Clinical trial NCT03250299
Conditions: Glioblastoma MGMT-Unmethylated Glioblastoma
Keywords: Glioblastoma Brain tumor Lisavanbulin BAL101553
Sponsor: Basilea Pharmaceutica
Start date: 2017-12-15; Completion date: 2022-08-24
Enrollment: 26 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This Phase I study investigated the side-effects and best dose of microtubule-targeted agent BAL101553 when given together with radiation therapy in treating patients with newly-diagnosed O6-methylguanine-DNA methyltransferase (MGMT) promoter unmethylated glioblastoma (GBM). Drugs used in chemotherapy, such as microtubule-targeted agent BAL101553, work in different ways to stop the growth of tumor cells, either by killing the cells, stopping them from dividing, or stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving microtubule-targeted agent BAL101553 and radiation therapy may work better in treating patients with GBM.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of microtubule-targeted agent BAL101553 (BAL101553) in combination with standard radiation in patients with newly diagnosed MGMT promoter unmethylated GBM.

SECONDARY OBJECTIVES:

I. To estimate safety and tolerability of the combination of BAL101553 in combination with standard radiation in patients with newly diagnosed MGMT promoter unmethylated GBM.

II. To determine overall and progression-free survival.

OUTLINE: This was a dose escalation study of the microtubule-targeted agent BAL101553.

Patients received BAL101553 orally (PO) once daily (QD) for 6 weeks, concurrent with standard radiation therapy (RT) 5 days per week for 6 weeks in the absence of disease progression or unacceptable toxicity.

This treatment period was followed by a 4-week no-treatment period. The duration of study treatment was defined as these 6 weeks of treatment plus the 4 weeks of rest.

The safety evaluation period was the 10 weeks from start of treatment

After completion of study treatment, patients were followed up at 30 days, and then every 2 months for 2 years and then every 6 months thereafter.

Arms: arm 1: Fixed 3+3 dose escalation of BAL101553 (7 days per week), combined with RT days 1-5 for 6 weeks followed by 4 week rest.
Interventions: intervention 1: Microtubule-Targeted Agent BAL101553 intervention 2: Radiation Therapy
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo radiation therapy

Protocol documents:
Prot_000.pdf: 




  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
  
   
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
   
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
  
 
 
 
  
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
   
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
    
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
   
   
 
 
 
 
 
 
   
   
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
  
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 




  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
   
 
  
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
  
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
    
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
  
 
 
   
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
  
  
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
   
 
 
 
  
   
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 




  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                    
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
                    
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
   
  
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
  
  
 
 
  
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 






  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
   
 
  
 
 
 
 
 
  
   
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
  
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
   
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
   
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
  
 
  
 
 
  
   
  
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 






  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    




  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
  
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
   
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
    
 
 
 
   
  
 
  
 
 
  
  
 
  
 
 
  
 
  
 
 




  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
  
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
  
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
    
 
 
  
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
    
 
 
  
  
 
 
 
 
 
 
 
 
  
    
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  








  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
  
 
  
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
  
 
 
  


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 






  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 




  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
   
   
 
  
  
 
 
 
  
 
 
 
 
 
  
 
 
  
  
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
   
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
  
 
  
  
  
 
  
 
 
 
 
  
  
  
  
   
   
  
  
   
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
   
 
 
  
  
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
  
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
   
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
   
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
           


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
   
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
    
 
 
  
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  




  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
  
 
 
 
  
  
 
 
  
 
 
  
 
 
 
  
  
 
  
 
   
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
 
 
 
 
 
  
  
  
 
   
 
  
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
   
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
   
 
  
  
 
 
  
  
 
  
  
 
  
 
 
 
 
 
  
  
  
 
   
 
  
 
 
 
 
 
 
 
 
 
   
 
  
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
  
 
   
  
 
 
 
 
 
  
 
  
 
  
 
   
  
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
   
 
 
 
 
 
  
   
 
  
 
 
  
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
  
 
 
  
  
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
  
 
  
 
 
 
   
 
  
  
  
  
 
 
  
  
 
 
 
 
  
 
   
  
 
 
 
  
  
 
   
 
  
 
 
 
  
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
BAL101553 
STATISTICAL ANALYSIS PLAN 
CDI-CS-004 
 
Phase I Study to Determine the Safety and Tolerability of the Oral Microtubule 
Destabilizer BAL101553 in Combination with Standard Radiation in Patients with 
MGMT Promoter Unmethylated Newly Diagnosed Glioblastoma 
 
Document version: 
Version 1.0 
Date: 
29 September 2022 
Study protocol version date: 
14 January 2022 
Number of pages: 
18 
 
 
 
 
 
Confidentiality statement 
The information contained in this document is commercial confidential information which is the property 
of Basilea Pharmaceutica International Ltd, Allschwil, or is under its control. This information is provided 
only for the purposes identified within the document, and may not be disclosed by the recipient to any 
third party without prior written authorization from Basilea Pharmaceutica International Ltd, Allschwil. If 
it is determined that disclosure to a third party is required by applicable law or regulations, the party to 
whom the information is disclosed must be informed that the information is confidential and that it may 
not be further disclosed without prior written authorization from Basilea Pharmaceutica International Ltd, 
Allschwil. 
Note: This is an electronically controlled document. 
 




BAL101553  
CDI-CS-004 
 
Statistical Analysis Plan 
29 September 2022 / Version 1.0 
 
 
Confidential – Proprietary information of Basilea Pharmaceutica International Ltd, Allschwil 
Page 3 of 18 
 
 
TABLE OF CONTENTS 
LIST OF TABLES .............................................................................................................. 4 
1 
INTRODUCTION ........................................................................................................ 6 
2 
STUDY OBJECTIVES, ENDPOINTS AND DESIGN ............................................... 6 
2.1 
Study Objectives .................................................................................................. 6 
2.1.1 Primary objective ............................................................................................. 6 
2.1.2 Secondary objectives ........................................................................................ 6 
2.2 
Study Endpoints ................................................................................................... 6 
2.2.1 Primary endpoint .............................................................................................. 6 
2.2.2 Secondary endpoints ........................................................................................ 6 
2.3 
Study design ......................................................................................................... 7 
2.4 
Dose escalation ..................................................................................................... 8 
2.4.1 Assessments ..................................................................................................... 8 
2.4.2 Planned sample size ....................................................................................... 10 
2.5 
Interim analyses .................................................................................................. 10 
3 
ANALYSIS POPULATIONS .................................................................................... 10 
3.1 
Full analysis population (FAP) .......................................................................... 10 
3.2 
Safety population ................................................................................................ 11 
3.3 
PK population ..................................................................................................... 11 
3.4 
Maximum tolerated dose-determining population ............................................. 11 
4 
STATISTICAL CONSIDERATIONS AND ANALYSIS ......................................... 11 
4.1 
Derived variables ................................................................................................ 11 
4.2 
Handling of missing data and/or invalid data and outliers ................................. 12 
4.2.1 Missing dates and times ................................................................................. 12 
4.2.2 Pharmacokinetic data ..................................................................................... 12 
5 
STATISTICAL PLAN AND METHODS .................................................................. 13 
5.1 
Background characteristics ................................................................................ 13 
5.1.1 Patient disposition .......................................................................................... 13 
5.1.2 Protocol deviations ......................................................................................... 13 
5.1.3 Demographic and baseline characteristics ..................................................... 14 
5.1.4 Medical history ............................................................................................... 14 
5.2 
Efficacy analysis ................................................................................................ 14 
5.2.1 Overall survival .............................................................................................. 14 
5.2.2 Progression-free survival ............................................................................... 14 
5.3 
Pharmacokinetic analysis ................................................................................... 14 


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5.4 
Safety analysis .................................................................................................... 15 
5.4.1 Dose-limiting toxicity .................................................................................... 15 
5.4.2 Treatment exposure and radiation therapy ..................................................... 15 
5.4.3 Adverse events ............................................................................................... 16 
5.4.4 Laboratory evaluation .................................................................................... 17 
5.4.5 Vital signs....................................................................................................... 17 
5.4.6 ECG results .................................................................................................... 17 
5.4.6.1 Outlier analysis ............................................................................................ 18 
5.4.7 Physical examination ..................................................................................... 18 
5.4.8 Prior and concomitant medications ................................................................ 18 
5.4.9 MRI Scan ....................................................................................................... 18 
5.4.10 Neurological examination ............................................................................ 18 
6 
CHANGES FROM THE PLANNED ANALYSIS IN STUDY PROTOCOL .......... 18 
 
LIST OF TABLES 
Table 1 
Schedule of assessments .......................................................................... 9 
 
 
 


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LIST OF ABBREVIATIONS 
AE  Adverse event 
CI  Confidence interval 
CRF  Case report form 
CTCAE  Common Terminology Criteria for Adverse Events 
DLT  Dose-limiting toxicity 
ECG  Electrocardiogram 
FAP  Full analysis population 
MRI  Magnetic resonance imaging 
MTD  Maximum tolerated dose 
OS  Overall Survival 
PFS  Progression-free survival 
PK  Pharmacokinetic(s) 
PT  Preferred Term 
RT  Radiotherapy 
SAE  Serious adverse event 
SAP  Statistical analysis plan 
SOC  System Organ Class 
 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the detailed procedures for performing the 
statistical analyses and producing tables, listings, and figures in the study described in 
Basilea Pharmaceutica International Ltd. (Basilea) Protocol ABTC-1601. The version of 
the protocol at the time of preparation of this SAP is dated 14 January 2022. 
At the time of writing this document, the study is ongoing. 
2 
STUDY OBJECTIVES, ENDPOINTS AND DESIGN 
2.1 
Study Objectives 
2.1.1 
Primary objective 
The primary objectives of this study is to determine the maximum tolerated dose (MTD) 
of BAL101553 in combination with standard radiation in patients with newly diagnosed 
MGMT promoter unmethylated GBM. 
2.1.2 
Secondary objectives 
The secondary objectives are: 
x To estimate safety and tolerability of BAL101553 in combination with standard 
radiation in patients with newly diagnosed MGMT promoter unmethylated GBM. 
x To determine overall and progression-free survival. 
x To assess the pharmacokinetics (PK) of BAL101553 and BAL27862. 
x To explore expression of tissue biomarkers, including BubR1, stathmin, and EB1 at 
baseline (exploratory biomarkers). 
2.2 
Study Endpoints 
2.2.1 
Primary endpoint 
The primary study endpoint is the frequency and characteristics of dose-limiting toxicities 
(DLT), which are relevant for determination of the MTD of BAL101553.  
2.2.2 
Secondary endpoints 
Secondary endpoints are: 
x Safety/Toxicity:  
 Incidence, frequency, severity, type, and relationship of adverse events (AEs) and 
serious AEs (SAEs) 
 Changes in laboratory tests, vital signs, and electrocardiogram (ECG) data. 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 or 5.0 is 
used for scoring toxicity and adverse events. 
x Efficacy endpoints: 
 Overall survival (OS). 


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 Progression-free survival (PFS). 
x PK variables calculated using noncompartmental analysis for BAL101553 (if 
applicable) and for BAL27862 will comprise: Cmax, Tmax, AUCs, and if possible t1/2, 
systemic clearance, and volume of distribution. The PK dose proportionality will also 
be assessed  
x Expression of BubR1, stathmin, and EB1 at baseline (exploratory biomarker) will be 
addressed separately. 
2.3 
Study design 
This is a phase 1, open-label, multicenter, dose-finding study of BAL101553 when given 
in combination with radiotherapy (RT) in patients with newly diagnosed MGMT promoter 
unmethylated GBM. All subjects must have had histological confirmation of GBM, either 
by biopsy or by resection. 
Following tumor resection, patients will begin an assigned BAL101553 dose in 
combination with the standard 6 weeks of radiation. 
Oral BAL101553 will be given once daily (7 days a week) for 6 weeks, concurrent with 
standard RT. This will be followed by a 4-week no-treatment period. The duration of study 
treatment will be defined as these 6 weeks of treatment plus 4 weeks of rest. The safety 
data will be collected during this entire period. 
After the 4-week rest period following the 6 weeks of treatment, patients will be off study 
treatment and should continue standard-of-care treatment with adjuvant temozolomide and 
appropriate follow-up. 
 
Figure 1: Study design schema 
A modified 3+3 design will be used for dose-finding (see protocol for details). To prevent 
unreasonable delay in completing each cohort, 5 patients will be enrolled onto a dose cohort 
to ensure 3 evaluable patients at the end of the 10-week treatment period. It is planned to 
test up to 5 pre-specified dose levels of BAL101553, the starting dose will be 4 mg per 
day. 
The overall sample size for the trial is not fixed. It depends on the number of dose levels 
being tested. 


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2.4 
Dose escalation 
Five patients will be enrolled at each dose level to ensure 3 evaluable patients at the end of 
the toxicity evaluation period. Accrual to the next dosing level will not start until a 
minimum of 10 weeks after the final patient is accrued to the lower dosing level. Dose 
escalation rules follow a 3+3 design in principle. 
- 
If less than 1/3 of evaluable patients (i.e. 0/3, 0/4, 0/5, 1/4, or 1/5)  in a cohort 
experience DLT, then a new cohort will be treated at the next higher dose level. 
- 
If one of three evaluable patients in a cohort experiences DLT, then three additional 
patients will be treated at the same dose level. 
- 
If 2-3 patients in a cohort or ≥3 in case of 2 cohorts treated at the dose level 
experience DLT, then the MTD will have been exceeded, and no further dose 
escalation will occur. The previous dose level will be considered as the MTD. 
- 
If only three evaluable patients were treated at a dose level under consideration as 
the MTD, then three additional patients will be accrued. If no more than two of the 
six patients at that dose level experience a DLT, then that dose level will be 
confirmed as the MTD. If three or more patients in that cohort experience DLT, 
then the previous dose level will be studied in the same fashion.  
2.4.1 
Assessments 
Table 1 presents a summary of the schedule of assessments performed from Baseline 
through the Follow-up visit (Cross-references in the footnotes are to protocol sections). 




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13. A serum sodium level of  < 130 mmol/L (CTCAE Grade 3) that is symptomatic or not reversible within 3 days, or 
that re-occurs upon study drug continuation or re-initiation at the same dose, is a DLT. Under these circumstances, 
study treatment must be discontinued temporarily or permanently, depending on the improvement/normalization of 
sodium levels (see Protocol – Section 5.1). Serum sodium  testing must be repeated twice a week until recovered to 
≥ 130 mmol/L. 
14. If SBP ≥ 160 mmHg or DBP ≥ 100 mmHg, initiate intervention, Protocol - Section 4.6.2. Patients with SBP ≥ 160 
mmHg or DBP ≥ 100 mmHg must take BP daily until < 160 mmHg AND DBP < 100 mmHg. Patients should record 
BP readings in the pill diary (Protocol - Appendix I) 
15. Perform weekly during RT+BAL101553 treatment (Days 8, 15, 22, 29, 36, 43); after RT is complete, perform every 
other week (Day 57 and off treatment). 
16. Record all medications taken within 14 days prior to baseline (screening) visit. 
17. ECG assessments to be done pre-dose and 2 h (± 30 mins) post-BAL101553 administration on Days 1, 8, 15, 22, 29 
and 36 (±1day from Day 8 onwards). A final ECG will be taken within 7 days after the final dose of BAL101553. 
Patients with any abnormal ECG readings during the study will have an additional ECG performed at the end of the 
10-week study period. 
18. PK samples will be collected on Days 1 and 22: pre-dose and 0.5 h, 1 h, 2 h (up to 3 h), 4 h, 6 h (± 15 mins) and 
24 h (± 1 h) post-dose (see Protocol - Section 9.5.1). 
19. New study drug will be dispensed to patients at study visits at weekly intervals. All safety parameters (including 
laboratory safety parameters and MMSE®) applicable for assessing the ability for a patient to continue receiving study 
medication must be reviewed at any study visit prior to dispensing new study medication (see Protocol – Section 5.2). 
20. The MMSE®,21 will be performed predose on Day 1 (=baseline) and weekly during RT+BAL101553 treatment when 
no Neuro Exam is planned (Days 8, 15, 29, 36, 43). Based on the MMSE® Score, a Neuro Exam will be scheduled 
within 1 calendar day if both of the following conditions apply: score < 26 and decline against baseline > 3; see 
Protocol - Section 5.2.2.  
 
Patients will be followed until death. Patients will only be off study at the time of death. 
Patients will be followed every two months for progression, for up to one year from the 
off-treatment date. All patients will be followed for survival every 2 months for the first 2 
years; after 2 years, patients will be followed every 6 months until death. 
2.4.2 
Planned sample size 
The overall sample size for the trial is not fixed. It depends on the number of dose levels 
being tested. 
The 3+3 design does not require sample size specification; the escalation is continued until 
the maximum administered dose (i.e., a dose with an unacceptable number of DLT) is 
observed. In total, 26 patients are included in the study. 
2.5 
Interim analyses 
No interim analyses are planned. 
3 
ANALYSIS POPULATIONS 
3.1 
Full analysis population (FAP) 
The FAP includes all patients who received at least one partial or complete dose of study 
drug, based on the intent-to-treat principle. The FAP will be used for analyzing efficacy. 
Considering that all patients were treated, all analyses will be performed on the safety 
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3.2 
Safety population 
All patients who received at least one full or partial dose of BAL101553 and had at least 
one post-baseline safety assessment must be included in the safety analysis populations. 
The safety analysis population will be used for all safety related analyses (AEs, vital signs, 
laboratory data, etc.).  
Patients will be primarily analyzed according to their originally-assigned dose level. 
3.3 
PK population 
All patients who received at least one full dose of BAL101553 must be included in the PK 
analysis population.  
Protocol deviations that have an impact on the calculation or interpretation of 
concentrations or PK parameters will be listed in the PK report. 
3.4 
Maximum tolerated dose-determining population 
The MTD-determining population includes all patients from the safety set who meet the 
following minimum criteria: 
x Received at least one dose of BAL101553 and has experienced a DLT; 
x Have completed ≥80% of their expected dose of BAL101553 for the 6 weeks of 
combined treatment and 4 weeks of rest (10 weeks total). 
Patients who do not meet these minimum evaluation requirements will be regarded as 
ineligible for the MTD-determining population. These patients will be included in the 
safety population but will be excluded from the MTD-determining population. 
 
4 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
4.1 
Derived variables 
The following derived variables will be applied throughout the study: 
x Baseline is defined as the last available assessment prior to first study treatment 
administration (including unscheduled assessments). 
x Adverse event duration (in days, hours or fractions of hours) will be calculated as:  
 (<event end date.time> minus <event onset date.time>) in days or hours. 
If only the date is collected: 
 ((<event end date> minus <event onset date>) + 1) in days. 
x The following algorithm will be used for the study day determination: 
 Day 1 = Day of first study drug administration (i.e., Day 1). The day before Day 1 
is Day −1. 
 Prior to Day 1 the algorithm is (<visit/examination date> minus <date of first study 
drug administration>) 
 Day 1 and subsequent days = (<visit/examination date> minus <date of first study 
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x Duration of exposure (in days) will be calculated as: (<date of last study drug 
administration> minus <date of first study drug administration>) + 1. 
x The progression status will be as reported in the case report form (CRF). 
4.2 
Handling of missing data and/or invalid data and outliers 
4.2.1 
Missing dates and times 
Incomplete/partial dates will be replaced by derived variables and imputed using the 
following rules: 
x If the day of the month is missing, it is imputed to be the 15th if not in the month of 
treatment. In the event that this leads to inconsistencies with other available data for 
the patient or if in the month of treatment, the imputation values will be handled case-
by-case. 
x If both the day and month are missing, they are imputed to be 30 June if not in the year 
of treatment. In the event that this leads to inconsistencies with other available data for 
the patient or if in the year of treatment, the imputation values will be handled case-by-
case. 
x Missing years will be left as missing. 
x Missing time will be replaced by ‘00:00’ for start times and ‘23:59’ for end times if 
time is required. 
x Missing minutes will be replaced by ‘00’ for start times and ‘59’ for end times if time 
is required. 
4.2.2 
Pharmacokinetic data 
Treatment of outliers 
Individual concentration-time points, if considered anomalous, may be excluded from the 
analysis at the discretion of the pharmacokineticist following a review of the available 
documentation. Any such exclusion will be outlined in the PK report.  
Entire individual treatment profiles for a subject may be excluded following review of the 
available documentation. However, results of analysis with and without the excluded 
profiles may be presented in the PK report. Any such exclusion will be clearly listed in the 
PK report along with justification for exclusion. 
Non-quantifiable concentrations 
All concentration values reported as no results (not collected or not determined) values will 
be treated as missing. For the calculation of concentration summaries, all concentrations 
below the quantifiable limit (BLQ) will be treated as 0. 
For the purpose of calculating PK parameters and plotting mean and individual 
concentration time profiles, BLQ values will be treated as zero prior to the first measurable 
concentration. After the first measurable concentration, subsequent BLQ values will be 
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5 
STATISTICAL PLAN AND METHODS 
The statistical analysis will be performed using the software package SAS version 9.4 or 
higher (SAS Institute Inc., Cary, NC 27513, USA). All individual patient data, and results 
of statistical analyses, will be presented in individual patient data listings and statistical 
summary tables.  
In general, continuous variables will be summarized using the following standard 
descriptive summary statistics: mean, standard deviation, median, minimum, maximum 
and number of observations. Categorical data will be described using frequency and 
percentage. Shift tables will be provided, where appropriate. One additional decimal point 
will be used for mean, median, Q1, Q3, and two additional decimal points will be used for 
standard deviation. Percentages will be rounded to one decimal place or more if most 
results are close to 0 or 100.  
Any changes in the planned statistical methods will be documented in the clinical study 
report. 
The following international dictionaries will be used for medical coding: 
x Medical History events: MedDRA (version 24.0 or later) 
x Adverse events: MedDRA (version 24.0 or later) 
x Prior cancer related surgery (MedDRA Version 24.0 or later) 
x Prior and concomitant procedures (MedDRA Version 24.0 or later) 
 
Concentration-time profiles of BAL0101553 and BAL27862 will be analyzed by 
noncompartmental methods and/or nonlinear least squares regression using Phoenix 
WinNonlin (Build 8.3 or higher; Certara, Princeton, New Jersey, USA). The PK analysis 
will be reported in a separate report. 
5.1 
Background characteristics 
5.1.1 
Patient disposition 
Enrollment and disposition data will be presented for each patient in data listings, and 
summarized by frequency tables. A disposition of patients includes the number and 
percentage of patients for the following categories: patients who completed the study 
treatment, patients who discontinued study treatment early with reasons for 
discontinuation. 
Inclusion and exclusion criteria violations and patient enrollment eligibility will be 
presented by dose level and patient in data listings. 
5.1.2 
Protocol deviations 
Protocol deviations reported during the course of the study will be listed. 
Reported protocol deviations will be reviewed prior to database lock. 


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5.1.3 
Demographic and baseline characteristics 
Demographic and baseline characteristics of the safety population, including age at 
baseline, gender, race, ethnicity, height, weight, and disease characteristics, will be 
summarized by dose level using descriptive statistics or frequency tables, as appropriate. 
Percentages will be based on the number of patients with available observations in the 
safety population. 
Demographic information and baseline characteristics will be presented in data listings 
sorted by dose level and patient. 
5.1.4 
Medical history 
Diseases present at baseline as well as previous surgeries will be presented in data listings 
sorted by dose level and patient. 
Medical history data will be summarized by dose level, system organ class (SOC), and 
preferred term (PT) using the safety population. Prior surgeries characteristics will also be 
summarized by dose level for the safety population. 
5.2 
Efficacy analysis 
5.2.1 
Overall survival 
OS is defined as the time from Day 1 dosing to the date of death. Patients who have not 
died at study closure will be censored at the time of last known alive. 
OS will be summarized for the safety population overall. The median time to death, as well 
as 25th and 75th percentiles, will be determined by Kaplan-Meier method. Its 95% CI will 
be performed using the Brookmeyer-Crowley method. The associated survival curve will 
be displayed. 
OS will be listed by dose level and patient. 
5.2.2 
Progression-free survival 
PFS is the interval between Day 1 dosing and the earliest date of progression or death due 
to any cause in the absence of progression. Patients who have not progressed or died at 
study closure will be censored at the time of their last assessment without progression. 
If a patient has no post-baseline progression assessment, the PFS will be censored to 0 
days. 
PFS will be summarized for the safety population overall. Same statistics and curves than 
for OS will be displayed. 
PFS will be listed by dose level and patient. 
5.3 
Pharmacokinetic analysis 
Individual 
subject 
plasma 
concentration-time 
curves 
will 
be 
analyzed 
by 
noncompartmental methods. PK parameters will be presented as listings and descriptive 
summary statistics by dose groups and PK days. Individual and mean cohort plots of 


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concentration versus time will be constructed. Dose proportionality will be evaluated using 
the power model. 
Pharmacokinetic parameters and variables will be calculated for BAL101553 (if 
applicable) and BAL27862 according to standard equations using actual sampling times if 
available. 
Following administration, Cmax and Tmax will be obtained directly from the experimental 
observations. If multiple maxima occur at equal concentrations, the first temporal value 
will be taken. 
AUC will be calculated using the linear up/log down trapezoidal rule, using actual elapsed 
time since the start of oral administration. 
The number of data points included in the regression for determination of λz and t½ after 
single-dose will be determined by visual inspection, but a minimum of 3 data points in the 
terminal phase, excluding Cmax, will be required to estimate λz. The λz values (and 
consequently t½, CL/F, Vd/F and AUCinf) will be considered unreliable estimates if the 
time period over which an individual λz was estimated is less than twice the resultant t½ 
or if the adjusted coefficient of determination ‘Rsq’ is less than or equal to 0.75.  
The proportion of AUCinf due to extrapolation (AUCextrap) will also be calculated and 
expressed as a percentage. The value of AUCextrap should be less than or equal to 20% for 
AUCinf to be considered to be well estimated. If AUCextrap is higher than 20%, then the 
values of AUCinf, CL/F, and Vd/F will be considered unreliable and therefore excluded 
from the summaries. 
5.4 
Safety analysis 
Safety assessments will be conducted throughout the entire study period. Analyses will be 
performed using safety population, unless otherwise specified. 
The safety evaluations will include analyses of adverse events, laboratory assessments 
(hematology, biochemistry, cardiac troponin, and coagulation), ECG, magnetic resonance 
imaging (MRI) scan, and vital signs. 
5.4.1 
Dose-limiting toxicity 
The DLTs will be listed by dose level and patient. 
5.4.2 
Treatment exposure and radiation therapy 
The duration (in days) of BAL101553 exposure, the actual dose received, and treatment 
compliance (as collected in the CRF), will be listed by patient and summarized using 
descriptive statistics by dose level. 
Any other treatment exposure information will also be included in the listing. 
Study drug dose interruptions and reductions will be listed by patient. 
The duration (in days) of radiation therapy, the actual dose, and percentage (as collected in 
the CRF) received will be listed by patient and summarized using descriptive statistics by 
dose level. 


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Any other radiation therapy information will also be included in the listing. 
5.4.3 
Adverse events 
Treatment-emergent events are defined as all events occurring after BAL101553 treatment 
begins. Any adverse event starting prior to the first study drug administration will be 
reported as medical history. The relationship of an AE to study drug and RT is recorded as 
unrelated, unlikely, possible, probable, or definite. 
For analysis purposes, ‘related to BAL101553’ AEs will be those reported as possible, 
probable, definite, or those for which the relationship is unknown. 
Adverse events will be presented in data listings including dose level, patient, dates/times, 
study day of event, MedDRA SOC, PT, duration of the event, seriousness, CTCAE grade, 
intensity, drug adjustment, treatment taken, relationship to study drug, relationship to RT, 
and outcome. 
An overview table (including only treatment-emergent AEs) will also be presented with 
the number (and percentage) of patients and number of events with: 
x Any AE 
x Related to BAL101553 AEs 
x CTCAE grade 3/4 AEs 
x CTCAE grade 3/4 related AEs 
x SAEs 
x Related SAEs 
x AEs leading to dose modifications (i.e., dose reduced or dose interrupted) 
x Related AEs leading to dose modifications (i.e., dose reduced or dose interrupted) 
x AEs leading to study drug discontinuation 
x Related AEs leading to study drug discontinuation 
x AEs leading to death 
x Related AEs leading to death. 
This table will be displayed by dose level. 
All treatment-emergent AEs and treatment-emergent AEs related to treatment will be 
summarized by incidence rate tables broken down by: 
x SOC and PT. 
x SOC, PT, and worst CTCAE grade.  
x SOC, PT, and drug relationship. 
Serious treatment-emergent AEs, treatment-emergent AEs leading to dose modifications, 
leading to study drug discontinuation, or leading to death will be also summarized by SOC 
and PT. The same analyses will be repeated for related AEs. 


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5.4.4 
Laboratory evaluation 
The laboratory tests for safety analyses comprise the following: 
x Hematology: Hemoglobin, Platelet count, White blood cell count, Neutrophil count, 
Lymphocyte count,  
x Serum biochemistry: Sodium, Potassium, Creatinine, Albumin, Alkaline phosphatase, 
Total and direct bilirubin, Aspartate amino transferase, Alanine amino transferase, 
Phosphate (inorganic phosphorus), Calcium, Magnesium. 
x Cardiac troponin: Cardiac Troponin I, Cardiac Troponin T 
x Coagulation: International normalized ratio, Partial Prothrombin Time and activated 
Partial Thromboplastin Time.  
Laboratory values will be converted into SI units and the severity grade determined based 
on CTCAE. 
Descriptive statistics for each laboratory analyte at each assessment time will be tabulated 
by dose level. The change from baseline will also be summarized by dose level. 
An analysis of individual patient changes by dose level will be presented using shift tables 
showing the change from CTCAE grade/intensity at baseline to the worst CTCAE 
grade/intensity (including unscheduled assessments) during the study. 
The laboratory parameters will be presented in data listings sorted by dose level, patient, 
study day, study time, and analyte. Out-of-range values will be flagged with h (high) or 
l (low). 
5.4.5 
Vital signs 
Summary statistics by dose level and scheduled time point will be presented for each vital 
sign. The change from baseline will also be presented. 
The mean maximum change from baseline (the average of the maximum change between 
baseline and all timepoints post baseline) will also be presented. 
The number of patients with values outside marked reference ranges will also be tabulated 
by dose level and scheduled time point. 
The vital signs marked reference ranges are: 
x  Diastolic blood pressure: < 60 mmHg or > 100 mmHg. 
x  Systolic blood pressure: < 80 mmHg or > 180 mmHg. 
x  Pulse: < 40 beats/min or > 120 beats/min. 
x Temperature: < 36.0 degrees Celsius or > 38.5 degrees Celsius. 
Vital sign assessments will be presented for each patient in a data listing by dose level. 
5.4.6 
ECG results 
The 12-lead ECG results (QTcF interval reported in the CRF) and changes from baseline 
will be summarized using standard descriptive statistics by dose level and scheduled time 
point. 


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ECG results will be presented for each patient in a data listing by dose level. 
5.4.6.1 
Outlier analysis 
The number and percentage of patients with maximum on-treatment value of QTcF 
interval, categorized as ≤ 450 msec, > 450 msec and ≤ 480 msec, > 480 msec and 
≤ 500 msec, and > 500 msec, as well as maximum on-treatment change from baseline value 
of QT/QTc intervals, categorized as < 5 msec, ≥ 5 msec and < 10 msec, ≥ 10 msec and < 
20 msec, ≥ 20 msec and < 30 msec, ≥ 30 msec and < 60 msec, and ≥ 60 msec will be 
tabulated based on scheduled and unscheduled 12-lead ECG measurements. 
5.4.7 
Physical examination 
General physical examination assessments will be listed by dose level, patient, and study 
day. 
5.4.8 
Prior and concomitant medications  
Medications and significant non-drug therapies prior to and after first administration of the 
study drug will be listed by dose level and patient. 
5.4.9 
MRI Scan 
MRI Scan results will be presented for each patient in a data listing by dose level. 
5.4.10 
Neurological examination 
Neurological and Mini-Mental State examination results will be presented for each patient 
in a data listing by dose level. 
6 
CHANGES FROM THE PLANNED ANALYSIS IN STUDY 
PROTOCOL 
OS and PFS will use the “Day1 dosing” date instead of “initial diagnosis” date as starting 
point. For OS, event rate will not be estimated, only median and quartiles will be estimated 
using Kaplan-Meier method. 
Only the number and percentage of patients who experienced grade 3 or above toxicity will 
be displayed, no 95% CI confidence interval will be estimated.