Study of Glembatumumab Vedotin (CDX-011) in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to see whether CDX-011 (glembatumumab vedotin, an antibody-drug conjugate) is effective in treating patients who have advanced Triple-Negative Breast Cancer (TNBC), and whose tumor cells make a protein called glycoprotein NMB (gpNMB), which CDX-011 binds to. The study will also further characterize the safety of CDX-011 treatment in this patient population.

Detailed Description
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CDX-011 consists of an antibody attached to a drug, monomethyl auristatin E (MMAE), that can kill cancer cells. The antibody delivers the drug to cancer cells by attaching to a protein called glycoprotein NMB (gpNMB) that is expressed on the cancer cell. The MMAE is then released inside of the cell, where it interferes with cell growth and may lead to cell death. This study will examine the efficacy and safety of CDX-011 in patients with advanced TNBC that makes the gpNMB protein. The effect of CDX-011 will be compared to treatment with capecitabine. Eligible patients who enroll in the study will be randomly assigned (by chance) to receive treatment with CDX-011 or with capecitabine. For every three patients enrolled, two will receive CDX-011 and one will receive treatment with capecitabine. All patients enrolled in the study will be closely monitored to determine if their cancer is responding to treatment and for any side effects that may occur.

Official Title
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A Randomized Multicenter Pivotal Study of CDX-011 (CR011-vcMMAE)in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (The METRIC Study)

Conditions
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Metastatic gpNMB Over-expressing Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: CDX-011
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Among other criteria, patients must meet all of the following conditions to be eligible for the study: Diagnosed with metastatic (i.e., cancer that has spread) TNBC minimal or no expression of estrogen and progesterone receptors (ER/PR) <10% of cells positive by immunohistochemistry HER 2 staining 0 or 1+ by IHC or copy number <4.0 signals/cell Documented progression of disease based on radiographic, clinical or pathologic assessment during or subsequent to the last anticancer regimen received. Breast cancer tumor confirmed to express gpNMB. This will be determined by submitting a tissue sample from the advanced (locally advanced/recurrent or metastatic) disease setting to a central laboratory for analysis. Received no more than two prior chemotherapy treatments for advanced (locally advanced/recurrent or metastatic) breast cancer. Prior chemotherapy treatment must have contained an anthracycline (e.g. doxorubicin or Doxil) if clinically indicated and a taxane (eg: Taxol). ECOG performance status of 0 - 1. Adequate bone marrow, liver and renal function. Exclusion: Among other criteria, patients who meet any of the following conditions are NOT eligible for the study: Progression/recurrence of breast cancer during or within 3 months of completion of neoadjuvant or adjuvant chemotherapy. 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. Previously received capecitabine and discontinued due to progression or intolerance; previously received CDX-011 or other MMAE containing agents. Active systemic infection requiring treatment. Infection controlled by oral therapy will not be exclusionary. Chronic use of systemic corticosteroids.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Capecitabine<br>Capecitabine will be administered on Days 1 through 14 of each 21 day cycle. | Drug: Capecitabine<br> <br> |
| Experimental: Drug: CDX-011<br>CDX-011 administered as an intravenous infusion on Day 1 of each 21 day cycle. | Drug: CDX-011<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or progression in a non-target lesion, or the appearance of new lesions. The primary analysis of PFS was based on PFS events determined retrospectively by the central independent review committee, blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria. | Evaluated every 6 - 9 weeks following treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the percentage of patients who achieve best overall response of complete or partial response. The analysis of ORR was based on ORR events determined retrospectively by the central independent review committee, blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Complete Response (CR) = Disappearance of all target lesions and non-target lesions, Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions with no progression in non-target lesions and no new lesions. | Evaluated every 6 - 9 weeks following treatment initiation | 
| Duration of Response | Duration of response (DOR) is the number of months from the time criteria are first met for either CR or PR, until the first date that PD is objectively documented. The analysis of DOR was determined retrospectively by the central independent review committee,blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Complete Response (CR) = Disappearance of all target lesions and non-target lesions, Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions with no progression in non-target lesions and no new lesions. | Evaluated every 6 - 9 weeks following treatment initiation | 
| Overall Survival | Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause. | During treatment and 3 months from end of treatment through end of study or approximately up to 5 years. | 
| Adverse Events (AE) | The percentage of patients experiencing one or more adverse events will be summarized by treatment arm, relationship to study drug, and severity. | Usually following at least 1 cycle of study treatment (1 dose of CDX-011 or capecitabine and until discontinuation of follow-up) | 
| Pharmacokinetics (PK) | Concentration of the antibody drug conjugate (ADC), total antibody (TA) and free MMAE will be determined. | Following 1 dose of CDX-011. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Breast Cancer, Locally advanced breast cancer, Breast cancer, Triple negative, Estrogen, Progesterone, HER2 receptors, Targeted treatment for breast cancer, Antibody-drug-conjugate, Breast Neoplasms, CDX-011, gpNMB, METRIC, Glembatumumab vedotin, Triple Negative Breast Cancer, TNBC