Trial Outcomes & Findings for A Study of Dalotuzumab (MK-0646) in Breast Cancer Patients (MK-0646-013) (NCT NCT00759785)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

48 participants

Primary outcome timeframe

Up to 12 Days Post-dose

Results posted on

2018-08-15

Participant Flow

Participant milestones

Participant milestones
Measure	ER-positive Luminal B (ER+) ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Overall Study STARTED	26	22
Overall Study Treated	25	20
Overall Study COMPLETED	14	17
Overall Study NOT COMPLETED	12	5

Reasons for withdrawal

Reasons for withdrawal
Measure	ER-positive Luminal B (ER+) ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Overall Study Participant sample not evaluable	11	2
Overall Study Participant sample lost	0	1
Overall Study Protocol Violation	1	0
Overall Study Physician Decision	0	1
Overall Study Withdrawal by Subject	0	1

Baseline Characteristics

A Study of Dalotuzumab (MK-0646) in Breast Cancer Patients (MK-0646-013)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ER-positive Luminal B (ER+) n=26 Participants ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) n=22 Participants Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Total n=48 Participants Total of all reporting groups
Age, Continuous	58.8 Years STANDARD_DEVIATION 15.7 • n=5 Participants	55.1 Years STANDARD_DEVIATION 14.1 • n=7 Participants	57.1 Years STANDARD_DEVIATION 14.9 • n=5 Participants
Sex: Female, Male Female	26 Participants n=5 Participants	22 Participants n=7 Participants	48 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	ER-positive Luminal B (ER+) n=14 Participants ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) n=17 Participants Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Percentage of Participants Demonstrating a Decrease in the Growth Factor Signature (GFS)	28.6 Percentage of participants Interval 13.1 to 49.2	17.6 Percentage of participants Interval 6.7 to 35.2

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	ER-positive Luminal B (ER+) n=12 Participants ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) n=9 Participants Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Percentage of IGF1R Positive Participants With a Decrease in GFS by Cohort	25.0 Percentage of participants Interval 9.6 to 47.5	11.1 Percentage of participants Interval 1.2 to 36.8

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	ER-positive Luminal B (ER+) n=1 Participants ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) n=5 Participants Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Percentage of IGF1R Negative Participants With a Decrease in GFS by Cohort	0.0 Percentage of participants Interval 0.0 to 90.0	20.0 Percentage of participants Interval 2.1 to 58.4

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	ER-positive Luminal B (ER+) n=13 Participants ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) n=13 Participants Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Change From Baseline in IGF1R Membrane H-Score After a Single Dose of Dalotuzumab	-104.5 H-score Interval -235.0 to -4.0	-11.5 H-score Interval -105.0 to 100.0

Adverse Events

ER-positive Luminal B (ER+)

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Triple Negative (TN)

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	ER-positive Luminal B (ER+) n=25 participants at risk ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) n=20 participants at risk Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Gastrointestinal disorders Diarrhoea	0.00% 0/25 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	5.0% 1/20 • Number of events 1 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab
Infections and infestations Breast abscess	0.00% 0/25 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	5.0% 1/20 • Number of events 1 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab
Infections and infestations Breast cellulitis	0.00% 0/25 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	5.0% 1/20 • Number of events 1 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab
Nervous system disorders Syncope	4.0% 1/25 • Number of events 1 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	0.00% 0/20 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab

Other adverse events

Other adverse events
Measure	ER-positive Luminal B (ER+) n=25 participants at risk ER-positive Luminal B participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.	Triple Negative (TN) n=20 participants at risk Triple Negative participants received a single dose of dalotuzumab 20 mg/kg infused over 60-120 minutes.
Gastrointestinal disorders Nausea	4.0% 1/25 • Number of events 2 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	20.0% 4/20 • Number of events 5 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab
General disorders Fatigue	4.0% 1/25 • Number of events 1 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	15.0% 3/20 • Number of events 3 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab
Injury, poisoning and procedural complications Procedural pain	0.00% 0/25 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	10.0% 2/20 • Number of events 2 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab
Metabolism and nutrition disorders Decreased appetite	0.00% 0/25 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab	10.0% 2/20 • Number of events 2 • Up to 12 Days Post-dose Adverse events for all participants who received a single dose of dalotuzumab

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The sponsor must review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation and can delete information identified as confidential prior to submission.
Publication restrictions are in place

Restriction type: OTHER