Early Detection and Screening of Hematological Malignancies - SANGUINE

Study Overview
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Brief Summary
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This is a multicenter, open-label, non-interventional controlled study to identify and characterize the epigenetic signatures for a set of hematological malignancies: Multiple myeloma (MM), pre-MM conditions [smoldering MM (SMM) and monoclonal gammopathy of undetermined significance (MGUS)], Hodgkin lymphoma (HL), non-Hodgkin aggressive lymphoma NHL [diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Marginal Zone Lymphoma (MZL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and subjects at risk and control subjects with no malignant disease.

Detailed Description
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Subjects will be screened for eligibility and then, after signing an Informed Consent Form, the first peripheral blood sample will be obtained. Periodical blood samples will be obtained from the participants. Relapse patients will have their retrospective blood samples analyzed to identify early signs of disease. The first stage (discovery phase) will include at least 30 patients from each of the following groups: MM, pre-MM conditions (SMM and MGUS), HL, aggressive NHL (DLBCL, HGL, FL, and MZL transformed to large cell lymphoma), FL, MZL, AML, MDS, and control subjects with no malignant disease. In the second stage, at least 250 patients with MM and 250 patients with NHL, and at least 100 patients with each of the remaining hematological malignancies mentioned above will be tested. Out of these patients, AML, lymphoma and MM patients will be followed-up at the clinical sites. Periodic sampling will be defined according to disease type and progression rate. Blood and plasma samples will be stored in the clinical sites until relapse diagnosis. At this stage, blood samples will be analyzed retrospectively on the HemaChip. The screening, enrollment and blood collection can begin in the first stage of the trial, in order to allow a maximum follow-up period for at-risk subjects as part of the study and to meet the recruitment goals. The last stage consists of the screening of a larger group of subjects with a high risk of blood cancer. This stage will include three populations: up to 1000 follow-up patients from each blood cancer: AML, lymphoma, and MM, up to 600 elderly patients (>65 years old) at risk of developing MM, and up to 400 first-degree relatives of patients (and in particular siblings). In order to allow a maximum follow-up period for at-risk subjects as part of the study, and to meet the recruitment goals, the screening, and enrollment can begin in the first stage of the trial. The last stage consists of screening a larger group of subjects at risk of developing MM / lymphoproliferative disorder. This stage will include 400 elderly patients (>65 years old) and 500 first-degree relatives of patients (and in particular siblings). The screening, enrollment, and sample collection can begin in the first stage of the trial, in order to allow a maximum follow-up period for at-risk subjects as part of the study and to meet the recruitment goals. In all stages, the age and sex-matched subgroups will be considered and matched. During the follow-up period, demographic and baseline parameters including sex, age, race, height and weight, medical history, smoking status, details of initial diagnosis and treatment history, concomitant medications as well as adverse events (AEs) of special interest (see section 9.1), (serious) AEs related to study procedures, treatment for the disease, disease response and survival status will be collected (as applicable).

Official Title
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Early Detection and Screening of Hematological Malignancies - SANGUINE

Conditions
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Hematologic Malignancy

Intervention / Treatment
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* Diagnostic Test: Blood sampling for HemaChip screening/diagnostic testing
* Diagnostic Test: Bone marrow sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General criteria for all study populations: Male and female subjects ≥18 years of age Ability to understand and willingness to sign a written informed consent document. For Patients with hematological malignancies: 1. Patients who have been diagnosed, have measurable disease and/or are being monitored/followed up due to one of the following conditions: MM, pre-MM conditions (SMM and MGUS), HL, aggressive NHL (DLBCL), FL, MZL, AML, MDS that did not yet undergo any treatment. NOTE: Patients diagnosed with DLBCL that is transformed from FL or MZL, and patients diagnosed with AML secondary to MDS or MPN, that were treated for their primary disease (FL/MZL/MDS/MPN) prior to study enrollment, are eligible. For subjects at risk for developing the investigated hematological malignancies: First-degree relatives; Elderly subjects ≥ 65 years of age. Exclusion Criteria: Patients/subjects with current co-diagnosis of another type of cancer; Patients/subjects with a known active or prior cancer (other than defined as study population), occurring within the last 2 years (even if considered to be in complete remission). Patients/subjects with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection; Patients/subjects with active inflammatory autoimmune disease that requires treatment with immunosuppressive/ immunomodulation agents; Patients/subjects with known human immunodeficiency virus (HIV) positive; Patients/subjects with known active Hepatitis A/B/C or past hepatitis C; Subjects that are likely to be noncompliant with the protocol, or felt to be unsuitable by the investigator for any other reason.

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with Hematological Malignancies - Discovery stage<br>The first stage (discovery phase) will include at least 30 patients from each of the following groups: MM, pre-MM conditions (SMM and MGUS), HL, aggressive NHL (DLBCL, HGL, FL, MZL, AML, MDS. NOTE: Patients diagnosed with DLBCL that is transformed from FL or MZL, and patients diagnosed with AML secondary to MDS or MPN, that were treated for their primary disease (FL/MZL/MDS/MPN) prior to study enrollment, are eligible. For patients, it is expected, after signing the informed consent, that the serial samplings will be performed during the disease follow-up according to the standard clinical practice and/or recommended schedule and disease assessment plan. Bone marrow samples will be obtained at Tel-Aviv Sourasky Medical Center (TASMC) from up to 50 MM patients and up to 50 AML patients that undergo bone marrow aspiration as part of the standard care procedure. | Diagnostic Test: Blood sampling for HemaChip screening/diagnostic testing<br>* Classification of a broad spectrum of blood cancers based on detection of epigenetic biomarkers from genomic DNA, cell-free (cf) DNA, exosomal DNA, RNA and non-coding RNA. The identified biomarkers will include proteins, metabolites, and other characteristic biomolecules. Year 1: During the discovery phase, all tests will be conducted by JaxBio and TAU with the aid of technical service providers. At this stage, microarray measurements will be performed on a commercial platform that will be purchased from Agilent / Illumina. All reagents needed for the test will be either purchased or produced in-house. Years 2-3: Throughout the second phase of the project, a custom targeted microarray, HemaChip will be developed and used for all tests. The HemaChip and custom reagents will be distributed to partners' labs and all tests will be conducted at the clinical sites. Additional validation tests will be conducted by JaxBio and TAU, as needed.<br>* Other names: HemaChip;|
| Patients with Hematological Malignancies - Second stage<br>In the second stage, at least 250 patients with MM and 250 patients with NHL and at least 100 patients with each of the remaining hematological malignancies mentioned above will be tested. Out of these patients, AML, lymphoma and MM patients will be followed-up at the clinical sites. Periodic sampling will be defined according to disease type and progression rate. Blood and plasma samples will be stored in the clinical sites until relapse diagnosis. At this stage, blood samples will be analyzed retrospectively on the HemaChip. The screening, enrollment, and sample collection can begin in the first stage of the trial, in order to allow a maximum follow-up period for at-risk subjects as part of the study and to meet the recruitment goals. | Diagnostic Test: Blood sampling for HemaChip screening/diagnostic testing<br>* Classification of a broad spectrum of blood cancers based on detection of epigenetic biomarkers from genomic DNA, cell-free (cf) DNA, exosomal DNA, RNA and non-coding RNA. The identified biomarkers will include proteins, metabolites, and other characteristic biomolecules. Year 1: During the discovery phase, all tests will be conducted by JaxBio and TAU with the aid of technical service providers. At this stage, microarray measurements will be performed on a commercial platform that will be purchased from Agilent / Illumina. All reagents needed for the test will be either purchased or produced in-house. Years 2-3: Throughout the second phase of the project, a custom targeted microarray, HemaChip will be developed and used for all tests. The HemaChip and custom reagents will be distributed to partners' labs and all tests will be conducted at the clinical sites. Additional validation tests will be conducted by JaxBio and TAU, as needed.<br>* Other names: HemaChip;|
| subjects at risk of developing MM / lymphoproliferative disorder - Third stage<br>The last stage consists of screening of a larger group of subjects at risk of developing MM / lymphoproliferative disorder. This stage will include 400 elderly patients (>65 years old) and 500 first-degree relatives of patients (and in particular siblings). The screening, enrollment, and sample collection can begin in the first stage of the trial, in order to meet the recruitment goals. Follow-up patients, at-risk individuals for MM, and at-risk first-degree relatives will donate blood periodically according to the follow-up plan. | Diagnostic Test: Blood sampling for HemaChip screening/diagnostic testing<br>* Classification of a broad spectrum of blood cancers based on detection of epigenetic biomarkers from genomic DNA, cell-free (cf) DNA, exosomal DNA, RNA and non-coding RNA. The identified biomarkers will include proteins, metabolites, and other characteristic biomolecules. Year 1: During the discovery phase, all tests will be conducted by JaxBio and TAU with the aid of technical service providers. At this stage, microarray measurements will be performed on a commercial platform that will be purchased from Agilent / Illumina. All reagents needed for the test will be either purchased or produced in-house. Years 2-3: Throughout the second phase of the project, a custom targeted microarray, HemaChip will be developed and used for all tests. The HemaChip and custom reagents will be distributed to partners' labs and all tests will be conducted at the clinical sites. Additional validation tests will be conducted by JaxBio and TAU, as needed.<br>* Other names: HemaChip;|
| Control subjects with no malignant disease- Discovery stage<br>Control subjects with no malignant disease that serve as controls are expected to donate blood a single time. Following this donation, their participation will end. At Tel-Aviv Sourasky Medical Center (TASMC) up to 50 bone marrow samples will be taken from healthy volunteers that will undergo hip or knee replacement surgery. | Diagnostic Test: Blood sampling for HemaChip screening/diagnostic testing<br>* Classification of a broad spectrum of blood cancers based on detection of epigenetic biomarkers from genomic DNA, cell-free (cf) DNA, exosomal DNA, RNA and non-coding RNA. The identified biomarkers will include proteins, metabolites, and other characteristic biomolecules. Year 1: During the discovery phase, all tests will be conducted by JaxBio and TAU with the aid of technical service providers. At this stage, microarray measurements will be performed on a commercial platform that will be purchased from Agilent / Illumina. All reagents needed for the test will be either purchased or produced in-house. Years 2-3: Throughout the second phase of the project, a custom targeted microarray, HemaChip will be developed and used for all tests. The HemaChip and custom reagents will be distributed to partners' labs and all tests will be conducted at the clinical sites. Additional validation tests will be conducted by JaxBio and TAU, as needed.<br>* Other names: HemaChip;Diagnostic Test: Bone marrow sampling<br>* as part of the discovery stage, bone marrow samples will be obtained at Tel-Aviv Sourasky Medical Center (TASMC) from up to 50 MM patients and up to 50 AML patients that undergo bone marrow aspiration as part of the standard care procedure. Additionally, up to 50 bone marrow samples will be taken from healthy volunteers that will undergo hip or knee replacement surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarker discovery | define a set of differential epigenetic biomarkers that uniquely identify the following conditions: MM, pre-MM conditions (SMM and MGUS), HL, aggressive NHL (DLBCL, HGL, FL and MZL transformed to large cell lymphoma), FL, MZL, de novo AML, secondary AML, MDS and healthy subjects. | 36 month | 
| Validation of Hemachip | Validating the discovery platform (HemaChip) as a diagnostic tool for various blood cancers. | 36 month | 
| Early detection for hematological malignancies | Towards early detection - Patients, at risk of relapse tested periodically to evaluate early detection capability of the HemaChip. | 36 month | 
| population screening for hematological malignancies | Towards population screening - evaluate the sensitivity and specificity for screening in populations at risk for developing the investigated cancers: (i) elderly (>65 years old) at high risk to develop MM; (ii) first degree relatives of the conditions described above. | 36 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, Pre-MM conditions, Hodgkin lymphoma, Non-Hodgkin aggressive lymphoma & diffuse large B cell lymphoma, High grade lymphoma, Follicular lymphoma, Marginal zone lymphoma, transformed to large cell lymphoma], acute myeloid leukemia, Myelodysplastic syndrome