Back to resultsIntra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients
Primary Purpose
Myeloproliferative Neoplasm
Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Vactosertib
Sponsored by
About this trial
This is an interventional treatment trial for Myeloproliferative Neoplasm focused on measuring Anemia
Eligibility Criteria
Inclusion Criteria:
Patients who meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, MPN-U).
- Patients with MF must have DIPSS+ Intermediate or High-risk MF (primary of post-PV/ET).
- Anemia as defined by HGB < 10 g/dL, or transfusion of ≥ 2 packed red blood cell (PRBC) unit within the past 4 weeks with HGB ≤8.5g/dL.
Ineligible, unsuitable or refractoriness to ESA therapy defined as any of the following:
- Serum erythropoietin (EPO) >125 U/L.
- Proven ESA unsuitability is defined by history of any of the following:
- Loss of erythroid hematologic improvement while receiving stable or increased ESA dose; or
- ESA-attributed toxicity that, in the treating physician's opinion, makes ESA therapy unsuitable for subject.
- ESA refractoriness defined by lack of erythroid hematologic improvement to ESA:27
- Less than 1.5 g/dL increase in hemoglobin after at least 6 weeks of ESA therapy; or
- Ongoing transfusion dependence that has not been reduced by > 4U over an 8-week period compared to ESA pre-treatment 8 weeks.
- Acceptable Cardiovascular status
Exclusion Criteria:
- Any other serious medical condition which in the Investigator's opinion would preclude safe participation in the study.
- Patients with history of TIA or stroke within the past 12 months are excluded.
- Female subjects who are breastfeeding, or intend to breastfeed, during the study or in the 30 days following the last dose of study drug are excluded.
Sites / Locations
- Weill Medical College of Cornell UniversityRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment arm
Arm Description
Vactosertib intra-patient dose finding cohort.
Outcomes
Primary Outcome Measures
Number of adverse events
To establish a safe and tolerable dose and schedule of vactosertib in Philadelphia chromosome negative Myeloproliferative Neoplasms by recording all adverse events in patients receiving any dose of the drug. All adverse events will be documented accurately regardless of relationship to the study drug. The investigators will assess each adverse event and determine relatedness to study drug.
Change in symptoms of the disease while taking vactosertib
To assess the efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring symptomatic response. Symptomatic responses will be recorded as the change in scores on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) from baseline through to the end of study. The MPN-SAF-TSS is a questionnaire with questions related to different symptoms that are graded from 0 (not present) through 10 (worst imaginable). The scores are calculated by adding the score for each question at each time the questionnaire is completed. All scores will be compared to the score that was calculated at baseline to determine if there was a symptom response. A symptom response is defined as a change in score by more than 50% decrease from baseline.
Change in spleen size while taking vactosertib
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring splenic response. Splenic response will be measured by the change from baseline in spleen volume on a sonogram of the upper left quadrant (at the end of Tier treatment) and in the change from baseline of the spleen length measured by palpation (at each visit until the end of study).
Change in transfusion dependency while taking vactosertib
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change from baseline of transfusion dependency.This will be measured by comparing the number of transfusions a subject required in the 8 weeks prior to beginning therapy to the number of transfusions required while on study.
Change in hemoglobin values while taking vactosertib
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change in hemoglobin values from baseline. This will be measured by obtaining Complete Blood Counts (CBC) at every study visit.
Change in EPO levels while taking vactosertib
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change in EPO levels from baseline. Serum EPO levels will be measured on day 1 of each cycle.
Secondary Outcome Measures
Change in MPN driver mutation ratios in patients taking vactosertib
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproloferative Neoplasms. This will be determined by measuring the change in blood (and/or marrow) allelic ratio of MPN driver mutations (JAK2, CALR or MPL).
Histologic change in the bone marrow
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproloferative Neoplasms. This will be measured by the histologic response patients have to vactosertib. Histologic response will be measured by change in bone marrow biopsy cellularity and fibrosis grade.
Change in Molecular activity of vactosertib
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproloferative Neoplasms. This will be measured by looking at the SMAD2/3 phosphorylation measured by flow cytometry of peripheral blood and/or bone marrow hematopoietic cells or by immunohistochemical staining of bone marrow biopsy sections.
Full Information
NCT ID
NCT04103645
First Posted
September 18, 2019
Last Updated
December 19, 2022
Sponsor
Weill Medical College of Cornell University
1. Study Identification
Unique Protocol Identification Number
NCT04103645
Brief Title
Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients
Official Title
A 2-tiered, Phase 2, Rule-based, Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib (TEW-7197) in the Treatment of Anemic Patients With Philadelphia Chromosome-negative MPNs (Ph-neg MPNs)
Study Type
Interventional
2. Study Status
Record Verification Date
December 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 22, 2019 (Actual)
Primary Completion Date
September 1, 2023 (Anticipated)
Study Completion Date
September 1, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Weill Medical College of Cornell University
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
This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferetive neoplasms. TGFβ signaling is known to be abnormally high in patients with myeloproliferative neoplasms and it is thought that abnormal TGFβ signals cause many of the problems with blood cell formation in these diseases. The study design allows all patients to receive the study drug, vactosertib. The dose of vactosertib is individualized within a pre-set range based upon its effectiveness and tolerability. A total of up to 37 patients will be treated.
Detailed Description
This is a two-tiered single arm Phase 2 trial of vactosertib (TEW-7197) for the treatment of anemia in Ph-neg MPNs. Both tiers use a rule-based, accelerated dose escalation scheme to efficiently assess the potential of vactosertib to safely and effectively treat anemic patients with Ph-neg MPNs. The first tier of this trial (Tier 1) is an intra-patient dose finding study in 12 patients that uses a low starting dose of vactosertib for all patients. For each patent, the treatment dose is escalated according to prospectively-defined rules, and a toxicity and treatment effect algorithm during the period of 16 weeks (4 treatment cycles). If pre-established efficacy and safety endpoints are met (section 5.4, section 9.1, section 11.1), then Tier 1 of the study will be followed by a Tier 2 expansion study with an additional 25 patients for a period of 24 weeks (6 treatment cycles).
Vactosertib will be administered as monotherapy and therefore patients must be off cytoreductive therapies such as interferon, ruxolitinib, hydroxyurea, DNA hypomethylating agents or other cytotoxic chemotherapy prior to enrollment for a period of at least 14 days or 5 half-lives, whichever is longer. Supportive care measures including packed red blood cell (PRBC) transfusions for HGB <7g/dL, or symptomatic anemia, will be permitted. Administration of erythropoiesis stimulating agents (ESAs), however, will not be permitted on the trial (patients recruited would have serum EPO >125 U/L above which the benefit of ESAs is not supported).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloproliferative Neoplasm
Keywords
Anemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
This is an intra-patient dose finding study which starts with low dose of vactosertib.
Masking
None (Open Label)
Allocation
N/A
Enrollment
37 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment arm
Arm Type
Experimental
Arm Description
Vactosertib intra-patient dose finding cohort.
Intervention Type
Drug
Intervention Name(s)
Vactosertib
Other Intervention Name(s)
TEW-7197
Intervention Description
This drug is a TGF-Beta receptor type 1 inhibitor, by inhibiting phosphorylation of the ALK5 substrates SMAD2 and SMAD3. This inhibition could promote regeneration of normal human stem cells and proliferation of erythroid progenitors to treat the underlying hypoproliferative anemia in advanced MPNs.
Primary Outcome Measure Information:
Title
Number of adverse events
Description
To establish a safe and tolerable dose and schedule of vactosertib in Philadelphia chromosome negative Myeloproliferative Neoplasms by recording all adverse events in patients receiving any dose of the drug. All adverse events will be documented accurately regardless of relationship to the study drug. The investigators will assess each adverse event and determine relatedness to study drug.
Time Frame
16 weeks
Title
Change in symptoms of the disease while taking vactosertib
Description
To assess the efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring symptomatic response. Symptomatic responses will be recorded as the change in scores on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) from baseline through to the end of study. The MPN-SAF-TSS is a questionnaire with questions related to different symptoms that are graded from 0 (not present) through 10 (worst imaginable). The scores are calculated by adding the score for each question at each time the questionnaire is completed. All scores will be compared to the score that was calculated at baseline to determine if there was a symptom response. A symptom response is defined as a change in score by more than 50% decrease from baseline.
Time Frame
From baseline through 40 weeks
Title
Change in spleen size while taking vactosertib
Description
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring splenic response. Splenic response will be measured by the change from baseline in spleen volume on a sonogram of the upper left quadrant (at the end of Tier treatment) and in the change from baseline of the spleen length measured by palpation (at each visit until the end of study).
Time Frame
From baseline through 40 weeks
Title
Change in transfusion dependency while taking vactosertib
Description
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change from baseline of transfusion dependency.This will be measured by comparing the number of transfusions a subject required in the 8 weeks prior to beginning therapy to the number of transfusions required while on study.
Time Frame
From baseline through 40 weeks
Title
Change in hemoglobin values while taking vactosertib
Description
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change in hemoglobin values from baseline. This will be measured by obtaining Complete Blood Counts (CBC) at every study visit.
Time Frame
From baseline through 40 weeks
Title
Change in EPO levels while taking vactosertib
Description
To assess efficacy of vactosertib in treating anemic patients with Philadelphia chromosome negative Myeloproliferative Neoplasms by measuring erythropoietic response. Erythropoietic response will be measured by the change in EPO levels from baseline. Serum EPO levels will be measured on day 1 of each cycle.
Time Frame
From baseline through 40 weeks
Secondary Outcome Measure Information:
Title
Change in MPN driver mutation ratios in patients taking vactosertib
Description
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproloferative Neoplasms. This will be determined by measuring the change in blood (and/or marrow) allelic ratio of MPN driver mutations (JAK2, CALR or MPL).
Time Frame
From baseline through 40 weeks
Title
Histologic change in the bone marrow
Description
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproloferative Neoplasms. This will be measured by the histologic response patients have to vactosertib. Histologic response will be measured by change in bone marrow biopsy cellularity and fibrosis grade.
Time Frame
From baseline through 40 weeks
Title
Change in Molecular activity of vactosertib
Description
To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproloferative Neoplasms. This will be measured by looking at the SMAD2/3 phosphorylation measured by flow cytometry of peripheral blood and/or bone marrow hematopoietic cells or by immunohistochemical staining of bone marrow biopsy sections.
Time Frame
From baseline through 40 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients who meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, MPN-U).
Patients with MF must have DIPSS+ Intermediate or High-risk MF (primary of post-PV/ET).
Anemia as defined by HGB < 10 g/dL, or transfusion of ≥ 2 packed red blood cell (PRBC) unit within the past 4 weeks with HGB ≤8.5g/dL.
Ineligible, unsuitable or refractoriness to ESA therapy defined as any of the following:
Serum erythropoietin (EPO) >125 U/L.
Proven ESA unsuitability is defined by history of any of the following:
Loss of erythroid hematologic improvement while receiving stable or increased ESA dose; or
ESA-attributed toxicity that, in the treating physician's opinion, makes ESA therapy unsuitable for subject.
ESA refractoriness defined by lack of erythroid hematologic improvement to ESA:27
Less than 1.5 g/dL increase in hemoglobin after at least 6 weeks of ESA therapy; or
Ongoing transfusion dependence that has not been reduced by > 4U over an 8-week period compared to ESA pre-treatment 8 weeks.
Acceptable Cardiovascular status
Exclusion Criteria:
Any other serious medical condition which in the Investigator's opinion would preclude safe participation in the study.
Patients with history of TIA or stroke within the past 12 months are excluded.
Female subjects who are breastfeeding, or intend to breastfeed, during the study or in the 30 days following the last dose of study drug are excluded.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joseph M Scandura, MD, PhD
Phone
646-962-2700
Email
jms2003@med.cornell.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Niamh Savage
Phone
212-746-1493
Email
nis2049@med.cornell.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph M Scandura, MD, PhD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Weill Medical College of Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joseph Scandura, MD, PhD
Phone
212-746-6736
Email
jms2003@med.cornell.edu
First Name & Middle Initial & Last Name & Degree
Niamh Savage
Phone
212-746-1493
12. IPD Sharing Statement
Plan to Share IPD
No
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Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients
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