Cixutumumab and Temsirolimus for Patients With Bone and Soft-tissue Sarcoma

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  www.thelancet.com/oncology Published online March 8, 2013 http://dx.doi.org/10.1016/S1470-2045(13)70049-4 1 ArticlesCixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial Gary K Schwartz, William D Tap, Li-Xuan Qin, Michael B Livingston, Samir D Undevia, Bartosz Chmielowski, Mark Agulnik, Scott M Schuetze, Damon R Reed, Scott H Okuno, Joseph A Ludwig, Vicki Keedy, Petra Rietschel, Andrew S Kraft, Douglas Adkins, Brian A Van Tine, Bruce Brockstein, Vincent Yim, Christiana Bitas, Abdul Abdullah, Cristina R Antonescu, Mercedes Condy, Mark A Dickson, Shyamprasad Deraje Vasudeva, Alan L Ho, L Austin Doyle, Helen X Chen, Robert G Maki Summary Background  Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and effi cacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods  We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings  Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3–4. The most common grade 3–4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%). Interpretation  The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination. Funding  National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center. Introduction About 13 000   cases of soft-tissue and bone sarcoma are diagnosed annually in the USA. 1  The median survival from diagnosis for patients with metastatic disease is about 10–18 months. 2  In view of the toxicity and limited effi cacy of chemotherapy, patients with advanced and metastatic disease are appropriate candidates for investigational treatments. Insulin-like growth factor-1 (IGF-1), IGF-2, and IGF-binding protein (IGF-BP) are expressed in various sarcoma subtypes, which suggests that IGF-1 receptor (IGF-1R) inhibition might be applicable in sarcomas. 3  IGF-1R is activated by the growth factor ligands IGF-1 and IGF-2, resulting in receptor autophosphorylation, which   leads to the activation of many signalling cascades, including the PI3K–Akt–mTOR pathway. Several lines of evidence have suggested that IGF-1R signalling is crucial to the biological changes in Ewing’s sarcoma and that targeting IGF-1R can inhibit tumour growth. 4–8  However, in two large phase 2 trials in Ewing’s sarcoma, treatment with IGF-1R-targeting monoclonal antibodies, R1507 and figitumumab, resulted in overall response rates of only 10% and 14% and median progression-free survival (PFS) of 1·3 and 1·9 months, respectively. 9,10 Combined inhibition of both IGF-1R and mTOR signalling represents a novel approach for treatment of sarcoma. 11,12  Blockade of mTOR alone paradoxically ac-tivates Akt. 13  This finding might explain the dis appointing Published Online March 8, 2013http://dx.doi.org/10.1016/S1470-2045(13)70049-4See Online/Comment http://dx.doi.org/10.1016/S1470-2045(13)70089-5 Department of Medicine  (Prof G K Schwartz MD, W D Tap MD, V Yim BA, C Bitas BA, A Abdullah BA, M A Dickson MD, S D Vasudeva MA, A L Ho MD) , Department of Epidemiology-Biostatistics (L-X Qin PhD) , Department of Pathology (Prof C R Antonescu MD) , and Department of Nursing (M Condy RN) , Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Medicine, Levine Cancer Institute, Charlotte, NC, USA (Prof M B Livingston MD) ; Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA (S D Undevia MD) ; Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA (B Chmielowski MD) ; Department of Medicine, Northwestern University, Chicago, IL, USA (M Agulnik MD, B Brockstein MD) ; Department of Medicine, University of Michigan, Ann Arbor, MI, USA (S M Schuetze MD) ; Department of Sarcoma, Moffi tt Cancer Center, Tampa, FL, USA (D R Reed MD) ; Department of Oncology, Mayo Clinic, Rochester, MN, USA (Prof S H Okuno MD) ; Department of Sarcoma Medical Oncology, University of Texas M D Anderson Cancer Center, Houston, TX, USA (J A Ludwig MD) ; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA (V Keedy MD) ; Department of Medicine, Albert Einstein Cancer Center, Bronx, NY, USA (P Rietschel MD) ; Department of Medicine, Medical University of South Carolina Hollings  Articles 2 www.thelancet.com/oncology Published online March 8, 2013 http://dx.doi.org/10.1016/S1470-2045(13)70049-4 Cancer Center, Charleston, SC, USA (Prof A S Kraft MD) ; Department of Medicine, Washington University in St Louis, St Louis, MO, USA (Prof D Adkins MD, B A Van Tine MD) ; Investigational Drugs Branch, National Cancer Institute, Bethesda, MD, USA (Prof L A Doyle MD, Prof H X Chen MD) ; and Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA (Prof R G Maki MD)Correspondence to:Prof Gary K Schwartz, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA schwartg@mskcc.org single-drug activity with mTOR inhibitors, such as temsirolimus, in patients with soft-tissue sar coma. 14   However, IGF-1R inhibition suppresses mTOR-induced Akt activation and sensitises tumour cells to mTOR inhibitors. 13  Pretreatment of rhabdomyosarcoma cell lines with the IGF-1R antibody h7C10 resulted in blockade of rapamycin-induced Akt activation and in an enhanced antiproliferative effect compared with either drug alone. 12   The IGF-1R antibody R1507 similarly enhanced the effect of rapamycin by downregulating IGF-1R and blocking the reactivation of phosphorylated Akt (p-Akt) in a broad range of sarcoma cell lines. 15  For sarcoma cell lines in which there was no IGF-1R expression, the combination of R1507 and rapamycin was ineffective. 15   Based on such data, phase 1 studies of the combination of IGF-1R and mTOR inhibitors in sarcoma have been undertaken. 16,17  The fully humanised IgG1-monoclonal-antibody-targeting IGF-1R cixutumumab can be combined safely with the mTOR inhibitor temsirolimus at respective doses of 6 mg/kg and 25 mg (flat dose) weekly. 16  We therefore initiated a phase 2 trial of cixutumumab and temsirolimus in bone and soft-tissue sarcoma with stratification according to IGF-1R status. We hypothesised that IGF-1R expression by the tumour would be crucial to identify the clinical benefit of this drug combination and would be independent of histological subtype. Because response to IGF-1R antibody treatment on the basis of histological subtype alone has been scarce, we believed that upfront stratification by IGF-1R expression would result in an improved clinical benefit. Therefore, rather than stratify by histological subtype, we assessed clinical benefit according to IGF-1R expression by immuno histochemistry. Methods Patients We undertook a multicentre, open-label, phase 2, non-randomised trial in 19 cancer centres in the USA. Patients aged at least 16 years were eligible if they had an Eastern Cooperative Oncology Group performance status of 0 or 1, histologically or cytologically confirmed sarcoma of soft tissue or bone, and measurable metastatic or locally advanced disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and if they had received at least one but not more than four previous treatments and had adequate organ function (defined by a normal complete blood count [absolute neutrophil count ≥1·5 × 10⁹/L, platelet count ≥100 × 10⁹/L], liver function tests [total bilirubin ≤1·5 × institutional upper limit of normal [ULN] and aspartate aminotransferase and alanine amino-transferase ≤3 × ULN], and renal function [serum creatinine ≤1·5 × ULN). Patients with hyper glycaemia, defined as fasting serum glucose above 6·66 mmol/L,   or those already on oral antidiabetic or insulin treatment were excluded from the study, as were those who received previous IGF-1R or mTOR inhibitors.The study was undertaken in accordance with the Declaration of Helsinki. All patients provided written informed consent before enrolment after being informed about the purpose and the investigational nature of the study. The institutional review boards of all participating centres reviewed and approved the protocol. Procedures All patients had IGF-1R testing on archival tissue by immunohistochemistry at Memorial Sloan-Kettering Cancer Center   (MSKCC; New York, NY, USA). Im muno-histochemistry was done on 4-µm formalin-fixed paraffi n embedded slides using pre-diluted IGF-1R antibodies (Ventana, Ventana Medical Systems, Tucson, AZ, USA) according to published methods. 18  The scoring for IGF-1R expression was quantitated on a 0–3+ scale: 0–1+, no staining or faint or weak staining; 2+, moderate staining; and 3+, strong staining. Only staining of 2+ to 3+ (cytoplasmic or membrane or both) was deemed positive. Scoring for IGF-1R expression was done by central pathology review (Cristina Antonescu, MSKCC) so as to minimise the inter-patient variability with immuno-histochemistry.Patients were assigned to one of three groups: those in group A had IGF-1R-positive sarcomas of soft tissue; those in group B had IGF-1R-positive sarcomas of bone; and those in group C had IGF-1R-negative sarcomas of bone and soft tissue. All patients received weekly treatment with cixutumumab (6 mg/kg intravenous) over 1 h followed 1 h later (30 min if the first two doses were tolerated) by temsirolimus (25 mg intravenous) in 6-week cycles.If grade 3 or 4 neutropenia or thrombocytopenia occurred, temsirolimus and cixutumumab were re-spectively reduced by one (20 mg and 5 mg/kg) or two (15 mg and 4 mg/kg) dose levels. For hyperglycaemia of grade 1 toxicity or greater, oral antidiabetic treatment or insulin was started. For symptomatic grade 3 or any grade 4 hyperglycaemia, cixutumumab was reduced by one or two dose levels. For any grade 1 hepatic toxicity (bilirubin, alanine aminotransferase, or aspartate aminotransferase) the temsirolimus dose was reduced immediately by two dose levels (15 mg). Hyperlipidaemia was treated with medical management rather than by dose reduction. Patients were assessed weekly for adverse events.Clinical and radiological (contrast CT or MRI of chest, abdomen, and pelvis) assessments were obtained every 6 weeks. Plasma samples for measurement of IGF-1 and IGF-BP3 concentrations by ELISA assay (R&D Systems, Minneapolis, MN, USA) were taken before treatment and on weeks 3 and 7. Plasma measurements were a requirement at MSKCC but were optional at other sites.All patients treated   at MSKCC were required to undergo tumour biopsies before and after treatment unless deemed clinically inappropriate. Biopsies were flash frozen in liquid nitrogen before treatment and between weeks 2 and 3 for assessment of total IGF-1R, p-Akt, total Akt, phosphorylated S6 (p-S6), and total S6 by western blots according to standard techniques. 15  Equal  Articles www.thelancet.com/oncology Published online March 8, 2013 http://dx.doi.org/10.1016/S1470-2045(13)70049-4 3 loading of protein was confirmed by tubulin and GAPDH staining, and relative protein expression was quantified by densitometry assessment with ImageJ. All primary antibodies were obtained from Cell Signaling (Boston, MA, USA). The primary endpoint was PFS at 12 weeks in the first 54 patients assigned to each treatment group, as assessed by RECIST 1.1. Secondary endpoints were overall survival, overall disease response, and correlation of plasma bio markers with clinical outcome. A post-hoc analysis was done by histological subtypes on progression-free survival, overall survival, and response. Statistical analysis Based on historical controls, a PFS of over 40% at 3 months was deemed acceptable for second-line treatment and a PFS of less than 20% was deemed unacceptable. 19  We used a Simon optimal two-stage design for every arm such that the outcome of the study was assessed by the decision rule of the study design. 20  In particular, in stage 1, 19 patients were to be accrued. If fewer than five patients (26%) were progression free at 12   weeks, further accrual would cease and the combination therapy would be declared ineffective. If at least five patients in stage 1 were progression free then an additional 35 patients would be accrued in stage 2 for a total of 54 patients. If at least 16 patients were progression free at 12 weeks among the first 54    patients, the arm would be judged to have a positive result and the combination therapy would be worthy of further testing. This design had a power of 0·90 for establishing the treatment effect for a population 12-week PFS proportion of 40% using a type I error of 0·05. The probability of stopping each arm of the study early was 67% if the population 12-week PFS proportion was 20%.Analyses of effi cacy data were done for all patients who had received any study drug (intention-to-treat). For every arm, the proportion of patients remaining free of progression at 12 weeks was estimated and a one-sided 95% CI and a two-sided 90% CI were calculated. Median event-free times for all treated patients were estimated by the Kaplan–Meier method with a two-sided 95%   CI and were compared between groups by the log-rank test with a two-sided p   value. Correlation of plasma biomarkers for IGF-1 and IGF-BP3 to PFS at 12 weeks was examined by the Wilcoxon rank sum test with a two-sided p   value for absolute levels at baseline, week 3, or week 7 and for change of levels at week 3 or week 7 from baseline. R software (version 2.14.2) was used for all statistical analyses. Role of the funding source The sponsor of the study (National Cancer Institute) was involved in study design, data collection, and the decision to submit for publication in conjunction with the authors. The study sponsor had no role in data analysis, data interpretation, or writing of the report. TotalIGF-1R positiveIGF-1R negative Chondrosarcoma3820 (53%)18 (47%)Chordoma61 (17%)5 (83%)Clear-cell tumour65 (83%)1 (17%)Ewing’s sarcoma6133 (54%)28 (46%)Gastrointestinal stromal tumour123 (25%)9 (75%)Leiomyosarcoma4526 (58%)19 (42%)Liposarcoma115 (45%)6 (55%)Malignant peripheral nerve sheath tumour119 (82%)2 (18%)Myxofibrosarcoma61 (17%)5 (83%)Osteosarcoma5233 (63%)19 (37%)Undifferentiated pleomorphic sarcoma199 (47%)10 (53%)Rhabdomyosarcoma107 (70%)3 (30%)Sarcoma, unspecified147 (50%)7 (50%)Solitary fibrous tumour1911 (58%)8 (42%)Spindle-cell tumour178 (47%)9 (53%)Synovial sarcoma1814 (78%)4 (22%)Others4319 (44%)24 (56%) Data are number (%). IGF-1R=insulin-like growth factor-1 receptor. Table 󰀱:  Insulin-like growth factor-1 receptor status according to histological subtype in at least five patients for all screened patients Figure 󰀱:  Trial profile IGF-1R=insulin-like growth factor-1 receptor. *Reasons for clinical screen failure: more than four treatments, brain metastases, abnormal laboratory values, congestive heart failure, or no measurable disease. †Other reasons included elected to undergo surgery, observation only, or radiation; unspecified reasons; or treatment was not covered by insurance. 54 assigned to IGF-1R-positive soft-tissue sarcoma and included in analysis of primary endpoint54 assigned to IGF-1R-positive bone sarcoma and included in analysis of primary endpoint3 included after protocol amendment 57 included in all efficacy and safety analyses54 included in all efficacy and safety analyses15 gave plasma samples and 9 had tissue biopsies23 gave plasma samples and 16 had tissue biopsies54 assigned to IGF-1R-negative soft-tissue and bone sarcoma and included in analysis of primary endpoint9 included after protocol amendment 63 included in all efficacy and safety analyses17 gave plasma samples and 7 had tissue biopsies388 screened for eligibility226 excluded 68 study group closed to patient accrual 48 decline in performance status 32 pursued alternative therapy 32 ineligible* 21 withdrew informed consent 25 other†162 eligible  Articles 4 www.thelancet.com/oncology Published online March 8, 2013 http://dx.doi.org/10.1016/S1470-2045(13)70049-4 GKS, L-XQ, VY, CB, AA, CRA, MC, MAD, SDV, ALH, and RGM had access to the raw data. The corresponding author (GKS) had full access to all the data in the study and had final responsibility for the decision to submit for publication. Results From Nov 18, 2009, to April 11, 2012, 388 patients were screened for IGF-1R expression by immunohisto-chemistry. Of these, 211 (54%) were IGF-1R positive and 177 (46%) were IGF-1R negative across many sarcoma subtypes (table 1). Patients were then enrolled into a treatment group at the discretion of the treating physicians until 54 patients had been enrolled in each group. All groups met the requirements for stage 1 before enrollment continued. The remainder of the screened patients were excluded because the study arm was closed to patient accrual or the patient did not meet protocol eligibility, had poor performance status, withdrew consent, elected to seek hospice or other treatments, or for other reasons (figure 1). On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group and nine in the IGF-1R-negative sarcoma group, giving a total of 57 patients with IGF-1R-positive soft-tissue sarcoma (group A), 54 with IGF-1R-positive bone sar coma (group B), and 63 with IGF-1R-negative sarcoma (group C). This protocol amendment was made because of over enrolment into group A (patients who consented before enrolment was halted) and on the basis of promising results in first 54 patients in group C.   Table 2 shows the baseline demographics and patient charac-teristics, including the most common histological sub-types by IGF-1R status, for all treated patients. The mean number of previous systemic regimens was two (range one to four). After the first stage of enrolment, more than five patients in each group were progression free at 12 weeks. By intention-to-treat analysis, of the 54 patients in each group in the srcinal cohort (ie, before the protocol amendment), 17 patients (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43) in the IGF-1R-positive soft-tissue sarcoma group, 19 patients (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47) in the IGF-1R-positive bone sarcoma group, and 21 patients (39%; one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) in the IGF-1R-negative group were progression free at 12 weeks.After the protocol amendment and inclusion of add-itional patients, 17 of 57 patients (30%; one-sided 95% CI lower bound 20%; two-sided 90% CI 20–41) in the IGF-1R-positive soft-tissue sarcoma group and 26 of 63 (41%; one-sided 95% CI lower bound 31%; two-sided 90% CI 31–52) in the IGF-1R-negative group were pro-gression free at 12 weeks. At the time of final analysis, the median follow-up of survivors was 18·6 months (range 2·9–30·9). The median PFS by Kaplan–Meier estimates for all treated patients was 6·9 weeks (95% CI 5·9–12·0) for the IGF-1R-positive soft-tissue sarcoma group, 10·6 weeks (6·0–15·3) for the IGF-1R-positive bone sarcoma group, and 11·6 weeks (9·3–17·9) for the IGF-1R-negative group (figure 2A).Based on 98 deaths and a median duration of follow-up of 18·6 months (range 2·9–30·9), the median overall survival in all treated patients (n=174) was 18·9 months (95% CI 13·1 to not reached [NR]) for patients with IGF-1R-positive soft-tissue sarcoma, 14·2 months (7·6 to NR) for patients with IGF-1R-positive bone sarcoma, and 14·7 months (10·6 to NR) for patients with IGF-1R-negative sarcoma; figure 2B). All deaths were due to disease progression.Nine patients achieved a partial response: one (2%) of 57 patients in the IGF-1R-positive soft-tissue sarcoma group, six (11%) of 54 patients in the IGF-1R-positive bone sarcoma group, and two (3%) of 63 patients in the IGF-1R-negative group. There were no complete responses.Analysis of plasma biomarkers in 55 patients (15 in the IGF-1R-positive soft-tissue sarcoma group, 23 in the IGF-1R-positive bone sarcoma group, and 17 in the IGF-1R-positive soft-tissue sarcoma (n=57)IGF-1R-positive bone sarcoma (n=54)IGF-1R-negative sarcoma (n=63) Age (years)50 (19–82)38 (18–73)55 (19–78)SexMen22 (39%)32 (59%)40 (63%)Women35 (61%)22 (41%)23 (37%)ECOG PS039 (68%)30 (56%)31 (49%)118 (32%)24 (44%)32 (51%)Previous treatments114 (25%)15 (28%)18 (29%)226 (46%)17 (31%)17 (27%)314 (25%)16 (30%)24 (38%)43 (5%)6 (11%)4 (6%)Mean number of previous treatments2·12·32·3Most common histological subtypeEwing’s sarcoma or primitive neuroectodermal embriogenic tumour1197Osteosarcoma0186Chondrosarcoma0116Leiomyosarcoma15011Undifferentiated pleomorphic sarcoma6310Synovial sarcoma803Solitary fibrous tumour404Malignant peripheral nerve sheath tumour501Well-differentiated and dedifferentiated liposarcoma301Gastrointestinal stromal tumour202Others13312 Data are mean (range), number (%), or number. ECOG PS=Eastern Co-operative Oncology Group performance status. Table 󰀲:  Demographics and baseline characteristics See Online for appendix
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