CDX-011: Clinical Program
TREATMENT FOR METASTATIC BREAST CANCER AND ADVANCED MELANOMA
Our first antibody-drug conjugate (ADC) product candidate, CDX-011 (formerly CR011-vcMMAE), is in development for the treatment of locally advanced or metastatic breast cancer and stage III and IV melanoma. CDX-011 is a fully-human monoclonal antibody-drug conjugate that targets glycoprotein NMB (GPNMB). GPNMB, also known as osteoactivin, is a protein overexpressed by multiple tumor types, including melanoma, breast cancer and glioma. 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. CDX-011 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. Two Phase 1/2 studies of CDX-011, one for the treatment of locally advanced or metastatic breast cancer and the second for the treatment of stage III and IV melanoma, have been conducted. For presentations discussing results of these trials, click here.
| Closed to enrollment |
| Phase 1/2: Locally Advanced or Metastatic Breast Cancer |
| Phase 1/2: Unresectable Stage III or Stage IV Melanoma |
Phase 1/2: Locally Advanced or Metastatic Breast Cancer
This study evaluated the safety and activity of CDX-011 in patients with locally advanced and metastatic breast cancer. CDX-011 was administered intravenously once every 3 weeks to cohorts of 3-6 patients at escalating doses, to confirm the maximum tolerated dose (MTD) in breast cancer patients, followed by a Phase 2 trial portion to to further evaluate the safety and efficacy of CDX-011.
As presented at the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) in 2009, this was a positive Phase 2 study of CDX-011 in a population of forty-two advanced breast cancer patients who were heavily pretreated (median of seven prior regimens). As previously seen in melanoma patients, the 1.88 mg/kg dose was well tolerated. Dose-limiting toxicity was limited to neuropathy. Other adverse events included fatigue, rash, nausea, vomiting, hair loss and neutropenia. The primary efficacy endpoint for the trial, which called for at least 20% of the Phase 2 patients to be progression-free at twelve weeks, was met. At the time of presentation, 35% of evaluable Phase 2 patients were without progression of disease at twelve weeks. For all evaluable patients at the Phase 2 dose level, 13% achieved confirmed or unconfirmed Partial Responses (PR) while 60% of those with measurable disease experienced some reduction in tumor size. The target, GPNMB, was frequently expressed in this patient population (in 71% of the patients), and expression of GPNMB was associated with improved outcomes following treatment with CDX-011. Both patients who achieved an objective, confirmed Partial Response expressed GPNMB, with response durations of 23+ to 27 weeks. In the seven patients who received the Phase 2 dose and whose tumors expressed GPNMB, 29% had confirmed Partial Responses, 71% had decreases in tumor size, and all achieved at least stable disease with duration from 17.3 to 26.9 weeks. In patients whose tumors expressed GPNMB, median progression-free survival (PFS) was 18.3 weeks, compared to median PFS of 5.9 weeks for patients whose tumors did not express GPNMB, and 9.1 weeks for all patients treated at the Phase 2 dose. In addition, encouraging results were seen in patients with “triple-negative disease” where treatment options are relatively limited due to lack of hormone receptor or HER2-neu expression. In the 10 patients with triple negative disease, 71% of those tested expressed GPNMB, 78% of the evaluable patients had tumor shrinkage, and the median PFS was 17.9 weeks.Phase 1/2: Unresectable Stage III or Stage IV Melanoma
This study evaluated the safety, tolerability and pharmacokinetics of CDX-011 in patients with unresectable stage III or stage IV melanoma. CDX-011 was administered intravenously once every 3 weeks to cohorts of 3-6 patients at escalating doses, until reaching the maximum tolerated dose (MTD), followed by a Phase 2 trial portion to further evaluate the safety and efficacy of CDX-011.
Data from the first thirty-six patients enrolled in this trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2009. Of the patients enrolled, 94% had Stage IV disease of which two-thirds were classified as M1c, the poorest risk group. The maximum tolerated dose was established at 1.88 mg/kg, given every three weeks. The study successfully met its primary activity endpoint, with an objective response rate of 15%, and median duration of response of 5.3 months. The median overall progression-free survival (PFS) was 4.4 months and 6-month PFS was 36%. Tumor shrinkage was observed in 58% of patients, and 20 patients had best response of stable disease. Dermatologic adverse events consisting of rash, alopecia, and pruritus were the most common toxicities in this study. Other adverse events included fatigue, diarrhea, anorexia and nausea. Grade 3 or 4 neutropenia was observed in 5 patients. The absence of rash in the first cycle of treatment predicted shorter progression-free survival. Additionally, in a subset of patients with tumor biopsies, high levels of tumor expression of GPNMB appeared to correlate with favorable outcome.