Date: 2016-04-27
Type of information: Initiation of the trial
phase: 1-2
Announcement: initiation of the trial
Company: Celldex Therapeutics (USA - NJ) PrECOG (USA - PA)
Product: glembatumumab vedotin (CDX-011)
Action
mechanism: antibody drug conjugate. Glembatumumab vedotin (CDX-011) is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB), a transmembrane protein that is expressed in subcellular compartments and on the surface of multiple cell types. A number of cancers, including breast cancer, cutaneous and uveal melanoma, small cell lung cancer, osteosarcoma, renal cell cancer and glioblastoma overexpress gpNMB relative to normal tissue. Overexpression of gpNMB has been shown to promote the invasion and metastasis of hepatocellular carcinoma, glioma and breast cancer cells, decrease tumor cell apoptosis and promote angiogenesis in preclinical models. gpNMB expression has also been associated with poor clinical outcomes in small cell lung cancer, renal cell cancer, glioblastoma and breast cancer. Glembatumumab vedotin is produced by covalently linking a fully human immunoglobulin G2 monoclonal antibody against gpNMB (CR011) to monomethyl auristatin E (MMAE), a potent mitotic spindle formation inhibitor. Glembatumumab vedotin binds to gpNMB on tumor cells and, after internalization, releases MMAE, which, in turn, inhibits mitosis, leading to cell death and apoptosis. The MMAE toxin may also be released by dying cells into the tumor microenvironment, resulting in the "bystander effect" of killing neighboring tumor cells.
Disease: squamous cell carcinoma of the lung
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: Patients with advanced or metastatic, gpNMB-expressing squamous cell carcinoma of the lung who have failed a prior platinum-based chemotherapy regimen will receive glembatumumab vedotin. This Phase 1/2 study will enroll patients with gpNMB-positive stage IIIB or IV non-small cell lung cancer (NSCLC) of squamous histology who have previously been treated with platinum-based chemotherapy. gpNMB positivity will be determined by a greater than, or equal to, five percent gpNMB expression in tumor epithelial cells. Glembatumumab vedotin will be administered once every three weeks until disease progression or intolerance. The study is expected to include 10 sites in the United States. The study will include a dose-escalation phase followed by a two-stage Phase 2 portion (Simon two-stage design). The Phase 1, dose-escalation portion of the study will assess the safety and tolerability of glembatumumab vedotin at the current dose of 1.9 mg/kg and then 2.2 mg/kg in order to determine whether higher dosing is feasible in this population. The first stage of the Phase 2 portion will enroll approximately 20 patients, and if at least two patients achieve a partial response or complete response, a second stage may enroll an additional 15 patients. The primary objective of the Phase 2 portion of the study is to assess the anti-tumor efficacy of glembatumumab vedotin in squamous cell lung cancer as measured by objective response rate (ORR). Secondary objectives of the study include analyses of safety and tolerability and further assessment of anti-tumor activity across a broad range of endpoints. (NCT02713828 )
Latest
news: * On April 27, 2016, Celldex Therapeutics announced that it has initiated an open-label Phase 1/2 safety and tolerability study of glembatumumab vedotin in patients with unresectable stage IIIB or IV, gpNMB-expressing, advanced or metastatic squamous cell carcinoma (SCC) of the lung, who have progressed on prior platinum-based chemotherapy. Celldex has entered into a collaborative relationship with PrECOG, LLC, which represents a research network established by the Eastern Cooperative Oncology Group (ECOG), and PrECOG, LLC will conduct the study. Glembatumumab vedotin is currently being evaluated in patients with metastatic triple negative breast cancers that overexpress gpNMB in the registrational METRIC study, as well as in a Phase 2 study in patients with advanced melanoma who have progressed after at least one checkpoint inhibitor therapy and, if applicable, BRAF- or MEK-targeted therapy. It has been previously evaluated in a Phase 2 study in advanced breast cancer (the EMERGE study), a Phase 1/2 study in advanced breast cancer and a Phase 1/2 study in patients with unresectable stage III or IV melanoma. Also, Celldex and the National Cancer Institute (NCI) have entered into a Cooperative Research and Development Agreement (CRADA) under which the NCI is sponsoring two studies of glembatumumab vedotin—one in uveal melanoma and one in pediatric osteosarcoma. Both studies are currently open to enrollment.
