safety and efficacy study of sotatercept in adults with transfusion dependent diamond blackfan anemia

Conditions: Diamond Blackfan Anemia

Summary: the purpose of this study is to determine the safety and dosing of drug sotatercept, as a subcutaneous injection, to stimulate production of red blood cell production. to be given every 28 days for up to four doses.

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. protocol amendment: the protocol has been amended to include an additional enrollment of 20 subjects with two additional dose levels of sotatercept (0.075 mg/kg and 0.100 mg/kg ) to be given with or without a prednisone boost. 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.

Eligibility criteria:
inclusion criteria: * \>/= 18 years of age * dba diagnosed * rbc transfusion- dependence (defined as \>/= 10 cc/kg of rbc per 28 days average) * karnofsky performance scale \>/= 70 * females of childbearing potential are to use birth control during study participation and for 112 days following the last dose of sotatercept * males must agree to use a latex condom during any sexual contact with females of childbearing potential while participating in the study and for 112 days following the last dose of sotatercept * agreement to adhere to the study visit schedule, understand and comply with all protocol requirements * understand and sign a written informed consent exclusion criteria: * creatinine clearance \< 30 ml/min * sgot \> 3x upper limit of normal, sgpt \> 3x upper limit normal, or bilirubin \>3x upper limit normal * heart disease (ny heart association classification of \>/= 3 * history of hypertension * subjects currently responsive to corticosteroids for treatment of diamond blackfan anemia * treatment with another investigational drug or device \<56 days pre-study entry * pregnant or lactating females * cancer

Keywords: diamond blackfan anemia dba blackfan diamond anemia congenital pure red cell aplasia aase-smith ii syndrome aase syndrome anemia, congenital pure red cell aplasia, congenital pure red cell bda congenital hypoplastic anemia erythrogenesis imperfecta hypoplastic congenital anemia inherited erythroblastopenia pure red cell aplasia bone marrow failure syndrome