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

Sponsor
Weill Medical College of Cornell University (Other)
Overall Status
Recruiting
CT.gov ID
NCT04103645
Collaborator
(none)
37
Enrollment
1
Location
1
Arm
57.3
Anticipated Duration (Months)
0.6
Patients Per Site Per Month

Study Details

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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).

Study Design

Study Type:
Interventional
Anticipated Enrollment :
37 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
This is an intra-patient dose finding study which starts with low dose of vactosertib.This is an intra-patient dose finding study which starts with low dose of vactosertib.
Masking:
None (Open Label)
Primary Purpose:
Treatment
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)
Actual Study Start Date :
Nov 22, 2019
Anticipated Primary Completion Date :
Sep 1, 2023
Anticipated Study Completion Date :
Sep 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment arm

Vactosertib intra-patient dose finding cohort.

Drug: Vactosertib
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.
Other Names:
  • TEW-7197

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of adverse events [16 weeks]

      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.

    2. Change in symptoms of the disease while taking vactosertib [From baseline through 40 weeks]

      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.

    3. Change in spleen size while taking vactosertib [From baseline through 40 weeks]

      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).

    4. Change in transfusion dependency while taking vactosertib [From baseline through 40 weeks]

      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.

    5. Change in hemoglobin values while taking vactosertib [From baseline through 40 weeks]

      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.

    6. Change in EPO levels while taking vactosertib [From baseline through 40 weeks]

      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

    1. Change in MPN driver mutation ratios in patients taking vactosertib [From baseline through 40 weeks]

      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).

    2. Histologic change in the bone marrow [From baseline through 40 weeks]

      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.

    3. Change in Molecular activity of vactosertib [From baseline through 40 weeks]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    Patients who meet the WHO 2016 criteria for a Ph-neg MPN (including PV, ET, MF, MDS/MPN, MPN-U).

    • Patients with DIPSS Int-2 or High-risk MF (primary of post-PV/ET) must have had inadequate response to ruxolitinib

    • Patients with PV or ET should be refractory or unresponsive to hydroxyurea, anagrelide or other available therapy.

    • 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Weill Medical College of Cornell University New York New York United States 10021

    Sponsors and Collaborators

    • Weill Medical College of Cornell University

    Investigators

    • Principal Investigator: Joseph M Scandura, MD, PhD, Weill Medical College of Cornell University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Weill Medical College of Cornell University
    ClinicalTrials.gov Identifier:
    NCT04103645
    Other Study ID Numbers:
    • 19-06020285
    First Posted:
    Sep 25, 2019
    Last Update Posted:
    Dec 21, 2021
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Weill Medical College of Cornell University
    Anemia
    Additional relevant MeSH terms:
    Myeloproliferative Disorders

    Study Results

    No Results Posted as of Dec 21, 2021