Trial Outcomes & Findings for A Study of MLN0264 in Participants With Cancer of the Stomach or Gastroesophageal Junction (NCT NCT02202759)
NCT ID: NCT02202759
Last Updated: 2017-05-15
Results Overview
ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Recruitment status
TERMINATED
Study phase
PHASE2
Target enrollment
38 participants
Primary outcome timeframe
Day 21, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 17 months)
Results posted on
2017-05-15
Participant Flow
Participants took part in the study at 24 investigative sites in Belgium, Spain, United Kingdom and the United States from 04 August 2014 to 15 January 2016.
Participants with a diagnosis of metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing Guanylyl Cyclase C (GCC) were enrolled in 1 treatment group, MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle.
Participant milestones
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Overall Study
STARTED
|
9
|
15
|
14
|
|
Overall Study
COMPLETED
|
0
|
0
|
0
|
|
Overall Study
NOT COMPLETED
|
9
|
15
|
14
|
Reasons for withdrawal
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Overall Study
Study Terminated by Sponsor
|
3
|
3
|
3
|
|
Overall Study
Withdrawal by Subject
|
2
|
1
|
1
|
|
Overall Study
Reason not Specified
|
4
|
11
|
10
|
Baseline Characteristics
A Study of MLN0264 in Participants With Cancer of the Stomach or Gastroesophageal Junction
Baseline characteristics by cohort
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=15 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
Total
n=38 Participants
Total of all reporting groups
|
|---|---|---|---|---|
|
Age, Continuous
|
60.1 years
STANDARD_DEVIATION 7.70 • n=5 Participants
|
62.9 years
STANDARD_DEVIATION 12.78 • n=7 Participants
|
62.9 years
STANDARD_DEVIATION 7.86 • n=5 Participants
|
62.2 years
STANDARD_DEVIATION 9.89 • n=4 Participants
|
|
Sex: Female, Male
Female
|
1 Participants
n=5 Participants
|
5 Participants
n=7 Participants
|
1 Participants
n=5 Participants
|
7 Participants
n=4 Participants
|
|
Sex: Female, Male
Male
|
8 Participants
n=5 Participants
|
10 Participants
n=7 Participants
|
13 Participants
n=5 Participants
|
31 Participants
n=4 Participants
|
|
Race/Ethnicity, Customized
Hispanic or Latino
|
0 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
1 participants
n=4 Participants
|
|
Race/Ethnicity, Customized
Not Hispanic or Latino
|
9 participants
n=5 Participants
|
14 participants
n=7 Participants
|
12 participants
n=5 Participants
|
35 participants
n=4 Participants
|
|
Race/Ethnicity, Customized
Not Reported
|
0 participants
n=5 Participants
|
1 participants
n=7 Participants
|
1 participants
n=5 Participants
|
2 participants
n=4 Participants
|
|
Race/Ethnicity, Customized
White
|
9 participants
n=5 Participants
|
15 participants
n=7 Participants
|
12 participants
n=5 Participants
|
36 participants
n=4 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
0 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
1 participants
n=4 Participants
|
|
Race/Ethnicity, Customized
Asian
|
0 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
1 participants
n=4 Participants
|
|
Region of Enrollment
Belgium
|
1 participants
n=5 Participants
|
0 participants
n=7 Participants
|
1 participants
n=5 Participants
|
2 participants
n=4 Participants
|
|
Region of Enrollment
United States
|
6 participants
n=5 Participants
|
8 participants
n=7 Participants
|
8 participants
n=5 Participants
|
22 participants
n=4 Participants
|
|
Region of Enrollment
United Kingdom
|
0 participants
n=5 Participants
|
2 participants
n=7 Participants
|
2 participants
n=5 Participants
|
4 participants
n=4 Participants
|
|
Region of Enrollment
Spain
|
2 participants
n=5 Participants
|
5 participants
n=7 Participants
|
3 participants
n=5 Participants
|
10 participants
n=4 Participants
|
|
Height
|
169.7 cm
STANDARD_DEVIATION 7.49 • n=5 Participants
|
167.8 cm
STANDARD_DEVIATION 9.85 • n=7 Participants
|
171.1 cm
STANDARD_DEVIATION 9.38 • n=5 Participants
|
169.4 cm
STANDARD_DEVIATION 9.05 • n=4 Participants
|
|
Weight
|
71.51 kg
STANDARD_DEVIATION 11.253 • n=5 Participants
|
71.67 kg
STANDARD_DEVIATION 17.060 • n=7 Participants
|
72.75 kg
STANDARD_DEVIATION 12.597 • n=5 Participants
|
72.03 kg
STANDARD_DEVIATION 13.913 • n=4 Participants
|
|
Body Surface Area
|
1.832 m^2
STANDARD_DEVIATION 0.1683 • n=5 Participants
|
1.818 m^2
STANDARD_DEVIATION 0.2520 • n=7 Participants
|
1.854 m^2
STANDARD_DEVIATION 0.2014 • n=5 Participants
|
1.835 m^2
STANDARD_DEVIATION 0.2113 • n=4 Participants
|
PRIMARY outcome
Timeframe: Day 21, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 17 months)Population: Response-Evaluable population included all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment.
ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the investigator using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=13 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
|
0 percentage of participants
|
14 percentage of participants
|
0 percentage of participants
|
SECONDARY outcome
Timeframe: From the first dose through 30 days after the last dose of study medication (Up to 10.7 months)Population: Safety population included all participants who received any amount of MLN0264.
An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event. Relationship of each AE to study drug will be determined by the Investigator.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=15 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
AEs
|
8 participants
|
15 participants
|
14 participants
|
|
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
SAEs
|
2 participants
|
5 participants
|
0 participants
|
SECONDARY outcome
Timeframe: From the first dose through 30 days after the last dose of study medication (Up to 10.7 months)Population: Safety population included all participants who received any amount of MLN0264.
Participants with at least one post-baseline potentially clinically significant serum chemistry, hematology, coagulation or urinalysis result. Clinically significant results are those that were assessed by the investigator to be Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=38 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
Chemistry
|
8 participants
|
—
|
—
|
|
Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
Hematology
|
13 participants
|
—
|
—
|
|
Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
Coagulation
|
24 participants
|
—
|
—
|
|
Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
Urinalysis
|
0 participants
|
—
|
—
|
SECONDARY outcome
Timeframe: Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 10.7 months)Population: Safety population included all participants who received any amount of MLN0264.
Participants with at least one potentially clinically significant post-baseline vital sign finding including measurements of diastolic and systolic blood pressure, heart rate, and oral temperature.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=38 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Number of Participants With Potentially Clinically Significant Vital Signs Findings
|
0 participants
|
—
|
—
|
SECONDARY outcome
Timeframe: Time Frame: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months)Population: Response-Evaluable population included all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment.
PFS is defined as the time in days from the date of first study drug administration to the date of first documentation of disease progression or death. 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 a measurable increase in a non-target lesion, or the appearance of new lesions.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=13 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Progression Free Survival (PFS)
|
40 days
Interval 38.0 to 311.0
|
49 days
Interval 38.0 to 316.0
|
87 days
Interval 39.0 to 427.0
|
SECONDARY outcome
Timeframe: From first documented response until disease progression (Up to 16.7 months)Population: Participants from the Response-Evaluable population, all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment, who had response.
Duration of response is defined as the time in days from the date of first documentation of a confirmed response to the date of first documentation of disease progression. Per RECIST v1.1 for target lesions and assessed by magnetic resonance imaging (MRI) - CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=2 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Duration of Response
|
45.5 days
Interval 1.0 to 90.0
|
—
|
—
|
SECONDARY outcome
Timeframe: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months)Population: Response-Evaluable population included all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment.
Disease control rate is defined as the percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) with a minimum of 12 weeks' duration. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of the Longest Diameter (LD) of target lesions, taking as reference the baseline sum LD and no new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) of target lesions, taking as reference the smallest sum LD since the treatment started and no new lesions. Investigator response is based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=13 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Disease Control Rate
|
11 percentage of participants
|
36 percentage of participants
|
54 percentage of participants
|
SECONDARY outcome
Timeframe: Until death or 6 months after the last patient completes treatment-whichever occurs first (Up to 17 months)Population: Response-evaluable population, all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 postbaseline response assessment.
Overall survival is defined as the time in days from the date of first study drug administration to the date of death.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=13 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Overall Survival (OS)
|
230 days
Interval 79.0 to 394.0
|
156 days
Interval 49.0 to 505.0
|
206 days
Interval 24.0 to 427.0
|
SECONDARY outcome
Timeframe: Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose.Population: Cmax was not a pre-specified secondary outcome measure. No data was collected.
Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.Population: Pharmacokinetic (PK)-Evaluable population included all participants who received at least 1 dose of MLN0264 and who had sufficient MLN0264 concentration-time data to permit reliable estimation of MLN0264 exposure. "n" in the categories is the number of participants with data available at the given time-point.
Blood samples were collected and sent to a laboratory to be tested for serum concentrations of MLN0264.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=38 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
MLN0264 Serum Concentrations
Cycle 1 Day 1, 10 Minutes Post-Dose (n=37)
|
37.0434 μg/mL
Standard Deviation 9.93577
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 1 Day 1, 4 Hours Post-Dose (n=38)
|
26.0047 μg/mL
Standard Deviation 6.27538
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 1 Day 3, 48 Hours Post-Dose (n=35)
|
7.0839 μg/mL
Standard Deviation 1.64899
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 2 Day 1, Pre-Dose (n=36)
|
0.7466 μg/mL
Standard Deviation 2.68737
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 2 Day 4, 72 Hours Post-Dose (n=33)
|
4.9140 μg/mL
Standard Deviation 1.05592
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 3 Day 1, 10 Minutes Post-Dose (n=19)
|
31.1505 μg/mL
Standard Deviation 8.74114
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 3 Day 1, 4 Hours Post-Dose (n=19)
|
25.1787 μg/mL
Standard Deviation 5.49543
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 3 Day 3, 48 Hours Post-Dose (n=14)
|
6.7360 μg/mL
Standard Deviation 1.56940
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 3 Day 4, 72 Hours Post-Dose (n=15)
|
5.8887 μg/mL
Standard Deviation 3.05461
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 3 Day 15, 336 Hours Post-Dose (n=18)
|
0.6807 μg/mL
Standard Deviation 0.25869
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 4 Day 1, Pre-Dose (n=16)
|
0.3916 μg/mL
Standard Deviation 0.16462
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 4 Day 1, 10 Minutes Post-Dose (n=15)
|
32.3427 μg/mL
Standard Deviation 8.33045
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
|
32.3500 μg/mL
Standard Deviation 6.77408
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 11 Day 1, Pre-Dose (n=1)
|
0.7760 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 11 Day 1, 10 Minutes Post-Dose (n=1)
|
56.8400 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 12 Day 1, Pre-Dose (n=1)
|
0.7350 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 14 Day 1, Pre-Dose (n=1)
|
1.0260 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 14 Day 1, 10 Minutes Post-Dose (n=1)
|
41.9200 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
End of Treatment (n=26)
|
0.3323 μg/mL
Standard Deviation 0.21216
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 1 Day 1, Pre-Dose (n=37)
|
0.0000 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 1 Day 4, 72 Hours Post-Dose (n=35)
|
4.4939 μg/mL
Standard Deviation 1.25657
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 1 Day 8, 168 Hours Post-Dose (n=38)
|
1.6795 μg/mL
Standard Deviation 0.71586
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 1 Day 15, 336 Hours Post-Dose (n=36)
|
0.5778 μg/mL
Standard Deviation 0.22063
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 2 Day 1, 10 Minutes Post-Dose (n=36)
|
32.1622 μg/mL
Standard Deviation 9.61463
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 2 Day 1, 4 Hours Post-Dose (n=36)
|
26.0278 μg/mL
Standard Deviation 9.43156
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 2 Day 3, 48 Hours Post-Dose (n=36)
|
7.7186 μg/mL
Standard Deviation 2.04169
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 2 Day 8, 168 Hours Post-Dose (n=35)
|
1.7813 μg/mL
Standard Deviation 0.49456
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 2 Day 15, 336 Hours Post-Dose (n=36)
|
0.6959 μg/mL
Standard Deviation 0.27579
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 3 Day 1, Pre-Dose (n=19)
|
0.4905 μg/mL
Standard Deviation 0.77805
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 3 Day 8, 168 Hours Post-Dose (n=18)
|
1.5078 μg/mL
Standard Deviation 0.48401
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 5 Day 1, Pre-Dose (n=7)
|
0.4757 μg/mL
Standard Deviation 0.18995
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 5 Day 1, 10 Minutes Post-Dose (n=7)
|
33.9286 μg/mL
Standard Deviation 7.14793
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 6 Day 1, Pre-Dose (n=8)
|
0.4915 μg/mL
Standard Deviation 0.34173
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 6 Day 1, 10 Minutes Post-Dose (n=8)
|
30.3850 μg/mL
Standard Deviation 7.79913
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 6 Day 4, 72 Hours Post-Dose (n=7)
|
5.0676 μg/mL
Standard Deviation 1.54862
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 6 Day 8, 168 Hours Post-Dose (n=6)
|
1.6910 μg/mL
Standard Deviation 0.40781
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 7 Day 1, Pre-Dose (n=3)
|
0.5097 μg/mL
Standard Deviation 0.20409
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 7 Day 1, 10 Minutes Post-Dose (n=3)
|
31.0133 μg/mL
Standard Deviation 8.23430
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 8 Day 1, Pre-Dose (n=3)
|
0.5677 μg/mL
Standard Deviation 0.24180
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 8 Day 1, 10 Minute Post-Dose (n=3)
|
31.6467 μg/mL
Standard Deviation 8.93229
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 9 Day 1, Pre-Dose (n=2)
|
0.9290 μg/mL
Standard Deviation 0.49639
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 12 Day 1, 10 Minutes Post-Dose (n=1)
|
49.8800 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 13 Day 1, Pre-Dose (n=1)
|
0.8870 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
MLN0264 Serum Concentrations
Cycle 13 Day 1, 10 Minutes Post-Dose (n=1)
|
41.6400 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
SECONDARY outcome
Timeframe: Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.Population: PK-Evaluable population included all participants who received at least 1 dose of MLN0264 and who had sufficient MLN0264 concentration-time data to permit reliable estimation of MLN0264 exposure. "n" in the categories is the number of participants with data available at the given time-point.
Blood samples were collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=38 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 3 Day 1, 4 Hours Post-Dose (n=19)
|
33.2692 μg/mL
Standard Deviation 9.42530
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 3 Day 3, 48 Hours Post-Dose (n=14)
|
15.9500 μg/mL
Standard Deviation 5.08026
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 3 Day 4, 72 Hours Post-Dose (n=15)
|
12.8393 μg/mL
Standard Deviation 4.56059
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 3 Day 8, 168 Hours Post-Dose (n=18)
|
7.5035 μg/mL
Standard Deviation 2.01984
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 6 Day 1, 10 Minutes Post-Dose (n=8)
|
39.9300 μg/mL
Standard Deviation 10.13066
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 6 Day 4, 72 Hours Post-Dose (n=7)
|
14.7957 μg/mL
Standard Deviation 4.09897
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 6 Day 8, 168 Hours Post-Dose (n=6)
|
9.6217 μg/mL
Standard Deviation 1.53148
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 7 Day 1, Pre-Dose (n=3)
|
3.3417 μg/mL
Standard Deviation 1.64015
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 8 Day 1, Pre-Dose (n=3)
|
3.0573 μg/mL
Standard Deviation 1.21148
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 8 Day 1, 10 Minute Post-Dose (n=3)
|
32.6333 μg/mL
Standard Deviation 5.94980
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 1 Day 1, Pre-Dose (n=37)
|
0.0000 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 1 Day 1, 10 Minutes Post-Dose (n=37)
|
41.8154 μg/mL
Standard Deviation 10.05341
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 1 Day 1, 4 Hours Post-Dose (n=38)
|
35.7626 μg/mL
Standard Deviation 8.46954
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 1 Day 3, 48 Hours Post-Dose (n=35)
|
16.0664 μg/mL
Standard Deviation 3.26969
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 1 Day 4, 72 Hours Post-Dose (n=35)
|
11.7461 μg/mL
Standard Deviation 2.60098
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 1 Day 8, 168 Hours Post-Dose (n=38)
|
6.1851 μg/mL
Standard Deviation 1.73972
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 1 Day 15, 336 Hours Post-Dose (n=36)
|
3.3926 μg/mL
Standard Deviation 1.00149
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 2 Day 1, Pre-Dose (n=36)
|
2.5995 μg/mL
Standard Deviation 3.79916
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 2 Day 1, 10 Minutes Post-Dose (n=35)
|
43.4749 μg/mL
Standard Deviation 9.71796
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 2 Day 1, 4 Hours Post-Dose (n=36)
|
35.6691 μg/mL
Standard Deviation 10.26134
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 2 Day 3, 48 Hours Post-Dose (n=36)
|
18.4167 μg/mL
Standard Deviation 4.07769
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 2 Day 4, 72 Hours Post-Dose (n=33)
|
13.3398 μg/mL
Standard Deviation 3.23987
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 2 Day 8, 168 Hours Post-Dose (n=35)
|
7.3613 μg/mL
Standard Deviation 1.87974
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 2 Day 15, 336 Hours Post-Dose (n=36)
|
4.3511 μg/mL
Standard Deviation 1.47322
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 3 Day 1, Pre-Dose (n=19)
|
2.5274 μg/mL
Standard Deviation 1.54088
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 3 Day 1, 10 Minutes Post-Dose (n=19)
|
41.3674 μg/mL
Standard Deviation 11.88629
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 3 Day 15, 336 Hours Post-Dose (n=18)
|
4.2384 μg/mL
Standard Deviation 1.66059
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 4 Day 1, Pre-Dose (n=16)
|
2.9082 μg/mL
Standard Deviation 1.03729
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 4 Day 1, 10 Minutes Post-Dose (n=15)
|
45.4333 μg/mL
Standard Deviation 13.84498
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 5 Day 1, Pre-Dose (n=7)
|
3.2396 μg/mL
Standard Deviation 0.88493
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 5 Day 1, 10 Minutes Post-Dose (n=7)
|
43.0629 μg/mL
Standard Deviation 7.30566
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 6 Day 1, Pre-Dose (n=8)
|
3.0810 μg/mL
Standard Deviation 1.29133
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 7 Day 1, 10 Minutes Post-Dose (n=3)
|
42.1667 μg/mL
Standard Deviation 8.75528
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 9 Day 1, Pre-Dose (n=2)
|
3.0440 μg/mL
Standard Deviation 0.98429
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
|
45.8000 μg/mL
Standard Deviation 7.04278
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 11 Day 1, Pre-Dose (n=1)
|
4.2420 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 11 Day 1, 10 Minutes Post-Dose (n=1)
|
44.3000 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 12 Day 1, Pre-Dose (n=1)
|
4.1020 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 12 Day 1, 10 Minutes Post-Dose (n=1)
|
47.3800 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 13 Day 1, Pre-Dose (n=1)
|
4.9900 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 13 Day 1, 10 Minutes Post-Dose (n=1)
|
55.2600 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 14 Day 1, Pre-Dose (n=1)
|
5.6750 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Cycle 14 Day 1, 10 Minutes Post-Dose (n=1)
|
61.5000 μg/mL
Standard Deviation 0.00000
|
—
|
—
|
|
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
End of Treatment (n=26)
|
2.5393 μg/mL
Standard Deviation 1.32302
|
—
|
—
|
SECONDARY outcome
Timeframe: Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.Population: PK-Evaluable population included all participants who received at least 1 dose of MLN0264 and who had sufficient MLN0264 concentration-time data to permit reliable estimation of MLN0264 exposure. "n" in the categories is the number of participants with data available at the given time-point.
Blood samples were collected and sent to a laboratory to be tested for MMAE.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=38 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 2 Day 15, 336 Hours Post-Dose (n=36)
|
0.579 ng/mL
Standard Deviation 0.6221
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 3 Day 1, Pre-Dose (n=19)
|
0.094 ng/mL
Standard Deviation 0.1240
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 3 Day 1, 10 Minutes Post-Dose (n=18)
|
0.428 ng/mL
Standard Deviation 0.4487
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 3 Day 1, 4 Hours Post-Dose (n=19)
|
2.302 ng/mL
Standard Deviation 1.8893
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 13 Day 1, Pre-Dose (n=1)
|
0.074 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 13 Day 1, 10 Minutes Post-Dose (n=1)
|
0.132 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 14 Day 1, Pre-Dose (n=1)
|
0.081 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 1 Day 1, Pre-Dose (n=37)
|
0.000 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 1 Day 1, 10 Minutes Post-Dose (n=37)
|
0.473 ng/mL
Standard Deviation 0.6503
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 1 Day 1, 4 Hours Post-Dose (n=38)
|
2.659 ng/mL
Standard Deviation 1.5489
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 1 Day 3, 48 Hours Post-Dose (n=35)
|
6.153 ng/mL
Standard Deviation 3.2773
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 1 Day 4, 72 Hours Post-Dose (n=35)
|
5.856 ng/mL
Standard Deviation 3.4519
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 1 Day 8, 168 Hours Post-Dose (n=38)
|
2.945 ng/mL
Standard Deviation 1.8899
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 1 Day 15, 336 Hours Post-Dose (n=36)
|
0.532 ng/mL
Standard Deviation 0.6693
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 2 Day 1, Pre-Dose (n=36)
|
0.116 ng/mL
Standard Deviation 0.1118
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 2 Day 1, 10 Minutes Post-Dose (n=35)
|
0.425 ng/mL
Standard Deviation 0.2697
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 2 Day 1, 4 Hours Post-Dose (n=36)
|
2.665 ng/mL
Standard Deviation 1.7137
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 2 Day 3, 48 Hours Post-Dose (n=36)
|
6.746 ng/mL
Standard Deviation 4.2361
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 2 Day 4, 72 Hours Post-Dose (n=33)
|
6.111 ng/mL
Standard Deviation 3.6283
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 2 Day 8, 168 Hours Post-Dose (n=35)
|
2.898 ng/mL
Standard Deviation 2.2974
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 3 Day 3, 48 Hours Post-Dose (n=14)
|
4.493 ng/mL
Standard Deviation 2.6877
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 3 Day 4, 72 Hours Post-Dose (n=15)
|
3.638 ng/mL
Standard Deviation 1.8570
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 3 Day 8, 168 Hours Post-Dose (n=18)
|
2.135 ng/mL
Standard Deviation 1.7030
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 3 Day 15, 336 Hours Post-Dose (n=17)
|
0.342 ng/mL
Standard Deviation 0.3637
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 4 Day 1, Pre-Dose (n=16)
|
0.081 ng/mL
Standard Deviation 0.0865
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 4 Day 1, 10 Minutes Post-Dose (n=15)
|
0.304 ng/mL
Standard Deviation 0.1781
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 5 Day 1, Pre-Dose (n=7)
|
0.084 ng/mL
Standard Deviation 0.0331
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 5 Day 1, 10 Minutes Post-Dose (n=7)
|
0.278 ng/mL
Standard Deviation 0.1325
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 6 Day 1, Pre-Dose (n=8)
|
0.093 ng/mL
Standard Deviation 0.0654
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 6 Day 1, 10 Minutes Post-Dose (n=7)
|
0.322 ng/mL
Standard Deviation 0.2232
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 6 Day 4, 72 Hours Post-Dose (n=7)
|
6.183 ng/mL
Standard Deviation 3.3587
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 6 Day 8, 168 Hours Post-Dose (n=6)
|
2.417 ng/mL
Standard Deviation 1.6379
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 7 Day 1, Pre-Dose (n=3)
|
0.044 ng/mL
Standard Deviation 0.0083
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 7 Day 1, 10 Minutes Post-Dose (n=3)
|
0.115 ng/mL
Standard Deviation 0.0439
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 8 Day 1, Pre-Dose (n=3)
|
0.058 ng/mL
Standard Deviation 0.0103
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 8 Day 1, 10 Minute Post-Dose (n=3)
|
0.132 ng/mL
Standard Deviation 0.0425
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 9 Day 1, Pre-Dose (n=2)
|
0.021 ng/mL
Standard Deviation 0.0291
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)
|
0.158 ng/mL
Standard Deviation 0.0721
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 11 Day 1, Pre-Dose (n=1)
|
0.093 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 11 Day 1, 10 Minutes Post-Dose (n=1)
|
0.186 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 12 Day 1, Pre-Dose (n=1)
|
0.087 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 12 Day 1, 10 Minutes Post-Dose (n=1)
|
0.167 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
Cycle 14 Day 1, 10 Minutes Post-Dose (n=1)
|
0.165 ng/mL
Standard Deviation 0.0000
|
—
|
—
|
|
Serum Concentration of Monomethyl Auristatin E (MMAE)
End of Treatment (n=25)
|
0.173 ng/mL
Standard Deviation 0.3359
|
—
|
—
|
SECONDARY outcome
Timeframe: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months)Population: Response-Evaluable Population was defined as all participants with measurable disease who receive at least 1 dose of MLN0264 and have at least 1 postbaseline response assessment.
The number of participants with the best percentage of tumor reduction from baseline in the sum of the diameter was calculated.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=13 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Number of Participants With Reduction From Baseline in Tumor Size
|
1 participants
Interval 38.0 to 311.0
|
2 participants
Interval 38.0 to 316.0
|
4 participants
Interval 42.0 to 427.0
|
SECONDARY outcome
Timeframe: Approximately 20 monthsPopulation: Safety population included all participants who received any amount of MLN0264.
Analysis of GCC protein expression levels in tumor tissue (fresh biopsy pretreatment and whenever a biopsy is considered medically safe and technically feasible) was performed using a semiquantitative immunohistochemistry (IHC) assay and the total GCC H-Score was determined. GCC H-score is based on the sum of the 0 to 300 H-score for cytoplasmic staining and the 0 to 300 H-score for apical staining for a total possible H-score 0 to 600. Separate consent was required to obtain archival tumor specimens for GCC expression assessment prior to screening.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=15 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC)
|
74.8 scores on a scale
Interval 27.0 to 100.0
|
154.6 scores on a scale
Interval 110.0 to 230.0
|
344.3 scores on a scale
Interval 260.0 to 480.0
|
SECONDARY outcome
Timeframe: Pre-dose of each 21 day cycle and 30 days after last dose of study medication (Up to 10.7 months)Population: Safety Population included all participant who received any amount of MLN0264.
Blood samples were collected to assess the immunogenicity of MLN0264 (ATA development) using a laboratory test. Neutralizing ATA assessment was performed for ATA-positive samples only.
Outcome measures
| Measure |
MLN0264 1.8 mg/kg (GCC Low)
n=9 Participants
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC Intermediate)
n=15 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
MLN0264 1.8 mg/kg (GCC High)
n=14 Participants
MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score \>120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
|
|---|---|---|---|
|
Number of Participants With Antitherapeutic Antibodies (ATA)
|
0 participants
|
3 participants
|
1 participants
|
Adverse Events
MLN0264 1.8 mg/kg
Serious events: 7 serious events
Other events: 37 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
MLN0264 1.8 mg/kg
n=38 participants at risk
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.
|
|---|---|
|
Gastrointestinal disorders
Diarrhoea
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Gastrointestinal disorders
Dysphagia
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Gastrointestinal disorders
Upper gastrointestinal hemorrhage
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour hemorrhage
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Blood and lymphatic system disorders
Anaemia
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Cardiac disorders
Supraventricular tachycardia
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Hepatobiliary disorders
Bile duct obstruction
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
|
Injury, poisoning and procedural complications
Hip fracture
|
2.6%
1/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
|
Other adverse events
| Measure |
MLN0264 1.8 mg/kg
n=38 participants at risk
MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.
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Nervous system disorders
Neuropathy peripheral
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Nervous system disorders
Tremor
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Psychiatric disorders
Confusional state
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Psychiatric disorders
Depression
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Renal and urinary disorders
Proteinuria
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Blood and lymphatic system disorders
Anaemia
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15.8%
6/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Blood and lymphatic system disorders
Neutropenia
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13.2%
5/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Abdominal pain
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Ascites
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Constipation
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23.7%
9/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Diarrhoea
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15.8%
6/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Dysphagia
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7.9%
3/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Gastrooesophageal reflux disease
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Nausea
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52.6%
20/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Stomatitis
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7.9%
3/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Gastrointestinal disorders
Vomiting
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26.3%
10/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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General disorders
Asthenia
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26.3%
10/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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General disorders
Fatigue
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31.6%
12/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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General disorders
Oedema peripheral
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18.4%
7/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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General disorders
Pain
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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General disorders
Pyrexia
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Infections and infestations
Urinary tract infection
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Injury, poisoning and procedural complications
Fall
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Investigations
Blood alkaline phosphatase increased
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Investigations
Gamma-glutamyltransferase increased
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Investigations
Neutrophil count decreased
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Investigations
Weight decreased
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7.9%
3/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Decreased appetite
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28.9%
11/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Dehydration
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7.9%
3/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Hyperglycaemia
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7.9%
3/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Hypoalbuminaemia
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Hypocalcaemia
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Hypokalaemia
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Hypomagnesaemia
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Metabolism and nutrition disorders
Hyponatraemia
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Musculoskeletal and connective tissue disorders
Back pain
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Musculoskeletal and connective tissue disorders
Musculoskeletal pain
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7.9%
3/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Musculoskeletal and connective tissue disorders
Myalgia
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Musculoskeletal and connective tissue disorders
Pain in extremity
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Nervous system disorders
Dizziness
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Nervous system disorders
Hypoaesthesia
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Respiratory, thoracic and mediastinal disorders
Dyspnoea
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10.5%
4/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Respiratory, thoracic and mediastinal disorders
Orthopnoea
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Skin and subcutaneous tissue disorders
Alopecia
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13.2%
5/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Vascular disorders
Deep vein thrombosis
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5.3%
2/38 • From the first dose through 30 days after the last dose of study drug (up to 10.7 Months)
At each visit the investigator documented any occurrence of AEs and abnormal laboratory findings. Any event spontaneously reported by participant or observed by investigator was recorded, irrespective of relation to study treatment.
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Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
- Publication restrictions are in place
Restriction type: OTHER