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Cancer Therapy: Clinical

Cancer Therapy: Clinical Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-SensitiveTyrosine Kinases MichaelC.Heinrich,
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Cancer Therapy: Clinical Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-SensitiveTyrosine Kinases MichaelC.Heinrich, 1 Heikki Joensuu, 2 George D. Demetri, 3 Christopher L. Corless, 1 Jane Apperley, 5 Jonathan A. Fletcher, 4 Denis Soulieres, 6 Stephan Dirnhofer, 7 Amy Harlow, 1 AjiaTown, 1 Arin McKinley, 1 Shane G. Supple, 10 John Seymour, 11 Lilla Di Scala, 8 Allan van Oosterom, 12 Richard Herrmann, 9 Zariana Nikolova, 8 and Grant McArthur 11 for the ImatinibTarget Exploration Consortium Study B2225 Abstract Purpose: To evaluate the activity of imatinib in treating advanced, life-threatening malignancies expressing one or more imatinib-sensitive tyrosine kinases. Experimental Design: This was a phase II, open-label, single arm study. Patients z15 years old with malignancies showing histologic or molecular evidence of expression/activation of imatinibsensitive tyrosine kinases were enrolled. Patients were treated with 400 or 800 mg/d imatinib for hematologic malignancy and solid tumors, respectively. Treatment was continued until disease progression or unacceptable toxicity. The primary objective was to identify evidence of imatinib activity with tumor response as the primary end point. Results: One hundred eighty-six patients with 40 different malignancies were enrolled (78.5% solid tumors, 21.5% hematologic malignancies). Confirmed response occurred in 8.9% of solid tumor patients (4 complete, 9 partial) and 27.5% of hematologic malignancy patients (8 complete, 3 partial). Notable activity of imatinib was observed in only five tumor types (aggressive fibromatosis, dermatofibrosarcoma protuberans, hypereosinophilic syndrome, myeloproliferative disorders, and systemic mastocytosis). A total of 106 tumors were screened for activating mutations: five KIT mutations and no platelet-derived growth factor receptor mutations were found. One patient with systemic mastocytosis and a partial response to therapy had a novel imatinibsensitive KIT mutation (D816T). There was no clear relationship between expression or activation of wild-type imatinib-sensitive tyrosine kinases and clinical response. Conclusion: Clinical benefit was largely confined to diseases with known genomic mechanisms of activation of imatinib target kinases. Our results indicate an important role for molecular characterization of tumors to identify patients likely to benefit from imatinib treatment. Imatinib mesylate is a small-molecule selective inhibitor of the tyrosine kinases ABL, Abl-related gene product (ARG), KIT, CSF-1R, and platelet-derived growth factor receptors a and h (PDGFRA and PDGFRB, respectively; refs. 1 4). Dysregulation Authors Affiliations: 1 Oregon Health & Science University Cancer Institute and Portland VA Medical Center, Portland, Oregon; 2 Helsinki University Central Hospital, Helsinki, Finland; 3 Harvard Medical School and Dana-Farber Cancer Institute; 4 Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts; 5 Hammersmith Hospital and Imperial College School of Medicine, London, United Kingdom; 6 Centre Hospitalier de l Univesite de Montre al, Montreal, Canada; 7 Institute for Pathology; 8 Novartis Pharma AG; 9 University Hospital, Basel, Switzerland; 10 Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia; 11 Peter MacCallum Cancer Institute, East Melbourne, Australia; and 12 UZ Gasthuisberg Dienst Oncology, Leuven, Belgium Received 10/26/07; revised 1/18/08; accepted 1/30/08. Grant support: Novartis Pharma AG and ava Merit Review Grant (M.C. Heinrich). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Michael C. Heinrich, Department of Hematology and Medical Oncology, Portland VA Medical Center, R&D-19, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR Phone: ; Fax: ; F 2008 American Association for doi: / ccr of imatinib-sensitive tyrosine kinases is a key factor in the pathogenesis of several malignancies, and imatinib treatment dramatically benefits patients with such cancers (5). Notably, imatinib is effective in patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia and metastatic gastrointestinal stromal tumors (6 9), with the latter commonly having pathogenic mutations of the imatinibsensitive tyrosine kinases KIT (80-85% of cases) or PDGFRA (5% of cases; refs ). To determine new malignancies that are responsive to imatinib therapy, we conducted a phase II, open-label, single arm study. A total of 186 patients with life-threatening malignancies known to express one or more imatinib-sensitive tyrosine kinases were enrolled between February 2001 and December Patients were eligible for enrollment if their disease had proven refractory to standard therapy or if no proven conventional therapy existed. Correlative studies were conducted to identify potential predictors of imatinib response. Materials and Methods Study design and patients. This was an open-label, multinational, multicenter exploratory phase II study (Imatinib Target Exploration Clin Cancer Res 2008;14(9) May 1, 2008 Cancer Therapy: Clinical Consortium Study B2225). Patients were eligible for enrollment if they had a life-threatening malignancy known to be associated with one or more imatinib-sensitive tyrosine kinases that had proven refractory to standard therapy or if no proven conventional therapy existed. Protein expression of imatinib-sensitive tyrosine kinases was determined by immunohistochemistry at local hospitals for KIT, PDGFRA, or PDGFRB and confirmed by a central laboratory (Institute of Pathology, Basel, Switzerland). Additional inclusion criteria were age z15 y, an Eastern Cooperative Oncology Group performance status of 0 to 2, and a life expectancy of 3 mo in the absence of any intervention. Patients with gastrointestinal stromal tumor, prostate cancer, small cell lung cancer, glioma, Ph+ acute lymphoblastic leukemia, or chronic myelogenous leukemia were excluded from this study. Adequate end organ function [defined as total bilirubin 1.5 upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase 2.5 ULN (or 5 ULN if hepatic disease involvement is present), creatinine 1.5 ULN, neutrophils /L, and platelets /L] was required for enrollment eligibility. In addition, patients could not have other serious or uncontrolled medical conditions. Treatment with other investigational agents or chemotherapy within 4 wk of study entry was not permitted. Institutional review board approval at each participating center and written informed consent from each subject were obtained. Additional written consent was required for retrieval investigational use of tissue samples. Treatment. Imatinib mesylate (Novartis) was supplied as 100-mg capsules that were taken orally. In patients with hematologic malignancies, the initial dose of imatinib was 400 mg/d, with escalation to 300 or 400 mg twice daily, if no significant disease improvement occurred after the first 4 to 8 wk on therapy. In patients with solid tumors, the initial dose of imatinib was 400 mg twice daily, with escalation to 500 mg twice daily, if no significant disease improvement occurred after the first 4 to 8 wk on therapy. Treatment continued until disease progression or unacceptable toxicity. Dose interruptions and reductions were allowed for prospectively defined hematologic and nonhematologic toxicities, as previously described (8). Study objectives. The primary objective was to identify evidence of imatinib activity in any of the studied malignancies. The primary end point was efficacy as assessed by tumor response. Secondary objectives included evaluating the expression and activation status of the relevant tyrosine kinase or associated effector molecules, and evaluating the relationship between changes in tyrosine kinase or effector molecules and clinical outcomes. Safety was assessed by evaluating adverse events, clinical laboratory parameters, vital signs, and physical examination findings and by monitoring concomitant medication use. Assessments. Physical examination, evaluation of Eastern Cooperative Oncology Group performance status, body weight, hematology and blood chemistry testing, and disease measurement were done at baseline and repeated after 4 and 12 wk of therapy and at 12-wk intervals thereafter. Overall best response was measured according to modified Southwest Oncology Group criteria and the investigator s assessment of tumor response (13). In patients with solid tumors, the status of tumor lesions was assessed by computed tomography or magnetic resonance imaging whenever possible. Skin lesions were evaluated for surface area, depth, thickness, and consistency. For patients with hematologic malignancies, response was assessed by blood counts and bone marrow analyses. For patients with myelofibrosis, consensus criteria from the International Working Group were used (14). Efficacy results are based on the last formal evaluation done in December 2004 and supplemented with personal communication with individual investigators. Personal communication was used to obtain additional clinical and molecular data on patients with hypereosinophilic syndrome because many of these patients had prolonged drug treatment and had evolving clinical responses. Evaluation of KIT expression and kinase activation. One entry criterion for enrollment of cases of solid tumors was KIT (CD117) positivity in at least 50% of the tumor cells, as detected by immunohistochemistry done by local pathology laboratories. Central review of the CD117 stains was conducted at the Institute of Pathology, University Hospital Basel, Switzerland. In addition, parallel sections of the tumors were stained for CD117 using a standardized protocol, as previously described (15). Patients were consented to undergo tumor biopsy procedures before and f1 mo after beginning imatinib therapy. Consent for these biopsy procedures was obtained independently from consent to participate in the therapeutic study. Immunoblot analysis using snap-frozen biopsies was done to identify total and tyrosine-phosphorylated KIT, ABL1, ABL2, PDGFRA, and PDGFRB, using positive controls as previously described (16). Expression and phosphorylation of the signaling intermediates AKT, mitogen-activated protein kinase, and signal transducer and activator of transcription 3 were also evaluated (17). Thirty-five patient consented to a baseline, pretreatment biopsy. Twenty-five of these patients consented to an additional on-treatment biopsy. Genomic mechanisms of oncogenic kinase activation were also investigated using available pathology specimens from 106 consenting patients. For these genotyping analyses, PCR amplification of genomic DNA for KIT (exons 9, 11, 13, and 17), PDGFRA (exons 12, 14, and 18), and PDGFRB (exons 11 and 17) was done, and amplicons were screened for mutations using denaturing, high-pressure liquid chromatography (WAVE, Transgenomic, Inc.), as previously described (10, 16, 18). Mutant forms of KIT were cloned with the substitution D816V or D816T and transiently expressed by transfection in Chinese hamster ovary cells, as previously described. The transfected cells were exposed to varying concentrations of imatinib, and cell extracts were assessed for total and phosphorylated KIT protein by immunoblotting (18). Statistical analysis. There was only one analysis population for efficacy and safety analyses, consisting of all patients who received at least one dose of study medication. The number of different indications analyzed was not predefined; similarly, the number of patients per indication was not prospectively stipulated. Enrollment of up to 10 patients per disease category was allowed initially, with enrollment of additional patients being contingent on suggestion of clinical efficacy. Because the study was intended to indicate proof of concept about the activity of imatinib in the studied diseases to support future clinical trials, no inferential methods were used and, therefore, power considerations did not apply to the choice of sample size. Data from all centers included in the study were pooled and summarized using descriptive statistics. Results Patient disposition. Between February 2001 and December 2004, 186 patients with 40 different pathologic diagnoses were enrolled across 13 centers in North America, Europe, and Australia. At the time that this study was initiated, the original design was to enroll patients whose tumors expressed one or more imatinib-sensitive kinases. This was to be determined by immunohistochemistry at local hospitals for KIT, PDGFRA, or PDGFRB and confirmed by our central laboratory. However, as the trial progressed, several important operational issues were noted: (a) The central laboratory was unable to validate any immunohistochemical technique for assessing PDGFRA or PDGFRB. (b) Although KIT immunohistochemistry was beginning to be widely used for the diagnosis of gastrointestinal stromal tumor, it became apparent that many laboratories had problems with false-positive results on non-gastrointestinal stromal solid tumors (15, 16). (c) Some cases that lacked KIT expression as assessed by the central laboratory had clinical evidence of objective response or prolonged stable disease. (d) New imatinib-responsive diseases were being reported in the Clin Cancer Res 2008;14(9) May 1, Activity of Imatinib in Life-Threatening Malignancies literature but there was no rapid way to make the drug available for further clinical investigation, especially outside of North America (e.g., hypereosinophilic syndrome, chronic myelomonocytic leukemia with PDGFRB translocations, dermatofibrosarcoma protuberans, and chordoma; refs ). In response to these issues, the study criteria were modified to allow patient entry based on published evidence of a potential role for KIT, PDGFRA, or PDGFRB in the biology of a given tumor. This evidence could include (a) preclinical studies of protein expression by tumor cell lines or by cells in archival pathology specimens; (b) cell models indicating imatinib responsiveness of a tumor type; (c) report of a genomic mechanism for activation of an imatinib-sensitive kinase (e.g., COL1A1-PDGFB fusion in dermatofibrosarcoma protuberans); or (d) publication of a report of an objective patient response to imatinib treatment. Following revision of the entry criteria, we limited the enrollment to V10 patients for any given disease indication, unless at least one of the first 10 patients had an objective response. For descriptive purposes, patients were retrospectively divided into two groups: those with solid tumors (78.5%) and those with hematologic malignancies (21.5%). Of the enrolled patients, 172 (92.5%) discontinued treatment before the planned 2 years of imatinib therapy. The most common reason for discontinuation was an unsatisfactory therapeutic effect (59.7% of patients). Baseline demographics and disease characteristics. The mean age of the population was 47.9 years, with most patients (82.3%) 65 years old. Gender was relatively balanced for the patient population as a whole and most patients (94.6%) were Caucasian. Most patients (76.9%) were diagnosed at least 12 months before study enrollment; 60.8% were diagnosed at least 24 months before study enrollment. Patients with solid tumors tended to be suffering from recurrence or progression of disease, with the first recurrence most often having occurred z3 months before study entry. Clinical results: solid tumors. The mean (FSD) imatinib dose intensity administered to patients with solid tumors was F mg/d, and the median duration of treatment was 2.5 months (range, months). Overall, 28.8% and 8.2% of solid tumor patients received imatinib for z5 and z20 months, respectively. The median time to progression in patients with solid tumors was 2.5 months (Fig. 1). Patients with solid tumors receiving imatinib for z20 months had the following tumor types: adenoid cystic carcinoma (1 of 12, 8.3%), aggressive fibromatosis (3 of 20, 15.0%), chordoma (2 of 5, 40.0%), dermatofibrosarcoma protuberans (3 of 12, 25.0%), liposarcoma (2 of 11, 18.2%), and synovial sarcoma (1 of 16, 6.2%). Response data for each disease category are shown in Table 1. Confirmed responses occurred in 8.9% of the patients with solid tumors [four complete responses (CR) and nine partial responses (PR)]. Four confirmed CRs were seen in patients with dermatofibrosarcoma protuberans two of these patients had an initial PR to imatinib therapy but obtained a CR after surgery and have remained disease free. Confirmed PRs occurred in solid tumor patients with aggressive fibromatosis, dermatofibrosarcoma protuberans, and synovial sarcoma. No confirmed CRs or PRs were observed in patients with adenoid cystic carcinoma, chondrosarcoma, chordoma, leiomyosarcoma, liposarcoma, melanoma, Ewing s sarcoma, rhabdoymyosarcoma, desmoplastic round cell tumor, malignant schwannoma, osteosarcoma, breast cancer, or mesothelioma. In addition, no confirmed responses were observed for 16 other disease conditions for which only a single patient was enrolled (Table 1). Among the chordoma patients, the majority showed stable disease (4 of 5, 80.0%), with no patients having progressive disease. Clinical results: hematologic malignancies. The mean (FSD) imatinib dose intensity administered to patients with hematologic malignancies was F mg/d, and the median duration of treatment was 5.6 months (range, Fig. 1. Kaplan-Meier plot of time to progression in patients with solid tumors Clin Cancer Res 2008;14(9) May 1, 2008 Cancer Therapy: Clinical Table 1. Response to imatinib by indication (analysis population, N = 186) Main indication CR, n (%) PR, n (%) SD, n (%) PD, n (%) Unknown, n (%) Median TTP (95% CI), mo Putative target Solid tumors: sarcoma Synovial sarcoma (n = 16) 0 1 (6.3) 3 (18.8) 11 (68.8) 1 (6.3) 1.1 ( ) KIT Dermatofibrosarcoma 4 (33.3) 6 (50.0) 0 1 (8.3) 1 (8.3) 23.9 (7.7-1) PDGFRB protuberans (n = 12) Leiomyosarcoma (n = 11) (9.1) 8 (72.7) 2 (18.2) 1.1 ( ) KIT Liposarcoma (n = 11) (45.5) 6 (54.5) ( ) KIT Chondrosarcoma (n = 7) (14.3) 5 (71.4) 1 (14.3) [ ] KIT Ewing s sarcoma (n = 4) (75.0) 1 (25.0) [ ] KIT/PDGFR Angiosarcoma (n = 2) (100) 0 [ ] KIT/PDGFR Rhabdomyosarcoma (n = 2) (100) 0 [ ]* PDGFR Aggressive fibromatosis 0 2 (10.0) 8 (40.0) 7 (35.0) 3 (15.0) 9.1 ( ) PDGFRA (n = 20) Chordoma (n = 5) (80.0) 0 1 (20.0) [ ] PDGFRB Desmoplastic small (100) 0 [ ] KIT, PDGFR round cell tumor (n =5) Neurofibrosarcoma (n = 3) (66.7) 0 1 (33.3) [ ] PDGFR Malignant schwannoma (50.0) 1 (50.0) [ ]* PDGFR (n =2) Osteosarcoma (n = 2) (100) 0 [ ]* PDGFR Solid tumors: nonsarcoma Adenoid cystic (50.0) 5 (41.7) 1 (8.3) 5.7 ( ) KIT carcinoma (n = 12) Mesothelioma (n = 6) (50.0) 3 (50.0) [ ] PDGFRB Malignant melanoma (n = 5) (80.0) 1 (20.0) [ ] KIT Intraocular melanoma (100) 0 [ ] KIT (n =3) Breast carcinoma (n = 2) (50.0) 1 (50.0) [ ]* KIT/PDGFR Hematologic malignancies Hypereosinophilic 5 (35.7) 1 (7.1) 1 (7.1) 6 (42.9) 1 (7.1) 8.4 (2.33-1) PDGFRA/KIT syndrome (n = 14) Multiple myeloma (n = 6) (100) 0 [ ] KIT Myelofibrosis (n = 8) (62.5) 1 (12.5) 2 (25) [ ] PDGFRB Myeloproliferative 3 (42.9) 1 (14.3) 0 2 (28.6) 1 (14.3) [ ] PDGFRB disorders (n = 7) Systemic mastocytosis (n =5) 0 1 (20.0) 1 (20.0) 0 3 (60.0) [ ] KIT/PDGFRA NOTE: Other indications included only one patient: endometrial sarcoma (PD), fibrosarcoma breast (SD), fibrosarcoma ovary (PD), ovarian sarcoma (PD), pleural sarcoma (SD), adenocarcinoma (unknown), hemangiopericytoma (PD), malignant fibrous histiocytoma (PD), malignant mesenchymoma (PD), ovarian stromal tumor (PD), ovarian carcinoma (PD), rectal carcinoma (PD), renal cell carcinoma (
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