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The Use of Trifluoperazine in Transfusion Dependent DBA (DBA)

Primary Purpose

Diamond Blackfan Anemia, Pure Red Cell Aplasia

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Trifluoperazine
Sponsored by
Adrianna Vlachos, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diamond Blackfan Anemia focused on measuring Diamond Blackfan Anemia

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Boston Children's hospital
  • The Feinstein Institute for Medical Research

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Cohort A

Cohort B

Cohort C

Cohort D

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Number of Participants With Treatment-related Adverse Events as Assessed by the Simpson-Angus Scale and CTCAE v4.0
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.

Secondary Outcome Measures

Full Information

First Posted
May 23, 2019
Last Updated
November 18, 2022
Sponsor
Adrianna Vlachos, MD
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1. Study Identification

Unique Protocol Identification Number
NCT03966053
Brief Title
The Use of Trifluoperazine in Transfusion Dependent DBA
Acronym
DBA
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Terminated
Why Stopped
Supporter terminated study due to slow subject accrual secondary to COVID pandemic limiting travel to research site.
Study Start Date
September 13, 2019 (Actual)
Primary Completion Date
October 13, 2021 (Actual)
Study Completion Date
October 13, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Adrianna Vlachos, MD

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diamond Blackfan Anemia, Pure Red Cell Aplasia
Keywords
Diamond Blackfan Anemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
Dose escalation study
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort A
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort B
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort C
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort D
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Trifluoperazine
Other Intervention Name(s)
TFP
Intervention Description
Trifluoperazine (TFP)1mg, 2mg, 5mg, or 10mg will be given once daily by mouth for 21 days
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-related Adverse Events as Assessed by the Simpson-Angus Scale and CTCAE v4.0
Description
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.
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Adrianna Vlachos, MD
Organizational Affiliation
Northwell Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
Boston Children's hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
The Feinstein Institute for Medical Research
City
Manhasset
State/Province
New York
ZIP/Postal Code
11030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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The Use of Trifluoperazine in Transfusion Dependent DBA

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