Celldex Announces Publication of Glembatumumab Vedotin Phase 1/2 Studies in the Journal of Clinical Oncology
Sep 30 14
Celldex Therapeutics, Inc. announced the publication of two papers highlighting early studies of glembatumumab vedotin in breast cancer and metastatic melanoma in the Journal of Clinical Oncology. 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. 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. 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 great 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.
Celldex Therapeutics, Inc. Initiates Pilot Study of CDX-301 in Allogeneic Hematopoietic Stem Cell Transplantation
Sep 25 14
Celldex Therapeutics, Inc. announced the initiation of a pilot study of CDX-301 for the mobilization and transplantation of allogeneic hematopoietic stem cells in patients with hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT). The study will explore the utility of CDX-301, also known as FMS-like tyrosine kinase-3 ligand or Flt3L, alone and in combination with Mozobil(R) and is supported by preclinical data demonstrating that the combination of CDX-301 and Mozobil increased hematopoietic stem cell mobilization and improved transplantation of mobilized cells. The open-label, pilot study will enroll up to 36 participants, or 18 recipient/donor pairs, ages 18 to 65 across two sequentially enrolled cohorts in approximately 10 clinical trial sites in the United States. Study participants include patients (recipients) with specified hematologic malignancies (AML, ALL, MDS, CML, NHL and CLL) and Human Leukocyte Antigen (HLA) sibling-matched healthy volunteers (donors). The primary objective is to assess the safety and tolerability of CDX-301 when given with or without Mozobil. Secondary endpoints will evaluate the adequacy of the resultant grafts as determined by CD34+ yield, the cellular composition of the resultant grafts, and the safety and effectiveness of the resulting grafts across multiple measures.
Celldex Therapeutics, Inc. Presents at 2014 Morgan Stanley Global Healthcare Conference, Sep-08-2014 01:25 PM
Sep 3 14
Celldex Therapeutics, Inc. Presents at 2014 Morgan Stanley Global Healthcare Conference, Sep-08-2014 01:25 PM. Venue: The Grand Hyatt Hotel, New York, New York, United States. Speakers: Anthony S. Marucci, Chief Executive Officer, President and Director.