Aggregation in the frozen state when stored above the glass transition temperature is a consequence of balance between rate of crystallization leading to loss of cryoprotectant, rate of aggregation of the unfolded protein molecules, and rate of refolding that prevents aggregation.
Although cytotoxic chemotherapy remains the standard treatment for recurrent/progressive endometrial cancer, clinical benefit is short-lived and toxicity significant. Despite the high frequency of genomic aberrations characterizing endometrial cancer, the development of molecularly targeted agents has been challenged by an incomplete understanding of molecular predictors of response. This single arm study demonstrates an encouraging signal of activity for cabozantinib across different histologic and molecular subtypes of endometrial cancer. The observation of increased frequency of responses in patients with tumors harboring CTNNB1 mutation or concurrent KRAS and PTEN/PIK3CA mutations, is hypothesis-generating for future studies. The results reported here not only provide support for the further evaluation of cabozantinib in endometrial cancer, but also justify the critical need for endometrial cancer drug studies to be inclusive, enrolling broad, molecularly-characterized, patient populations to facilitate insights into the heterogeneity of clinical benefit, and factors predictive of resistance and response.
5524 Background: Recurrent/metastatic EC has a poor prognosis with no standard 2ndline therapy. Cabo is a multi-targeted kinase inhibitor of MET, VEGFR, TIE2, AXL & KIT, relevant in epithelial-stromal cross-talk. The role of MET/HGF in aggressive EC biology, where transient benefit of VEGF-targeting is due to MET/HGF, TIE2 & AXL, provides rationale for MET targeting in EC. Methods: PHL86 (NCI#9322/NCT01935934) is a multi-centre, phase II trial of cabo (60mg oral daily dose) in pts with EC recurring within a year of adjuvant chemotherapy (ctx), or with progression after 1 line of ctx for metastatic disease. Experimental (E) cohort was stratified by histology (serous (SER) vs endometroid (END)) in a Simon two-stage design for co-primary endpoints of response rate ( > 30%) & 12-week progression-free-survival (PFS) ( > 55%). Activity was defined as > 7 partial responses (PRs) or > 15 instances of 12 wk-PFS in 36 pts. Pts with rare histology EC were treated in a parallel exploratory (Ex) cohort. Results: From May 2013 to Nov 2016, 102 pts (E: 71; Ex: 31) have been treated with cabo after prior radiation (59) and/or ctx (no. lines: 1(77); 2(22)). Cabo was well tolerated with common toxicities of fatigue, nausea, diarrhea & hand-foot syndrome. Most frequent Grade 3/4 toxicity was hypertension (32/101 pts). Fistula/perforation occurred in 4 of 71 SER/END pts & 4 of 31 Ex pts; no risk factors were identified. In 33 END pts, 6 PRs & 24 instances of > 12-wk PFS were observed; median PFS is 4.8 mths (95% CI: 4.4 – 6.4) with estimated 6-mth PFS of 43% (95% CI: 27 to 59%). In 34 SER pts, 4 PRs & 20 instances of > 12-wk PFS were observed; median PFS is 4.0 mths (95% CI: 2.7 – 4.7) with estimated 6-mth PFS of 30% (95% CI: 15 to 46%). 4 pts have had PFS > 12 mths, 1 SER pt remains on study after 25mths. Mutational analysis demonstrated presence of KRAS with PTEN or PIK3CA mutations in 9 (SER/END) pts, of whom 8/9 pts met 12-wk PFS endpoint, with a median PFS 5.9 mth (4.1 to 15.4). Conclusions: Cabo has single agent activity in END and SER EC with durable disease control. Concurrent mutation in KRAS/PTEN/PIK3CA may enrich for response. The current data support further evaluation of cabo in EC. Clinical trial information: NCT01935934.
5587 Background: Carcinosarcoma (CS) is a rare ( < 5%) aggressive subtype of endometrial cancer (EC). Patients (pts) with progression on platinum-based chemotherapy (CTX) have limited options, there is no standard 2ndline treatment and median progression-free survival (PFS) is < 2months (mt), 6-mt PFS less than 20%. Limited molecular data on CS aligns with epithelial EC, providing rationale for evaluating similar strategies such as targeting MET and angiogenesis. Cabozantinib (cabo) is multi-targeted tyrosine kinase inhibitor against MET, VEGFR, TIE2, RET, AXL and KIT. Methods: PHL-86 (NCI#9322/NCT01935934) is a multi-centre, non-randomized, phase II trial of cabo (60 mg oral daily dose on a 28-day cycle) in EC pts recurring within a year of adjuvant CTX or with progression after 1stline of CTX for metastatic disease. Pts with rare histology including CS, were enrolled in an exploratory cohort. Activity of interest for further evaluation was defined as 4 responses (either partial response [PR] or 12-wk PFS) out of 10 pts of a given histotype. CT scans were performed after cycle 3 and every 2 cycles thereafter. Results: From 2013 to 2016, 32 pts were treated in the exploratory cohort, 19 pts with CS. Median age was 66 years (range 25-75); prior treatment included CTX (17: 1 line, 6: 2 lines) and/or radiation (11). Fifteen pts were evaluable for response, with 1 PR (7%) and 8 pts with 12-wk PFS (53%). Median PFS was 3 mt (95% CI: 2.7 – 4.6) with estimated 6-mt PFS of 13% (2 to 33%). Toxicity evaluation is available for 19 pts. Common events were fatigue and GI upset. Most frequent > Grade3 toxicities were hypertension (5), anemia (4), diarrhea (2). Four pts had GI fistula (2) or perforation (2). Mutation profiling in archival tissue showed TP53 (73%), PIK3CA (40%), KRAS (27%), PTEN(13%) with > 1 mutation present in 14/15 pts analyzed. The 1 pt with no somatic mutations had a PR (31% decrease) on cabo (PFS 6.7mt). Conclusions: Cabo in CS cohort met the predefined endpoint for further evaluation and compares favourably with other agents in this poor prognosis disease. Larger studies are required to define depth and durability of response and identify relevant biomarkers. Clinical trial information: NCT01935934.
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