Natural Killer (NK) Cells in Combination With Interleukin-2 (IL-2) and Transforming Growth Factor Beta (TGFbeta) Receptor I Inhibitor Vactosertib in Cancer
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|ClinicalTrials.gov Identifier: NCT05400122|
Recruitment Status : Recruiting
First Posted : June 1, 2022
Last Update Posted : December 1, 2022
|Condition or disease||Intervention/treatment||Phase|
|Colorectal Cancer Hematologic Malignancy Rectum Cancer Acute Myeloid Leukemia Myelodysplastic Syndromes Acute Lymphoblastic Leukemia Chronic Myeloid Leukemia Chronic Lymphocytic Leukemia Hodgkin Lymphoma Non Hodgkin Lymphoma Myeloproliferative Syndrome Plasma Cell Myeloma||Drug: Vactosertib Drug: Fludarabine Phosphate Drug: Cyclophosphamide Drug: IL-2 Drug: Natural Killer Cells||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Approximately 12 subjects will be enrolled in this trial and all will receive a preparative regimen consisting of lymphodepleting chemotherapy agents followed by two infusions of ex vivo-expanded NK cells in combination with vactosertib and IL-2 (Proleukin®).|
|Masking:||None (Open Label)|
|Official Title:||A Phase Ib Study to Evaluate Safety and Persistence of ex Vivo Expanded Universal Donor NK Cells in Combination With IL-2 and TGFbeta Receptor I Inhibitor Vactosertib in Patients With Locally Advanced/Metastatic Colorectal Cancer and Relapsed/Refractory Hematologic Malignancies|
|Actual Study Start Date :||September 9, 2022|
|Estimated Primary Completion Date :||June 1, 2023|
|Estimated Study Completion Date :||December 1, 2023|
Experimental: Experimental Infusion
Preparative Regimen Administration:
Investigational Agent Administration:
Vactosertib is a highly selective, potent inhibitor of the protein serine/threonine kinase activity of transforming growth factor (TGF)-β receptor type 1 (TGFBR1; also known as activin receptor-like kinase 5 [ALK5]). Vactosertib inhibits the phosphorylation of the ALK5 substrates Smad2 and Smad3, as well as the intracellular signaling of TGF-β.
Drug: Fludarabine Phosphate
Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoroara-ATP. This metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA synthesis.
Other Name: Fludara
Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity.
Proleukin® (aldesleukin) has been shown to possess the biological activities of human native interleukin-2. In vitro studies performed on human cell lines demonstrate the immunoregulatory properties of Proleukin, including: a) enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines; b) enhancement of lymphocyte cytotoxicity; c) induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and d) induction of interferon-gamma production.
The in vivo administration of Proleukin in animals and humans produces multiple immunological effects in a dose dependent manner. These effects include activation of cellular immunity with profound lymphocytosis, eosinophilia, and thrombocytopenia, and the production of cytokines including tumor necrosis factor, IL-1 and gamma interferon. In vivo experiments in murine tumor models have shown inhibition of tumor growth
Other Name: Proleukin
Drug: Natural Killer Cells
Adoptive NK cell therapy has demonstrated the potential for cancer immunotherapy in various malignancies with particular potential in hematologic malignancies including acute myeloid leukemia (AML), and colon cancer [14, 19-23]. This therapeutic approach is extremely well tolerated in patients even when massive numbers of cells are utilized (~109 NK cells/kg). In fact, studies suggest that high doses of NK cells are not only well tolerated but have potential to lead to higher levels of efficacy.
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]) [ Time Frame: Within 28 days of NK cell infusion ]This will be defined as the incidence of Grade ≥ 2 treatment-related adverse events
- Persistence of donor NK cells [ Time Frame: 7 days post-treatment ]This will be defined as the presence of donor NK cells in recipient blood as determined by short tandem repeat (STR)-chimerism at a frequency of >10%.
- Persistence of donor NK cells [ Time Frame: 14 days post-treatment ]This will be defined as the presence of donor NK cells in recipient blood as determined by STR-chimerism at a frequency of >10%.
- Persistence of donor NK cells [ Time Frame: 21 days post-treatment ]This will be defined as the presence of donor NK cells in recipient blood as determined by STR-chimerism at a frequency of >10%.
- Persistence of donor NK cells [ Time Frame: 28 days post-treatment ]This will be defined as the presence of donor NK cells in recipient blood as determined by STR-chimerism at a frequency of >10%.
- Clinical Response [ Time Frame: 28 days post-treatment ]This will be defined as a change in size of measurable disease on CT scans (colorectal cancer) or by standard methods for hematologic malignancies (e.g. bone marrow biopsy for AML)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05400122
|Contact: Jennifer Eva Selfridge, MD PhD||18006412422||CTUReferral@UHhospitals.org|
|United States, Ohio|
|University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center||Recruiting|
|Cleveland, Ohio, United States, 44106|
|Contact: Jennifer E. Selfridge 800-641-2422 CTUReferral@UHhospitals.org|
|Principal Investigator:||Jennifer Eva Selfridge, MD PhD||University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center|