Validation of a Predictive Model of Response to Romiplostim in Patients With IPSS Low or Intermediate-1 Risk MDS and Thrombocytopenia

Study Overview
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Brief Summary
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There are currently no licensed drugs in the EU to treat thrombocytopenia in MDS patients classified as IPSS low/int-1. Prior studies with romiplostim (a TPO receptor agonist) in MDS found that baseline concentration of TPO as well as transfusion history were predictive of subsequent response in a retrospective model. The current prospective study has the aim to explore whether both pretreatment variables (endogenous TPO, TPO-level, platelet transfusion history) can predict the response to subsequent short-term treatment with romiplostim.

Detailed Description
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Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies of the pluripotent hematopoietic stem cells characterized by clonal hematopoiesis, progressive bone marrow failure, and the propensity to transform to acute myeloid leukemia (AML) (Malcovati et al., 2013). There are currently no licensed drugs in the EU to treat thrombocytopenia in MDS patients classified as IPSS low/int-1. Prior studies with romiplostim (a TPO receptor agonist) in MDS found that baseline concentration of TPO as well as transfusion history were predictive of subsequent response in a retrospective model. Classically, MDS is associated with apoptosis and excessive proliferation, resulting in a combination of a hyper-cellular marrow and peripheral cytopenia. The rationale for using romiplostim in MDS is to stimulate normal progenitor cells to increase platelet counts. Upon correction of thrombocytopenia, responding MDS patients should have a decreased risk of bleeding and a reduction in platelet transfusions (Giagounidis et al., 2014). This reduction in platelet transfusions may in turn decrease the risks of alloimmunization and the resultant morbidity and costs associated with that condition.

Official Title
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Prospective Validation of a Predictive Model of Response to Romiplostim in Patients With IPSS Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS) and Thrombocytopenia - the EUROPE-trial

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: N-Plate / romiplostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet the following inclusion/exclusion criteria to be eligible for the study. Must understand and voluntarily sign the informed consent form Age older 18 years at the time of signing the informed consent form Must be able to adhere to the study visit schedule and other protocol requirements Diagnosis of MDS using the 2008 WHO classification for myeloid neoplasms as assessed during the screening period Per MDS IPSS, low or intermediate-1 risk MDS as assessed during the screening period The mean of the 2 platelet counts taken within 4 weeks prior to stratification must be: ≤ 30 x 109/L (with no individual count > 30 x 109/L during the screening period), with or without a history of bleeding associated with the diagnosis of MDS, OR < 50 x 109/L (with no individual count >60 x 109/L during the screening period), with a history of bleeding associated with the diagnosis of MDS (A standard of care platelet count taken prior to Informed consent may be used as 1 of the 2 counts taken within 4 weeks prior to stratification) Adequate liver function, as evidenced by ALT ≤ 3 times the laboratory normal range, AST ≤ 3 times the laboratory normal range and total bilirubin ≤ 2 times the laboratory normal range Bone marrow aspirate (central diagnostics) with cytogenetics (local) within 8 weeks of starting first dose of investigational product Female subjects of childbearing potential† must: Agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy and for 4 weeks after the end of study drug therapy, even if she has amenorrhoea. This applies unless the subject commits to absolute and continued abstinence confirmed on a monthly basis. Male patients who wish to participate in the study and their partner may become pregnant must agree also to reliable contraception during the study and for three months thereafter. The following are effective methods of contraception* Implant, - Levonorgestrel-releasing intrauterine system (IUS), Medroxyprogesterone acetate depot, Tubal sterilization, Sexual intercourse with a vasectomised male partner only; Ovulation inhibitory progesterone-only pills (i.e., desogestrel) Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days before the start of study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence. Exclusion Criteria: Pregnant or lactating females IPSS intermediate-2 or high-risk ≥ 5% blasts in the bone marrow as determined by central morphology during screening Previous treatment with any thrombopoietic growth factor Prior history of hematopoietic stem cell transplantation, leukemia, aplastic anemia or other non-MDS related bone marrow stem cell disorder Active or uncontrolled disease including infections or cancer Unstable angina, congestive heart failure (NYHA > class II), uncontrolled hypertension History of arterial thrombosis (e.g., stroke or transient ischemic attack) within the past year History of venous thrombosis that currently requires anti-coagulation therapy Prior use of sc or iv AZA. Receipt of G-CSF, peg-G-CSF, or GM-CSF,IL-11, ESA or LEN within 4 weeks of the first dose of romiplostim Planned receipt of peg-G-CSF or GM-CSF after the first dose of investigational product Subjects of reproductive potential who are not using adequate contraceptive precautions, in the judgment of the investigator. A double barrier method is defined as 2 methods of contraception, for example 2 actual barrier methods, or 1 actual barrier method and 1 hormonal method. Known hypersensitivity to any recombinant E. coli-derived product (eg, Nplate, Infergen, Neupogen, Somatropin, and Actimmune) Inability to comply with study procedures. Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s) Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Stratification into group 1 if Score (Baseline-TPO Level and previous thrombocyte transfusions) are +3 TPO based model to predict subsequent response to romiplostim in MDS patients with IPSS Low/Int-1 according to a model developed by Sekeres et. al./ BJH 2014 | Drug: N-Plate / romiplostim<br>* medical intervention in 3 patient groups (MDS patients with IPSS Low/Int-1) that are stratified according to their baseline TPO-Level and previous transfusions<br>|
| Experimental: Group 2<br>Stratification into group 2 if Score (Baseline-TPO Level and previous thrombocyte transfusions) are -1 or -2 TPO based model to predict subsequent response to romiplostim in MDS patients with IPSS Low/Int-1 according to a model developed by Sekeres et. al./ BJH 2014 | Drug: N-Plate / romiplostim<br>* medical intervention in 3 patient groups (MDS patients with IPSS Low/Int-1) that are stratified according to their baseline TPO-Level and previous transfusions<br>|
| Experimental: Group 3<br>Stratification into group 3 if Score (Baseline-TPO Level and previous thrombocyte transfusions) are -6 TPO based model to predict subsequent response to romiplostim in MDS patients with IPSS Low/Int-1 according to a model developed by Sekeres et. al./ BJH 2014 | Drug: N-Plate / romiplostim<br>* medical intervention in 3 patient groups (MDS patients with IPSS Low/Int-1) that are stratified according to their baseline TPO-Level and previous transfusions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hematologic Improvement of Platelets (HI-P) After 4 Months on Therapy | The primary efficacy endpoint was the rate of HI-P defined as an absolute increase of platelet count to ≥ 30/nL for patients starting at > 20/nL or an increase of platelets from < 20/nL to > 20/nL and by at least 100%, according to IWG 2006 criteria lasting for ≥ 8 weeks after at least 16 Weeks of romiplostim treatment. | after 4 months on therapy (week 16) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Hematologic Improvement | Cumulative rate of hematologic improvement of platelets (HI-P), erythrocytes (HI-E) and neutrophil granulocytes (HI-N). None of the patients achieved simultaneous response of HI-P, HI-E and HI-N. | week 16 | 
| The Incidence of Disease Progression to Higher Stage MDS or AML | The incidence of disease progression to higher stage MDS or AML according to WHO (increase in blast percentage of ≥ 20 %) | week 16 | 
| Increase of Peripheral Blasts During Therapy |  | week 16 | 
| Association of the Presence of Certain Mutations With Disease Progression in a Retrospective Analysis |  | week 16 | 
| Incidence of Bleeding Events |  | up to 12 months | 
| Type, Incidence and Severity of All Adverse Events Including Clinically Significant Changes in Laboratory Values |  | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS classified as IPSS low/int-1