APG101 in Myelodysplastic Syndrome

Study Overview
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Brief Summary
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It has been shown in preclinical experiments with bone marrow from patients with myelodysplastic syndrome that APG101 rescues erythrocytes from premature cell death. This is expected to translate in an improved erythropoiesis and ameliorated anemia in MDS patients. APG101 might, therefore, be a valuable addition to current treatments of low- or intermediate MDS patients suffering from anaemia. Transfusion-dependent patients with low or intermediate risk MDS according to WHO Prognostic Scoring Scale (WPSS) can be included in this study. Treatment consists of 100mg APG101 intravenous as a weekly treatment over 12 weeks + 6 months follow up phase. Primary objective of the trial is safety and tolerability of APG101; secondary objectives are Hematologic, cytologic and cytogenetic response rate using modified International Working Group (IWG) response criteria Incidence and time to leukemic progression at 37 weeks OS (Overall survival) at 37 weeks

Official Title
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APG101 in Transfusion-Dependent Patients With Low or Intermediate Risk Myelodysplastic Syndrome

Conditions
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Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: Treatment with APG101
* Procedure: Bone marrow collection
* Procedure: Blood drawings


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Male and female patients with cytologically or histologically established diagnosis of de novo MDS according to the WHO-classification, either previously treated or untreated, presenting with low or intermediate risk features according to WHO prognostic status scale (WPSS) Diagnosis of MDS with a medullary blast count of less than 5% has to be established or confirmed by bone marrow morphology MDS with 5q deletion only if Lenalidomide is not a treatment option Red blood cell transfusion dependency of at least 4 units of packed red blood cells (PRBC) during the last 8 weeks before inclusion. Only PRBC transfusions given for a Hb level ≤ 9g/dl or a haemoglobin level > 9g/dl, if clinically indicated (e.g. coronary heart disease, long distance travel), will count. Patients refractory to Erythropoietin-stimulating agents (ESA) (as assessed after at least 8 weeks of treatment) or with a low possibility to respond to ESA treatment at least 18 years old, smoking or non-smoking, of any ethnic origin ECOG performance status ≤ 2 Suitable veins or existing port system for intra-venous infusion Adequate contraception Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form MDS with medullary blast count ≥ 5% Chronic monomyeloic leucemia (CMML) Therapy-related / secondary MDS High-risk karyotype according to WPSS Patients scheduled for bone marrow or stem cell transplant within the next 6 months Parallel treatment with ESA or with other experimental therapy Prior chemotherapy (including Vidaza) Treatment within the last 6 weeks with histone deacetylase (HDAC) inhibitors or ESAs Treatment within any other clinical trial parallel to the treatment phase of the current study or within 30 days before inclusion Active uncontrolled infection HIV, active hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection Any other condition / treatment or past medical history of diseases with poor prognosis that, in the opinion of the investigator, might interfere with the study History of or current drug or substance abuse History of other (haemato-) oncological disease (except for non-melanoma skin cancer and adequately treated in situ carcinoma of the cervix) Inability to understand the protocol requirements, instructions and study-related restrictions, the nature, scope, and possible consequences of the study Unlikely to comply with the protocol requirements, instructions and study-related restrictions; e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of completing the study Subject is the investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the study. Hypersensitivity to recombinant proteins or excipients in the investigational drug Pregnancy or breast feeding Vulnerable patients (e.g., minors or persons kept in detention)

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 100 mg APG101 weekly over 12 weeks<br>Single arm open label study. Patient receive 100 mg APG101 i.v. weekly over 12 weeks with a 6 monthly follow-up phase | Drug: Treatment with APG101<br>* Patients will be treated 12 weeks with 100 mg APG101 intravenous weekly<br>Procedure: Bone marrow collection<br>* During the study, bone marrow will be collected 4 times to assess study objectives<br>Procedure: Blood drawings<br>* During the study, blood will be drawn at different time points to assess study objectives<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Evaluation of adverse events (AEs) and serious adverse events (SAEs). Evaluation of electrocardiograms (ECGs), abdominal ultrasound, anti-drug antibodies (ADA), changes in lymphocyte subpopulations / activation markers and changes in performance status (ECOG). Any side effects potentially related to the APG101 treatment are evaluated. | During the whole study (37 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival (OS) is defined as time from start of study treatment to death from any cause | OS is captured for 37 weeks (during study) | 
| Changes in transfusion frequency | Changes in transfusion frequency will be evaluated as those are early signs of an improval in erythropoiesis | During the whole study. Baseline values are compared to values under treatment with APG101 (e.g baseline compared to week 12 and week 37) | 
| Changes of different parameters (e.g. histologic, cytologic, cytogenetic) in bone marrow according to Chesson criteria | By assessing different parameters (cytologic, hematologic, cytogenetic), safety as well as efficacy of treatment with APG101 can be evaluated | During the study (37 weeks) | 
| Changes in hemoglobin (Hb) level | Changes in Hb level will be evaluated as those are early signs of an improval in erythropoiesis | During the study (37 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS, Myelodysplastic syndrome, Low and intermediate risk, Transfusion-dependent patients, Transfusion, Anemia