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Annals of Oncology Advance Access originally published online on August 14, 2007
Annals of Oncology 2008 19(1):173-177; doi:10.1093/annonc/mdm419
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sarcomas

Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate

H. Joensuu1,*, F. De Braud2, P. Coco4, T. De Pas2, C. Putzu2, C. Spreafico4, P. Bono1, S. Bosselli2, T. Jalava3, D. Laurent3 and P. G. Casali4

1 Department of Oncology, University Central Hospital of Helsinki, Helsinki, Finland
2 Department of Oncology, European Institute of Oncology, Milano, Italy
3 Bayer Schering Pharma AG, Berlin, Germany
4 Adult Sarcoma Medical Oncology Unit, Istituto Nazionale Tumori, Milano, Italy

* Correspondence to: Dr H. Joensuu, Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00029 Helsinki, Finland. Tel: +358-9-471 73208; Fax: +358-9-471 74202; E-mail: heikki.joensuu{at}hus.fi


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Background: We evaluated safety and efficacy of PTK787/ZK222584 (PTK/ZK), a novel tyrosine kinase inhibitor of KIT, platelet-derived growth factor receptors and vascular endothelial cell growth factor receptors (VEGFRs), in patients with imatinib-resistant gastrointestinal stromal tumor (GIST). This is the first study of PTK/ZK in this population.

Patients and methods: Patients with metastatic GIST that had progressed after ≥ 4-week treatment with imatinib mesylate were eligible. Prior VEGFR-2 inhibitor therapy was not permitted. PTK/ZK 1250 mg orally once-daily was administered to 15 patients (accrued as a two-stage procedure), most of whom (n = 11) had been unsuccessfully treated with imatinib 800 mg daily, until treatment failure. Patients were monitored at 4- to 8-week intervals.

Results: All 15 patients enrolled were eligible; two (13%) achieved partial response (PR), eight (53%) had stable disease (SD) ≥3 months, and five (33%) progressed. The clinical benefit rate (PR + SD) was 67% (95% CI 38% to 86%). Median time to progression was 8.5 months (range 0.9–24.8+ months). Three patients had not progressed at the time of analysis, including one PR at 24.8 months and two SDs at 16.6 and 18.6 months on treatment. PTK/ZK was generally well tolerated.

Conclusion: PTK/ZK 1250 mg p.o. once daily is active and well tolerated in patients with imatinib-resistant GIST.

Key words: gastrointestinal stromal tumor, vatalanib, imatinib, tyrosine kinase inhibitor, targeted therapy, c-kit


   introduction
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 Abstract
 introduction
patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Gastrointestinal stromal tumors (GISTs) are relatively rare tumors but nonetheless constitute the most common soft tissue sarcoma of the gastrointestinal tract [1–3]. The annual incidence of GISTs is 10–15 cases per million in population-based studies that include also the more indolent GISTs [4, 5]. Most GISTs (~80%) harbor an activating mutation of KIT, which encodes a tyrosine kinase that functions as the receptor of the stem-cell factor. Approximately 5% of GISTs have mutated PDGFRA that encodes platelet-derived growth factor receptor alpha (PDGFR{alpha}) tyrosine kinase, and 15% do not contain a mutation in either gene (‘wild-type’ GISTs) [6].

Imatinib mesylate, a tyrosine kinase inhibitor (TKI) of KIT, the PDGFRs, and a few other kinases, is the first effective systemic therapy for the treatment of metastatic GIST [7]. Before imatinib, chemotherapy regimens yielded response rates <10% [8], with 5-year survival rates as low as ~30% [9]. Imatinib therapy yields high response rates [partial response (PR), 48%–71%; stable disease (SD), 18%–33%], with 2-year progression-free and overall survival rates >50% and ~70%, respectively [10, 11]. Patients with GIST bearing KIT exon 11 mutations appear to respond more often and longer to imatinib therapy compared with those with KIT exon 9 mutations or with wild-type GIST [6]. In one long-term (52-month) follow-up study with imatinib therapy [12], the median survival was 45 months for patients with KIT exon 9 mutation but had not yet been reached for those with KIT exon 11 mutation.

Approximately 15% of patients with metastatic GIST have primary (initial) resistance to imatinib therapy, and most patients eventually develop secondary (acquired) resistance [13]. The most common cause for acquired resistance is new KIT or PDGFRA mutations that interfere with imatinib binding to the kinase [14]. Other mechanisms, such as activation of other receptor tyrosine kinases or cell signaling pathways, may also play a role.

Until recently, patients with imatinib-resistant GIST had few therapeutic options. Sunitinib malate (SU11248) is an oral multitargeted TKI that inhibits all three isoforms of the vascular endothelial cell growth factor receptor [VEGFR-1 (Flt-1), VEGFR-2 (KDR), and VEGFR-3 (Flt-4)], KIT, PDGFR{alpha}, PDGFRβ, colony-stimulating factor 1 receptor, Fms-like tyrosine kinase-3 receptor (FLT-3), and the receptor encoded by the ret proto-oncogene (RET). Sunitinib induces growth arrest and apoptosis of GIST-T1 cells along with inhibiting KIT [15, 16] and some KIT mutations associated with imatinib resistance [17]. Phase II and III clinical studies of sunitinib have shown activity and prolongation of time to progression (TtP) and overall survival compared with placebo for patients with imatinib-resistant GIST [18–20].

PTK787/ZK222584 (PTK/ZK; vatalanib; Bayer Schering Pharma AG, Berlin; Novartis, East Hanover, NJ) is an oral multitargeted TKI that inhibits all VEGFRs, KIT, and PDGFRs [21]. PTK/ZK reaches peak concentration (Tmax) in 1.0–2.5 h and has a half-life (t1/2) of 4.5 h, with no evidence of accumulation at steady-state following once-daily (QD) dosing. PTK/ZK has clinical activity in patients with several types of human cancer [22–28].

Because PTK/ZK inhibits not only activation of KIT and PDGFRs, considered crucial in the molecular pathogenesis of most GISTs, but also inhibits VEGFRs, which may be important in GIST progression, PTK/ZK has biological properties that may prove useful for treating imatinib-resistant GIST. The purpose of this study was to determine the efficacy and safety of PTK/ZK for the treatment of patients with imatinib-resistant GIST. This was the first clinical study of PTK/ZK in this population.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 funding
 Acknowledgements
 References
 
patients
Patients were recruited at three sites and were eligible if they had histologically, cytologically, or radiologically confirmed metastatic GIST; the presence of measurable tumor lesions as determined by Response Evaluation Criteria in Solid Tumors (RECIST), primary resistance (objective evidence of progression after ≥4 weeks' treatment) to imatinib with progression, or progression after initial response; and imatinib therapy that had been interrupted ≥5 days before study entry. Additional inclusion criteria were age ≥18 years, a World Health Organization performance status of zero to two, blood absolute neutrophil count (ANC) ≥1.5 x 109/l, platelets ≥100 x 109/l, hemoglobin ≥9 g/dl, aspartate aminotransferase and alanine aminotransferase ≤3.0 x upper limit of normal (ULN; ≤5.0 x ULN if liver metastases present), total urinary protein collected in 24 h ≤500 mg, serum creatinine ≤1.5 x ULN, 24-h creatinine clearance ≥50 ml/min, and life expectancy >3 months. Patients were excluded if they received chemotherapy <4 weeks before study entry, received a cumulative dose of doxorubicin >560 mg/m2 or epirubicin > 800 mg/m2, received KDR (VEGFR-2) inhibitor therapy (e.g. sunitinib) before study entry, had acute or chronic liver disease, or who were taking warfarin sodium. Written informed consent was obtained from each patient. The protocol and informed consent form were approved by an Independent Ethics Committee, and each investigator conducted the trial (clinicaltrials.gov identifier NCT00117299 [ClinicalTrials.gov] ) in accordance with the Declaration of Helsinki.

treatment plan
Patients were treated with PTK/ZK 1250 mg (five 250-mg tablets) orally (PO) QD until progressive disease (PD) or unacceptable toxicity occurred. Adverse events (AEs) were recorded at all visits. Treatment was interrupted if patients exhibited Common Terminology Criteria (CTC) grade 4 hypertension, ataxia or dizziness, or neutropenia; grade 3 transaminase or bilirubin elevation, ataxia or dizziness >10 days' duration (related to PTK/ZK), or any other grade 3 or 4 toxicity other than nausea or vomiting; grade 2 proteinuria (≥1.0 g) or hematuria; serum creatinine ≥2.0 x ULN; or thrombocytopenia with platelet count ≤25 x 109/l. If toxic effects resolved to CTC ≤ grade 1 with ANC ≥1.5 x 109/l and platelets ≥100 x 109/l, the dose was reduced to 1000 mg for the first episode of toxicity and to 750 mg for the second. Patients who exhibited a third episode of toxicity or had treatment delayed >3 weeks were discontinued from the study.

assessments
Computed tomography or magnetic resonance imaging was carried out at baseline, week 4, and every 4 weeks thereafter. Tumor response was assessed using RECIST [29]. Criteria required for determining complete response (CR) or PR had to be present at ≥4 weeks. Coagulation and serum panels were carried out at each visit and at discontinuation from the study. Chest radiographs were obtained at baseline, week 4, and week 12; electrocardiograms (ECGs) were obtained at baseline, week 4, week 12, and every 8 weeks thereafter. Urinalyses were carried out at baseline, week 2, week 4, and every 4 weeks thereafter. KIT and PDGFRA mutation analyses were not required for study entry.

statistical methods and sample size
Response (CR + PR) and SD rates were calculated by intent to treat. Response duration and duration of stabilized disease were calculated from the date of first occurrence of response to the date of disease progression, death, or last follow-up. Disease was required to fulfill the criteria of stabilized disease for a minimum duration of 3.0 months in order to be categorized as SD. TtP was defined as the date of treatment initiation to the date of PD or death due to cancer. Clinical benefit was defined as confirmed or unconfirmed CR or PR, or SD ≥3 months accompanied by relief of GIST-related symptoms. Mean values were expressed with standard deviations.

Six patients were entered into the study with the intent that if one or more patients exhibited a clinical benefit, nine additional patients (total = 15) would be accrued.


   results
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 Abstract
 introduction
 patients and methods
 results
discussion
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 Acknowledgements
 References
 
patient characteristics and dosing
Fifteen patients with metastatic or advanced GIST were enrolled from August 2004 to May 2005. Demographics and other baseline characteristics are presented in Table 1. The patient population was predominantly male and had a median age of 63 years. All patients had a good performance status (0 or 1), had secondary (acquired) resistance to imatinib, and were available for efficacy and toxicity analyses. Most had received imatinib 800 mg daily with a best response of PR or SD. None of the patients interrupted imatinib due to intolerance of the treatment. Patients underwent treatment with PTK/ZK for a median of 9.1 months (range 0.9–24.8+ months). No dose reductions were required. Twelve (80%) patients have completed the study, all of whom had PD upon discontinuation.


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  		Table 1. Patient characteristics

 
activity
Two (13%) patients achieved PR as best response according to RECIST criteria. Eight (53%) had SD lasting at least 3 months after PTK/ZK initiation (Table 2). Overall, 10 (67%) patients had a clinical benefit (67%; 95% CI 38% to 86%). The PRs lasted for 9.7 and 20.2+ months, and the median duration for SDs was 10.1 months (range 4.6–19.1+ months). The median TtP was 8.5 months (range 0.9–24.8+ months). Three patients have ongoing favorable responses: one patient with PR at 24.8 months after initiation of PTK/ZK and two with SD at 16.6 and 18.6 months after study entry.


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  		Table 2. Duration of response and TtP

 
safety
PTK/ZK 1250 mg QD was generally well tolerated. AEs reported for two or more patients, regardless of CTC grade, are presented in Table 3. The most frequently reported AEs were dizziness (n = 6; 40%); nausea (n = 5; 33%); proteinuria and asthenia (each, n = 4; 27%); and upper abdominal pain and pyrexia (each, n = 3; 20%). Most AEs were mild (grade 1 or 2). One patient exhibited a grade 2 ischemic ECG abnormality thought to be related to study medication. PTK/ZK treatment was discontinued for 25 days, after which study medication was resumed. The patient remains on study with an SD duration of 16.0+ months. There were no grade 3 AEs. The only grade 4 AEs were hypercalcemia and pain (each, n = 1; 7%); neither was suspected to be treatment related. The patient with grade 4 pain had study treatment interrupted and was hospitalized. The patient with grade 4 hypercalcemia recovered under i.v. furosemide [20 mg twice daily (b.i.d.)], oral dexamethasone sodium phosphate (64 gtt BID) for 3 days, and i.v. pamidronate (60 mg QD) treatment. There were no treatment-related deaths.


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  		Table 3. Adverse events

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
funding
 Acknowledgements
 References
 
Imatinib is currently the treatment of choice for patients with metastatic GIST. However, some patients exhibit primary resistance to imatinib; most will eventually develop secondary resistance. Current treatment options for imatinib-resistant GIST include imatinib dose escalation and sunitinib, and surgery or radiofrequency ablation when only one or a few growing metastases are present. The clinical benefit achieved with these treatments is usually relatively short. There is a compelling clinical need for novel, well-tolerated treatment for patients who have imatinib-resistant GIST and for those few patients who do not tolerate imatinib.

Our study, the first systematic clinical evaluation of PTK/ZK for patients with GIST, showed that PTK/ZK 1250 mg PO QD is active in imatinib-resistant patients. Ten (67%) of the 15 patients had either a durable disease stabilization or responded to PTK/ZK, three (20%) of whom had not progressed at the time of analysis with an ongoing SD or PR for 16.6 months or longer. PTK/ZK was generally well tolerated; nearly all AEs were grade 1 or 2. Tissue for gene mutation analyses was available only from two (13%) patients: one who progressed by week 8 had wild-type KIT and PDGFRA genes; the other, continuing in PR at 24.8 months, had a deletion mutation in KIT exon 11 (del V555-D572).

Efficacy observations in the present PTK/ZK study are compared with data reported in recent phase III [20] and phase II [18, 19] studies of sunitinib for imatinib-resistant GIST in Table 4. None of the studies reported CRs. Although our sample size is small, the PTK/ZK PR and SD rates appear similar to those observed in studies of sunitinib, but general comparisons of the SD rates are difficult because of differently reported definitions. The incidence and severity of AEs with PTK/ZK might compare favorably with those in sunitinib or the higher doses of imatinib [11], but comparisons between different patient series are difficult and may be misleading; most are reliably evaluated only in randomized controlled trials.


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  		Table 4. Activity of PTK/ZK and sunitinib in selected phase II and III studies of patients with imatinib-resistant GIST

 
Patients in our study were treated by QD dosing. Because PTK/ZK has a short half-life (4.5 h), b.i.d. dosing might potentially increase efficacy and decrease toxicity. In a phase I study [30], 150 to 1000 mg of PTK/ZK was administered b.i.d. to patients with solid tumors. PTK/ZK exposure increased with dosing up to 500 mg BID and appeared to reach a plateau at higher doses. Overall, total daily PTK/ZK doses ≥1000 mg appeared biologically active. Administration of PTK/ZK 1250 mg QD (n = 54) is being compared with b.i.d. dosing in an ongoing phase II study of patients with stage III or IV non-small-cell lung cancer in an attempt to maintain high serum drug levels.

We conclude that PTK/ZK was shown to be active for treatment of imatinib-resistant GIST despite the limited trial size. Most study participants had either disease stabilization or responded to treatment despite imatinib discontinuation before PTK/ZK initiation, which could have resulted in tumor flare. A few patients with imatinib-resistant GIST continued to benefit at the time of the study report, indicating possible durable benefit from PTK/ZK treatment. PTK/ZK also appears to be generally well tolerated in this setting. A larger phase II study evaluating PTK/ZK, administered b.i.d., is currently ongoing in the treatment of patients with imatinib-resistant GIST. This study will also evaluate efficacy and safety of PTK/ZK among GIST patients who have progressed during both imatinib and sunitinib treatment. Clinical trials are also warranted to evaluate responsiveness to PTK/ZK in association with KIT and PDGFRA mutations and other molecular features of GIST.


   funding
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
Acknowledgements
 References
 
Cancer Society of Finland, Academy of Finland, Helsinki University Central Hospital Research Funds, (TYH5206, TYH7206) the Nordic Cancer Union, and Bayer Schering Pharma AG, Berlin, Germany.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
References
 
The authors wish to acknowledge Nelson Erlick, for his editorial assistance in the preparation of this manuscript. Presented at the 42nd Annual Meeting of the American Society for Clinical Oncology, Atlanta, GA, June 2006

Received for publication February 1, 2007. Accepted for publication July 19, 2007.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
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