Date: 2016-10-09
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress
Company: Celldex Therapeutics (USA - NJ)
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: unresectable Stage III or IV melanoma
Therapeutic area: Cancer - Oncology - Rare diseases
Country: USA
Trial
details: The study is a Phase 2, open-label study of glembatumumab vedotin in patients with unresectable stage III or IV melanoma. Eligible patients must have received no more than four prior anticancer regimens, including no more than one prior chemotherapy-containing regimen, for advanced disease. Patients will receive glembatumumab vedotin every 3 weeks until disease progression or intolerance and then be followed for survival. Prior treatments must include ipilimumab and BRAF/MEK targeted agents, as applicable. The primary objective is to evaluate the anticancer activity of glembatumumab vedotin in advanced melanoma as measured by the objective response rate (ORR). Secondary endpoints include analyses of progression-free survival (PFS), duration of response (DOR), overall survival (OS), retrospective investigation of whether the anticancer activity of glembatumumab vedotin is dependent upon the degree of gpNMB expression in tumor tissue and safety.
Latest
news: * On October 9, 2016, Celldex Therapeutics presented positive results from the Company's Phase 2 study of glembatumumab vedotin in patients with stage III/IV checkpoint inhibitor-refractory, and, if applicable, BRAF/MEK inhibitor-refractory metastatic melanoma (n=62). Study results were presented at the ESMO 2016 Congress in Copenhagen in poster titled "A Phase 2 study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma." Study Highlights: The primary endpoint of the study (6 or more objective responses in the first 52 patients enrolled) was exceeded. 7 of 62 (11%) patients experienced a confirmed response, and an additional 3 patients also experienced single timepoint responses. Clinical Efficacy: * On December 4, 2014, Celldex Therapeutics announced that it has initiated an open-label Phase 2 study of glembatumumab vedotin (CDX-011) in patients with unresectable Stage III or IV melanoma.The study is expected to include up to 10 sites in the United States and will enroll approximately 60 patients. Glembatumumab vedotin was previously evaluated in a Phase 1/2 study in patients with unresectable stage III or stage IV melanoma, a Phase 1/2 study in advanced breast cancer, a Phase 2 study in advanced breast cancer (the EMERGE study) and is currently being evaluated in patients with metastatic triple negative breast cancers that overexpress gpNMB in the METRIC Study.
Median duration of response in this heavily pre-treated patient population was 6.0 months.
53% of patients experienced stable disease (with a minimum duration of six weeks).
A 52% disease control rate (patients without progression for greater than three months) was demonstrated.
52% of patients experienced tumor shrinkage.
Median progression-free survival (PFS) for all patients was 4.4 months.
Patients who experienced rash in Cycle 1 experienced a 20% confirmed response rate and a more prolonged PFS of 5.5 months [p=0.054; HR=0.52 (0.27, 1.02)].
This study was a Phase 2, open-label study of glembatumumab vedotin in patients with unresectable stage III (n=1; 2%) or stage IV (n=61; 98%) melanoma. The median number of prior therapies was three (range of 1 to 6). All patients had progressed after checkpoint therapy, and almost all patients had received both ipilimumab (n=58; 94%) and PD-1/PDL-1 (n=58; 94%) therapy. Twelve patients presented with BRAF mutation, and eleven had prior treatment with BRAF or BRAF/MEK targeted agents. Patients received glembatumumab vedotin every three weeks until disease progression or intolerance. The safety profile was consistent with prior studies of glembatumumab vedotin with rash, neutropenia, and neuropathy experienced as the most significant adverse events. Consistent with previous studies in melanoma and breast cancer, rash was associated with greater clinical benefit.
Primary Endpoint: Confirmed Response Rate (ORR) Met 7/62 (11%)
Duration of Response Median: 6.0 months
Range: 1.4 + to 8.6+
Any Response, Including Those not Confirmed at Subsequent Assessment 10/62 (16%)
Stable Disease 33/62 (53%)
Disease Control Rate 32/62 (52%)
Patients with Tumor Shrinkage 32/62 (52%)
Progression-free Survival Median: 4.4 months
Range: 0.4 to 15.8+
Tumor tissue (pre-treatment) was available for 58 patients at the time of analysis. All samples were gpNMB positive, and 79% of patients had tumors with 100% of their epithelial cells expressing gpNMB. Given both the high level of expression and the intensity of expression across this patient population, identifying a potential population for gpNMB enrichment is not feasible; therefore, all patients with metastatic melanoma could be evaluated as potential candidates for treatment with glembatumumab vedotin in future studies.
In August 2016, the Company announced that the primary endpoint had been met in this Phase 2 single-agent study of glembatumumab vedotin in metastatic melanoma (post-progression on/after checkpoint therapy) and that the Company was amending the protocol to add a second cohort of patients to a glembatumumab vedotin and varlilumab combination. This additional cohort is open to enrollment. Upon completion of enrollment in this cohort, the Company is exploring opening a new arm in the study to assess a glembatumumab vedotin and checkpoint combination. This rationale is strongly supported by preclinical data that suggest that the anti-tumor activity may be enhanced with the combination. In addition, due to their direct cytotoxic properties, microtubule-depolymerizing agents like MMAE also appear to convert tumor-resident tolerogenic dendritic cells into active antigen-presenting cells. The Company also intends to conduct exploratory analyses of pre-entry skin biopsies in future patients to investigate potential predictors of response to glembatumumab vedotin, given the association of rash and outcome.
