Below are summaries of three clinical studies and one preclinical study on Alveolar Soft Part Sarcoma as were presented at the 2017 annual meeting of the “Connective Tissue Oncology Society” (CTOS) in November 8-11.
Please click the titles of each one of the 3 clinical studies to read more information on the “clinical Trials.gov” website.
Ian Judson et al.,
Royal Marsden Hospital, London, United Kingdom
Objective: ASPS is rare (0.5-1% of soft tissue sarcomas), mainly affects young people and is unresponsive to conventional chemotherapy. Cediranib (C), a tyrosine kinase inhibitor (TKI), including vascular endothelial growth factor receptors, has shown significant activity in ASPS in single arm phase II trials. CASPS was designed to discriminate between the impact of C and the intrinsically indolent nature of ASPS.
Methods: CASPS compared C (30mg od) with placebo (P) in a 2:1 double blind randomization in pts age ≥16yrs with metastatic ASPS progressive in the previous 6 mths. Pts were unblinded at wk 24 or progression if sooner when those on P crossed over to C. The primary endpoint of % change in the sum of target marker lesions (TMLsum) between baseline and wk 24 or progression if sooner was compared between groups by Mann-Whitney test. Secondary endpoints were progression-free survival (PFS), wk 24 response rate (RR) and best response (RECIST v1.1), safety/tolerability, overall survival (OS). One-sided p-values and two-sided 90% condense intervals are reported.
Results: 48 pts were recruited between 07/2011 and 07/2016 from 12 sites (UK, Australia & Spain). 52% pts were female, median age 31. Most common grade ≥3 AEs on C were hypertension (19.4%), raised gamma GT (6.5%), diarrhoea (6.5%), asthenia (3.2%) and fatigue (3.2%), which were manageable by dose reduction. In the evaluable population (N=44) median change in TMLsum on C was −8.3% (IQR −26.5% to +5.9%) vs P: +13.4% (IQR −0.6% to +23.1%), one-sided p=0.0010. Best response by wk24 was partial response (PR) in 6/28 (21%) pts on C vs 0/16 on P (one-sided p=0.053), giving a RR of 21%. At wk24 3 pts were still in PR and 14 had stable disease, giving a 6 mth clinical benefit rate (CBR) of 61%. At the time of analysis 3 pts remained in PR with median response duration of 26+mths. The HR for PFS (C vs P) was 0.58 (90%CI 0.33-1.03, one-sided p=0.059), median PFS was 10.8 mths on C vs 3.7 mths on P. The HR for OS was 0.66 (95%CI 0.25-1.75) p=0.41. OS at 12mths was C: 94%; P: 66%, in spite of crossover. 12 C pts had received a prior TKI; this had no major impact on PFS.
Conclusion: CASPS confirms the activity of C in ASPS shown in previous trials. CASPS met its primary endpoint of a significant change in TMLsum at week 24 for C compared with P. There was a 7-month improvement in median PFS. Tumor tissue and serial blood samples will be analyzed for predictive and prognostic biomarkers.
Breelyn A. Wilky et al.,
University of Miami Miller School of Medicine, Miami, FL, USA
Objective: Inhibition of programmed-death 1 (PD1) by pembrolizumab (P) monotherapy produced overall response rates (ORR) of 19% in SARC028, a Phase II study in advanced soft tissue sarcomas (STS). Vascular endothelial growth factor (VEGF) promotes accumulation of suppressive immune cell phenotypes and cytokines. Combinations of anti-VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI) with checkpoint inhibitors increased immune cell infiltration and showed promising anti-tumor activity in other solid cancers. Axitinib (Ax) is a pan-VEGFR TKI with favorable progression-free survival (PFS) reported in Axi-STS, with acceptable toxicity in combination with P in renal cell carcinoma. We report initial toxicity and efficacy results of combination Ax plus P for patients (pts) with advanced STS.
Methods: We designed an open-label single institution Phase II trial of Ax plus P in 30 pts with advanced or metastatic STS, requiring radiographically progressing disease, adequate end-organ function and performance status. Pts received Ax at 5 mg PO twice daily with intra- patient dose escalation according to predefined toxicity thresholds, and concurrent P 200mg IV q21 days. Primarily endpoint was progression-free rate at 3 months (PFR), with secondary endpoints of toxicity, ORR, PFS, and overall survival. All patients underwent mandatory tumor biopsies and peripheral blood sampling for correlative immunoprofiling at baseline, 12 weeks and at progression.
Results: 28 of 30 pts have accrued to date. Enrolled sub- types: ASPS (29%), UPS (18%), LMS (21%), and other (29%). 3-month PFR by RECIST 1.1 for 18 evaluable pts was 56%, and 4 pts (22%) achieved partial response (PR). Responders include 3/3 (100%) currently evaluable ASPS pts (median tumor size decrease of 70%), and 1 pt with non-uterine LMS (tumor size decrease 55%). Clinical benefit was observed in 3 pts with RECIST progression at 3 months, suggesting a need for alternative response criteria such as Choi criteria. Ax plus P was overall well-tolerated, with P-related grade 3/4 toxicities in 3 pts (autoimmune hepatitis, arthritis and hyperglycemia), and Ax-related grade 3/4 toxicities in 2 pts (hypertriglyceridemia, spontaneous pneumothorax).
Updated response and toxicity data will be presented. Correlative immuno- profiling is ongoing.
Conclusion: Combination Ax plus P is feasible and well-tolerated, and shows early evidence of activity, particularly in ASPS pts. Clinical trial information: NCT02301039.
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Alice Chen et al.,
National Cancer Institute, Bethesda, MD, USA
Objective: Soft tissue sarcomas (STS) are a rare group of tumors (~1 % of adult cancers) arising mainly from embryonic mesoderm. Increased expression of VEGF and MET has been reported both in sarcoma cell lines and patients (pts) with STS. Cabozantinib, a multi-kinase inhibitor of MET, VEGFR2, AXL, RET, ROS1 is approved for treatment of renal cell carcinoma and medullary thyroid cancer. Dual targeting of VEGF and MET pathways with cabozantinib is hypothesized to result in clinical benefit for pts with STS. We are conducting a 2-stage, open-label, phase II trial of cabozantinib monotherapy (NCT 01755195) evaluating a dual-endpoint of response rate (CR+PR) of 30% vs. 10%, and a 6-month PFS rate of 65% vs 45% in pts with STS. Secondary objectives include measuring circulating levels of HGF, VEGF-A, soluble VEGFR2 (sVEGFR2), and soluble MET (sMET) pre- and post-treatment, which will be collected in the second stage pts.
Methods: Cabozantinib is administered orally at 60 mg po qd for 28d cycles. Eligibility criteria includes pts ≥18 years; ECOG PS ≤ 1, adequate organ functions. No cavitating mass or vessel-encasing lesions are permitted. Antitumor responses are determined using RECIST 1.1 criteria.
Results: The study has accrued 27 pts at NCI (Alveolar soft part sarcoma (ASPS) (6), leiomyosarcoma (5), clear cell sarcoma (3), liposarcoma (2), synovial sarcoma (2) and one each of embryonal sarcoma, MPNST, myxoid chondrosarcoma (MC), myoepithelioma, myxoid cell sarcoma, GIST). At time of analysis, 5 pts remain on study. Time on study 7-47 months. Four pts have confirmed PRs (2 ASPS, 1 liposarcoma, 1 MC); time to PR was 4 – 22 months and response duration averaged 39 months. Twelve pts have SD for six months. Median PFS was 9.6 months. Drug related grade 3/4 adverse events include 5 HTN (21%), 3 neutropenia (13%), 2 abdominal pain (8%), 2 lipase elevation (8%), 2 thromboembolic events (8%), and one each (4%) of left ventricular dysfunction, alkaline phosphatase elevation, enterocolitis, fatigue, mu- cositis, nausea, hand-foot syndrome, transaminitis. 8 pts required dose reductions, including 2 reductions in 3 pts.
Conclusion: This is the first phase II study of cabozantinib in STS. Having met our first stage response objective, we are accruing at multi-sites with plans to assess a total of 50 patients.
- AUTOPHAGY IN ALVEOLAR SOFT PART SARCOMA CONFERS MECHANISMS OF RESISTANCE TO CHEMOTHERAPY
Jared J. Barrott & Kevin B. Jones,
University of Utah, Salt Lake City, UT, USA
Objective: Altered metabolism is considered to be one of the new hallmarks of cancer. Autophagy is one major avenue of altered cancer metabolism, enabling cell survival under metabolic stress and promoting chemoresistance. The nuclear localization of MiTF/TFE3 family transcription factors has associated with upregulated transcription of autophagy genes in pancreatic cancer. Alveolar soft part sarcoma is a rare but deadly soft-tissue sarcoma, with a predilection for adolescent and young adult victims. Alveolar soft part sarcoma is noteworthy for its resistance to traditional cytotoxic chemotherapies. It consistently associates with a t(X;17) chromosomal translocation that produces the ASPSCR1-TFE3 target gene, bearing the DNA-binding domain from TFE3 and protein interaction domains from ASPSCR1. We have demonstrated that conditional expression of ASPSCR1-TFE3 is sufficient to drive alveolar soft part sarcomagenesis in the mouse with complete penetrance. Mouse tumors recapitulate human alveolar soft part sarcoma histology and transcriptomes faithfully. While the direct targets of ASPSCR1-TFE3 have been studied in a renal cell carcinoma cell line, they have not been studied in alveolar soft part sarcoma. Our objective was to identify the direct targets of ASPSCR1-TFE3 and how these targets confer resistance to doxorubicin.
Methods: The human cell lines expressing ASP-SCR1-TFE3, ASPS-1 and FUUR-1, as well as mouse tumors driven by expression of ASPSCR1-TFE3 were subjected to nuclear fractionation and chromatin immunoprecipitation using antibodies against ASPSCR1 and RNAPol2. Cells and tumors were further characterized for their presence of auotphagic flux by detection of LC3-II and abundance of lysosomal proteins LAMP1 and CTSD. Cell lines were treated with combination therapy using the autophagy inhibitor, chloroquine, and doxorubicin and compared to monotherapy and controls. Viability was assessed as well as changes in mitochondria, ROS production, and apoptosis. Furthermore, cells were analyzed by gas-chromatography mass spectrometry (GC-MS) for metabolites involved in cellular respiration and glycolysis. Lastly, mice were treated with either control, monotherapy of chloroquine (15 mg/kg) or doxorubicin (10 mg/kg), or combination therapy for up to 5 months. Mice on combination therapy showed a statistical improvement in survival of 3 months over control and doxorubicin treatments.
Results: We report not only the first genome-wide localization of the ASPSCR1-TFE3 oncoprotein on chromatin from alveolar soft part sarcoma cell lines and mouse tumors, but also its association with actively transcribed genes. Among these are found many genes related to autophagy, especially those related specifically to the nutrient responsive pathways that drive autophagy. We demonstrate high expression of autophagy-related lysosomes and proteins at baseline conditions in human tumors and cell lines and mouse tumors. We also demonstrate active autophagic flux even in the absence of stress conditions. Inhibition of autophagy has no apparent impact on survival of alveolar soft part sarcoma cells alone, but profoundly impacts their protein degradation pathways and the availability of amino acids for protein assembly in stress. Inhibition of autophagy strongly synergizes with chemotherapy to kill alveolar soft part sarcoma cells, suggesting it was a source mechanism for resistance. Furthermore, mice treated with combination therapy of autophagy inhibition and chemotherapy significantly extends life 3 months beyond control and single agents alone.
Conclusion: We have therefore demonstrated the direct targets of ASPSCR1-TFE3 in alveolar soft part sarcomas, including a number of autophagy genes that are expressed in these tumors, independently from nutrient deprivation or stress, rendering cells particularly resistant to many therapy-induced stresses. Inhibition of autophagy in alveolar soft part sarcoma causes the tumor cells to be more susceptible to chemotherapeutic stress.
_____________________________________________________
Yosef Landesman, Ph.D.
President & Cancer Research Director
Cure Alveolar Soft Part Sarcoma International (iCureASPS)
e-mail: landesmany@yahoo.com