Trials In Soft Tissue Sarcoma Research Articles

Clinical benefit and fragility evaluation of systemic therapy trials for advanced soft tissue sarcoma.

The clinical benefit of systemic anticancer therapies can be unclear despite positive trials, and outcomes may not translate to real-world practice. This study evaluated the benefit of soft tissue sarcoma (STS) treatments using the European Society of Medical Oncology Magnitude of Clinical Benefit Scale (MCBS) v1.1 and measured the robustness of STS trial results using Fragility Index (FI). Database searches for adult phase II or III trials in advanced STS (January 1998-December 2023) were performed. Therapies with trial outcomes that met the criteria for MCBS were scored 1-5 (≥4 represents substantial clinical benefit). For randomized clinical trials with positive time-to-event endpoints, the number of additional events that would render results nonsignificant, FI, was calculated and expressed as a proportion of the experimental arm size (fragility quotient [FQ]). Higher FI/FQ implies more robust results. Among 194 trials, 19 (9.8%) were phase III. Most phase II trials (146/175; 83.4%) had single-arm or non-comparative design. Trials that were eligible for MCBS scoring (n=78; 40.2%) evaluated 56 different agents/regimens. Median MCBS score was 2. Only three agents/regimens (all cytotoxic therapies) had an MCBS score ≥4. Among 47 randomized clinical trials, 16 (8 phase II; 8 phase III) trials had positive outcomes. Median FI was 7 (range, 2-52) and 10 trials (62.5%) had an FQ < 10%, with median of 7% (range, 1%-59%). Most systemic therapies in STS trials did not confer substantial clinical benefit per European Society of Medical Oncology-MCBS. Additionally, positive randomized trials were often fragile. Novel STS therapy trials should use clinically meaningful endpoints and real-world efficacy confirmation is essential, especially for less robust trials.

Fragility index analysis of systemic therapy clinical trials in soft tissue sarcoma (STS).

11581 Background: The fragility index (FI) measures the robustness of randomized clinical trials (RCT) that have positive results based on statistical p-values. It estimates the minimum number of events that are needed to reverse the trial results from positive to negative. Here, we perform FI analysis on RCTs evaluating systemic treatments for STS. Methods: A systematic search of the Medline and Embase databases for RCTs in adults with advanced STS (Jan 1998 to Dec 2023) was conducted. Gastrointestinal stromal tumor trials were excluded. The FI framework was adapted to allow the use of time-to-event (TTE) outcomes – progression-free survival (PFS) or overall survival (OS) as previously described (Desnoyers et al 2021). Survival tables were reconstructed from published data on positive TTE outcomes, using the Parmar Toolkit. Positive secondary endpoints were used only if the primary endpoint was negative. The number of additional events that would result in a non-significant effect for the hazard ratio (HR) of the positive endpoint of each trial (FI) was calculated and expressed as a proportion of the size of the experimental arm (fragility quotient; FQ). The number of censored patients – those who withdrew consent or were lost to follow-up (Cn) was noted. Results: Among 47 RCTs, 16 (8 phase II; 8 phase III) trials had positive outcomes. The primary endpoint was positive and used for FI analysis in 11/16 trials (68.8%). PFS was the most common positive outcome, evaluated in 13 trials (81.3%). The median FI was 6 (range 2 – 52), with FI &lt; 10 observed in 11 trials (68.8%). Median FQ was 7% (range 1 – 59%) and 10 trials (62.5%) had FQ &lt; 10%. Among 14 trials that reported data, Cn was ≥ FI in 7 trials (50%). Only 2 of 4 trials (50%) that led to regulatory approval had FI &gt; 10 or FQ &gt; 10%. Of the other 2, one drug approval was subsequently withdrawn (Table). Conclusions: Most positive clinical trials in STS were fragile and their outcomes may be confounded by the level of censoring. Real-world evaluation of approved systemic therapies and value scales such as ESMO Magnitude of Clinical Benefit scale or ASCO value framework are needed to confirm clinical benefit of systemic treatments in STS.[Table: see text]

QTPI: A quasi-toxicity probability interval design for phase I trials with multiple-grade toxicities.

The common terminology criteria for adverse events by the National Cancer Institute has greatly facilitated the revolution of drug development and an increasing number of Phase I trials have started to collect multiple-grade toxicity endpoints. Appropriate and yet transparent Phase I statistical designs for multiple-grade toxicities are therefore in great needs. In this article, we propose a quasi-toxicity probability interval (qTPI) design that incorporates a quasi-continuous measure of the toxicity probability () into the Bayesian theoretic framework of the interval based designs. Multiple-grade toxicity outcomes of each patient are mapped to according to a severity weight matrix. Dose-toxicity curve underlying the dosing decisions in the qTPI design is continuously updated using accumulating trial data. Numerical simulations investigating the operating characteristics of qTPI show that qTPI achieved better safety, accuracy and reliability compared to designs that rely on binary toxicity data. Furthermore, parameter elicitation in qTPI is simple and does not involve multiple hypothetical cohorts specification. Finally, a hypothetical soft tissue sarcoma trial with six toxicity types and grade 0 to grade 4 severity grades is illustrated with patient-by-patient dose allocation under the qTPI design.

Optimizing Histology-Specific Clinical Trials in Soft-Tissue Sarcoma—Are We There Yet?

Optimizing Histology-Specific Clinical Trials in Soft-Tissue Sarcoma—Are We There Yet?

Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials

BackgroundThe prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS).Patients and methodsThis retrospective analysis included all STS patients participating in early phase trials at Gustave Roussy and Léon Bérard between 1 January 2012 and 31 December 2020.ResultsOverall, 199 patients accounted for 214 inclusions in advanced STS. The most frequent histotypes were well-differentiated/dedifferentiated liposarcomas (n = 55), leiomyosarcomas (n = 53), synovial sarcomas (n = 22), undifferentiated pleomorphic sarcomas (n = 15), angiosarcomas (n = 12), and myxoid liposarcomas (n = 10). The median PFS was 2.8 months (95% confidence interval 2.7-4.1 months). The median PFS in the first, second, and later lines was 8.3, 5.4, and 2.6 months, respectively (P = 0.00015). The median PFS was 2.8 months in case of molecular screening, 4.1 months in case of histology-driven screening, and 1.6 months (P = 0.00014) in the absence of either screening modalities. In univariate analysis, histotype (P = 0.026), complex genomics (P = 0.008), number of prior lines (P < 0.001), prior anthracyclines (P < 0.001), number of metastatic sites (P = 0.003), liver metastasis (P < 0.001), lung metastasis (P < 0.001), absence of molecular or histology-driven screening (P < 0.001), first-in-human trials (P < 0.001), dose-escalation cohorts (P = 0.011), and Royal Marsden Hospital (RMH) score >1 (P < 0.001) were significantly associated with shorter PFS. In multivariate analysis, independent prognostic factors for shorter PFS were myxoid liposarcoma (P = 0.031), ≥2 prior lines of treatment (P = 0.033), liver metastasis (P = 0.007), and RMH score >2 (P = 0.006). Factors associated with improved PFS were leiomyosarcomas (P = 0.010), molecular screening (P = 0.025), and histology-driven screening (P = 0.010). The median overall survival rates were 36.3, 12.6, and 9.2 months in the first, second, and later lines, respectively (P = 0.0067). The grade 3-4 toxicity rate was 36%.ConclusionsEarly phase trials provide an active therapeutic option for STS, even in first-line settings. Molecular screening and histology-driven trials further improve the clinical benefit.

Response of Canine Soft Tissue Sarcoma to Stereotactic Body Radiotherapy.

Canine soft tissue sarcoma (STS) has served as a preclinical model for radiation, hyperthermia, experimental therapeutics, and tumor microenvironmental research for decades. Stereotactic body radiotherapy (SBRT) demonstrates promising results for the control of various tumors in human and veterinary medicine; however, there is limited clinical data for the management of STS with SBRT. In this retrospective study, we aimed to define overall efficacy and toxicity of SBRT for the treatment of macroscopic canine STS to establish this preclinical model for comparative oncology research. Fifty-two canine patients met inclusion criteria. Total radiation dose prescribed ranged from 20-50 Gy delivered in 1-5 fractions. Median progression-free survival time (PFST) was 173 days and overall survival time (OST) 228 days. Best overall response was evaluable in 46 patients, with 30.4% responding to treatment (complete response n = 3; partial response n = 11). For responders, OST significantly increased to 475 days vs. 201 days (P = 0.009). Prognostic factors identified by multivariable Cox regressions included size of tumor and metastasis at presentation. Dogs were 3× more likely to progress (P = 0.009) or 3.5× more likely to experience death (P = 0.003) at all times of follow up if they presented with metastatic disease. Similarly, every 100-cc increase in tumor volume resulted in a 5% increase in the risk of progression (P = 0.002) and death (P = 0.001) at all times of follow up. Overall, 30.8% of patients developed acute toxicities, 7.7% grade 3; 28.8% of patients developed late toxicities, 11.5% grade 3. Increased dose administered to the skin significantly affected toxicity development. SBRT serves as a viable treatment option to provide local tumor control for canine macroscopic STS, particularly those with early-stage disease and smaller tumors. The results of this study will help to define patient inclusion criteria and to set dose limits for preclinical canine STS trials involving SBRT.

ESMO Magnitude of Clinical Benefit Scale (MCBS): An evaluation of systemic treatment trials for soft tissue sarcomas (STS).

11553 Background: Patients with STS have poor prognosis in the metastatic setting. Although some treatment options are associated with improved outcomes, such as progression-free (PFS) or overall survival (OS), the overall magnitude of clinical benefit can be unclear. The ESMO MCBS is a validated and reproducible tool developed to quantify the clinical benefit of treatments evaluated in trials ( www.esmo.org/guidelines/esmo-mcbs ). Herein, we report the application of ESMO MCBS to systemic treatment trials involving metastatic STS patients. Methods: A systematic search of Medline, Embase and Cochrane databases for adult phase II and III trials in advanced STS (01/1998 to 12/2020) was carried out. Gastrointestinal stromal tumor trials were excluded. Outcomes, including but not limited to OS, PFS, objective response rate (ORR), toxicity and quality of life (QoL) data were extracted and analyzed. Studies with outcomes that met the criteria for ESMO MCBS v1.1 were evaluated to generate a score of 1 to 5 (score of ≥ 4: substantial benefit). MCBS scoring of each study was performed by at least 2 co-authors for consensus. Results: Among 3454 abstracts screened, a total of 140 Phase II and 28 phase IIII trials were identified. A total of 41 studies fulfilled the criteria for ESMO MCBS scoring. These include 5 phase III studies, as well as 9 randomized and 27 single-arm phase II trials. Fifteen studies involved specific histology, while remaining 26 studies were of all STS subtypes. Chemotherapy, alone or in combination was evaluated in 29 trials, while molecular-targeted agents (MTA) and immune checkpoint inhibitors (IO) were evaluated in 11 and 3 studies, respectively (Table). The median MCBS score was 2 (range 1-4), regardless of drug class or combination. Only 3 studies, all randomized in design, had a MCBS score of 4. All three trials were in the 2nd line setting or beyond, where there is no standard control treatment. None of the trials, irrespective of drug class had a score of 5 and no study showed evidence of significant improvement in QoL. The observed MCBS scores were low, partly because the trials evaluated mainly comprise single-arm studies without QoL assessments, restricting to a maximum MCBS score of 3. Conclusions: Most systemic therapy trials in advanced STS did not confer substantial clinical benefit when evaluated using MCBS. Although randomized phase 3 trials remain the gold standard of treatment evaluation, clinical benefit evaluation of STS trials using tools such as MCBS may be useful. Incorporation of QoL evaluation, even in single-arm studies should be prioritized in metastatic STS trials.[Table: see text]

Mini-Review on Targeted Treatment of Desmoplastic Small Round Cell Tumor.

Desmoplastic small round cell tumor (DSRCT) is a devastating disease which most commonly affects adolescents, with a male predominance. Despite the best multimodality treatment efforts, most patients will ultimately not survive more than 3–5 years after diagnosis. Some research trials in soft-tissue sarcoma and Ewing sarcoma include DSRCT patients but few studies have been tailored to the specific clinical needs and underlying cytogenetic abnormalities characterizing this disease such as the typical EWSR1-WT1 gene fusion. Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin growth factor (IGF)-1. Other biological pathways that are activated and expressed in DSRCT cells include endothelial growth factor receptor (EGFR), androgen receptor pathway, c-KIT, MET, and transforming growth factor (TGF) beta. Investigation of somatic mutations, copy number alterations (CNA), and chromosomes in DSRCT samples suggests that deregulation of mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) and DNA damage repair (DDR) may be important in DSRCT. This mini review looks at known druggable targets in DSRCT and existing clinical evidence for targeted treatments, particularly multityrosine kinase inhibitors such as pazopanib, imatinib, and sorafenib alone or in combination with other agents such as mTOR (mammalian target of rapamycin) inhibitors. The aim is to increase shared knowledge about current available treatments and identify gaps in research to further efforts toward clinical development of targeted agents.

XenoSarc: A comprehensive platform of patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) for early drug testing.

37 Background: STS is a family of rare, heterogeneous tumors with &gt; 70 subtypes. There is an urgent need for reliable preclinical models, especially for orphan subtypes of STS, given the limited treatment options. Methods: A panel of PDX models was established by s.c. implantation of fresh tumor specimens in athymic NMRI mice. Growing pieces of tumor were re-transplanted to next generations of mice. At each passage fragments were collected for histological/molecular characterization. A model was considered “established” after observing stable features for at least 2 passages. Ex-mouse tissue samples were stored, characterized by immunohistochemistry/flow cytometry and used for in vitro drug testing. Results: Between 2011-2019, 329 samples from 301 consenting patients were transplanted; 56 models are established, 16 additional models are in early passaging. Clinical information about donor and tumor (including sensitivity to standard and experimental agents) is available. The platform includes models of dedifferentiated lipo- (10 models), myxofibro- (8), leiomyo- (7), synovial (2), intimal (2), CIC-positive round cell (1), mesenchymal chondro- (1), extraskeletal osteo- (1), myxoid lipo- (1), myxoinflammatory fibroblastic (1), rhabdomyo- (2) and high-grade undifferentiated pleomorphic sarcoma (7), as well as GIST (8), MPNST (4) and epithelioid hemangioendothelioma (1). Models are well-characterized, with molecular information on copy number changes (low-coverage whole genome sequencing) and gene expression profile (RNA-Seq) available. We also constructed tissue microarrays from the xenografts which are used for target identification and model selection for preclinical studies. Xenografts are available for in vivo testing of novel agents, and results already served as a rationale for a number of prospective clinical trials. Conclusions: XenoSarc offers opportunities for studying the biology of a variety of sarcoma subtypes including ultra-rare entities and is a valuable tool for early drug screening in preparation of clinical STS trials. The platform is well maintained and continuously expanded, and available to collaborators from academia and industry.

1691P - Access to clinical trials for soft tissue sarcoma patients in Western and Eastern Europe

BackgroundSoft tissue sarcomas are a rare subgroup in adults and children with oncological diseases. Since the 1970s, after the introduction of doxorubicin as a chemotherapeutic agent for the treatment of soft tissue sarcoma, the treatment of metastatic and primary localized sarcoma has remained weak, although several new therapeutic agents have been identified in this time. Participating in clinical trials can help solve this problem in general and particularly in countries with a low level of access to innovative medicines. We performed qualitative and quantitative comparative analysis of clinical trials for soft tissue sarcoma patients in Western and Eastern Europe. MethodsBased on data from https://clinicaltrials.gov/ we searched for clinical trials that have been performed in 2009-2019 in 30 European countries (10 in Western and 20 in Eastern countries). Clinical trials by phases, type of therapy, soft tissue sarcoma type, stage of disease and status were studied. ResultsThe vast majority of soft tissue sarcoma trials have been performed in Western Europe (401/467) and of those 212/52.9% of were phase II; average number of trials per country was 40, ranging from 30 (Switzerland) to 92 (France). In Eastern Europe the average number of trials per country was 3 with a maximum of 23 (Poland); 45.5% of trials were phase III. Clinical trials in adults (> 18 years) in Eastern Europe and Western Europe (78.8% vs 75.3%), in patients younger than 18 years (21.2% vs 24.7%), respectively. For soft tissue sarcoma stages I-II, III, (unresectable)/IV 1.0, 17.5 and 81.5% trials, respectively, have been held in Western Europe, 0, 18.2 and 81.8% trials in Eastern Europe. The most frequent clinical trials studies of targeted therapy, chemotherapy and combination treatment, constituting 35.9%, 20.4% and 17.2% trials in Western Europe and in 18.2%, 27.3% and 16.7% trials in Eastern Europe, respectively. Only 14.1% of trials are currently recruiting patients in Eastern Europe while 85.9% of recruitment is in Western Europe. ConclusionsAccess to clinical trials for soft tissue sarcoma patients in Western and Eastern Europe is quite different. Participation in clinical trials could help as patients from countries with low access to innovative medicines or oncologists could get necessary experience. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

A phase I/II study of pembrolizumab (Pem) and doxorubicin (Dox) in treating patients with metastatic/unresectable sarcoma.

11009 Background: Patients with advanced soft tissue sarcomas (STS) treated with single agent Dox have a median progression-free survival (PFS) of 4.6 months (mo) and response rate (RR) of 14%. Dox sensitizes tumors to Pem through calreticulin release and killing of immunosuppressive cells. Thus we hypothesize that combining Dox + Pem will improve patient outcomes. Methods: A phase I/II trial (NCT02888665) evaluating Dox+Pem was designed for Dox naïve STS and select bone sarcomas with a 1° endpoints of safety (CTCAE v4.03) and response rate (RR) by RECIST 1.1. Patients received one “priming” dose of Pem (200mg IV) prior to starting Dox+Pem Q3wks. Dox+Pem was continued for up to 6 cycles, followed by Pem monotherapy for up to 2 years or progression. The phase I portion used a 3+3 design with 2 Dox doses (45 &amp; 75 mg/m2), followed by a Simon 2-stage expansion. A retrospective study of patients treated at our center on non-ifosfamide containing Dox trials (DoxT) was performed in order to compare our observed PFS with a comparable historic population. Results: Treatment was well tolerated; detailed safety data will be presented. No additional cardiac risk was observed. No DLTs were observed during phase I and 75mg/m2 was selected as the phase 2 Dox dose. The study met criteria for expansion to the 2nd stage. Though the planned enrollment was 41, the study closed after 37 as it was clear that the RR (22% , including phase I patients) would not meet the phase 2 RR target of 29%. However, 59% of patients had stable disease (disease control rate = 81%) with tumor regression in a majority of patients. The median PFS on Dox + Pem was 8.1 mo (95% CI: 6.3, 10.8). Patients treated with Dox + Pem had a significantly longer median PFS compared to the DoxT cohort (4.1 mo, 95%CI 3.0 – 6.6, p &lt; 0.001). Conclusions: Dox+Pem is well-tolerated. While this study failed to meet its 1° RR endpoint, a highly significant improvement in PFS was observed compared with historical controls. This is consistent with findings in other cancers, such as head &amp; neck, where improved clinical outcomes were observed without significant increase in RR by RECIST. A randomized trial of Dox +/- Pem should be carefully considered in light of recent negative trials in STS. Clinical trial information: NCT02888665.

Exposure\u2013response relationship of olaratumab for survival outcomes and safety when combined with doxorubicin in patients with soft tissue sarcoma

PurposeOlaratumab is a recombinant human IgG1 monoclonal antibody against PGDFRα. Olaratumab plus doxorubicin improved survivalversus doxorubicin in an open-label, randomised phase 2 soft tissue sarcoma (STS) trial. We characterised the olaratumab exposure–response relationship for progression-free survival (PFS), overall survival (OS), and safety.MethodsPFS and OS data from the 133 patients enrolled in the phase 2 study were analysed using time-to-event modelling. The effect of olaratumab on PFS/OS was explored using the trough serum concentration after cycle 1 (Cmin1) and the average concentration throughout treatment (Cavg). The rate of treatment-emergent adverse events (TEAEs) was compared across olaratumab exposure quartiles.ResultsPFS and OS were described by models with an exponential hazard function and inhibitory EMAX functions to describe the effect of olaratumab, regardless of the PK endpoint. The olaratumab EC50s for PFS (ECmin150 = 82.0 µg/mL, ECavg50 = 179 µg/mL) and OS (ECmin150 = 66.1 µg/mL, ECavg50 = 134 µg/mL) corresponded to the median and 25th percentile of Cmin1/Cavg in the study, respectively. Maximum predicted improvement in the hazard ratio for OS and PFS was approximately 75% and 60%, respectively. There was no change in the rate of TEAEs with increasing olaratumab serum levels.ConclusionsPFS/OS benefits occurred without a rate change in TEAEs across quartiles. Maximum benefit in OS was achieved in the upper three quartiles and a potential of early disease progression in the lower quartile of olaratumab serum exposure. These results prompted a loading dose strategy in the ongoing phase 3 STS trial.

Outcomes of Elderly Patients with Advanced Soft Tissue Sarcoma Treated with First-Line Chemotherapy: A Pooled Analysis of 12 EORTC Soft Tissue and Bone Sarcoma Group Trials.

Almost half of patients diagnosed with soft tissue sarcoma (STS) are older than 65 years; however, the outcomes of elderly patients with metastatic disease are not well described. An elderly cohort of patients aged ≥65 years was extracted from the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group database of patients treated with first-line chemotherapy for advanced STS within 12 EORTC clinical trials. Endpoints were overall survival (OS), progression-free survival (PFS), and response rate (RR). Of 2,810 participants in EORTC trials, there were 348 elderly patients (12.4%, median 68 years; interquartile range [IQR], 67-70; maximum 84 years) and 2,462 patients aged <65 years (median 49 years; IQR, 39-57). Most elderly patients had a performance status of 0 (n = 134; 39%) or 1 (n = 177; 51%). Leiomyosarcoma (n = 130; 37%) was the most common histological subtype. Lung metastases were present in 181 patients (52%) and liver metastases in 63 patients (18%). Overall, 126 patients (36%) received doxorubicin, 114 patients (33%) doxorubicin + ifosfamide, 43 patients (12%) epirubicin, 39 patients (11%) trabectedin, and 26 patients (7%) ifosfamide. Overall RR was 14.9% (n = 52), median PFS was 3.5 months (95% confidence interval [CI], 2.7-4.3), and median OS was 10.8 months (95% CI, 9.43-11.83). In patients aged <65 years, overall RR was 20.3% (n = 501), median OS was 12.3 months (95% CI, 11.9-12.9), and median PFS was 4.3 months (95% CI, 3.9-4.6). Elderly patients with metastatic STS treated with first-line chemotherapy were largely underrepresented in these EORTC STS trials. Their outcomes were only slightly worse than those of younger patients. Novel trials with broader eligibility criteria are needed for elderly patients. These trials should incorporate geriatric assessments and measurements of age-adjusted health-related quality of life. This analysis demonstrates that elderly patients with advanced soft tissue sarcoma are underrepresented in clinical trials of first-line chemotherapy by the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Furthermore, the elderly participants were generally of excellent performance status, which is not representative of an unselected elderly population. These data provide rationale for development of novel trials for elderly patients that are not only for "elite" patients but include comprehensive geriatric assessments for risk stratification. Because chemotherapy for advanced soft tissue sarcomas is largely given with palliative intent, incorporation of health-related quality of life measures with traditional endpoints will provide a more holistic approach to future clinical trials.

Aldoxorubicin: a tumor-targeted doxorubicin conjugate for relapsed or refractory soft tissue sarcomas.

Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS). The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. Aldoxorubicin is a prodrug of doxorubicin that binds to serum albumin immediately after administration through an acid-sensitive hydrazone linker and is subsequently transported to tumor tissues where the acidic environment cleaves the linker and facilitates delivery of a tumor-targeted drug payload. In clinical studies to date, there has been evidence of efficacy and mitigated cardiac toxicity. In this review, we comprehensively detail the clinical development of aldoxorubicin in STS to date. Specifically, we highlight available data on the pharmacokinetics and efficacy from Phase I, Phase II, and Phase III trials in advanced or metastatic STS. We conclude with considerations for future directions of investigation for this promising antitumor agent.

Simultaneous monitoring of pazopanib and its metabolites by UPLC–MS/MS

Pazopanib is a multi-targeted tyrosine kinase inhibitor (TKI) approved as first-line treatment for patients with advanced renal cell carcinoma (RCC) and as second-line treatment for patients with advanced soft tissue sarcoma (STS) previously treated with chemotherapy. The most common adverse events, observed during the RCC and STS trials, were gastrointestinal disorders, hypertension, fatigue, elevated ALAT and ASAT, but the molecular mechanisms explaining pazopanib toxicity remain unclear. Therapeutic activity is considered to be mainly dependent on pazopanib exposure as the primary metabolites are inactive or display low plasma concentrations, but metabolites may be involved in toxicity as relationships between metabolite profiles and toxicity have not been evaluated.We report here, for the first time, the validation of a method for the simultaneous quantification of pazopanib and semi-quantification of its metabolites (relative determination). As there are no standards available, pazopanib metabolites were generated with human liver microsomes (HLM) to provide controls in the development of an UPLC–MS/MS method for monitoring both pazopanib and metabolites. The optimised method was validated for specificity, linearity, sensitivity, precision, accuracy, matrix effect and stability. The coefficient of variation (CV%) for intra-day and inter-day precision varied from 2.1% to 7.9% and 5.6% to 13.1% respectively. The biases varied from −12% to 2.3% (intra-day) and 3.8% to 13.1% (inter-day) for accuracy evaluation. Intra-day and inter-day precision CV were respectively 20.1% and 19.6% and accuracy biases were between 20.7% (intra-day) and 3.8% (inter-day) at the limit of quantification. The recoveries from matrix samples spiked with pazopanib were respectively 102.6 ± 12.9% and 102.5 ± 1.2% at low and high levels of calibration range. No matrix effect was evidenced as demonstrated by the normalised matrix factor values: 1.3 ± 0.1 and 1.2 ± 0.2 respectively measured at low and high part of calibration range. A good stability of pazopanib was observed during short term, long term and in process storage conditions and after three freeze/thaw cycles.The method was applied to clinical samples from three patients treated with pazopanib to establish the metabolite profiles (semi-quantitative data) during treatment. The assessment of metabolite profiles could be useful to improve our understanding of the occurrence of adverse events and to improve pazopanib pharmacokinetic-pharmacodynamic relationships.

The fate of new fosfamides in phase III studies in advanced soft tissue sarcoma

For decades, doxorubicin alone or in combination with ifosfamide has been used in advanced soft tissue sarcoma (STS). In 2014, a comparison of doxorubicin alone versus the combination with ifosfamide (in the randomised phase III EORTC 62012) showed no difference in overall survival (OS), but a difference in response and progression-free survival (PFS) were observed in favour of the combination but at the expense of increased toxicity. Newer fosfamides, with slightly different modes of action, and potentially less toxicity, namely evofosfamide and palifosfamide have recently been tested in randomised phase III clinical trials in STS. The TH CR-406/SARC021 (June 2017) and the PICASSO III (September 2016) studies compared doxorubicin, as the standard arm, to doxorubicin in combination with evofosfamide and palifosfamide, respectively. In both studies, the combination arm produced increased response rates but at the expense of higher toxicity. However, there was no difference in OS or PFS in favour of the combination. Importantly, the median OS of patients receiving standard of care, doxorubicin, in both studies appeared improved from 12.8 months (95.5% CI 10.5–14·III) in the EORTC 62012 to 16.9 months (95% CI 14.8 to 22.9) in PICASSO III and 19.0 months (95% CI 16.2–22.4) in TH CR-406/SARC021. The results of these three randomised phase III studies highlight several critical issues related to the design and conduct of such trials in STS. We discuss these issues aiming to contribute to the ongoing debate about the optimal approach to perform clinical research in STS.

Abstract 5029: Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial

Abstract Introduction The treatment of locally advanced or metastatic soft tissue sarcoma remains a significant clinical challenge, with overall survival rates of approximately 12 months observed with current first line palliative chemotherapy. A recently completed randomised phase III clinical trial entitled GeDDiS (ISRCTN07742377), was designed to compare first line treatment with gemcitabine in combination with docetaxel (GemDoc) versus current standard treatment with doxorubicin. A pharmacogenetic sub-study was incorporated into the trial to assess potential impact of single nucleotide polymorphisms (SNPs) in genes associated with the pharmacology of the three drugs. Methods A total of 240 patients were recruited to the sub-study with 119 on the doxorubicin arm and 121 on the GemDoc arm. A 4 ml blood sample was taken from each participant and genomic DNA extracted. Individual candidate SNPs were assessed by Taqman PCR in 7 genes associated with doxorubicin pharmacology, 7 genes associated with gemcitabine and 5 genes associated with the pharmacology of docetaxel. Association between the SNPs and efficacy and toxicity was assessed. Results SNPs within the solute transporter SLC22A16, associated with the intracellular influx of doxorubicin, were associated with worse PFS (HR = 1.72, p=0.04) and decreased frequency of grade 3/4 adverse events (71% vs 48%, p=0.04) in the doxorubicin arm of the study but not in the GemDoc arm. Conclusions The association of genetic variants of SLC22A16 with decreased efficacy and decreased incidence of toxicity is consistent with a loss of function in the transporter and previous observation of increased AUC in pharmacokinetic studies assuming that distribution of the drug into target and collateral tissues is restricted. Citation Format: David Jamieson, Beatrice Seddon, Katja Kuever, Hakim-Moulay Dehbi, Sandra Strauss, Sandy Beare, Gareth Veal. Pharmacogenetics of doxorubicin, gemcitabine and docetaxel in the GeDDiS soft tissue sarcoma trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5029. doi:10.1158/1538-7445.AM2017-5029

Absence of progression, not extent of tumour shrinkage, defines prognosis in soft-tissue sarcoma – An analysis of the EORTC 62012 study of the EORTC STBSG

BackgroundAnthracycline-based chemotherapy remains the mainstay of first-line treatment in metastatic or advanced soft-tissue sarcoma (STS). Age, performance status, tumour histology and tumour grade are recognised prognostic factors; however, the prognostic value of tumour response and tumour shrinkage is ill-defined. MethodsPatients recruited to the European Organisation for Research and Treatment of Cancer 62012 trial with advanced intermediate or high-grade STS, who received at least one cycle of chemotherapy and one tumour assessment of response, were eligible for this study. Kaplan–Meier estimates of overall survival (OS) by tumour response were computed using a landmark approach after two, four, and six cycles of chemotherapy. The prognostic role of the kinetics of tumour response was analysed by Cox proportional hazards. ResultsThree hundred eighty-nine patients were included in this study. Compared to stable or responding patients, patients with progressive disease (PD) after two, four and six cycles of chemotherapy achieved a worse OS: hazard ratio [HR] 2.62 (95% confidence interval [CI] 1.72–4.00), p < 0.001; HR 2.23 (95% CI 1.4–3.56), p = 0.0001; and HR 3.16 (95% CI 1.96–5.08), p = 0.0001, respectively. However, patients with stable or responding disease achieved similar OS outcomes. Correspondingly, patients with an increase in tumour size by 10% or more correlated with a worse OS in Cox proportional hazard analysis. ConclusionsNo association between prognosis and amount of tumour shrinkage was detected. Interestingly, an increase in tumour size by at least 10% correlated with a worse OS, but re-defining PD as a ≥10% increase in tumour size did not translate into a better discrimination of survival outcomes for responders versus stable disease. Disease control rather than tumour response is a valuable end-point in advanced or metastatic STS receiving palliative anthracycline-based chemotherapy, supporting the use of time-to-event end-points in future STS trials.

Evolution of Randomized Trials in Advanced/Metastatic Soft Tissue Sarcoma: End Point Selection, Surrogacy, and Quality of Reporting.

Randomized controlled trials (RCTs) in soft tissue sarcoma (STS) have used varying end points. The surrogacy of intermediate end points, such as progression-free survival (PFS), response rate (RR), and 3-month and 6-month PFS (3moPFS and 6moPFS) with overall survival (OS), remains unknown. The quality of efficacy and toxicity reporting in these studies is also uncertain. A systematic review of systemic therapy RCTs in STS was performed. Surrogacy between intermediate end points and OS was explored using weighted linear regression for the hazard ratio for OS with the hazard ratio for PFS or the odds ratio for RR, 3moPFS, and 6moPFS. The quality of reporting for efficacy and toxicity was also evaluated. Fifty-two RCTs published between 1974 and 2014, comprising 9,762 patients, met the inclusion criteria. There were significant correlations between PFS and OS (R = 0.61) and between RR and OS (R = 0.51). Conversely, there were nonsignificant correlations between 3moPFS and 6moPFS with OS. A reduction in the use of RR as the primary end point was observed over time, favoring time-based events (P for trend = .02). In 14% of RCTs, the primary end point was not met, but the study was reported as being positive. Toxicity was comprehensively reported in 47% of RCTs, whereas 14% inadequately reported toxicity. In advanced STS, PFS and RR seem to be appropriate surrogates for OS. There is poor correlation between OS and both 3moPFS and 6moPFS. As such, caution is urged with the use of these as primary end points in randomized STS trials. The quality of toxicity reporting and interpretation of results is suboptimal.

Forty years of randomized trials in advanced/metastatic soft tissue sarcoma (STS): Endpoint selection, surrogacy and quality of reporting.

10513 Background: Randomized controlled trials (RCTs) in STS have utilized varying endpoints. Surrogacy of intermediate endpoints such as progression-free survival (PFS), response rate (RR), 3 mont...