bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II multicenter study of the IGF-1 receptor antibody cixutumumab (A12) and the mTOR inhibitor temsirolimus (TEM) in patients (pts) with refractory IGF-1R positive (+) and negative (-) bone and soft tissue sarcomas (STS).
Authors: Schwartz Gary K. , Tap William D. , Qin Li-Xuan , Livingston Michael B. , Undevia Samir D. , Chmielowski Bartosz , Agulnik Mark , Schuetze Scott , Reed Damon R. , Okuno Scott H. , Ludwig Joseph A. , Hande Kenneth R. , Rietschel Petra , Kraft Andrew S. , Adkins Douglas , Brockstein Bruce , Yim Vincent , Bitas Christiana , Antonescu Cristina , Maki Robert G. 
Published: March 2020

10003 Background: Preclinical studies demonstrate synergistic anti-tumor activity by inhibiting mTOR and IGF-1R. This study evaluated the safety and efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (+) STS (Arm A), IGF-1R (+) bone (Arm B), and IGF-1R (-) bone and STS (Arm C). Methods: An optimal Simon 2 stage design was used for each arm. The primary end-point was progression free survival (PFS) at 12 weeks. Based on historical data, a 40% PFS rate was considered promising and a 20% PFS non-promising (type I/ II error, 0.05/0.10). ≥5 PFSs at 12 weeks were required in the first 19 and ≥16 PFSs were required in a total of 54 pts to consider each arm positive. Key eligibility: measurable disease (RECIST 1.1), age ≥18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25 mg) were administered IV weekly. Pre and post treatment tumor biopsies and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R by immunohistochemistry (IHC; 54% +) and 171 were treated: mean age 47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities ≥10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT) analysis, each arm of the study achieved its primary 12 week PFS end-point (≥16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1), (0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0, 17.9), respectively, and for chondro (n=18), Ewing’s (n=24), and osteo (n=23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0), respectively. Westerns on 32 matched pair tumor biopsies indicate inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts (Arm C), 5 were IGF-1R (+) by western. Plasma biomarkers did not correlate with PFS. Conclusions: A12 and TEM met its primary end-point of improved PFS in pts with metastatic sarcoma. This effect was independent of IGF-1R status by IHC. These results support further clinical development of this combination in bone and STS.
A first-in-human, phase Ib combination study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a hedgehog inhibitor, GDC-0449, with a Notch inhibitor, RO4929097, in patients with advanced sarcoma.
Authors: Gounder Mrinal M. , Dickson Mark Andrew , Wu Nian , Ivy S. Percy , Carvajal Richard D. , D'Angelo Sandra P. , Keohan Mary Louise , Qin Li-Xuan , Erinjeri Joseph Patrick , Takebe Naoko , Tanner Lanier , Morales Rita , Condy Mercedes M , Ustoyev Yelena , Maki Robert G. , Tap William D. , Schwartz Gary K. 
Published: March 2020

10004 Background: Aberrant Hedgehog and Notch signaling is seen in sarcoma and anti-tumor activity is enhanced by inhibiting both pathways. This first in man Phase Ib study evaluated safety and efficacy of the combination of GDC-0449 (G), a smoothened inhibitor with RO4929097 (R), a gamma-secretase/notch inhibitor. Methods: The study evaluated fixed dose G (150 mg qd) for 21 days followed by G + R at either 10 mg (level 1) or 15 mg (level 2) QD. At MTD pts were evaluated with G + R (without “lead in” G) or single agent R. Pre and post treatment tumor biopsies were obtained to assess notch and hedgehog inhibition. PK was assessed for each drug. Key eligibility: advanced sarcoma, ECOG ≤ 2, age ≥ 18 and prior therapies ≤ 4. RECIST response was assessed Q6 wks. Results: 34 pts had a median age of 53 yrs (23-78), median priors 3 and various histologies [liposarcoma (7), chondrosarcoma (7), leiomyosarcoma (4), osteosarcoma (2), GIST (2) and other (12)]. No DLT was seen. Common (≥10 %) grade ≤3 toxicity was hypophosphatemia (18%). Systemic exposure (AUC0-24 and Cmax) of G was similar to established studies (not shown). AUC0-24 and Cmax of R was significantly lower (~70%) when administered with G (Table). However, measurement of unbound, free drug (Cfree) of R showed comparable levels between single agent R and G + R, but not when G was a “lead in” (Table). Target inhibition of the notch pathway (cleaved notch) and pAkt was observed in matched tumor biopsies with both arms. Durable SD was seen in both arms: myxoid chondrosarcoma (56 wks), liposarcoma (24+ wks), clear cell (21+ wks), desmoid (17+ wks), spindle cell (15+ wks) and chondrosarcoma (13+ wks). Conclusions: The combination of G+R is well tolerated and the RP2D is G 150 mg qd and R 15 mg qd without a “lead in” G. Despite reduction in total levels of R in the combination, free drug was similar and inhibits target. Disease stability was seen with R and R + G. Further clinical development of notch and hedgehog inhibitors in sarcomas is warranted. [Table: see text]
Localized angiosarcomas (AS): Identification of prognostic factors (PF) and analysis of treatment impact—Series from the French Sarcoma Group (GSF/GETO).
Authors: Lindet Clothilde , Neuville Agnes , Penel Nicolas , Lae Marick , Michels Jean-Jacques , Trassard Martine , Terrier Philippe , Birtwisle-Peyrottes Isabelle , Valo Isabelle , Collin Francoise , Chateau Marie-Christine , Robin Yves Marie , Coindre Jean-Michel 
Published: March 2020

10018 Background: AS represents less than 2% of all adult soft tissue sarcoma. PF and role of respective (neo)-adjuvant treatments in management of localized AS remain badly established. Methods: We have conducted a retrospective multicentre study (June 1980-October 2009) of 107 patients with localized AS. All cases have been centrally reviewed by pathologist expert. Univariate and multivariate analysis were conducted to identify independent PF. Overall survival (OS) and Local Recurrence Free Survival (LRFS) were estimated using the Kaplan-Meier method. Impact of treatments had been explored with Cox Model after adjustment to the PF. Results: The sex ratio was 18/89 (0.2). Median age was 71 years. 22% (24/107) and 62% (67/107) of patients developed AS in preexisting lymphoedema and in irradiated field, respectively. 71 cases (66%) were superficial. The most frequent primary locations were: limbs (35, 33%), chest wall (32, 29%) and breast (22, 20%). Grade was 1 in 21/103 (20%), 2 in 35/103 (34%) and 3 in 47/103 cases (46%). Treatments consisted in surgery, adjuvant radiotherapy and (neo)-adjuvant chemotherapy in, respectively, 95, 27 and 27 cases. R0 margin was obtained in 49 cases. The median OS and LRFS were, respectively, 38.8 months and 27 months. In multivariate analysis, the following PF influenced the OS: lymphedema (HR=2.02 [1.15-3.55]) and size>5 cm (HR=1.48 [1.01-2.45]). After adjustment to these PF, R0 margins was the sole treatment parameter improving the OS (HR=0.19 [0.05-0.73]). In multivariate analysis, the following PF influence the LRFS: Age>70 (HR=1.68 [1.02-2.76]) and pre-existing lymphedema (HR=2.07 [1.15-3.75]). After adjustment to these prognostic factors, R0 margins (HR=0.48 [0.38-0.69]) and adjuvant radiotherapy (HR=0.29 [0.10-0.83]) improved the LRFS. Conclusions: Pre-existing lymphedema, tumour size and age>70 are the major PF in patients with localized AS. The achievement of R0 margins is of major importance for improving the outcome whatever the endpoint (OS, LRFS) Adjuvant radiotherapy decreased the local recurrence. (Neo)-adjuvant chemotherapy does not influence survivals.
Tenosynovial giant cell tumor (TGCT)/pigmented villonodular synovitis (PVNS): Outcome of 313 patients before the era of kinase inhibitors.
Authors: Palmerini Emanuela , Pengo Stefano , Maki Robert G. , Staals Eric L. , Cioffi Angela , Alberghini Marco , Picci Piero , Ruggieri Pietro , Mapelli Sergio , Parafioriti Antonina , Morris Carol , Gronchi Alessandro , Casali Paolo Giovanni , Ferrari Stefano , Stacchiotti Silvia 
Published: March 2020

10022 Background: Tenosynovial giant cell tumor (TGCT) is a rare, usually benign neoplasm of synovium and tendon sheath. TGCT is classified as localized or diffuse according to the extent of synovial involvement. Surgery is the primary treatment, but the recurrence rate is high, with possible multiple recurrences, joint function deterioration and decline in quality of life. Recent data suggest a role for TKIs in advanced disease. In order to identify prognostic factors for recurrence, a retrospective pooled analysis was carried out in three institutions (Istituto Ortopedico Rizzoli, Bologna, Italy; Istituto Nazionale Tumori, Milano, Italy; Memorial Sloan Kettering Cancer Center, New York, USA). Methods: Clinical charts and pathology reports of patients (pts) treated in the period 1998-2008 were examined. Results: The study included 313 pts, 177 F and 136 M; median age: 36 years (range: 11-89 years). Most (64%) pts had tumors in the knee (15% ankle, 11% hip, 10% other). Tumor size was: <2 cm in 24% of pts, 2-5 cm in 44%, >5 cm in 32%. A diffuse pattern was reported in 69% of pts. The resection status was available in 289 pts: 51% had R0 surgery, 28% R1 and 21% R2. No metastases were documented. Local recurrence was reported in 76 pts (median time to recurrence: 15.7 months). With a median follow-up of 4.2 years, 5-year local recurrence-free survival (LRFS) was 66% (95% CI: 59 - 73). Size (< 2 cm 80% vs. 2-5 cm 67% vs. >5 cm 62%, p=0.04), gender (F 73% vs. M 56%, p=0.02), type (localized 78% vs. diffuse 61%, p=0.02), and resection status (R0 76% vs. R1 55%, vs. R2 57%, p=0.002) influenced 5-year LRFS, whereas age, tumor location and bone involvement did not. The 5-year 2nd LRFS was 43% (95% CI: 28 - 59). Multiple (2 to 5) local recurrences were observed in 39% of relapsed patients. Conclusions: The study confirms TGCT propensity to multiple local recurrences. Diffuse type, suboptimal surgery, male gender and larger tumors increase the recurrence risk. In order to improve the probability of local control, studies addressing the role of TKIs could be considered in subsets of patients.
Cetuximab and EGFR inhibitors in patients with neurological symptoms due to chordoma.
Authors: Linden Ola , Ehinger Mats , Kinhult Sara , Relander Thomas , Lundgren Lotta , Engellau Jakob , Kjellén Elisabeth 
Published: March 2020

10024 Background: Chordomas are rare tumours located along the neuraxis, showing limited sensitivity to radiotherapy and lack of response to chemotherapy. However, tyrosine kinase inhibitors (TKIs) have been reported to have an effect. Following the failure of single-agent treatment in a young patient using cetuximab, we decided to treat patients (pts) with neurological symptoms with dual targeting of the epidermal growth factor receptor (EGFR), based on a case report by Hof et al., who successfully used dual targeting of EGFR, and supporting in vitro data. Methods: Eight consecutive pts with neurological symptoms at referral were treated with cetuximab (250 mg/m2 weekly) and an EGFR signalling inhibitor (250 mg gefitinib or 150 mg erlotinib daily). The duration of treatment was not decided in advance. Results: EGFR expression on tumour cells was variable but present in all pts. Six pts were evaluable. One tetraplaegic pt died of an unknown cause and one pt on lithium carbonate discontinued treatment before the first follow-up due to renal toxicity. Four pts showed neurological improvement. Two of these regained and one improved the ability to walk, and a fourth, with a sacral tumour, improved his voiding ability. The fifth pt had clinically stable disease and, although the PET scan showed improvement, the treatment had to be discontinued due to skin toxicity. One pt showed progressive disease. In the four pts responding neurologically, improvement was noted already by the end of the third week. Three pts were retreated without failure while on treatment. The first pt who regained the ability to walk is still walking at 52+ months. This pt, while still responsive to cetuximab and erlotinib, has failed to respond to single-agent treatment with imatinib, sorafenib or everolimus. The second pt who regained walking ability had severe alcoholism and died while being treated. The third is still walking at 16+ months. All pts exhibited significant cutaneous side effects, in some cases necessitating intermittent interruption of therapy. Conclusions: Treatment with cetuximab and TKIs can thus achieve meaningful and long-lasting clinical improvement in pts with paresis due to chordoma, and is feasible in pts with limited comorbidities.
Lapatinib in advanced chordoma: A phase II study.
Authors: Stacchiotti Silvia , Tamborini Elena , Palassini Elena , Negri Tiziana , Marrari Andrea , Messina Antonella , Morosi Carlo , De Troia Beatrice , Longhi Alessandra , Palmerini Emanuela , Gronchi Alessandro , Pilotti Silvana , Casali Paolo Giovanni 
Published: March 2020

10026 Background: To report on a prospective Phase II, investigator-driven, collaborative study to explore the activity of lapatinib, a dual EGFR and ErbB2 inhibitor, in EGFR-positive advanced chordomas. Methods: From December 2009 to December 2011, 19 advanced progressing chordoma patients entered this study (mean age: 59 yrs – range = 35-75; PS: 0-3 - ≥2 = 52%; site: sacrum = 68%, spine = 21%, skull base = 11%; disease extent: metastatic = 68%, locally advanced = 32%). EGFR expression was evaluated by immunohistochemistry in all patients. EGFR activation was detected in 15 of 17 evaluable cases by phospho-arrays and/or real-time PCR and/or fluorescence immunostaining. EGFR FISH analysis showed high level of gene gain in 4. HerB2 status is under evaluation. Patients received lapatinib 1500 mg/day (dose intensity in excess of 1250 mg/day), until progression or toxicity. The primary study end-point was response rate (RR) as for Choi criteria extended to MRI. Secondary end-points were RR by RECIST, PFS by Choi, OS, clinical benefit rate (CBR) (CR+PR+SD≥6mos), correlation between EGFR status and response. Results: 16 pts are evaluable for response (3 too early); 4 patients are still on treatment. 3 patients (19%) had a partial response (PR) and 8 (50%) a stable disease (SD) as their best Choi response, corresponding to RECIST SD in all cases. The 3 cases with a PR by Choi had a minor decrease in size; another patient had a mixed response. The CBR was 19%. Median PFS as for Choi was 5.5 (range = 2-12+) months, with 1 patient being progression-free at 18 months. Toxicity was as expected. In one case treatment was interrupted due to side effects. No correlation was observed between EGFR expression/activation and response. Conclusions: This Phase II study showed a modest activity of lapatinib in chordoma. EGFR expression was not predictive of response. The clinical relevance of EGFR targeting in chordoma needs to be further investigated.
A phase III, multicenter, randomized trial of maintenance versus observation after achieving clinical response in patients with metastatic breast cancer who received six cycles of gemcitabine plus paclitaxel as first-line chemotherapy (KCSG-BR 0702, NCT00561119).
Authors: Im Young-Hyuck , Park Yeon Hee , Jung Kyung Hae , Im Seock-Ah , Sohn Joo Hyuk , Ro Jungsil , Kim Sung-Bae , Ahn Jin-Hee , Oh Do Youn , Han Sae-Won , Lee Soohyeon , Park In Hae , Lee Keun-Seok , Kim Jee Hyun , Kang Seok Yun , Lee Moon Hee , Park Hee Sook , Ahn Jin Seok 
Published: March 2020

1003 Background: Chemotherapy provides a survival benefit in patients with metastatic breast cancer (MBC), but the optimal duration of chemotherapy remains controversial. Primary purpose of the study was to evaluate whether the maintenance chemotherapy with gemcitabine/paclitaxel (GP), which is one of the two regimens which showed a survival gain from a randomized trial, is superior to observation in terms of progression free survival (PFS) in responding patients with MBC after 6 cycles of GP as first-line treatment. Methods: This study is a prospective, randomized, multi-center, phase III study. Patients who achieved response (CR+PR+SD) following 6 cycles of GP chemotherapy (gemcitabine 1250 mg/m2 on day 1 and 8 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks) randomized to maintenance till progression or observation arm. The trial was conducted by the Korean Cancer Study Group (KCSG). Results: Among total 324 patients enrolled between 2007 and 2010 from 10 centers, 231 responding patients to were randomly assigned to maintenance chemotherapy (n=116) or observation (n=115). Median age was 49 (range 28-76). The numbers of hormone receptor (HR)+ve and HR-ve patients were 172 (74.5%) and 59 (25.5%), respectively. The median No. of chemotherapy cycles in maintenance group was 12 (range 6-32). During median 33 months of follow-up, median PFS was superior in maintenance than in observation (12.0 vs. 8.3 months, p=0.030). Patients < age 50 years (hazard ratio 0.50, p=0.001) and HR-ve patients (hazard ratio 0.52, p=0.019) received more benefit from maintenance chemotherapy in terms of PFS. Median OS was superior in maintenance than in observation (36.8 vs 28.0 months, p=0.047). Neurotoxicity (≥ grade 2) was more common in maintenance than in observation without statistical significance (41.7% vs 33.3%, p=0.210). Serial assessment of Quality of Life (QoL) did not show any significant difference between two groups. Conclusions: Maintenance GP chemotherapy for responding patients with MBC showed clinical benefit in terms of PFS and OS without impairment of QoL.
Efficacy of a phosphoinositol 3 kinase (PI3K) inhibitor in gastrointestinal stromal tumor (GIST) models.
Authors: Van Looy Thomas , Wozniak Agnieszka , Sciot Raf , Floris Giuseppe , Manley Paul W. , Debiec-Rychter Maria , Schöffski Patrick 
Published: March 2020

10030 Background: PI3K signaling is crucial for GIST proliferation and survival. We assessed the efficacy of the PI3K inhibitor NVP-BEZ235 (BEZ), alone or in combination with imatinib (IM), in GIST xenografts. Methods: Nude mice were grafted bilaterally with human GIST, carrying either KIT exon 9 (GIST-BOE, dose-dependent IM resistant) or exon 11 (GIST-DFR, IM sensitive) mutations. Animals, randomized into four groups (n=8/group) were dosed orally for 2 weeks with either vehicle, IM (50mg/kg/bid), BEZ (10mg/kg/qd), or IM+BEZ. Treatment efficacy was assessed by tumor volume, histopathology and Western immunoblotting. Moreover tumor regrowth was evaluated for 3 weeks after treatment cessation. Results: As a single agent IM and BEZ stabilized tumor growth of both GIST-BOE and DFR. Moderate to significant tumor regression was observed in GIST-BOE under BEZ (by 27%), and IM+BEZ (66%), and also in GIST-DFR under IM (75%) and IM+BEZ (75%). In GIST-BOE significant reduction in mitotic index was observed under BEZ (8.5 fold) and IM+BEZ (8.5 fold) as compared to control. In GIST-DFR mitotic activity was virtually absent under all regimens. Apoptotic activity increased significantly after treatment with IM (5.5 fold) and IM+BEZ (14.0 fold) in GIST-DFR, whereas it was almost unaffected by BEZ as single agent, as well as in all treatment groups in GIST-BOE. By Western, PI3K signaling was incompletely inhibited in all groups in GIST-DFR, and after BEZ in GIST-BOE. Complete inhibition of PI3K signaling was observed only after combination treatment. After treatment cessation long-lasting growth-inhibition was observed in IM+BEZ treated GIST-DFR. Moreover, mitotic index after BEZ and BEZ+IM in GIST-DFR was lower than in control even after treatment withdrawal. Conclusions: BEZ shows significant efficacy in GIST xenografts. Furthermore, combination with IM shows synergistic and long-lasting effects even after treatment withdrawal, which is not the case with drugs routinely used for GIST treatment.
Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent nonresectable chondrosarcomas.
Authors: Merimsky Ofer , Bernstein-Molho Rinat , Kollender Yehuda 
Published: March 2020

10043 Background: Chondrosarcomas (CS) represent a heterogeneous group of rare sarcomas, poorly responsive to chemotherapy or radiotherapy. When local therapies in recurrent or metastatic disease are exhausted, chemotherapy plays a marginal role. Different molecular pathways have been shown to be activated in CS. In this retrospective study we summarize our experience in treating a cohort of patients with recurrent nonresectable CS with a combination of sirolimus and cyclophosphamide. Methods: Nine consecutive patients with nonresectable CS were offered off-label treatment with sirolimus and cyclophosphamide between 2007-2011. Tumor response, progression-free survival (PFS), adverse events and other relevant clinical data were analyzed. Results: The median patients’ age was 52 (range, 35-68). Median disease-free interval (DFI) since the primary diagnosis was 24 months. Median time from the disease recurrence to initiation of sirolimus and cyclophosphamide treatment was 20.9 months due to additional local surgical treatments/excision of metastases/slow and asymptomatic progression. One (11%) objective response was observed and five (56%) patients had stabilization of disease for at least 6 months. One patient has been treated for only 3.5 months and reported symptomatic improvement at this stage, two patients had progressive disease. Median time to treatment failure (TTF) was 15 months (range, 2.8-30.3). No significant adverse events were observed. Conclusions: Although advanced CS remains an incurable disease, our experience suggests that a combination of sirolimus and cyclophosphamide is well-tolerated and has meaningful clinical activity with clinical benefit rate of 67%. Further prospective studies are warranted.