Metastatic gpNMB Over-expressing Triple Negative Breast Cancer
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGCDX-011
DRUGCapecitabine
Sponsors
Celldex Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Among other criteria, patients must meet all of the following conditions to be eligible for the study: 1. 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 2. Documented progression of disease based on radiographic, clinical or pathologic assessment during or subsequent to the last anticancer regimen received. 3. 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. 4. Received no more than two prior chemotherapy treatments for advanced (locally advanced/recurrent or metastatic) breast cancer. 5. Prior chemotherapy treatment must have contained an anthracycline (e.g. doxorubicin or Doxil) if clinically indicated and a taxane (eg: Taxol). 6. ECOG performance status of 0 - 1. 7. 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: 1. Progression/recurrence of breast cancer during or within 3 months of completion of neoadjuvant or adjuvant chemotherapy. 2. Ongoing neuropathy or other chemotherapy or radiation-related toxicities that are moderate (Grade 2) or worse in severity. 3. Known brain metastases, unless previously treated and asymptomatic for 2 months and not progressive in size or number for 2 months. 4. Significant cardiovascular disease. 5. Previously received capecitabine and discontinued due to progression or intolerance; previously received CDX-011 or other MMAE containing agents. 6. Active systemic infection requiring treatment. Infection controlled by oral therapy will not be exclusionary. 7. Chronic use of systemic corticosteroids.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Evaluated every 6 - 9 weeks following treatment initiation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Evaluated every 6 - 9 weeks following treatment initiation | 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. |
| Duration of Response | Evaluated every 6 - 9 weeks following treatment initiation | 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. |
| Overall Survival | During treatment and 3 months from end of treatment through end of study or approximately up to 5 years. | Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause. |
| Adverse Events (AE) | Usually following at least 1 cycle of study treatment (1 dose of CDX-011 or capecitabine and until discontinuation of follow-up) | The percentage of patients experiencing one or more adverse events will be summarized by treatment arm, relationship to study drug, and severity. |
| Pharmacokinetics (PK) | Following 1 dose of CDX-011. | Concentration of the antibody drug conjugate (ADC), total antibody (TA) and free MMAE will be determined. |
Countries
Australia, Belgium, Canada, France, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
1531 patients screened to randomize 327 patients. Most common reasons for screen failure were tumor tissue inadequate/gpNMB negative (697), failure to meet other eligibility (256) and refused to participate (77).
Participants by arm
| Arm | Count |
|---|---|
| Capecitabine Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study. | 109 |
| CDX-011 CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study. | 218 |
| Total | 327 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Randomization and Treatment | Adverse Event | 10 | 32 |
| Randomization and Treatment | Did not receive treatment | 17 | 5 |
| Randomization and Treatment | Disease Progression | 70 | 159 |
| Randomization and Treatment | Physician Decision | 0 | 4 |
| Randomization and Treatment | Withdrawal by Subject | 6 | 3 |
| Survival Follow up | Lost to Follow-up | 0 | 6 |
| Survival Follow up | Various | 1 | 2 |
| Survival Follow up | Withdrawal by Subject | 15 | 6 |
Baseline characteristics
| Characteristic | Capecitabine | CDX-011 | Total |
|---|---|---|---|
| Age, Continuous | 55 years | 55 years | 55 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 11 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 99 Participants | 191 Participants | 290 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 16 Participants | 21 Participants |
| Number of cytotoxic regimens in advanced stage | 1 cytotoxic regimen | 1 cytotoxic regimen | 1 cytotoxic regimen |
| Number of prior relapses in advanced stage 0 | 21 participants | 45 participants | 66 participants |
| Number of prior relapses in advanced stage 1 | 58 participants | 122 participants | 180 participants |
| Number of prior relapses in advanced stage 2 | 24 participants | 42 participants | 66 participants |
| Number of prior relapses in advanced stage 3 | 6 participants | 9 participants | 15 participants |
| Prior Anthracycline Use | 95 Participants | 185 Participants | 280 Participants |
| Prior Taxane Use | 108 Participants | 218 Participants | 326 Participants |
| Progression Free Interval post last Taxane greater than 6 months | 58 Participants | 106 Participants | 164 Participants |
| Progression Free Interval post last Taxane less than or equal to 6 months | 51 Participants | 112 Participants | 163 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 20 Participants | 29 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 16 Participants | 23 Participants |
| Race (NIH/OMB) White | 91 Participants | 176 Participants | 267 Participants |
| Region of Enrollment Australia | 3 participants | 15 participants | 18 participants |
| Region of Enrollment Belgium | 2 participants | 6 participants | 8 participants |
| Region of Enrollment Canada | 7 participants | 5 participants | 12 participants |
| Region of Enrollment France | 4 participants | 14 participants | 18 participants |
| Region of Enrollment Germany | 5 participants | 9 participants | 14 participants |
| Region of Enrollment Italy | 6 participants | 7 participants | 13 participants |
| Region of Enrollment Spain | 5 participants | 13 participants | 18 participants |
| Region of Enrollment United Kingdom | 5 participants | 6 participants | 11 participants |
| Region of Enrollment United States | 72 participants | 143 participants | 215 participants |
| Sex: Female, Male Female | 109 Participants | 218 Participants | 327 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 65 / 92 | 134 / 213 |
| other Total, other adverse events | 91 / 92 | 211 / 213 |
| serious Total, serious adverse events | 19 / 92 | 71 / 213 |
Outcome results
Primary
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.
Time frame: Evaluated every 6 - 9 weeks following treatment initiation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Capecitabine | Progression Free Survival (PFS) | 2.8 months |
| CDX-011 | Progression Free Survival (PFS) | 2.9 months |
p-value: 0.761Log Rank
Secondary
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.
Time frame: Usually following at least 1 cycle of study treatment (1 dose of CDX-011 or capecitabine and until discontinuation of follow-up)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Capecitabine | Adverse Events (AE) | Patients with Grade 1 treatment related AE | 7 Participants |
| Capecitabine | Adverse Events (AE) | Patients with Grade 3 treatment related AE | 44 Participants |
| Capecitabine | Adverse Events (AE) | Patients with at least 1 treatment related AE | 84 Participants |
| Capecitabine | Adverse Events (AE) | Patients with Grade 4 treatment related AE | 8 Participants |
| Capecitabine | Adverse Events (AE) | Patients with Grade 2 treatment related AE | 33 Participants |
| Capecitabine | Adverse Events (AE) | Patients with Grade 5 treatment related AE | 0 Participants |
| Capecitabine | Adverse Events (AE) | Patients with at least 1 AE | 92 Participants |
| CDX-011 | Adverse Events (AE) | Patients with Grade 5 treatment related AE | 4 Participants |
| CDX-011 | Adverse Events (AE) | Patients with at least 1 AE | 211 Participants |
| CDX-011 | Adverse Events (AE) | Patients with at least 1 treatment related AE | 204 Participants |
| CDX-011 | Adverse Events (AE) | Patients with Grade 1 treatment related AE | 7 Participants |
| CDX-011 | Adverse Events (AE) | Patients with Grade 2 treatment related AE | 54 Participants |
| CDX-011 | Adverse Events (AE) | Patients with Grade 3 treatment related AE | 114 Participants |
| CDX-011 | Adverse Events (AE) | Patients with Grade 4 treatment related AE | 32 Participants |
Secondary
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.
Time frame: Evaluated every 6 - 9 weeks following treatment initiation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Capecitabine | Duration of Response | 4.2 months |
| CDX-011 | Duration of Response | 2.8 months |
Secondary
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.
Time frame: Evaluated every 6 - 9 weeks following treatment initiation
Population: Patients with measurable disease.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Capecitabine | Objective Response Rate (ORR) | 21 percentage of participants |
| CDX-011 | Objective Response Rate (ORR) | 26 percentage of participants |
p-value: 0.264Cochran-Mantel-Haenszel
Secondary
Overall Survival
Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause.
Time frame: During treatment and 3 months from end of treatment through end of study or approximately up to 5 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Capecitabine | Overall Survival | 8.7 months |
| CDX-011 | Overall Survival | 8.9 months |
p-value: 0.726Log Rank
Secondary
Pharmacokinetics (PK)
Concentration of the antibody drug conjugate (ADC), total antibody (TA) and free MMAE will be determined.
Time frame: Following 1 dose of CDX-011.
Population: Samples were obtained from 201 of 213 patients treated with CDX-011. A partial analysis provided below results. Additional analyses were not completed. Results should be interpreted with caution.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Capecitabine | Pharmacokinetics (PK) | Cycle 1 post infusion TA levels | 49.4 ug/ml |
| Capecitabine | Pharmacokinetics (PK) | Cycle 1 post infusion ADC levels | 58.6 ug/ml |
| Capecitabine | Pharmacokinetics (PK) | Cycle 1 post infusion MMAE levels | 0.0015 ug/ml |