Intra-patient Dose Escalation Study to Investigate Safety and Feasibility of Vactosertib in Treating Anemic MPN Patients

Study Overview
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Brief Summary
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This study assesses the potential of using a TGFβ receptor inhibitor for the treatment of anemic patients with myeloproliferative 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
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This is a two-tiered multi 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. 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, 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 concurrently with the patient's current treatment (if any). Prior to enrollment, patients must be on a stable dose of their current therapy for 3 months prior to entering the study. 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).

Official Title
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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)

Conditions
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Myeloproliferative Neoplasm

Intervention / Treatment
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* Drug: Vactosertib


Participation Criteria
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Eligibility Criteria
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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). For patients receiving cytoreductive therapy, they should be on a stable dose of current cytoreductive therapy for at least 3 months prior to C1D1. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is an intra-patient dose finding study which starts with low dose of vactosertib.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>Vactosertib intra-patient dose finding cohort. | Drug: Vactosertib<br>* 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.<br>* Other names: TEW-7197;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 16 weeks | 
| 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. | From baseline through 40 weeks | 
| 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). | From baseline through 40 weeks | 
| 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. | From baseline through 40 weeks | 
| 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. | From baseline through 40 weeks | 
| 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. | From baseline through 40 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Myeloproliferative Neoplasms. This will be determined by measuring the change in blood (and/or marrow) allelic ratio of MPN driver mutations (JAK2, CALR or MPL). | From baseline through 40 weeks | 
| Histologic change in the bone marrow | To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproliferative 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. | From baseline through 40 weeks | 
| Change in Molecular activity of vactosertib | To evaluate the on target molecular activity of vactosertib in anemic patients with Philadelphia negative Myeloproliferative 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. | From baseline through 40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anemia