Safety and Efficacy Study of Sotatercept in Adults With Transfusion Dependent Diamond Blackfan Anemia (ACE-011-DBA)

• Determine a safe and effective dose of sotatercept in adults with DBA and RBC transfusion dependence [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  Achieve a complete response transfusion- independent and Hemoglobin >9 gm/dl or a partial response- increase in transfusion interval from baseline and hemoglobin < 9gm/dl iith an increase in reticulocyte count
  
  

• Safety [ Time Frame: 9 months ] [ Designated as safety issue: Yes ]
  Assess type, frequency, and severity of adverse events and relationship to sotatercept according to the currently active minor version of the NCI Common Terminology for Adverse Events version 4.0
  
  
• Time to response [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  Length of time required to achieve a response
  
  
• Response duration [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  Length of time between transfusions
  
  
• Exploratory outcome improvement of bone density [ Time Frame: 9 months ] [ Designated as safety issue: No ]
  Improvement as measured by bone densitometry (DEXA scan)
  
  

This study is for adult patients with Diamond Blackfan Anemia who are currently being transfused every 3- 4 weeks.

The drug will be given as a subcutaneous injection within one of three dose levels. The first dose level (0.1 mg/kg) will include 3 subjects who will receive the same dose of the drug monthly for a total of 4 doses, as long as there are no dose- limiting toxicities (DLTs). A Dose limiting toxicity is defined as inability to deliver the scheduled doses because of toxicity >/= Grade 3, according to NCI Toxicity Grading Scale.

Once all 3 subjects have received and tolerated the low dose level, the next level will open (0.3 mg/kg)to 3 new subjects. Subjects will be monitored closely for response and side effects.

If more than 2 subjects have a dose limiting toxicity in the first dose level, then dose level -1 (0.05 mg/kg)will open, enrolling 3 more subjects. If more than 2 subjects at dose level -1, have dose limiting toxicities, the study will be discontinued. If there are no additional dose limiting toxicities, dose level -1 will be the maximum tolerated dose.

There are a total of 3 dose levels, not including dose level -1. Once the maximum tolerated dose has been reached, up to a total of 10 additional subjects will be enrolled.

Efficacy will be measured by response. A complete response will be determined if the subject no longer requires transfusion, while on study drug. A partial response will be measured by a reduction by 50% in need for transfusion.

Treatment modifications will be made based on evidence of side effects. Dose- escalation will be performed only if no side effects are reported and no efficacy is evidenced. Treatment will be stopped if hemoglobin is >12 gm/dl and/ or any >/+ grade 3 adverse event is related to sotatercept.

Study assessments will include:

• Physical exam (height, weight, vital signs and blood pressure)at screening, day 1 of each cycle and monthly for 3 months of follow up period as well as at study discontinuation.
• Additional blood pressure monitoring at day 1 of each cycle and weekly there after through cycle 4, monthly in follow up period and at study discontinuation.
• Karnofsky performance status at screening, day 1 of cycle 2 and day 1 of monthly follow up period for 3 months and study discontinuation.
• CBC reticulocyte count and ANC will be collected at day 1 of each cycle and weekly there after through cycle 4, monthly in follow up period and at study discontinuation.
• Blood chemistry, liver and kidney function will be assessed at screening, day 1 and 15 of cycle 1, day 1 of cycle 2, 3, 4 month 1 in follow up and at study discontinuation.
• Blood for iron status (serum iron, transferrin and %, ferritin) will be collected during the screening period, and at month 1 of the follow-up period as well as study discontinuation.
• Folate and B12 levels will be assessed during the screening period at day 1 of cycle 3 and again at study discontinuation.
• Urinalysis (creatinine, protein),at screening, day 15 of cycle 1, day 1 of cycles 2, 3, and 4 monthly during follow-up and at study discontinuation.
• Serum erythropoietin at screening, day 15 of cycle 1, day 1 of cycle 3, monthly during follow-up and at study discontinuation.
• FSH & LH (everyone), DHEA & testosterone (males only), estrogen & estradiol (females only)at screening, day 1 of cycles 2, 3, and 4, monthly during follow- up period and at study discontinuation.
• EKG & ECHO at screening, day 1 of cycle 3 first month of follow-up period and at study discontinuation
• Dexa Scan at screening, day 1 of monthly follow-up period and at study discontinuation
• Transfusion assessment at screening, day 1, 8, 15 and 22 of cycle 1, day 1 and 15 of cycles 2, 3, and 4, monthly during follow-up period and at study discontinuation.
• Response assessment at day 8, 15, 22 of cycle 1, day 1 and 15 of cycles2, 3, and 4, monthly for 3 months during follow-up period and at study discontinuation
• Adverse events, concomitant therapies to be assessed at day 1, 8, 15, and 22 of cycle 1, day 1 and 15 of cycles 2, 3, and 4, monthly during follow-up period and at study discontinuation
• Drug administration day 1 of cycles 1, 2, 3, and 4.