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

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Primary Purpose

Status

Withdrawn

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Captopril

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study-related procedure is done that is not part of standard medical care, with the understanding that consent may be withdrawn by the participants any time without prejudice to future medical care.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

NCT ID

NCT04629651

First Posted

November 10, 2020

Last Updated

October 9, 2023

Sponsor

Case Comprehensive Cancer Center

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.

Bone Marrow Fibrosis, Myeloproliferative Neoplasm

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial