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Captopril Use on the Degree of Marrow Fibrosis in Bone Marrow Fibrosis/Myeloproliferative Neoplasms

Primary Purpose

Bone Marrow Fibrosis, Myeloproliferative Neoplasm

Status
Withdrawn
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Captopril
Sponsored by
Case Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bone Marrow Fibrosis focused on measuring primary myelofibrosis (PMF), post-polycythemia vera/essential thrombocythemia-MF (secondary MF)

Eligibility Criteria

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

Inclusion Criteria:

  • Participants must have histologically confirmed diagnosis of primary myelofibrosis (PMF), or post-polycythemia vera/essential thrombocythemia-MF (i.e. secondary MF) by 2016 WHO criteria
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0 -2
  • Creatinine clearance >30 ml/minute
  • Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment. All men and women of childbearing potential must use acceptable methods of birth control throughout the study.
  • Participants should be able to give voluntary informed written consent to participate in the study. Informed consent will be obtained prior to enrollment and before any study-related procedure is done that is not part of standard medical care, with the understanding that consent may be withdrawn by the participants any time without prejudice to future medical care.

Exclusion Criteria:

  • Completed hematopoietic cell transplant (HCT)
  • Presence of >10% blasts in peripheral blood or on bone marrow examination
  • Screening blood pressure(BP)parameters of systolic BP < 100 and diastolic BP < 60
  • Splenic irradiation within 3 months prior to the first dose of captopril
  • Prior ACE inhibitor, angiotensin II receptor antagonist, or aliskiren use within 12 months prior to trial enrolment
  • Known allergy/hypersensitivity to ACE inhibitors
  • Participants receiving any other investigational agents
  • Pregnant or nursing participants - captopril is a risk category D and is excreted in breast milk
  • Participants with creatinine clearance <30 ml/minute or on dialysis
  • Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent

Sites / Locations

  • Cleveland Clinic, Case Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Captopril

Arm Description

In phase I, Cohorts of 3 patients each will receive doses of captopril with a goal dose of 150mg total by mouth (PO) daily. Initial dose per patient will start at 12.5 mg daily, which will then be increased on weekly intervals as tolerated. To be administered per the intra-patient dose escalation scheme below Phase I: Day 0: 12.5mg/day Day 7: 12.5mg twice daily Day 14: 12.5mg three times daily Day 21: 25mg three times daily Day 28: 50mg three times daily Phase II: The efficacy of captopril will be assessed in the Phase II portion. Captopril given at Maximum Tolerated Dose - bone marrow evaluation to be done at 6 months

Outcomes

Primary Outcome Measures

Change in degree of bone marrow fibrosis by World Health Organization WHO grade
Change in degree of bone marrow fibrosis by WHO grade. "Change" is defined as reduction by one grade (e.g. MF-3 to MF-2 or MF-2 to MF-1)

Secondary Outcome Measures

Change in spleen size by ultrasound
Change in spleen size in centimeters measured using abdominal ultrasound by an experienced radiologist. Spleen length will be asses for response
Change in spleen size by ultrasound
Change in spleen size in centimeters measured using abdominal ultrasound by an experienced radiologist. Spleen length will be asses for response
Change in symptom burden assessed using Myeloproliferative Neoplasm Symptom Assessment Form total symptom scores (MPN-SAF TSS)
Change in symptom burden assessed using MPN-SAF TSS The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
Change in symptom burden assessed using MPN-SAF TSS
Change in symptom burden assessed using Myeloproliferative Neoplasm Symptom Assessment Form total symptom scores (MPN-SAF TSS). The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
Response rate per International Working Group-Myeloproliferative Neoplasms Research and Treatment 2 (IWG-MRT) Criteria as measured by percent of participants with CR, PR, or CI
Includes Complete response (CR), partial remission (PR) or Clinical improvement (CI) CR: Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF AND Peripheral blood: Hemoglobin ≥10 g/dL and <upper normal limit (UNL); Neutrophil count ≥1 x 10^9/L and <UNL; Platelet count ≥100 x 10^9/L and <UNL;<2% immature myeloid cells Clinical: Resolution of disease symptoms; Spleen & liver not palpable; No evidence of extramedullary hematopoiesis (EMH) PR: Periph. blood: Hem. ≥10 g/dL and <UNL; Neutrophil count ≥1 x 10^9/L and <UNL; Platelet count ≥100 x 10^9/L & <UNL;<2% immature myeloid cells OR Bone marrow: [See CR] AND Peripheral blood: Hem. ≥85, but <10 g/dL & <UNL; Neutrophil count ≥1 x 10^9/L & <UNL; Platelet count ≥50, but <100 x 109/L and <UNL; <2% immature myeloid cells Clinical:[See CR] CI: Achievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia

Full Information

First Posted
November 10, 2020
Last Updated
October 9, 2023
Sponsor
Case Comprehensive Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04629651
Brief Title
Captopril Use on the Degree of Marrow Fibrosis in Bone Marrow Fibrosis/Myeloproliferative Neoplasms
Official Title
Phase I/II Prospective Trial Investigating the Safety and Efficacy of Captopril Use on the Degree of Marrow Fibrosis in Patients With Primary or Secondary Bone Marrow Fibrosis/Myeloproliferative Neoplasms
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Withdrawn
Why Stopped
PI discretion
Study Start Date
April 2024 (Anticipated)
Primary Completion Date
October 2024 (Anticipated)
Study Completion Date
October 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Case Comprehensive Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety and tolerability of captopril and evaluate the effectiveness captopril as measured by changes in the grade of bone marrow scar tissue. The change in spleen size by ultrasound will also be measured.
Detailed Description
Captopril is an investigational (experimental) drug that works by inhibiting the production of angiotensin II by blocking angiotensin converting enzyme. Reducing angiotensin II may reduce the bone marrow scar tissue in myelofibrosis. It is not approved by the Food and Drug Administration (FDA) for this indication. Participants in this study will be asked to have 2 bone marrow biopsies, a total of 3 blood samples, and fill out questionnaires asking about how you feel.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bone Marrow Fibrosis, Myeloproliferative Neoplasm
Keywords
primary myelofibrosis (PMF), post-polycythemia vera/essential thrombocythemia-MF (secondary MF)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Captopril
Arm Type
Experimental
Arm Description
In phase I, Cohorts of 3 patients each will receive doses of captopril with a goal dose of 150mg total by mouth (PO) daily. Initial dose per patient will start at 12.5 mg daily, which will then be increased on weekly intervals as tolerated. To be administered per the intra-patient dose escalation scheme below Phase I: Day 0: 12.5mg/day Day 7: 12.5mg twice daily Day 14: 12.5mg three times daily Day 21: 25mg three times daily Day 28: 50mg three times daily Phase II: The efficacy of captopril will be assessed in the Phase II portion. Captopril given at Maximum Tolerated Dose - bone marrow evaluation to be done at 6 months
Intervention Type
Drug
Intervention Name(s)
Captopril
Intervention Description
Oral, to be administered per the dose escalation scheme.
Primary Outcome Measure Information:
Title
Change in degree of bone marrow fibrosis by World Health Organization WHO grade
Description
Change in degree of bone marrow fibrosis by WHO grade. "Change" is defined as reduction by one grade (e.g. MF-3 to MF-2 or MF-2 to MF-1)
Time Frame
At 6 months
Secondary Outcome Measure Information:
Title
Change in spleen size by ultrasound
Description
Change in spleen size in centimeters measured using abdominal ultrasound by an experienced radiologist. Spleen length will be asses for response
Time Frame
At 3 months
Title
Change in spleen size by ultrasound
Description
Change in spleen size in centimeters measured using abdominal ultrasound by an experienced radiologist. Spleen length will be asses for response
Time Frame
At 6 months
Title
Change in symptom burden assessed using Myeloproliferative Neoplasm Symptom Assessment Form total symptom scores (MPN-SAF TSS)
Description
Change in symptom burden assessed using MPN-SAF TSS The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
Time Frame
At 3 months
Title
Change in symptom burden assessed using MPN-SAF TSS
Description
Change in symptom burden assessed using Myeloproliferative Neoplasm Symptom Assessment Form total symptom scores (MPN-SAF TSS). The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF TSS.
Time Frame
At 6 months
Title
Response rate per International Working Group-Myeloproliferative Neoplasms Research and Treatment 2 (IWG-MRT) Criteria as measured by percent of participants with CR, PR, or CI
Description
Includes Complete response (CR), partial remission (PR) or Clinical improvement (CI) CR: Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF AND Peripheral blood: Hemoglobin ≥10 g/dL and <upper normal limit (UNL); Neutrophil count ≥1 x 10^9/L and <UNL; Platelet count ≥100 x 10^9/L and <UNL;<2% immature myeloid cells Clinical: Resolution of disease symptoms; Spleen & liver not palpable; No evidence of extramedullary hematopoiesis (EMH) PR: Periph. blood: Hem. ≥10 g/dL and <UNL; Neutrophil count ≥1 x 10^9/L and <UNL; Platelet count ≥100 x 10^9/L & <UNL;<2% immature myeloid cells OR Bone marrow: [See CR] AND Peripheral blood: Hem. ≥85, but <10 g/dL & <UNL; Neutrophil count ≥1 x 10^9/L & <UNL; Platelet count ≥50, but <100 x 109/L and <UNL; <2% immature myeloid cells Clinical:[See CR] CI: Achievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia
Time Frame
Up to 1 year from end of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must have histologically confirmed diagnosis of primary myelofibrosis (PMF), or post-polycythemia vera/essential thrombocythemia-MF (i.e. secondary MF) by 2016 WHO criteria Eastern Cooperative Oncology Group (ECOG) Performance Status 0 -2 Creatinine clearance >30 ml/minute Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment. All men and women of childbearing potential must use acceptable methods of birth control throughout the study. Participants should be able to give voluntary informed written consent to participate in the study. Informed consent will be obtained prior to enrollment and before any study-related procedure is done that is not part of standard medical care, with the understanding that consent may be withdrawn by the participants any time without prejudice to future medical care. Exclusion Criteria: Completed hematopoietic cell transplant (HCT) Presence of >10% blasts in peripheral blood or on bone marrow examination Screening blood pressure(BP)parameters of systolic BP < 100 and diastolic BP < 60 Splenic irradiation within 3 months prior to the first dose of captopril Prior ACE inhibitor, angiotensin II receptor antagonist, or aliskiren use within 12 months prior to trial enrolment Known allergy/hypersensitivity to ACE inhibitors Participants receiving any other investigational agents Pregnant or nursing participants - captopril is a risk category D and is excreted in breast milk Participants with creatinine clearance <30 ml/minute or on dialysis Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aaron Gerds, MD
Organizational Affiliation
Cleveland Clinic, Case Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cleveland Clinic, Case Comprehensive Cancer Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44122
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
There is a plan to make all individual participant data (IPD) and related data dictionaries available. We will also make the protocol available.

Learn more about this trial

Captopril Use on the Degree of Marrow Fibrosis in Bone Marrow Fibrosis/Myeloproliferative Neoplasms

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