Date: 2016-10-20
Type of information: Initiation of the trial
phase: 1-2
Announcement: initiation of the trial
Company: TG Therapeutics (USA - NY)
Product: TGR-1202 and carfilzomib
Action
mechanism: phosphoinositide 3-kinase (PI3K) inhibitor/proteasome inhibitor. TGR-1202 (formerly known as RP5264) is an orally available PI3K delta inhibitor, targeting the delta isoform with nanomolar potency and several fold selectivity over the alpha, beta, and gamma isoforms of phosphoinositide 3-kinase. The delta isoform of PI3K is strongly expressed in cells of hematopoietic origin and is believed to be important in the proliferation and survival of B-cell lymphocytes. Inhibition of PI3K delta signaling with TGR-1202 has demonstrated robust activity in numerous pre-clinical models and primary cells from patients with hematologic malignancies. Carfilzomib belongs to the class of proteasome inhibitors. Proteasome inhibitors block the proteasome, a system in cells that breaks down proteins when they are no longer needed. When proteins in the cancer cells are not broken down by the proteasome, the cells eventually die, slowing down the growth of the cancer. Carfilzomib is the first irreversible, highly-selective, proteasome inhibitor for multiple myeloma. The irreversible binding to the targeted proteasome leads to a more sustained inhibition with minimal inhibition of other non-targeted enzymes.
Disease: relapsed and refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL)
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: This is an open label, phase I/II, dose-escalation study in the initial phase I followed by a phase II. The primary objective of the phase I is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of TGR-1202 and carfilzomib in participants with relapsed and refractory (R/R) non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). The safety and toxicity of this combination will be evaluated throughout the entire study. If the combination of TGR-1202 and carfilzomib is found to be feasible and an MTD is established, the phase II part of the study will be initiated. Phase II will consist of a 2-stage design of the combination of TGR-1202 and carfilzomib for participants with R/R NHL. (NCT02867618)
Latest
news: * On October 20, 2016, TG Therapeutics announced the launch of a Phase 1/2 study to evaluate the safety and efficacy of TGR-1202, the Company's oral PI3K delta inhibitor in combination with carfilzomib, the FDA-approved proteasome inhibitor, in patients with relapsed or refractory lymphoma. The rationale for combining these two agents is based on extensive preclinical work conducted as part of a research collaboration supported by TG Therapeutics at the Center for Lymphoid Malignancies, Columbia University Medical Center. Portions of this work were presented in an oral presentation at the American Society of Hematology Meeting in December 2015, by Dr. Changchun Deng of the Center for Lymphoid Malignancies. The presentation contained data demonstrating that the combination of TGR-1202 and carfilzomib was uniquely synergistic as compared to any other combination of a PI3K-delta inhibitor and proteasome inhibitor, including the combination of idelalisib and carfilzomib and idelalisib and bortezomib. Of particular interest, the combination of TGR-1202 and carfilzomib was found to potently inhibit cap dependent translation of c-Myc in all cell lines tested, including diffuse large B-Cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma, T-cell lymphoma, and chronic lymphocytic leukemia (CLL) cells. A more in depth presentation of the preclinical work has been submitted to a leading medical journal and is awaiting publication. In the Phase 1 portion, the study will evaluate the safety, tolerability, and appropriate dose of carfilzomib when combined with 800mg of TGR-1202. Once a recommended Phase 2 dose is identified, the Phase 2 portion will further evaluate the safety and effectiveness of the combination at the chosen dose. TG Therapeutics will supply the TGR-1202 and assume up to 50% for the cost for the trial. This study is currently open to enrollment at the Center for Lymphoid Malignancies, Columbia Presbyterian Medical Center, New York, NY. More information on this clinical study can be found at www.clinicaltrials.gov.
