Clinical trial NCT04103645: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Myeloproliferative Neoplasm
Keywords: Anemia
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
First posted: 2019-09-25
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is an intra-patient dose finding study which starts with low dose of vactosertib.
Primary purpose: TREATMENT

Brief summary: 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: 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).

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).
* 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.

Primary outcomes:
measure: Identify the safest, minimally effective starting dose level for patients on Tier 1
timeFrame: Baseline to week 16
measure: Identify dose limiting toxicities (DLTs) in patients with MPN enrolled on Tier 1
timeFrame: Baseline to week 12
measure: Identify the maximum tolerated dose (MTD) of vactosertib in patients with MPN enrolled on Tier 1
timeFrame: Baseline to week 12
measure: Number of Tier 2 patients who have achieved Erythropoietic response as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria
timeFrame: baseline to week 16
measure: Number of Tier 2 patients who have achieved clinical response in symptoms as defined by International Working Group (IWG) criteria
timeFrame: baseline to week 16
measure: Number of Tier 2 patients who have achieved splenic response in symptoms as defined by International Working Group (IWG) criteria
timeFrame: baseline to week 16
measure: Identify dose limiting toxicities (DLTs) in patients with MPN enrolled on Tier 2
timeFrame: baseline to week 12
measure: Identify the maximum tolerated dose (MTD) of vactosertib in patients with MPN enrolled on Tier 2
timeFrame: baseline to week 12
Secondary outcomes:
measure: Number of patients in which a histological response is seen
timeFrame: 16 weeks
measure: Number of patients in which a molecular response is seen
timeFrame: 16 weeks
measure: Number of patients in which a pharmacodynamic response is seen
timeFrame: 16 weeks
measure: Number of patients who have experienced any of the following: hematologic toxicities, infections, disease progression, and thrombosis events
timeFrame: baseline to 16 weeks
measure: Overall survival defined as the amount of time a patient is alive after starting study treatment
timeFrame: baseline to 16 weeks
measure: Progression free survival defined as the duration of time from start of treatment to time of progression
timeFrame: baseline to 16 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Joseph M Scandura, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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