A phase II trial of sitravatinib, a multireceptor tyrosine kinase inhibitor, in patients with advanced well-differentiated/dedifferentiated liposarcoma.
Authors: Oza Jay , Doshi Sahil , Lee Shing Mirn , Van Tine Brian Andrew , Choy Edwin , Oppelt Peter John , Singh-Kandah Shahnaz V. , Hernandez Susana , Singer Zoe , Balaji Swathi , Franks Lauren , Ingham Matthew , Schwartz Gary K. 
Published: June 2021

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Background: Well-differentiated/dedifferentiated liposarcoma (WD/DD LPS), a sarcoma of adipocytic origin, lacks effective treatment options for advanced disease. Pazopanib, a receptor tyrosine kinase (RTK) inhibitor active upon angiogenic RTKs, is approved for non-adipocytic sarcomas but failed to show activity in LPS. In a phase 2 study, pazopanib provided a progression-free rate at 12 weeks of 26% in LPS. Our preclinical work implicated IGF1R, MET, and PDGFRα/ß in liposarcomagenesis. Sitravatinib (S) is a novel, orally available, potent, small molecule RTK inhibitor active upon these and related targets. In preclinical WD/DD LPS models, S demonstrated significant activity in vitro and in vivo and appeared superior in efficacy to pazopanib, imatinib and crizotinib. Methods: We performed a phase II, single-arm, multi-center, Simon 2-stage study to evaluate S in adult pts with unresectable/metastatic WD/DD LPS who had received ≥ 1 prior line of systemic therapy and had evidence of disease progression ≤ 12 wks prior to enrollment. Pts received S 120 mg PO daily in continuous 21-day cycles. Primary endpoint was the progression-free rate at 12 wks (PFR12). Secondary endpoints were objective response rate (ORR), progression free survival (PFS) and safety/tolerability. Based upon historical controls, PFR12 ≤ 20% was considered inactive whereas PFR12 ≥ 40% was considered promising. If ≥ 3/13 met PFR12 in stage 1, the study proceeded to full accrual. If ≥ 9/29 met PFR12 overall, S was considered promising. Design provided 85% power with α= 0.10. A subset of pts underwent paired biopsies. Results: 29 pts initiated treatment and are evaluable. Median age was 62 yrs (range: 28-88). 16 (55%) were male. 28/29 had DD LPS. 3 pts remain on treatment and 26 pts have discontinued (22 for disease progression, 2 for adverse events). In the first stage, 5/13 pts met the PFR12 endpoint; therefore, the study proceeded to full accrual. Overall, 12/29 pts (41%) were progression-free at 12 weeks and the study met the primary endpoint. ORR by RECIST was 3.4%. Median PFS was 11.7 weeks (95% CI: 5.9 - 35.9 wks). 12/29 (41%) of pts experienced grade 3 treatment-related adverse events. Common S-related grade 3 AEs were hypertension (24%), fatigue (7%) and hyponatremia (7%). There were 2 grade 4 events (hypertension, reversible posterior leukoencephalopathy syndrome). Hypertension was easily managed with medication. A subset of pts underwent paired tumor biopsies that will be analyzed using next generation sequencing and reverse phase protein array. Conclusions: S met the predefined efficacy endpoint with 12/29 pts (41%) progression-free at 12 weeks, indicating clinically meaningful activity potentially superior to pazopanib. The drug was well tolerated. Further study of S in WD/DD LPS is warranted. Clinical trial information: NCT02978859.