Diamond Blackfan anemia (DBA) is a rare inherited pure red cell aplasia. The two main non-stem cell transplant therapeutic options are corticosteroids and red blood cell (RBC) transfusions. About 80% of DBA patients initially respond to corticosteroids, however, half of the patients cannot continue due to side effects or loss of response. These patients are then typically dependent on RBC transfusions throughout life. Each of these treatments is fraught with many side effects and significant morbidity and mortality are potential consequences of hematopoietic stem cell transplantation (SCT). The majority of individuals with DBA have mutations in genes encoding structural proteins of the small or large ribosomal subunit leading to deficiency of the particular ribosomal protein (RP). Using the RP deficient zebrafish embryo model, high throughput drug screens have demonstrated a strong hematologic response to several calmodulin inhibitors. One of these chemicals is trifluoperazine (TFP). TFP treatment of a mouse model of DBA also increased the red blood cell count and the hemoglobin (Hb) levels in the mice. TFP is a FDA-approved typical antipsychotic agent that has been available since 1958 with a well-known safety profile. In the United States, TFP is approved for the short-term treatment of generalized non-psychotic anxiety; treatment or prevention of nausea and vomiting of various causes; and, management of psychotic disorders.

This study aims to determine the safety/tolerability of TFP in adult subjects with DBA. TFP's expected dose-limiting toxicity is primarily neurologic (extrapyramidal) when used long-term at typical anti-psychotic doses (range 10-50 mg daily). Non-neurologic adverse effects in subjects with DBA have not been investigated. We will perform a dose escalation study to define the safety and tolerability of lower doses of this agent in subjects with DBA. To mitigate the potential risks of administering TFP to this new population, we will (1) start dosing at dose levels well below those prescribed for psychosis, (2) dose escalate to a maximum of 10 mg daily (the lowest dose typically prescribed for psychosis), and (3) perform weekly safety monitoring. Given the positive signal in DBA animal models and the 60-year clinical experience with higher doses of TFP, this drug warrants a trial in humans to assess tolerability in DBA.

This is a dose escalation safety/tolerability study to evaluate the presence of TFP-related adverse events in DBA subjects, and to determine the maximum tolerated dose (MTD) of TFP in DBA.

If tolerated, this trial will support either a proof of concept trial of low-dose TFP in DBA, or the advancement of a chemically modified TFP-like drug (to alleviate the neurologic toxicity) for the treatment of DBA.

• Diamond Blackfan Anemia
• Pure Red Cell Aplasia

• Experimental: Cohort A

  Cohort A: Three subjects will receive Trifluoperazine (TFP) 1 mg PO daily.

  • If there is no non-neurologic toxicity Grade 3 at the end of the 21 days, Cohort B will start.
  • If 1/3 subjects in Cohort A demonstrates toxicity Grade 3, an additional 3 subjects will be enrolled in Cohort A.
  • If 2 or more of the 6 subjects in Cohort A demonstrate toxicity Grade 3, the trial will be stopped; no MTD will be declared.
  • If less than 2 of the 6 subjects in Cohort A demonstrate toxicity Grade 3 within 21 days of starting therapy, Cohort B will start.
  Intervention: Drug: Trifluoperazine
• Experimental: Cohort B

  Cohort B: Three subjects will receive TFP 2 mg PO daily.

  • If there is no non-neurologic toxicity Grade 3 at the end of the 21 days, Cohort C will start.
  • If 1/3 subjects in Cohort B demonstrates toxicity Grade 3, an additional 3 subjects will be enrolled in Cohort B:
  • If 2 or more of the 6 subjects in Cohort B demonstrate toxicity Grade 3, the study will be stopped, and 1 mg/day will be declared the MTD.
  • If < 2 of the 6 subjects in Cohort B demonstrate toxicity Grade 3 within 21 days of starting therapy, Cohort C will start.
  Intervention: Drug: Trifluoperazine
• Experimental: Cohort C

  Cohort C: Three subjects will receive TFP 5 mg PO daily.

  • If there is no non-neurologic toxicity ≥ Grade 3 at the end of the 21 days, Cohort D will start.
  • If 1/3 subjects in Cohort C demonstrates toxicity Grade 3, an additional 3 subjects will be enrolled in Cohort C:
  • If 2 or more of the 6 subjects in Cohort C demonstrate toxicity Grade 3, the study will be stopped, and 2 mg/day will be declared the MTD.
  • If < 2 of the 6 subjects in Cohort C demonstrate toxicity Grade 3 within 21 days of starting therapy, cohort D will start.
  Intervention: Drug: Trifluoperazine
• Experimental: Cohort D

  Cohort D: Three subjects will receive TFP 10 mg PO daily.

  • If 0/3 subjects in Cohort D demonstrates toxicity Grade 3, the study will be stopped, and 10 mg/day will be declared the MTD.
  • If 1/3 subjects in Cohort D demonstrates toxicity Grade 3, an additional 3 subjects will be enrolled in Cohort D.
  • If 2 or more of the 6 subjects in Cohort D demonstrate toxicity Grade 3, the study will be stopped, and 5 mg/day will be declared the MTD.
  • If <2 of the 6 subjects in Cohort D demonstrate toxicity > Grade 3 within 21 days of starting therapy, 10mg/day will be declared the MTD.
  Intervention: Drug: Trifluoperazine

Inclusion Criteria:

• Men and women age: 18 years and <65 years of age.
• Weight: ≥45 kilograms.
• DBA diagnosed according to the DBA criteria (Vlachos, 2008)
• RBC transfusion-dependence (defined as 2 units packed RBCs per 28 days averaged over 84 days [12 weeks] prior to study entry)
• Calculated creatinine clearance > 30 mL/min
• Karnofsky performance status scale score ≥ 70
• Female subjects of childbearing potential must have a negative serum pregnancy test and use highly effective methods of birth control during the study
• Male subjects must agree to use a latex condom during any sexual contact with females of childbearing potential while participating in the study
• Agreement to adhere to the study visit schedule, understand and comply with all protocol requirements.

Exclusion Criteria:

• Liver: aspartate aminotransferase (AST) > 5 x the upper limit of normal (ULN), alanine aminotransferase (ALT) >5 x ULN, or bilirubin > 5 x ULN
• Heart disease (New York Heart Association classification of ≥ 3)
• History of angina
• Uncontrolled hypertension
• Subjects currently responsive to corticosteroids for treatment of DBA.
• Treatment with another investigational drug or device <56 days pre-study entry.
• Pregnant or lactating females
• Any history of severe allergic reaction requiring the use of epinephrine
• Known hypersensitivity to the study drug or other phenothiazines
• History or presence of extrapyramidal signs
• History of cancer