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Celldex Announces Publication of Glembatumumab Vedotin Phase 1/2 Studies in the Journal of Clinical Oncology

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Celldex Announces Publication of Glembatumumab Vedotin Phase 1/2 Studies in the Journal of Clinical Oncology September 30, 2014 Celldex Announces Publication of Glembatumumab Vedotin Phase 1/2 Studies in the Journal of Clinical Oncology HAMPTON, N.J., Sept. 30, 2014 (GLOBE NEWSWIRE) -- Celldex Therapeutics, Inc. (Nasdaq:CLDX) announced today the publication of two papers highlighting early studies of glembatumumab vedotin in breast cancer and metastatic melanoma in the Journal of Clinical Oncology (JCO). The papers, "A Phase 1/2 Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients with Advanced Melanoma" and "A Phase 1/2 Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients with Locally Advanced or Metastatic Breast Cancer" have been published as Early Release Articles on JCO's website and will appear in a future print edition. Glembatumumab vedotin is an investigational antibody-drug conjugate that targets and binds to 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. "gpNMB is emerging as a potentially important target for the treatment of cancer," said Tom Davis, MD, Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "The early data represented in these publications supported the creation of a broad clinical development program at Celldex to fully explore the utility of glembatumumab vedotin across a number of difficult to treat indications. With an ongoing study in triple negative breast cancer and planned studies in metastatic cutaneous melanoma, squamous cell lung cancer, uveal melanoma and pediatric osteosarcoma, we believe we will be able to greatly add to the growing understanding of gpNMB's role in cancer and glembatumumab vedotin's potential as a targeted agent." The article "A Phase 1/2 Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients with Advanced Melanoma," presents results from the first study of glembatumumab vedotin. The study initially evaluated dosing of glembatumumab vedotin on a once every 3 week (q3w) schedule. For this schedule, a Phase 1 dose escalation was followed by an open-label, single-arm, Phase 2 expansion cohort to further explore the safety and activity of the maximum tolerated dose (MTD). In addition, the study included parallel dose-escalation evaluation of alternate dosing regimens, with glembatumumab vedotin given on days 1 and 8 of a 21-day cycle (q2/3w) or weekly (qw). The primary objectives of this study were to evaluate the safety and pharmacokinetics of glembatumumab vedotin. The primary efficacy endpoint was the objective response rate (ORR) for the q3w expansion cohort. One hundred seventeen patients were treated using the q3w (n=79), q2/3w (n=15) or qw (n=23) schedules. The MTDs were 1.88, 1.5, and 1.0 mg/kg for the q3w, q2/3w and qw schedules, respectively. The most significant treatment-related toxicities were rash, fatigue, alopecia, neuropathy, and neutropenia. Three deaths were reported as potentially treatment related (resulting from pneumococcal sepsis, toxic epidermal necrolysis and renal failure) at doses exceeding the MTDs. In the q3w Phase 2 expansion cohort (n=34), five patients (15%) had a partial response (PR) and eight patients (24%) had stable disease for greater than or equal to 6 months. The overall response rate (ORR) was 2 of 6 (33%) for the q2/3w schedule MTD and 3 of 12 (25%) for the qw schedule MTD. Rash was correlated with a greater ORR and improved progression-free survival. In those patients whose gpNMB expression levels were measured, a trend toward prolonged PFS was seen for patients with tumors expressing higher levels of gpNMB. Subsequent Development in Metastatic Melanoma: The relationship between efficacy and tumor gpNMB expression will be prospectively explored in future trials using a revised, validated assay. A Phase 2 study is planned in patients with metastatic melanoma. The article, "A Phase 1/2 Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients with Locally Advanced or Metastatic Breast Cancer," presents results from a Phase 1 dose escalation study and an open-label Phase 2 expansion study. The primary objectives of the study were to evaluate safety and determine the recommended Phase 2 dose in locally advanced and metastatic breast cancer. The primary efficacy endpoint of the study was progression-free survival of greater than or equal to 30% at twelve weeks (PFS12). A total of 42 patients were enrolled, including 34 patients (six in dose escalation; 28 in expansion) treated at the 1.88 mg/kg dose (the "Phase 2 dose"), which was the pre-defined maximum dose, based on the experience in melanoma. Fatigue, rash, nausea, peripheral sensory neuropathy and neutropenia were the most frequent adverse events. Patients were heavily pretreated (median of seven prior anti-cancer regimens). PFS12 was 33% for the 27 evaluable patients treated in the Phase 2 expansion cohort. For secondary efficacy analyses, these 27 patients were pooled with the six additional patients treated at the Phase 2 dose (1.88 mg/kg) in the dose-escalation study portion. For all 33 evaluable patients treated at the Phase 2 dose, PFS12 was 36% and ORR was 12% (6% confirmed). Analyses of gpNMB expression was performed for 15 patients treated at the Phase 2 dose. Because this was the first clinical investigation targeting gpNMB in breast cancer, a positive result was defined by using a standard threshold of greater than or equal to 5% of epithelial or stromal cells expressing gpNMB. In this small sample, 80% were considered positive. All showed predominately stromal expression of gpNMB. Four patients had tumors with gpNMB expression in the epithelial compartment as well, although all had expression in less than 20% of epithelial cells. No responses were seen in the three patients with gpNMB-negative samples. Two patients who were gpNMB-positive experienced a confirmed durable PR. Expression of gpNMB was not assessed for an additional two patients that experienced a transient response. Ten evaluable patients treated at the Phase 2 dose had triple negative breast cancer (TNBC), as determined by local testing. In this population the ORR was 20% (10% confirmed), and PFS12 was 60%. All four patients who had both TNBC and gpNMB- positive tumors remained progression-free at 12 weeks. At the Phase 2 dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with TNBC, and 18.0 weeks for patients with gpNMB-positive tumors. Subsequent Development in Breast Cancer: After completing the Phase 1/2 study, a randomized Phase 2 study (EMERGE) was conducted in patients with advanced, gpNMB-expressing, heavily pretreated breast cancer to confirm and better characterize glembatumumab vedotin's activity in relation to distribution and intensity of gpNMB expression. Subgroup analyses in EMERGE suggested the greatest benefit from glembatumumab vedotin in patients whose tumors overexpressed gpNMB in 25% of epithelial cells, informing the threshold of 25% or greater gpNMB overexpression for future studies in breast cancer. Improved response rate and overall survival in patients with TNBC was also observed. A pivotal Phase 2 trial, the METRIC Study, is currently underway in patients (n=300) with metastatic, gpNMB overexpressing TNBC. These patients are randomly assigned (2:1) to receive glembatumumab vedotin or capecitabine. About Glembatumumab Vedotin Glembatumumab vedotin (CDX-011) is a fully-human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer and melanoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics' proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream, but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer -- with an initial focus in triple negative disease. In May 2010, the U.S. Food and Drug Administration (FDA) granted Fast Track designation to Celldex's glembatumumab vedotin for the treatment of advanced, refractory/resistant gpNMB-expressing breast cancer. Glembatumumab
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