Clinical Research Directory

Phase I Clinical Trial of ThINKK Adoptive Immunotherapy After Allogeneic Hematopoietic Transplantation in Children With Leukemia or Neuroblastoma

A first-in-class adoptive immunotherapy we called ThINKK, for Therapeutic Inducers of Natural Killer (NK) cell Killing, have been designed for use after hematopoietic stem cell transplantation (HSCT), where the proper stimulation of graft-derived NK cells has been shown to prevent relapse. ThINKK immunotherapy builds on our earlier research on NK cells and plasmacytoid dendritic cells (PDC) in cord blood and after HSCT. PDC are the sentinels of the immune system. Upon viral nucleic acids detection, PDC secrete a vast array of chemokines and cytokines that stimulate NK cells. PDC stimulation enhances NK cells killing of infected cells that express stress-induced molecules. Cancer cells also express stress-related molecules at their surface. However, NK cells do not receive PDC stimulation when fighting cancer. ThINKK therapy is designed to provide this necessary stimulation.

Study With Tocilizumab in Combination With Venetoclax and Azacitidine Chemotherapy in Patients With Acute Myeloid Leukemia

This is a phase 1, open label, interventional, single center, in patients with Acute Myeloid Leukemia (AML). This study will investigate dose escalation of tocilizumab in combination with venetoclax and azacitidine chemotherapy. The patient population will consist of adults men and women at least 18 years, who meet eligibility criteria. In this study propose combining tocilizumab with the standard treatment of azacitidine and venetoclax for patients with AML who are not eligible for intensive treatment.

Assesment of the Immune Response to RSV Vaccine in Patients With Myeloma, Lymphoma and Hematological Leukemia

A prospective study in which hematological oncology patients who were vaccinated against RSV will undergo a blood test to assess their immune response to the vaccine. As part of the study, hematological oncology patients with CLL, lymphoma, acute leukemia, myelodysplastic syndrome, and multiple myeloma, who are being monitored at the Hematology Institute at Ichilov, will be offered a blood test to evaluate their immune response to the RSV vaccine (serology, neutralizing antibodies, and cellular response). In the study, a blood sample of up to 10 ml will be taken in a chemistry tube and blood bank on the day of vaccination and about one month after that. The serological test will be conducted in the hospital's virology laboratory. The test result and its significance will be communicated to the patient by the treating hematologist in TASMC clinic. In this group of patients, a follow-up will be conducted over a 12-month period (during routine clinic visits) to document the incidence of RSV infection and complications related to the vaccine.

Involvement of CDA and/or dCK Metabolizing Enzymes in the Response to Azacytidine Treatment of Patients With Hematologic Malignancies

Until now, the development of personalized medicine in oncology has relied on the use of somatic biomarkers to help therapists choose the right molecule(s) to administer, based on the genetic and molecular profile of each hematological disease. In this project, investigators propose to extend the strategy of therapeutic individualization to the field of dosage targeting. Today, azacytidine is a standard treatment for patients with acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS), usually as monotherapy. According to the treatment regimen, azacytidine is prescribed at a standard dose (DS=75mg/m²/d), administered subcutaneously every day for 7 days. The treatment cycle is repeated every 28 days. No study has evaluated the relevance of "a priori" dose adjustment on an individual basis, according to each patient's pharmacogenetic data. In current practice, doses are adapted a posteriori, and reduced empirically, following the occurrence of observed toxicity (6 to 71% of patients) (Schuck A et al. 2017). This ex-post adjustment in the face of grade 3-4 toxicity is a loss of chance for the patient. Similarly, under-dosing patients for fear of toxicity is another loss of chance. Investigator's hypothesis is that the optimal dose of azacytidine depends not only on the characteristics of the patient's pathology (risk groups including cytogenetic and molecular biology data), but also on the patient's individual characteristics (genetic status of metabolic enzymes and transporters). A mathematical model of the PK/PD type could, on the basis of early observations of circulating levels, be capable of rapidly predicting the pharmacodynamic repercussions in each patient, thus enabling rapid individualization of dosages. In the future, such a tool could make it possible to propose dosage adjustments rapidly after treatment initiation, before toxicity occurs, by predicting azacytidine exposure levels, themselves correlated with the patient's clinical condition. Study design: In this open-label, paucicentric, non-randomized study, patients with AML and/or MDS, all of whom are receiving azacytidine-based chemotherapy as part of their standard treatment regimen, will be included. Each patient will be monitored for toxicities (EORTC), treatment response and progression-free survival. In addition to the standard care described above, each patient will undergo a series of constitutional genetic investigations conducted by NGS on markers linked to azacytidine pharmacokinetics (CDA, dCK). Another series of blood samples will be taken to calculate individual azacytidine pharmacokinetic parameters using a Bayesian approach. Expected results: This study should make it possible to correlate pharmacogenetics with patient plasma exposure, and ultimately improve the molecule's efficacy/toxicity balance by personalizing dosage regimens, which until now have been carried out on an empirical basis. Prospects: If the data are validated, a pre-therapeutic ADC assay could predict azacytidine pharmacodynamics and enable individual dose and/or dosage adjustment, as is the case with 5-FU and DPD.