
`53 (21–75)
`
`1 (0–1)
`
`88%
`24%
`71%
`
`27
`6
`4
`3
`3
`3
`5
`
`WHO, World Health Organization; GIST, Gastrointestinal Stromal
`Tumours.
`
`Ex. 1073-0003
`
`

`

`J. Verweij et al. / European Journal of Cancer 39 (2003) 2006–2011
`
`2009
`
`Table 2
`Side-effects (worst per patient; %)
`
`Side-effect
`
`Grade (NCI-CTC)
`
`Granulocytopenia
`Anaemia
`Oedema
`Fatigue
`Chills
`Rash
`Anorexia
`Diarrhoea
`Nausea
`Vomiting
`Bleeding
`
`0
`
`53
`8
`16
`24
`80
`31
`61
`53
`43
`57
`92
`
`1
`
`31
`49
`49
`29
`20
`43
`19
`27
`35
`33
`2
`
`2
`
`10
`31
`35
`35
`–
`12
`14
`16
`18
`4
`–
`
`3
`
`4
`10
`–
`12
`–
`14
`6
`4
`4
`6
`4
`
`4
`
`2
`2
`–
`–
`–
`–
`–
`–
`–
`–
`2
`
`NCI-CTC, National Cancer Institute-Common Toxicity Criteria.
`
`eyes and mainly involved the skin above the eye. Skin
`toxicity existed mainly of erythema that sometimes
`became crusty. Just like the periorbital oedema, it was
`most frequently self-limiting in most patients experien-
`cing these side-effects, despite continued treatment.
`Oedema, skin rashes and nausea decreased in severity
`over time (Fig. 1).
`
`3.3. Response
`
`All responses reported were subject to peer review and
`responses were classified according to the RECIST cri-
`teria. In an intent-to-treat analysis, in the GIST patients
`the current response rates are 4% complete remission
`(CR) (n=1), 67% partial remission (PR) (n=18), 19%
`
`Fig. 1. Decrease in the severity of side-effects over time: (a) Oedema; (b) skin rash; (c) nausea. CTC, Common Toxicity Criteria; Wk, week.
`
`Ex. 1073-0004
`
`

`

`2010
`
`J. Verweij et al. / European Journal of Cancer 39 (2003) 2006–2011
`
`suggestive of a diagnosis of GIST for sarcomas arising
`in the digestive tract or abdomen [11,15]. After oral
`administration, imatinib mesylate is rapidly absorbed
`with a dose-proportional exposure up to 1000 mg/day,
`albeit with large interindividual variations, and the
`terminal half-life (t1/2) is 10–23 h, resulting in 2–3-fold
`accumulation of drug at steady state.
`A previous EORTC phase I study [12] identified the
`highest feasible dose of imatinib mesylate in solid tumors
`to be 400 mg bid. Importantly, the objective response rate
`in GIST patients was as high as 69% and only 11% of the
`patients progressed, while 89% of symptomatic patients
`experienced total relief from symptoms, or major symp-
`tom improvement. A randomised phase II study, explor-
`ing lower doses, confirmed activity in GIST [13].
`To assess the activity of imatinib mesylate in GIST at
`the highest feasible dose of 400 mg bid, and to explore
`potential activity in other subtypes of STS, we per-
`formed a phase II study in these two groups.
`In 27 GIST patients, we confirmed activity that is
`similar to that observed in our phase I study [12]. Inter-
`estingly, this activity seems to be higher than that repor-
`ted in the United States (US) study [13]. Whether the
`difference is related to a difference in the applied dose, or
`simply to patient selection bias, remains to be elucidated.
`Recently two parallel phase III studies have been per-
`formed, one co-ordinated by the South West Oncology
`Group (SWOG), the other co-ordinated by the EORTC.
`Both studies compared a daily dose of 400 mg to one of
`800 mg. Given the interpatient variation in pharmacoki-
`netics, it is more likely that these large studies will be able
`to detect a dose–response relationship if there is one, than
`the above mentioned study [12], that was not designed or
`intended for this purpose. The SWOG study accrued 746
`patients, the EORTC-Italian Sarcoma Group (ISG)-
`Australasian Gastro-Internal Tumor Group (AGITG)
`study 946 patients, both accrued patients in less than one
`year. Despite this rapid accrual and the recent study clo-
`sure, it will be several years before the question of a pos-
`sible dose–response relationship can be answered,
`especially with respect to response duration.
`There is evidence that patients with different muta-
`tions of the KIT receptor respond differently to treat-
`ment. In the (randomised) phase II study, comparing
`400 with 600 mg/day, Blanke and colleagues [18] repor-
`ted a 70% response rate (RR) in patients with a muta-
`tion of exon 11 (the majority of patients), but in patients
`with wild-type KIT or mutations in exon 9, this rate was
`less than 20%. In 24 patients with KIT-negative STS
`other than GIST in this study, there were no objective
`responses and only one long-lasting SD was observed in
`a patient with a previously clearly progressive lipo-
`sarcoma. This is in total contrast to the findings in
`GIST, and in line with the data for inactive agents as
`previously studied by EORTC [19]. The other STS
`tumours were not selected for PDGFR expression, since
`
`Fig. 2. Time to progression, by histology: GIST versus other soft-
`tissue sarcomas (STS).
`
`stable disease (SD) (n=5) and 11% progression (PD)
`(n=3). While some patients responded early after the
`start of treatment, in others this response took a long
`time to occur. The median time to onset of response was
`113 days. Responses and stable diseases seem to be
`long-lasting, with 73% of GIST patients free from pro-
`gression at 1 year (Fig. 2).
`In the other STS group, there were no objective
`responses or regressions, and only 29% of patients
`experienced a stable disease with an estimated duration
`of 176 days. The median time to progression in this
`group of patients was 58 days (Fig. 2).
`
`4. Discussion
`
`The treatment of metastatic STS continues to be dif-
`ficult because of a paucity of active agents. The only two
`agents with proven activity are doxorubicin and ifosfa-
`mide [6–10], and these lack activity in the subset of
`GISTs for which there is currently no standard medical
`treatment (EORTC, data on file).
`Imatinib mesylate is a protein-tyrosine kinase inhibitor
`which potently inhibits the ABL tyrosine kinase (TK) in
`vitro and in vivo. The drug was found to be highly active
`in clinical studies in chronic myeloid leukaemia (CML)
`expressing the fusion protein BCR-ABL [16].
`In addition, imatinib mesylate is a potent inhibitor of
`the receptor tyrosine kinases for PDGF and stem cell
`factor (SCF), and inhibits PDGF- and SCF-mediated
`biochemical events [17]. The tyrosine kinases are a
`family of phospho-transferase enzymes that
`include
`many growth factor receptors and are frequently pro-
`ducts of proto-oncogenes. Furthermore, PDGF has
`been suggested to be a major mitogen for connective
`tissue cells. In almost all sub-types of STS, over-
`expression of PDGF has been reported, while KIT
`overexpression although not strictly specific, is highly
`
`Ex. 1073-0005
`
`

`

`J. Verweij et al. / European Journal of Cancer 39 (2003) 2006–2011
`
`2011
`
`based on previous reports this was assumed to be a
`common feature. The lack of clinical activity in this
`group may be due to a less important role for PDGF in
`tumour growth, particularly in STS, or may be related
`to the reduced sensitivity of PDGFR to imatinib mesy-
`late, leading to the need for a higher dose for inhibition.
`Our results at the very least suggest that patients with
`STS that lack KIT expression should not be offered
`imatinib mesylate treatment outside of specific study
`protocols. It is likely that such patients should only be
`considered for imatinib mesylate treatment within study
`protocols if there is evidence of KIT expression and
`perhaps only in the presence of an exon 11 mutation of
`KIT, given the relative insensitivity of tumours with
`wild-type receptors or other activating mutations.
`The toxicity of imatinib mesylate given at a dose of
`800 mg daily was manageable. Skin rash and periorbital
`oedema seem to be self-limiting despite continued treat-
`ment in most patients experiencing these side-effects.
`Bleeding at tumour sites, a feature known to be related
`to GIST, also occurred, but was not common and was
`never considered to be a severe event. Whether the
`occurrence of haemorrhage soon after the initiation of
`treatment was disease- or drug-related or both is
`unclear. Further studies should help to elucidate this.
`The profile of side-effects confirms the impression
`reported in the extended part of the published phase I
`study [12], that the drug at this dose is generally safe.
`This profile may reflect the presence of the drug target
`KIT on normal cells outside the digestive tract such as
`mast cells, melanocytes, basal cells of the epidermis and
`salivary gland epithelium.
`In conclusion, imatinib mesylate is well tolerated at a
`dose of 400 mg bid. This dose is highly active in patients
`with c-KIT-positive GIST, but patients with other STS
`subtypes unselected for a molecular target are unlikely to
`benefit. Further studies in GIST are currently exploring
`the possibility of a dose–effect relationship.
`
`References
`
`1. Brennan MF, Alektti KM, Maki RG. Soft tissue sarcomas. In
`DeVita VT, Hellman S, Rosenberg SA, eds. Cancer Principles and
`Practice of Oncology, 6th edn. Philadelphia, Lippincott, Williams
`and Wilkins, 2001, 1841–1890.
`2. Flugstad DL, Wilke CP, McNutt MA, et al. Importance of sur-
`gical resection in the successful management of soft tissue sar-
`coma. Arch Surg 1999, 134, 856–861.
`
`3. O’Sullivan B, Wylie J, Catton C, Gutierrez E, Swallow CJ,
`Wunder J. The local management of soft tissue sarcoma. Semin
`Radiat Oncol 1999, 9, 328–348.
`4. Dirix LY, van Oosterom AAT. Soft tissue sarcomas in adults.
`Curr Opin Oncol 1999, 11, 285–295.
`5. Tepper JE, Suit HD. Radiation therapy of soft tissue sarcomas.
`Cancer 1985, 55, 2273–2277.
`6. Verweij J, Mouridsen HT, Nielsen OS, et al. The present state of
`the art in chemotherapy for soft tissue sarcomas in adults: the
`EORTC point of view. Crit Rev Oncol Hematol 1995, 20, 193–
`201.
`7. Benjamin RS, Legha SS, Patel SR, et al. Single agent ifosfamide
`studies in sarcomas of soft tissue and bone: the MD Anderson
`experience. Cancer Chemother Pharmacol 1993, 31(Suppl. 2),
`174–179.
`8. Schoenfeld DA, Rosenbaum C, Hortom J, et al. A comparison
`of Adriamycin versus vincristine and Adriamycin, and cyclo-
`phosphamide versus vincristine, actinomycin-D, and cyclo-
`phosphamide for advanced sarcoma. Cancer 1982, 50, 2757–
`2762.
`9. Borden EC, Amato DA, Rosenbaum C, et al. Randomised com-
`parison of three Adriamycin regimens for metastatic soft tissue
`sarcomas. J Clin Oncol 1987, 5, 840–850.
`10. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus
`CYVADIC versus doxorubicin plus ifosfamide in first-line treat-
`ment of advanced soft tissue sarcomas: a randomised study of the
`EORTC Soft Tissue and Bone Sarcoma Group. J Clin Oncol
`1995, 13, 1537–1545.
`11. Mietinnen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal
`stromal tumors: recent advances in understanding of thier biol-
`ogy. Hum Pathol 1999, 30, 1213–1220.
`12. Van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy
`of
`imatinib (STI571)
`in metastatic gastrointestinal
`stromal
`tumors: a phase I study. Lancet 2001, 358, 1421–1423.
`13. Demetri GD, von Mehren M, Blanke Ch, et al. Efficacy and
`safety of Imatinib mesylate in advanced gastrointestinal stromal
`tumors. N Engl J Med 2002, 347, 472–480.
`14. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to
`evaluate the response to treatment in solid tumors. J Natl Cancer
`I 2000, 92, 205–216.
`15. Graadt van Roggen JF, Van Velthuysen MLF, Hogendoorn
`PCW. The
`histopathological
`differential
`diagnosis
`of
`tumours. J Clin Pathol 2001, 54, 96–
`gastrointestinal
`stromal
`103.
`16. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a
`specific inhibitor of the BCR-ABL tyrosine kinase in chronic
`myeloid leukaemia. N Engl J Med 2002, 344, 1084–1086.
`17. Savage DG, Antman KA. Imatinib mesylate: a novel oral tar-
`geted therapy. N Engl J Med 2002, 346, 683–693.
`18. Blanke CD, von Mehren M, Joensuu H, et al. Evaluation of the
`safety and efficacy of an oral molecularly targeted therapy,
`STI571,
`in patients with unresectable or metastatic gastro-
`intestinal stromal tumors (GISTs) expressing c-KIT (CD117).
`Proc Am Soc Clin Oncol 2001, 20, 1a.
`19. Van Glabbeke M, Verweij J, Judson I, Nielsen OS. Progression-
`free rate as the principal end-point for phase II trials in soft-tissue
`sarcomas. Eur J Cancer 2002, 38, 543–549.
`
`Ex. 1073-0006
`
`