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 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. EMERGE, a Phase 2b trial in GPNMB-expressing breast cancer, is ongoing.

Phase 2b: A Study of CDX-011 (CR011-vcMMAE) in Patients With Advanced GPNMB-expressing Breast Cancer (EMERGE)

This study will examine the effectiveness and safety of CDX-011 in patients with advanced breast cancer that expresses GPNMB. Eligible patients who enroll in the study will be randomly assigned by chance to receive treatment with CDX-011 or with a chemotherapy chosen by their study doctor from a list of currently available drugs ("Investigator's Choice" chemotherapy). For each three patients enrolled, two will receive CDX-011 and one will receive treatment with "Investigator's Choice". Patients initially assigned to "Investigator's Choice" chemotherapy may be offered the option to “cross-over” to receive treatment with CDX-011 if their cancer worsens during this initial treatment. All patients enrolled in the study will be closely monitored to determine if their cancer is responding to treatment, for any side effects that may occur, and for survival information.

Patient Eligibility

Among other criteria, patients must meet all of the following conditions to be eligible for the study:

• 18 years of age or older.
• Locally advanced or metastatic breast cancer.
• Previous treatment with at least two but no more than five prior chemotherapy treatments for progressive, recurrent or metastatic breast cancer.
• Unless not a candidate for these agents, prior therapies must have included a taxane, an anthracycline, capecitabine and ixabepilone, as well as trastuzumab and lapatinib for patients whose tumors are positive for the human epidermal growth factor receptor 2 (HER2). (Patients who received incomplete courses of therapy with these agents due to intolerance will be eligible.)
• Breast cancer tumor confirmed to express GPNMB. This will be determined by submitting a tissue sample (obtained during a diagnostic biopsy or surgery) to a central laboratory for analysis.

Among other criteria, patients who meet any of the following conditions are NOT eligible to be in the study:

• Ongoing neuropathy or other chemotherapy or radiation-related toxicities that are moderate (Grade 2) or worse in severity.
• Known brain metastases, unless previously treated and asymptomatic for 2 months and not progressive in size or number for 2 months.
• Significant cardiovascular disease or any other underlying medical condition that, in the Investigator's opinion, will make the administration of study treatment (CDX-011 or chemotherapy) hazardous or would obscure the interpretation of side effects.

Please click here for more information about this trial, including a list of clinical trial sites and contact information for prospective patients.

Closed to Enrollment

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 further evaluate the safety and efficacy of CDX-011.

As presented at ASCO 2010, 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 anti-cancer regimens). As previously seen in melanoma patients, the 1.88 mg/kg dose was well tolerated. Dose-limiting toxicity was limited to neuropathy. The most common treatment-related toxicities were fatigue, rash, nausea, alopecia (hair loss), neutropenia and vomiting. The primary endpoint for the study, progression-free survival (PFS) rate at 12 weeks for the Phase 2 study portion, has been met, with a 12-week PFS rate of 35% (9 of 26). For all patients treated at the maximum dose level, tumor shrinkage was seen in 62% (16/26) and PFS was 9.1 weeks. A subset of 10 patients had triple-negative disease, a more aggressive breast cancer subtype that carries a high risk of relapse and reduced survival as well as limited therapeutic options due to lack of over-expression of HER2/neu, estrogen and progesterone receptors. In these patients, 78% (7/9) had any tumor shrinkage, 12-week PFS rate was 70% (7/10), and median PFS was 17.9 weeks. In the small subset of patients with significant tumoral expression of GPNMB, overall response rate was 22%, median PFS was 17.3 weeks, and the 12-week PFS rate was 67%.

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.

As presented at ASCO 2010, CDX-011 was found to be active in advanced melanoma patients in the study. In the Phase 2 expansion study, CDX-011 was administered at the pre-defined maximum tolerated dose (MTD) once every three weeks. The primary activity endpoint of overall response rate (ORR) in the cohort was achieved with an ORR of 15% (5/34). Median progression free survival (PFS) was 3.9 months. More frequent dosing schedules were evaluated in two additional, parallel dose-escalation arms in which patients received CDX-011 weekly or twice every three weeks. At the maximum tolerated doses in these schedules, the response rate was observed to be 20% (n=15) and 33% (n=6), respectively. To date, 83% (33/40) of patients with tumor sample analyzed by immunohistochemistry were positive for GPNMB expression. Preliminary data suggest an increase in PFS in patients with high tumoral GPNMB expression. The subset of seven patients, whose tumors were found to express high amounts of GPNMB, and who were treated at the maximum tolerated doses across all dosing schedules, demonstrated a median PFS of 4.9 months. The development of rash, which may be associated with the presence of GPNMB in the skin, correlated with greater PFS. The most frequent treatment-related adverse events included rash, fatigue, alopecia (hair loss), pruritus, diarrhea and neuropathy.

For publications and poster presentations discussing results of these trials, click here.