BIOmarker Driven Trial of VEGFR2 Inhibitor in Advanced or Metastatic Sarcoma

After standard chemotherapy and surgery for the localized disease, pulmonary metastases of bone and soft tissue sarcoma occurs in up to 40% of cases and still remain challenging without satisfactory regimen. Apatinib has been reported as a novel oral kinase inhibitor of receptor tyrosine (TKI) targeting VEGFR2 as an angiogenesis inhibitor. Previous studies indicated that Apatinib, as well as other novel VEGFR inhibitor (such as Regorafenib, Cabozantinib, Pazopanib ), showed a promising anti-sarcoma activity with a 4 month progression free rate (PFR) ranging from 40 to 60% in advanced bone and soft tissue sarcoma after multi-line chemotherapy failure. However, the significant inter-individual variability of the agents suggests a lack of predictive biomarker for its clinical use. Furthermore, up to 10~30% of patients may encounter pneumothorax, a potentially life-threatening consequence. Other common debilitating adverse effects (AEs) include surgical wound complication, hand foot skin reaction, etc.

Our preliminary data (Presented in ESMO poster session and ESMO Asia oral session in 2019) suggests that rs2071559_VEGFR2 604A>G polymorphism is associated pulmonary tumor cavitation (predisposes one to pneumothorax), hair depigmentation, superior anti-tumor efficacy. Therefore, the investigators aim to explore the clinical signficance of pneumothorax incidence as well as the efficacy of Apatinib monotherapy for advanced bone and soft tissue sarcoma in association with VEGFR-2 (KDR) 604 genotype. We aim to further conduct our clinical study in two cohorts: the observational study cohort and the prospective clinical trial cohort.

In the observational cohort, we recruited patients with anti-angiogenic TKIs who encounter pneumothorax during the course of the treatment from nation-wide as a real world study. We review the radiological features of their tumor (such as cavitation, location, etc.) and the medical history of the pre-treatment. We then prospectively follow up the oncological outcomes and the respiratory outcomes given that all pneumothoraces are treated with multidisciplinary approaches to minimize the adverse effect of pneumothoax and maximize the duration of response to anti-angiogenic TKIs. We expect that the patients with pneumothorax (an efficacy related toxicity), if managed actively, will have a durable progression-free survival compared to historical control. Blood samples will also be collected for genotyping VEGFR2 604A>G polymorphism status as a validation to our preliminary findings.

In the prospective clinical trial cohort, we formally designed a prospective single-arm, open-label, biomarker-driven phase II clinical trial to explore the efficacy of Apatinib, a novel anti-angiogenic oral inhibitor, in biomarker-based selective patients as follows: With all comers(biomarker positive and negative) allowed to be enrolled, only VEGFR-2 (KDR) 604A>G polymorphism positive will be measured for the primary endpoint of the study according to our sample size estimation . The primary objective is to hypothesize that the progression-free rate (PFR) of Apatinib in this population is ≥ 70% at 4 months (tremendous higher than non-biomarker driven historical control), against the null hypothesis of PFR ≤ 50% as in the general sarcoma patients. Using Simon's two stage design, we are going to recruit 9 biomarker-positive patients in the first stage. If the primary objective was reached in >3 patients, study continue to recruit a total of 28 biomarker-positive patients. The primary endpoint will be considered met if 18 or more patients achieve PFR at 4 months. Considering the potential lost to follow-up, a total of 30 patients with biomarker positive is needed in this trial. Biomarker-negative patients will be analyzed as a non-comparative control without pre-specified sample size, which is expected to be similar to the historical control of advanced bone and soft tissue sarcoma.