Clinical trial NCT04072042: BIOmarker Driven Trial of VEGFR2 Inhibitor in Advanced or Metastatic Sarcoma
Official title: A Biomarker Driven, Open Label, Phase II Study of VEGFR2 Inhibitor Apatinib in Patients With Recurrent or Refractory Advanced Bone and Soft Tissue Sarcoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Sarcoma
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
First posted: 2019-08-28
Enrollment: 30
Sex: ALL
Minimum age (years): 8
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: In each of the treatment arm, we recruit patients according to the biomarker status and hypothesize that the anti-angiogenic therapeutic efficay would be higher than historical control as a biomarker-driven approach.
Primary purpose: TREATMENT

Brief summary: The aim of this study is to evaluate the efficacy and safety of Apatinib monotherapy for relapsed or refractory advanced bone and soft tissue sarcoma with VEGFR-2 (KDR) 604A\>G polymorphism as predictive biomarker

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. age between 8 and 65 years;
2. diagnosis of histologically confirmed advanced bone and soft tissue sarcoma excluding adipocytic tumor;
3. identification of pulmonary lesion is mandatory;
4. refractory to prior treatment consisted of standard National Comprehensive Cancer Network (NCCN) guideline recommended first-line chemotherapy;
5. Eastern Cooperative Oncology Group(ECOG) performance status 0-2 with a life expectancy \>3 months;
6. adequate renal, hepatic, and hemopoietic function;normal or controlled blood pressure;
7. advanced stage that complete surgical resection of all lesions are infeasible;
8. no serious thoracic comorbidities with adequate pulmonary function for daily living;
9. previously treated with tyrosine kinase inhibitors (TKIs) for less than 8 weeks but off treatment due to manageable complications such as wound complications or pneumothorax without adequate interventions. The complications is resolved and disappeared at enrollment.

Exclusion Criteria:

1. have had other kinds of malignant tumors at the same time;
2. cardiac insufficiency or arrhythmia;
3. uncontrolled complications, such as diabetes mellitus and so on;
4. coagulation disorders or Hemorrhagic diseases ;
5. pleural or peritoneal effusion that needs to be handled by surgical treatment;
6. combined with other infections or wound complications;
7. wound dystrophy, poor soft-tissue around implantation risky of non-healing given angiogenesis inhibitor at baseline;
8. previously treated with VEGFR TKIs for more than 8 weeks
9. previous treated with VEGFR TKIs but off treatment due to oncological assessment or dose-limiting complications given adequate interventions.

Primary outcomes:
measure: 4 month-progression free rate (PFR) in each of the 3 cohorts
timeFrame: 4 months from recruitment
Secondary outcomes:
measure: progression free rate (PFR) in biomarker negative control in each of the 3 cohorts
timeFrame: 4 months from recruitment
measure: progression free survival(PFS) between biomarker positive and negative patients in each of the 3 cohorts
timeFrame: Baseline until disease progression or death, whichever occurs first, assessed for an average of 8 months
measure: Correlation of biomarker positivity with overall survival (OS)
timeFrame: Baseline until death, assessed for an average of 24 months
measure: ORR, DCR and DOR between biomarker positive and negative patients in each of the 3 cohorts
timeFrame: Baseline until disease progression or death, whichever occurs first, assessed for an average of 8 months
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: through study completion, an average of 8 months
measure: Correlation of KDR polymorphism with pulmonary lesion cavitation/pneumothorax
timeFrame: 4 months from recruitment
measure: Correlation of KDR polymorphism with hair depigmentation
timeFrame: 4 months from recruitment
measure: Correlation of CSF1R polymorphism (rs10079250) with wound complication
timeFrame: through study completion, an average of 8 months
measure: Correlation of PDGFRα polymorphism (rs35597368) with hand foot skin reaction
timeFrame: through study completion, an average of 8 months
measure: Early identification of AEs as predictive biomarker
timeFrame: Baseline until disease progression or death, whichever occurs first, assessed for an average of 8 months
Other outcomes:
measure: Exploratory outcome: Subgroup analysis of progression-free survival(PFS)
timeFrame: Baseline until disease progression or death, whichever occurs first, assessed for an average of 8 months
measure: Exploratory outcome: the molecular analysis of tumor sample in each of the 3 cohorts
timeFrame: through study completion, an average of 8 months
measure: Exploratory outcome: the pattern of disease progression between different cohorts and different sub-group within each cohort
timeFrame: Baseline until disease progression or death, whichever occurs first, assessed for an average of 8 months
measure: Exploratory outcome: 1.0-mm CT scan for pulmonary assessment
timeFrame: Baseline until disease progression or death, whichever occurs first, assessed for an average of 8 months
Locations:
city: Shanghai
country: China
facility: Ruijin Hospital Shanghai Jiao Tong University School of Medicine
state: Shanghai
Study officials:
affiliation: Shanghai Jiao Tong University School of Medicine
name: Weibin Zhang
role: PRINCIPAL_INVESTIGATOR
References: