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Phase II Study of Cediranib in Patients with Advanced Gastrointestinal Stromal Tumors Or Soft-Tissue Sarcoma

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Phase II Study of Cediranib in Patients with Advanced Gastrointestinal Stromal Tumors Or Soft-Tissue Sarcoma Published OnlineFirst April 8, 2014; DOI: 10.1158/1078-0432.CCR-13-1881 Clinical Cancer Cancer Therapy: Clinical Research Phase II Study of Cediranib in Patients with Advanced Gastrointestinal Stromal Tumors or Soft-Tissue Sarcoma Ian Judson1, Michelle Scurr1, Kate Gardner1, Elizabeth Barquin1, Marcelo Marotti2, Barbara Collins2, Helen Young2, Juliane M. Jurgensmeier€ 2, and Michael Leahy3 Abstract Purpose: Cediranib is a potent VEGF signaling inhibitor with activity against all three VEGF receptors and KIT. This phase II study evaluated the antitumor activity of cediranib in patients with metastatic gastro- intestinal stromal tumor (GIST) resistant/intolerant to imatinib, or metastatic soft-tissue sarcomas (STS; ClinicalTrials.gov, NCT00385203). Experimental Design: Patients received cediranib 45 mg/day. Primary objective was to determine the antitumor activity of cediranib according to changes in 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography (18FDG-PET) tumor uptake in patients with GIST using maximum standardized uptake values (SUVmax). Secondary objectives included objective tumor response and tolerability in patients with GIST/ STS. Results: Thirty-four of 36 enrolled patients were treated (GIST n ¼ 24; STS n ¼ 10). At day 29, five patients had confirmed decreases in SUVmax (10% from day 8) and two had confirmed partial metabolic responses (25% decrease), but arithmetic mean percentage changes in SUVmax, averaged across the cohort, were not significant at day 8 [6.8%; 95% confidence interval (CI), 19.95–33.54) or day 29 (4.6%; 95% CI, 8.05– 17.34). Eleven patients with GIST achieved a best objective tumor response of stable disease; eight achieved stable disease 16 weeks. In patients with STS, four of six with alveolar soft-part sarcoma (ASPS) achieved confirmed and durable partial responses. The commonest adverse events were diarrhea (85%), fatigue (74%), and hypertension (68%). Conclusions: In patients progressing on imatinib/sunitinib, cediranib 45 mg/day demonstrated evi- 18 dence of activity by FDG-PET, but did not reduce average SUVmax. Evidence of antitumor activity was seen in ASPS. Clin Cancer Res; 1–10. Ó2014 AACR. Introduction Imatinib mesylate is a tyrosine kinase inhibitor (TKI) a Gastrointestinal stromal tumors (GIST) are the most with activity against KIT, PDGFR , and ABL. Imatinib is an common type of sarcoma in the gastrointestinal tract, most effective treatment for unresectable and/or metastatic commonly arising from the stomach; they are generally malignant GIST, and as adjuvant therapy following resec- characterized by expression of the receptor tyrosine kinase tion of high-risk cases (4, 5). However, most patients KIT (1). In the majority of cases, the disease is driven by eventually experience disease progression while on treat- activating mutations in KIT and, less commonly, mutations ment because of the development of secondary mutations in the platelet-derived growth factor receptor-a (PDGFRA) (2, 3). Sunitinib, a multitargeted TKI with activity against a b gene (2, 3). PDGFR , PDGFR , KIT, VEGF receptors 1–3 (VEGFR1–3), colony-stimulating factor receptor 1, fms-related tyrosine kinase 3, and other kinases, is available as second-line therapy for imatinib-refractory GIST, but is only effective fi 1 2 Authors' Af liations: Royal Marsden Hospital, London; AstraZeneca, in a proportion of cases as some secondary mutations confer Macclesfield; and 3Christie Hospital NHS Foundation Trust, Manchester, United Kingdom resistance to both imatinib and sunitinib (6). A number of other TKIs have also demonstrated activity against GIST, Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). including regorafenib, a close analogue of sorafenib and also an inhibitor of VEGFRs. In a prospective randomized Current address for K. Gardner: Christchurch Public Hospital, Christ- church, New Zealand; and current address for J.M. Jurgensmeier,€ Yale trial comparing regorafenib with placebo in patients who School of Medicine, New Haven, CT had progressed on both imatinib and sunitinib, regorafenib Corresponding Author: Ian Judson, Sarcoma Unit, Royal Marsden Hos- produced an improvement in median progression-free sur- pital, Fulham Road, London, SW3 6JJ, United Kingdom. Phone: 44-208- vival of 3.9 months (HR 0.27, P < 0.0001; ref. 7). 722-4303; Fax: 44-208-642-7979; E-mail: [email protected] Cediranib is an oral, highly potent, VEGF signaling doi: 10.1158/1078-0432.CCR-13-1881 inhibitor with activity against all three VEGFRs and addi- Ó2014 American Association for Cancer Research. tional activity versus KIT (8–10). In vitro, cediranib has been www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst April 8, 2014; DOI: 10.1158/1078-0432.CCR-13-1881 Judson et al. objective response to cediranib in a patient with this disease; Translational Relevance a World Health Organization (WHO) performance status of Gastrointestinal stromal tumor (GIST) is generally 0–2; and a life expectancy >12 weeks qualified for study driven by activating mutations in the KIT or PDGFRA entry. Eligible patients were required to have one or more genes. The tyrosine kinase inhibitor imatinib mesylate is measurable lesions, 10 mm in the longest diameter by an effective treatment for unresectable/metastatic GIST, spiral CT scan or 20 mm with conventional techniques, for but is associated with acquired treatment resistance RECIST assessment. An additional criterion for patients owing to development of secondary mutations. Cedir- with GIST was one or more measurable lesions 20 mm anib, a potent inhibitor of all three VEGF receptors with for 18FDG-PET assessment. additional activity against KIT, demonstrated promising Exclusion criteria included untreated or unstable central antitumor activity in early clinical studies. This phase nervous system metastases, radiotherapy within 4 weeks of II cediranib monotherapy study used 2[18F]fluoro-2- study entry, or other concomitant anticancer therapy deoxy-D-glucose positron emission tomography (except steroids). Previous treatment with sunitinib or 18 ( FDG-PET) to assess preliminary antitumor activity in imatinib mesylate had to be stopped at least 14 days before imatinib-resistant/intolerant GIST patients; individual starting cediranib, and no TKI therapy was permitted during patients had sustained decreases in uptake, with two baseline investigations (i.e., 18FDG-PET scans). Specific experiencing confirmed a partial metabolic response. exclusion criteria related to 18FDG-PET assessments were Prolonged disease stabilization (16 weeks) occurred applied to patients with GIST, including type I insulin- in eight patients with GIST who had previously pro- dependent diabetes, poorly controlled type II insulin-inde- gressed on imatinib, including patients who had also pendent diabetes or fasting blood glucose >10 mmol/L (200 received sunitinib previously. mg/dL), and radiotherapy within the previous 4 weeks or planned radiotherapy if covering the only 18FDG-PET- assessable lesion. shown to inhibit two mutant forms of KIT (V654A, N822K) Study objectives associated with secondary resistance to imatinib, but has The primary objective was to determine the preliminary not been shown to inhibit all mutants thought to be antitumor activity of cediranib in patients with GIST by responsible for the development of resistance to imatinib utilizing 18FDG-PET scans to assess maximum standardized and sunitinib (10). In phase I and II studies, cediranib has uptake value (SUVmax) at baseline, and following 8 days and demonstrated evidence of antitumor activity in patients 4 weeks (day 29) of cediranib dosing, with central review of with advanced solid tumors, both as a single agent and in all scans. Secondary objectives included response assess- 18 combination with other anticancer strategies (11–17). ment by investigator review using FDG-PET (SUVmax)in Previous studies have suggested that 2[18F]fluoro-2- patients with GIST following 8 days and 4 weeks (day 29) of deoxy-D-glucose positron emission tomography (18FDG- cediranib dosing, and an evaluation of cediranib efficacy by PET) in GIST may be a useful tool to evaluate treatment objective tumor response (RECIST; version 1.0) in GIST and response to new therapies and may provide more informa- STS (ASPS), assessed every 12 weeks. A planned central tion than computed tomography (CT), especially in rela- review of response by RECIST in patients with GIST was tion to early indications of response to imatinib (18). The performed and central review of CT images from STS primary aim of this open-label, phase II study was to patients was included as an ad-hoc analysis. Also included investigate the antitumor activity of cediranib, as measured was an assessment of safety and tolerability. Additional by 18FDG-PET, in patients with metastatic GIST resistant or 18FDG-PET and CT parameters, including total lesion vol- intolerant to imatinib mesylate (ClinicalTrials.gov number: ume, were also analyzed by central review. Exploratory NCT00385203). In addition, an assessment of antitumor objectives included the effect of cediranib on soluble KIT, activity by objective tumor response, using Response Eval- VEGF, and soluble VEGFR-2 (sVEGFR-2). uation Criteria in Solid Tumors (RECIST; version 1.0), was performed. A subsidiary aim was to evaluate the activity of Study design the drug in patients with alveolar
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