Breast Cancer
Conditions
Brief summary
A study to evaluate the response of growth factor signatures (GFS) to a single dose of dalotuzumab in participants with triple negative (TN) or estrogen receptor (ER)-positive luminal B breast cancer. The primary hypothesis is that dalotuzumab will induce a decrease in the GFS in at least 40% of participants.
Interventions
DRUGdalotuzumab (MK0646)
Single intravenous infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant has operable stage I-IIIa breast cancer of the following subtypes: (1) estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer; (2) ER-positive tumor meeting one of the following criteria: histologic grade 3; histologic grade 2 and PR-negative; histologic grade 2 and Ki67 antigen ≥10%. Tumor is at least 2 cm in diameter as assessed by physical or radiographic exam * Participant is female and ≥18 years of age
Exclusion criteria
* Participant is pregnant, breastfeeding or planning to become pregnant while in the study * Participant has received prior chemotherapy, biological therapy or radiation * Participant has participated in a clinical trial in the last 30 days * Participant has a history of drug or alcohol abuse in the last year * Participant is human immunodeficiency virus (HIV) positive. Patient has a history of Hepatitis B or C * Participant has poorly controlled diabetes mellitus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Demonstrating a Decrease in the Growth Factor Signature (GFS) | Up to 12 Days Post-dose | GFS was measured by microarray analysis of the entire 101 gene signature expression. The GFS is quantified as the change in gene expression between two separate samples collected from the same participant. A log (base 10) ratio of expression in the post-dose sample was generated relative to the reference in both the Up and DOWN arms of the gene signature. A log ratio value of zero indicated no change in the expression between the two samples. GFS was calculated as the mean log ratio of genes in the UP arm minus mean log ratio of genes in the Down arm. GFS was compared for paired samples (pre-dose and post-dose) by a T-statistic calculated as the GFS divided by its standard error. Responders to therapy had a T-statistic that was smaller than the threshold 1st percentile of student's T-distribution and were counted as having a decrease in GFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of IGF1R Positive Participants With a Decrease in GFS by Cohort | Up to 12 Days Post-dose | Insulin-like Growth Factor Receptor Type 1 (IGF1R) expression was measured in pre-dose biopsy samples using an immunohistochemistry assay to establish baseline IGF1R positivity. Biopsy samples were considered IGF1R positive if at least 10% of tumor cells stain with intensity 1+ or greater based on staining criteria of very weak (+/-); weak (1+); moderate (2+); or strong (3+). GFS response was correlated with IGF1R expression for ER-positive luminal B and triple negative cohorts. |
| Percentage of IGF1R Negative Participants With a Decrease in GFS by Cohort | Up to 12 Days Post-dose | Biopsy samples were considered IGF1R negative if less than 10% of tumor cells stain. GFS response was correlated with IGF1R expression for ER-positive luminal B and triple negative cohorts. |
| Change From Baseline in IGF1R Membrane H-Score After a Single Dose of Dalotuzumab | Baseline and Up to 12 Days | IGF1R expression was measured in pre and post-dose biopsy samples using an immunohistochemistry assay. Results were expressed as an IGF1R membrane H-score. The H-score was calculated from the percentage of cells staining very weak (+/-); weak (1+); moderate (2+); or strong (3+) and obtained by the formula: (3 x percentage of strongly staining nuclei) + (2 x percentage of moderately staining nuclei) + (1 x percentage of weakly staining nuclei) + (0.5 x percentage of weakly staining nuclei). The H-score ranges from 0 to 300; with a score of 0 representing the absence of IGF1R expression and an H-score of 300 representing maximum IGF1R expression. A decrease in IGF1R membrane H-score was an indication of target engagement by dalotuzumab. A larger decrease in H-score correlated with a greater target engagement |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ER-positive Luminal B (ER+) ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes. | 26 |
| Triple Negative (TN) Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes. | 22 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Participant sample lost | 0 | 1 |
| Overall Study | Participant sample not evaluable | 11 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | ER-positive Luminal B (ER+) | Triple Negative (TN) | Total |
|---|---|---|---|
| Age, Continuous | 58.8 Years STANDARD_DEVIATION 15.7 | 55.1 Years STANDARD_DEVIATION 14.1 | 57.1 Years STANDARD_DEVIATION 14.9 |
| Sex: Female, Male Female | 26 Participants | 22 Participants | 48 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 | — / — | — / — |
| other Total, other adverse events | 2 / 25 | 4 / 20 |
| serious Total, serious adverse events | 1 / 25 | 1 / 20 |
Outcome results
Primary
Percentage of Participants Demonstrating a Decrease in the Growth Factor Signature (GFS)
GFS was measured by microarray analysis of the entire 101 gene signature expression. The GFS is quantified as the change in gene expression between two separate samples collected from the same participant. A log (base 10) ratio of expression in the post-dose sample was generated relative to the reference in both the Up and DOWN arms of the gene signature. A log ratio value of zero indicated no change in the expression between the two samples. GFS was calculated as the mean log ratio of genes in the UP arm minus mean log ratio of genes in the Down arm. GFS was compared for paired samples (pre-dose and post-dose) by a T-statistic calculated as the GFS divided by its standard error. Responders to therapy had a T-statistic that was smaller than the threshold 1st percentile of student's T-distribution and were counted as having a decrease in GFS.
Time frame: Up to 12 Days Post-dose
Population: All participants who received a single dose of dalotuzumab and had evaluable baseline and post-dose biopsy samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ER-positive Luminal B (ER+) | Percentage of Participants Demonstrating a Decrease in the Growth Factor Signature (GFS) | 28.6 Percentage of participants |
| Triple Negative (TN) | Percentage of Participants Demonstrating a Decrease in the Growth Factor Signature (GFS) | 17.6 Percentage of participants |
Secondary
Change From Baseline in IGF1R Membrane H-Score After a Single Dose of Dalotuzumab
IGF1R expression was measured in pre and post-dose biopsy samples using an immunohistochemistry assay. Results were expressed as an IGF1R membrane H-score. The H-score was calculated from the percentage of cells staining very weak (+/-); weak (1+); moderate (2+); or strong (3+) and obtained by the formula: (3 x percentage of strongly staining nuclei) + (2 x percentage of moderately staining nuclei) + (1 x percentage of weakly staining nuclei) + (0.5 x percentage of weakly staining nuclei). The H-score ranges from 0 to 300; with a score of 0 representing the absence of IGF1R expression and an H-score of 300 representing maximum IGF1R expression. A decrease in IGF1R membrane H-score was an indication of target engagement by dalotuzumab. A larger decrease in H-score correlated with a greater target engagement
Time frame: Baseline and Up to 12 Days
Population: All participants who received a single dose of dalotuzumab, had evaluable baseline and post-dose biopsy samples, and had H-score data available for pre- and post-dose measurements.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ER-positive Luminal B (ER+) | Change From Baseline in IGF1R Membrane H-Score After a Single Dose of Dalotuzumab | -104.5 H-score |
| Triple Negative (TN) | Change From Baseline in IGF1R Membrane H-Score After a Single Dose of Dalotuzumab | -11.5 H-score |
Secondary
Percentage of IGF1R Negative Participants With a Decrease in GFS by Cohort
Biopsy samples were considered IGF1R negative if less than 10% of tumor cells stain. GFS response was correlated with IGF1R expression for ER-positive luminal B and triple negative cohorts.
Time frame: Up to 12 Days Post-dose
Population: All participants who received a single dose of dalotuzumab, were IGF1R negative at baseline, and had evaluable postdose biopsy samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ER-positive Luminal B (ER+) | Percentage of IGF1R Negative Participants With a Decrease in GFS by Cohort | 0.0 Percentage of participants |
| Triple Negative (TN) | Percentage of IGF1R Negative Participants With a Decrease in GFS by Cohort | 20.0 Percentage of participants |
Secondary
Percentage of IGF1R Positive Participants With a Decrease in GFS by Cohort
Insulin-like Growth Factor Receptor Type 1 (IGF1R) expression was measured in pre-dose biopsy samples using an immunohistochemistry assay to establish baseline IGF1R positivity. Biopsy samples were considered IGF1R positive if at least 10% of tumor cells stain with intensity 1+ or greater based on staining criteria of very weak (+/-); weak (1+); moderate (2+); or strong (3+). GFS response was correlated with IGF1R expression for ER-positive luminal B and triple negative cohorts.
Time frame: Up to 12 Days Post-dose
Population: All participants who received a single dose of dalotuzumab, were IGF1R positive at baseline, and had evaluable postdose biopsy samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ER-positive Luminal B (ER+) | Percentage of IGF1R Positive Participants With a Decrease in GFS by Cohort | 25.0 Percentage of participants |
| Triple Negative (TN) | Percentage of IGF1R Positive Participants With a Decrease in GFS by Cohort | 11.1 Percentage of participants |