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The Use of Trifluoperazine in Transfusion Dependent DBA (DBA)

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ClinicalTrials.gov Identifier: NCT03966053
Recruitment Status : Recruiting
First Posted : May 29, 2019
Last Update Posted : March 3, 2020
Sponsor:
Information provided by (Responsible Party):
Adrianna Vlachos, Feinstein Institute for Medical Research

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Diamond Blackfan Anemia Pure Red Cell Aplasia Drug: Trifluoperazine Phase 1 Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Dose escalation study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II, Open Label Study to Determine Safety of Trifluoperazine (TFP) in Adults With Red Blood Cell Transfusion-Dependent Diamond Blackfan Anemia
Actual Study Start Date : September 13, 2019
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : June 1, 2022


Arm Intervention/treatment
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.
Drug: Trifluoperazine
Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days
Other Name: TFP

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.
Drug: Trifluoperazine
Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days
Other Name: TFP

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.
Drug: Trifluoperazine
Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days
Other Name: TFP

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.
Drug: Trifluoperazine
Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days
Other Name: TFP




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by the Simpson-Angus Scale and CTCAE v4.0 [ Time Frame: The subjects will be evaluated weekly for 4 weeks after the start of the 21-day course, 3 weeks while on the study drug and one week after completion. ]

    Each subject will undergo weekly safety assessment using the Simpson-Angus Extrapyramidal Side Effects Scale to determine the safety of TFP in this new population of patients. The subjects will also undergo weekly bloodwork to evaluate for any liver or kidney abnormalities as well as a complete blood count and reticulocyte count. All dosed subjects will be followed for an additional 1 week after discontinuing study drug (post-study safety follow-up). There will be no more than 6 subjects enrolled at any particular time.

    Treatment will be discontinued for any subject if their Hb is > 12 gm/dL , and not associated with RBC transfusions.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03966053


Contacts
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Contact: Eva Atsidaftos, MA 516-562-1504 eatsidaf@northwell.edu
Contact: Maryam Hussain, MPH 516-562-1505 mhussain9@northwell.edu

Locations
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United States, New York
The Feinstein Institute for Medical Research Recruiting
Manhasset, New York, United States, 11030
Contact: Eva Atsidaftos, MA    516-562-1504    eatsidaf@northwell.edu   
Contact: Maryam Hussain, MPH    516-562-1505    mhussain9@northwell.edu   
Principal Investigator: Adrianna Vlachos, MD         
Sub-Investigator: Jeffrey M Lipton, MD, PhD         
Sub-Investigator: Johnson M Liu, MD         
Sponsors and Collaborators
Adrianna Vlachos
Investigators
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Principal Investigator: Adrianna Vlachos, MD Northwell Health
  Study Documents (Full-Text)

Documents provided by Adrianna Vlachos, Feinstein Institute for Medical Research:
Informed Consent Form  [PDF] September 18, 2018


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Responsible Party: Adrianna Vlachos, Head, Bone Marrow Failure Program, Feinstein Institute for Medical Research
ClinicalTrials.gov Identifier: NCT03966053    
Other Study ID Numbers: 17-0748
First Posted: May 29, 2019    Key Record Dates
Last Update Posted: March 3, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Adrianna Vlachos, Feinstein Institute for Medical Research:
Diamond Blackfan Anemia
Additional relevant MeSH terms:
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Anemia
Anemia, Diamond-Blackfan
Red-Cell Aplasia, Pure
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Bone Marrow Diseases
Genetic Diseases, Inborn
Trifluoperazine
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action