Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

15 patients with DLBCL with chemoresistance or relapsed less than 2 years after completion of first-line therapy

15 patients with DLBCL with chemosensitivity without relapse within 2 years following the end of first-line therapy.

Large-cell B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma and accounts for about 40% of new cases. Although the DLBCL is a single entity in the WHO classification, several subgroups with different prognoses are recognized. These subgroups take into account the tumor localization (primitive cerebral lymphoma, serous lymphoma, intravascular or exclusive lymph node) or a particular molecular signature (GCB profile, germline center B cell or ABC, activated B cell). Despite the introduction of immunotherapy, treatment failures are common. Overall survival at 5 years is estimated to be between 26 and 73%. This highlights the important heterogeneity of this pathology and therefore the need for biomarkers prognosis. Recently, an increase in monocytes in the blood of DLBCL patients has been proposed as a prognostic factor for independent survival. This marker of poor prognosis is also found in many solid.

Monocytes are effectors of the inflammatory response. They have different functional profiles depending on the level of expression of CD14 and CD16. Four subtypes of monocytes are distinguished: classical (CD14posCD16neg), intermediate (CD14posCD16pos) and non-classical (CD14lowCD16pos); the latter population is divided into two sub-groups depending on the expression of the SLAN protein. The different monocytic subpopulations have very diverse functions ranging from an immunosuppressive profile to an activation of the immune system. CD14posCD16neg monocytes are specialized in phagocytosis, production of oxygen derivatives (ROS) and pro-inflammatory cytokine secretion in response to microbial infection. CD14dimCD16pos monocytes are specialized in immune surveillance and produce proinflammatory cytokines such as TNFα and IL-1β in response to LPS stimulation.7 The Slanpos subpopulation produces IL-12 and thus has pro-inflammatory properties. Finally, CD14posCD16pos monocytes have controversial functions. For some authors, they produce the immunomodulatory cytokine IL-10, inhibit the proliferation of CD4 T lymphocytes and induce the recruitment of regulatory T lymphocytes, while for others they produce TNF-α, a pro- inflammatory.From a practical point of view CD14 and CD16 expression forms a continuum, which translates into complexity in the phenotypic definition of these cells and explains the contradictory data on their functionalities. Interestingly, in a laboratory work and in the course of publication, this fraction is increased in the blood of DLBCL patients compared to healthy donors (manuscript in preparation), on the contrary the monocytic fraction CD14dimCD16 pos is decreased in these patients.

In the end, if the increase in monocytes is known to be poor prognosis in patients with DLBCL, the monocyte fraction involved and the monocytic functions involved in this phenomenon are not known.

Since 2011, the Clinical and Biological Hematology Services have a database from a research protocol (BMS_LyTrans). This protocol includes patients with DLBCL as well as healthy patients, in order to allow the biological characterization of biomarkers in this pathology. Thus, we have blood samples and analysis of certain monocyte subtypes by flow cytometry at diagnosis, in more than 100 patients with DLBCL.

Primary objective :

Describe and compare the distribution of the different monocytic subpopulations according to the chemosensitivity profile (group 1) or chemoresistance (group 2) of patients with DLBCL and healthy donors (group 3), and identify their specific functionalities.

Secondary objective :

To determine the prognostic impact in terms of progression-free survival (EFS) of the distribution of the monocytic sub-population (s) defined i during the primary objective, in a retrospective study (BMS Ly Trans)

Design/Methodology : Retrospective, observational, monocentric study.

1. - Part 1: Phenotypic and functional study of monocytic sub - populations of patients with DLBCL.

   - Patient selection from the BMS_LyTrans database : Group 1: 15 patients with DLBCL with chemoresistance or relapse less than 2 years after completion of first-line therapy.

   Group 2: 15 patients with DLBCL with chemosensitivity without relapse within 2 years following the end of first-line treatment.

   Group 3: 15 healthy patients.

   A - Irish Lab (Nashville)

   - Phenotypic analysis by mass cytometry: This new technology allows the integration of multiple data with membrane markers, intracytoplasmic proteins as well as transcription factors, thus providing global modeling of signaling pathways

   B - UMR 917 (Rennes) 8 months Cell sorting: The four subtypes of monocytes described above will be sorted by flow cytometry according to the expression of CD14, CD16 and Slan.

   - High-throughput transcriptional analysis: cell lysis and real-time PCR in order to study the expression of genes involved in the mechanisms of immunomodulation.Bio-informatics, Integrated analysis: The set of clinical, transcriptomic and proteomic data will be analyzed in an integrated way using tools and algorithms working within the Irish lab.
2. - 2nd part (Rennes) - 6 months : Populations differentially expressed between groups in part 1 will be analyzed on a cohort of 100 samples. These parameters will be analyzed jointly after integration in a database, uni- and multivariate analysis and the survival probability will be calculated for groups with a log-rank test.

Expected benefits :

1. - To allow a better understanding of the monocyte compartment in DLBCL, particularly with regard to the immunosuppressive capacity of some of these cellular subtypes.
2. - To refine the interest of the biomarker "monocyte level" on EFS in patients with DLBCL, highlighting the monocyte subtype involved.
3. - To continue the collaboration between the two sites, which will allow to combine technologies and expertise present in Rennes (patient recruitment, cell sorting, molecular analysis (Biomark)) or in Nashville (CyTOF, bioinformatics, integrated analysis).

Patient selection from the BMS_LyTrans database

SMOLY : Phenotype and Functions of Monocyte Subtypes in High Grade B Lymphoma: Towards New Biomarkers?

Increased proportion of one or more monocytic sub-populations (s) and / or modulation of the markers tested in one of the three groups studied.

Difference of EFS in the validation cohort between patients with DLBCL having an increased proportion of one or more monocytic subpopulation (s) or modulation of the markers suspected in the descriptive phase, and the others.

Vanderbilt University

Rennes University Hospital

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Standard Chemotherapy

Cary Presant, MD

A previous preliminary study performed at Vanderbilt University with funding from the Leukemia Society of America demonstrated that the response of leukemia cells in vitro to the chemotherapeutic agent idarubicin in the microculture kinetic assay for apoptosis (MiCK assay) predicted survival in patients with newly diagnosed acute myeloid leukemia (AML). In this previous study, achievement of complete response (CR) to induction therapy with idarubicin and cytarabine was used as the clinical indicator for determining whether leukemia specimens taken prior to treatment were sensitive or not sensitive in the MiCK assay. This group of patients has been followed for 7 years and their long term survival rates show that their responses in the MiCK assay to idarubicin but not cytarabine predict survival. In the present proposal a separate group of patients with newly diagnosed AML will be recruited to provide leukemia cell samples that will be used to establish criteria for sensitivity and non-sensitivity to idarubicin and cytarabine in the MiCK assay. The achievement of CR will be used to determine in vitro sensitivity as it was done in the previous study. With the in vitro sensitivities as determined in this proposed study, the long term survivals of patients in the previous study will be analyzed prospectively.

The proposed study is expected to have an approximate duration of one year. Patient population will include newly diagnosed AML patients with both de novo AML and AML arising from a previously diagnosed myelodysplastic syndrome. The study will not include patients with previously treated leukemia that has relapsed

A previous preliminary study performed at Vanderbilt University with funding from the Leukemia Society of America demonstrated that the response of leukemia cells in vitro to the chemotherapeutic agent idarubicin in the microculture kinetic assay for apoptosis (MiCK assay) predicted survival in patients with newly diagnosed acute myeloid leukemia (AML). In this previous study, achievement of complete response (CR) to induction therapy with idarubicin and cytarabine was used as the clinical indicator for determining whether leukemia specimens taken prior to treatment were sensitive or not sensitive in the MiCK assay. This group of patients has been followed for 7 years and their long term survival rates show that their responses in the MiCK assay to idarubicin but not cytarabine predict survival. In the present proposal a separate group of patients with newly diagnosed AML will be recruited to provide leukemia cell samples that will be used to establish criteria for sensitivity and non-sensitivity to idarubicin and cytarabine in the MiCK assay. The achievement of CR will be used to determine in vitro sensitivity as it was done in the previous study. With the in vitro sensitivities as determined in this proposed study, the long term survivals of patients in the previous study will be analyzed prospectively.

STUDY DESIGN

1. Recruit patients and assign them unique number at the time of sample collection. All samples and data will be recorded by unique number. The key to the unique numbers assigned to each patient will be kept by the principal investigators at Vanderbilt.
2. After obtaining informed consent, collect specimens from patients whose induction therapy will include cytarabine and idarubicin. Collect and ship to DiaTech by overnight courier fifty (50) bone marrow or peripheral blood \[if available, both bone marrow and peripheral blood\] specimens from newly diagnosed patients with AML. Newly diagnosed AML patients include those diagnosed de novo or arising from a previously diagnosed myelodysplastic syndrome, but do not include patients with previously treated leukemia that has relapsed. An adequate specimen for analysis will contain sufficient numbers of viable leukemia cells to perform the MiCK assay with 7 doses of cytarabine and 7 doses of idarubicin..
3. Each patient's clinically recognized predictors of leukemia treatment outcome will be recorded. These predictors include age, sex, presence or absence of preceding myelodysplastic syndrome, blood leukocyte count at diagnosis, percentage of leukemic cells in the blood, and leukemic cell karyotype.

Use of the MiCK Assay for Apoptosis in AML

Use of the MiCK Assay for Apoptosis to Predict Complete Remission in Acute Myeloid Leukemia

DiaTech Oncology and Vanderbilt University

Pierian Biosciences

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Digestive System Diseases

Adenocarcinoma

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Hypersensitivity

Fallopian Tube Neoplasms

Peritoneal Neoplasms

Carcinoma

Neoplasms, Glandular and Epithelial

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Abdominal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Peritoneal Diseases

Fallopian Tube Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

MiCK Assay

2.0 Study Objectives: 2.1 To evaluate the ability of the MiCK assay to predict the outcome of chemotherapy of cancer patients for first-line treatment.

2.2 To evaluate the ability of the MiCK assay to guide chemotherapy of cancer patients in a third-line, refractory treatment setting (exclusive of anti-VEGF)

1. 0 Background and Rationale: Despite the use of aggressive treatment protocols, less than 10% of cancer patients with an advanced disease respond to the therapy. There is a variety of different cancer drug regimens, all of which have approximately the same probability of clinical effectiveness. Identification of those patients who will or will not respond to a specific chemotherapy is important for making decisions regarding chemotherapy regimens as well as alternative management approaches. A laboratory test that could help to determine the sensitivity of an individual patient's tumor cells to specific chemotherapeutic agents would be valuable in choosing the optimal chemotherapy regimen for that patient with an expectation of increasing the response rate to the therapy. Several types of in vitro assays that measure tumor cell survival following exposure to cytotoxic agents have been evaluated for their ability to predict chemotherapy outcomes. As a group, these assays are referred to as drug resistance assays. In a resistance assay, the surviving tumor cells can be detected directly by their exclusion or metabolism of specific dyes. Alternatively, since some of tumor cells are proliferating, their survival can be detected by measurement of DNA synthesis by radiolabeled precursor incorporation or demonstration of clonogenic potential by growth into colonies in semi-solid culture medium. In several clinical studies, these assays were useful in detecting drug resistance and in predicting a poor prognosis for cancer patients. However, these resistance assays cannot detect sensitivity of an individual patient's tumor cells to a specific drug. Therefore, new methods determining drug-sensitivity of the tumor cells of an individual patient and, thus, capable of both predicting a positive treatment outcome and guiding chemotherapy, would be of significant value.

Recently, Dr. Kravtsov has developed an automated microculture kinetic (MiCK) assay for measuring drug induced apoptosis in tumor cells. Apoptosis is a distinct mode of cell death which occurs under physiological conditions and yet can be induced in malignant cells by chemical and physical factors including antitumor drugs. During the last decade, it has been recognized that chemotherapeutic agents exert their antitumor activity by triggering apoptosis in susceptible tumor cells. This implies that the MiCK assay for apoptosis provides a mechanism-based approach to studying effects of cytotoxic agents on tumor cells. Unlike "resistance" assays that measure a fraction of cells surviving drug exposure, the MiCK assay measures a fraction of tumor cells killed by a chemotherapeutic agent via mechanism of apoptosis. Therefore the MiCK assay determines drug sensitivity, rather than resistance. Recently the MiCK assay has been shown to predict complete remission rate and survival in acute myeloid leukemia patients better than clinical criteria did. In a limited study, the MiCK assay has been used to direct chemotherapy of the leukemia patients .

The MiCK assay has also been used to study drug-induced apoptosis in solid tumors, including neuroblastoma and colon adenocarcinoma cell lines. More recent data accumulated by DiaTech has demonstrated that the MiCK assay can detect drug induced apoptosis in primary cultures of tumor cells isolated from patients with ovarian carcinoma, gastric carcinoma, metastatic breast cancer and high grade soft tissue sarcoma. Based on these data, we suggest that the MiCK assay may be used to detect drug sensitivity profiles of individual patients with various types of solid tumors. This, in turn, may provide a way to tailor chemotherapy to an individual patient's drug sensitivity profile, and, thus, improve treatment outcomes, decrease adverse effects of the chemotherapy, increase the quality of patient's life, and reduce the treatment cost.

Testing Drug Sensitivity of Ovarian, Fallopian and Primary Peritoneal Adenocarcinomas

Application of the Microculture Kinetic (MiCK) Assay for Apoptosis to Testing Drug Sensitivity of Ovarian, Fallopian and Primary Peritoneal Adenocarcinomas

Skin and Connective Tissue Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Breast Neoplasms

Sarcoma

Lung Neoplasms

Neoplasms, Connective and Soft Tissue

Breast Diseases

Skin Diseases

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Soft Tissue Sarcoma

Laboratory Assay

Chemotherapy doctor determined from results

Mick Assay

Pat Whitworth, MD

Alexander Zweibach, MD, PhD

Karl Rogers, MD

DiaTech is a private company performing patient specific cancer chemosensitivity testing for patients and physicians. DiaTech Oncology is doing this clinical study to see if an experimental new technology called the microculture kinetic (MiCK) assay will predict treatment outcome and can help to direct the chemotherapy of cancer subjects. This study is focused on subjects diagnosed with breast, ovarian, lung, and colon malignancies and low-grade lymphomas.

Study Objectives:

* To evaluate the ability of the MiCK assay to predict the outcome of chemotherapy of cancer patients.
* To evaluate the ability of the MiCK assay to guide chemotherapy of cancer patients.

Chemotherapy Drug Sensitivity Microculture (MiCK) Assay for Apoptosis

Application of the Microculture Kinetic (MiCK) Assay for Apoptosis to Drug Testing Sensitivity of Solid Tumors

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Patient is followed within the usual care for stage 4 colorectal cancer

For patients in the Oncogramme® group, chemotherapy will be adapted to Oncogramme® results.

Patient is followed within the usual care for stage 4 colorectal cancer, but an Oncogramme test will be made and chemotherapy will be adapted to the results.

Oncogramme®

Muriel Mathonnet, MD

Currently, chemotherapies are empirically administered to patients treated for colorectal cancer (CRC). Selection is based on the efficacy of a protocol previously determined on the largest number (consensus treatment), the decision-making process being weighted by patient's intrinsic criteria. However, each patient is unique, due to the inter- and intratumoral heterogeneity inherent in any cancer, partly explaining the unsatisfactory response rates observed for available chemotherapies. Functional sensitivity tests offer the possibility to adapt the treatment to each patient: they are based on an ex vivo study of the responses of the tumor cells (survival / death) to the different molecules / therapeutic combinations (chemotherapy or targeted therapy) likely to be administered to the patient. This response, translated into a tumor-specific sensitivity profile, can be used by the clinicians to determine the most appropriate therapeutic protocol. By increasing the therapeutic efficacy from the first line and reducing the deleterious side effects associated with multiple drug cycles, the sensitivity test transforms the consensus approach into personalized medicine, providing patients with improved progression free survival (PFS) associated with an improvement in the quality of life. Oncomedics has developed Oncogramme®, a CE-labeled in vitro diagnostic medical device that has already demonstrated the ability to predict chemosensitivity in a recent pilot study of metastatic CRC (prediction with 84% chance of success of tumor sensitivity to chemotherapy, vs. 50% maximum for chemotherapy administered according to the consensus method). The hypothesis that patients treated with a metastatic CRC for which systemic chemotherapy is adapted using Oncogramme® have better response rates, PFS and quality of life than patients treated according to usual practice, with optimization of the costs of care. To our knowledge, this is the only fully standardized test available, where each step and reagents of the procedure are mastered. The reliability of the procedure makes it possible to render a personalized result for each patient in 97% of the cases. In addition, the analysis is specifically centered on tumor cells using a method using fully defined, developed and validated media and reagents for each cancer, including CRC. The method of revealing the effect of the therapies identifies the proportion of dead cells in each condition, whatever their physiological state (proliferation / quiescence), by determining the percentage of living and killed cells, thus ensuring high sensitivity

Patients corresponding to the inclusion criteria and having a histologically proven metastatic CRC on biopsies or primary tumor excision and / or one or more metastatic sites will be recruited prospectively and randomized into two groups.

1. Usual care group: no Oncogramme will be made.
2. Oncogramme group: Taking of tumor fragments on the histological piece by an anatomopathological physician at the time of the histological examination and placing samples in the transport medium. The Oncogramme will be performed by Oncomedics on all specimens. Results will be returned to clinicians within 15 days.

For both groups, the adjuvant treatment will be decided in the multidisciplinary consultation meeting (MCM), according to the recommendations in force and adapted to the general medical condition of the patient. For patients in the Oncogramme group, chemotherapy will be adapted to Oncogramme.

The result of Oncogramme® will not give to the patient.

Study of the Therapeutic Response and Survival of Patients With Metastatic Colorectal Cancer (Stage IV) and Treated According to the Guidelines of a Chemosensitivity Test, Oncogramme® (ONCOGRAM)

Study of the Therapeutic Response and Survival of Patients With Metastatic Colorectal Cancer (Stage IV) and Treated According to the Guidelines of a Chemosensitivity Test, Oncogramme®

The event studied is the occurrence of the progression or death of the patient during the year following the inclusion in the study. The progression of the patient is determined by the RECIST (Response Evaluation Criteria in Solid Tumors).

Percentage of patients in each response category to first-line treatment administered, evaluated by RECIST in each of the two groups.

The event study is the death of the patient during the 6 months and the year following the inclusion.

The event considered is death due to illness during the 6 months and the year following the inclusion. The attribution of the death to the illness will be made by the adjudication committee.

Calculation of the Incremental Cost / Efficiency Ratio (ICER) expressed in euros per year of life gained without occurrence of death or progression to 1 year of the adapted chemotherapeutic treatment according to the results of Oncogramme® using EQ5D-5L s

Calculation of the Incremental Cost / Utility Ratio (ICUR) expressed in euros per QALY gained at 1 year of the adapted chemotherapeutic treatment according to the results of Oncogramme® using EQ5D-5L scale.

Compare the quality of life of patients at 3 months, 6 months, 9 months and 1 year between the two groups using the EQ5D-5L questionary score.

If there is no adaptation of the treatment to the results of Oncogramme®, describe the criteria that led to the failure to take into account the results of Oncogramme®

Describe and compare in both groups the proportion of grade 3 and higher adverse events related to chemotherapy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
SMOLY : Phenotype and Functions of Monocyte Subtypes in High Grade B Lymphoma: Towards New Biomarkers?	NCT03672682	DLBCL		18 Years - 70 Years	Rennes University Hospital
Use of the MiCK Assay for Apoptosis in AML	NCT00286845	Leukemia, Myelo...	Standard Chemot...	18 Years -	Pierian Biosciences
Testing Drug Sensitivity of Ovarian, Fallopian and Primary Peritoneal Adenocarcinomas	NCT00443196	Adenocarcinoma Ovarian Neoplas... Fallopian Tube ... Peritoneal Neop...	MiCK Assay	-	Pierian Biosciences
Testing Drug Sensitivity of Ovarian, Fallopian and Primary Peritoneal Adenocarcinomas	NCT00443196	Adenocarcinoma Ovarian Neoplas... Fallopian Tube ... Peritoneal Neop...	MiCK Assay	-	Pierian Biosciences
Chemotherapy Drug Sensitivity Microculture (MiCK) Assay for Apoptosis	NCT00243685	Breast Neoplasm... Lung Neoplasms Ovarian Neoplas... Sarcoma, Soft T...	Laboratory Assa... Mick Assay	18 Years - 85 Years	Pierian Biosciences
Study of the Therapeutic Response and Survival of Patients With Metastatic Colorectal Cancer (Stage IV) and Treated According to the Guidelines of a Chemosensitivity Test, Oncogramme® (ONCOGRAM)	NCT03133273	Colorectal Canc... Chemotherapy	Oncogramme®	18 Years -	University Hospital, Limoges

Spots Global Cancer Trial Database for chemosensitivity