Adenocarcinoma of the Stomach, Gastroesophageal Junction Expressing Guanylyl Cyclase C
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to assess the efficacy, safety and tolerability of MLN0264 in patients with recurrent or metastatic guanylyl cyclase C (GCC)-positive adenocarcinoma of the stomach or gastroesophageal junction.
Detailed description
The drug being tested in this study is called MLN0264. MLN0264 is being tested to treat tumors in people who have metastatic or recurrent gastric or gastroesophageal junction malignancies expressing guanylyl cyclase C (GCC). Participants will be analyzed in cohorts based on GCC expression: low=combined H-score 10-109, intermediate=combined H-score 110-249, high=combined IHC H-score \>250. This study will assess tumor size reduction in patients who are administered MLN0264. The study enrolled 38 patients. All participants will be administered MLN0264 at 1.8 mg/kg as a single, 30-minute, intravenous (IV) infusion on Day 1 of each 3-week treatment cycle, followed by a rest period of 20 days. Participants will continue to receive MLN0264 for up to 1 year or until disease progression or unacceptable toxicity occurs. This multi-centre trial will be conducted worldwide. The overall time to participate in this study is approximately 19 months. Participants will make 3 to 6 visits to the clinic per treatment cycle, an end-of-treatment visit 30 days after the last dose of study medication, and follow-up assessments every 12 weeks until death or 6 months after the last patient completes treatment - whichever occurs first.
Interventions
DRUGMLN0264
MLN0264 IV infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female participants 18 years of age or older when written informed consent is obtained. 2. Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the stomach or gastroesophageal junction with immunohistochemistry (IHC) evidence of guanylyl cyclase C (GCC) expression indicated by an H-score of 10 or greater. 3. Treatment with 1 or more prior chemotherapies for advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. 4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. All scans and x-rays used to document measurable disease must be done within 28 days before enrollment (ascites and bone lesions are not considered measureable disease). 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before enrollment. 6. Female participants who: * Are postmenopausal for at least 1 year before the screening visit, OR * Are surgically sterile, OR * If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilized (ie, status postvasectomy), who: * Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception.) 7. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. 8. Adequate organ and hematological function as evidenced by the following laboratory values within 14 days before enrollment: * Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L * Platelet count ≥ 100 x 10\^9/L * Hemoglobin ≥ 9 g/dL * Activated partial thromboplastin time (aPTT) ≤ 1.5 x the upper limit of the normal range (ULN) per institutional laboratory normal range * International normalized ratio (INR) ≤ 1.5 x ULN * Serum creatinine ≤ 1.5 x ULN * Total bilirubin ≤ 1.5 x ULN * Albumin ≥ 3g/dL * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN * Serum lipase ≤ 3 x ULN and serum amylase within the normal range 9. Resolution of all toxic effects of prior treatments except alopecia to Grade 0 or 1 by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. 10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
Exclusion criteria
1. Radiotherapy within 4 weeks before enrollment. 2. Concurrent treatment or treatment within 4 weeks of study entry with any other investigational agent or chemotherapy. 3. Female participants who are lactating and breastfeeding or have a positive pregnancy test during the Screening period. 4. Uncontrolled, clinically significant, symptomatic cardiovascular disease within 6 months before enrollment, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication. 5. Treatment with any medication that has a clinically relevant potential risk of prolonging the QT interval or inducing torsades de pointes that cannot be discontinued or switched to a different medication before starting study drug. 6. Participants with electrocardiogram (ECG) abnormalities considered by the investigator to be clinically significant, or repeated baseline prolongation of the rate-corrected QT interval (QTc). 7. Ongoing or clinically significant active infection as judged by the investigator. 8. Signs of peripheral neuropathy (PN) ≥ NCI CTCAE Grade 2. 9. Concomitant chemotherapy, hormonal therapy, immunotherapy, or any other form of cancer treatment. 10. Use of strong cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks before the first dose of study drug. 11. Any preexisting medical condition of sufficient severity to prevent full compliance with the study. 12. History of or current neoplasm other than gastric adenocarcinoma, except for curatively treated nonmelanoma skin cancer or in situ carcinoma of the cervix uteri. 13. Known diagnosis of human immunodeficiency virus (HIV) infection (testing is not mandatory). 14. Symptomatic brain metastases. 15. Ongoing anticoagulant therapy (eg, aspirin, coumadin, heparin).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Day 21, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 17 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the first dose through 30 days after the last dose of study medication (Up to 10.7 months) | 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. |
| Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings | From the first dose through 30 days after the last dose of study medication (Up to 10.7 months) | 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. |
| Number of Participants With Potentially Clinically Significant Vital Signs Findings | Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 10.7 months) | 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. |
| Progression Free Survival (PFS) | 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) | 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. |
| Duration of Response | From first documented response until disease progression (Up to 16.7 months) | 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. |
| Disease Control Rate | 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) | 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. |
| Overall Survival (OS) | Until death or 6 months after the last patient completes treatment-whichever occurs first (Up to 17 months) | Overall survival is defined as the time in days from the date of first study drug administration to the date of death. |
| MLN0264 Serum Concentrations | 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. | Blood samples were collected and sent to a laboratory to be tested for serum concentrations of MLN0264. |
| Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | 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. | Blood samples were collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies. |
| Serum Concentration of Monomethyl Auristatin E (MMAE) | 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. | Blood samples were collected and sent to a laboratory to be tested for MMAE. |
| Number of Participants With Reduction From Baseline in Tumor Size | 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) | The number of participants with the best percentage of tumor reduction from baseline in the sum of the diameter was calculated. |
| Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC) | Approximately 20 months | 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. |
| Number of Participants With Antitherapeutic Antibodies (ATA) | Pre-dose of each 21 day cycle and 30 days after last dose of study medication (Up to 10.7 months) | 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. |
| Cmax: Maximum Observed Serum Concentration for MLN0264 | 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. | Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve. |
Countries
Belgium, Spain, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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+. | 9 |
| 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+. | 15 |
| 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+. | 14 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Reason not Specified | 4 | 11 | 10 |
| Overall Study | Study Terminated by Sponsor | 3 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | MLN0264 1.8 mg/kg (GCC Low) | MLN0264 1.8 mg/kg (GCC Intermediate) | MLN0264 1.8 mg/kg (GCC High) | Total |
|---|---|---|---|---|
| Age, Continuous | 60.1 years STANDARD_DEVIATION 7.7 | 62.9 years STANDARD_DEVIATION 12.78 | 62.9 years STANDARD_DEVIATION 7.86 | 62.2 years STANDARD_DEVIATION 9.89 |
| Body Surface Area | 1.832 m^2 STANDARD_DEVIATION 0.1683 | 1.818 m^2 STANDARD_DEVIATION 0.252 | 1.854 m^2 STANDARD_DEVIATION 0.2014 | 1.835 m^2 STANDARD_DEVIATION 0.2113 |
| Height | 169.7 cm STANDARD_DEVIATION 7.49 | 167.8 cm STANDARD_DEVIATION 9.85 | 171.1 cm STANDARD_DEVIATION 9.38 | 169.4 cm STANDARD_DEVIATION 9.05 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 9 participants | 14 participants | 12 participants | 35 participants |
| Race/Ethnicity, Customized Not Reported | 0 participants | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White | 9 participants | 15 participants | 12 participants | 36 participants |
| Region of Enrollment Belgium | 1 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment Spain | 2 participants | 5 participants | 3 participants | 10 participants |
| Region of Enrollment United Kingdom | 0 participants | 2 participants | 2 participants | 4 participants |
| Region of Enrollment United States | 6 participants | 8 participants | 8 participants | 22 participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 13 Participants | 31 Participants |
| Weight | 71.51 kg STANDARD_DEVIATION 11.253 | 71.67 kg STANDARD_DEVIATION 17.06 | 72.75 kg STANDARD_DEVIATION 12.597 | 72.03 kg STANDARD_DEVIATION 13.913 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 37 / 38 |
| serious Total, serious adverse events | 7 / 38 |
Outcome results
Primary
Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 14 percentage of participants |
| MLN0264 1.8 mg/kg (GCC High) | Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 0 percentage of participants |
Secondary
Cmax: Maximum Observed Serum Concentration for MLN0264
Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.
Time frame: 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.
Secondary
Disease Control Rate
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.
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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Disease Control Rate | 11 percentage of participants |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Disease Control Rate | 36 percentage of participants |
| MLN0264 1.8 mg/kg (GCC High) | Disease Control Rate | 54 percentage of participants |
Secondary
Duration of 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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Duration of Response | 45.5 days |
Secondary
Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC)
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.
Time frame: Approximately 20 months
Population: Safety population included all participants who received any amount of MLN0264.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC) | 74.8 scores on a scale |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC) | 154.6 scores on a scale |
| MLN0264 1.8 mg/kg (GCC High) | Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC) | 344.3 scores on a scale |
Secondary
MLN0264 Serum Concentrations
Blood samples were collected and sent to a laboratory to be tested for serum concentrations of MLN0264.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 3 Day 1, Pre-Dose (n=19) | 0.4905 μg/mL | Standard Deviation 0.77805 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 3 Day 1, 10 Minutes Post-Dose (n=19) | 31.1505 μg/mL | Standard Deviation 8.74114 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 3 Day 1, 4 Hours Post-Dose (n=19) | 25.1787 μg/mL | Standard Deviation 5.49543 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 3 Day 3, 48 Hours Post-Dose (n=14) | 6.7360 μg/mL | Standard Deviation 1.5694 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 6 Day 4, 72 Hours Post-Dose (n=7) | 5.0676 μg/mL | Standard Deviation 1.54862 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 7 Day 1, Pre-Dose (n=3) | 0.5097 μg/mL | Standard Deviation 0.20409 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 11 Day 1, 10 Minutes Post-Dose (n=1) | 56.8400 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 1 Day 1, Pre-Dose (n=37) | 0.0000 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 1 Day 1, 10 Minutes Post-Dose (n=37) | 37.0434 μg/mL | Standard Deviation 9.93577 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 1 Day 1, 4 Hours Post-Dose (n=38) | 26.0047 μg/mL | Standard Deviation 6.27538 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 1 Day 3, 48 Hours Post-Dose (n=35) | 7.0839 μg/mL | Standard Deviation 1.64899 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 1 Day 4, 72 Hours Post-Dose (n=35) | 4.4939 μg/mL | Standard Deviation 1.25657 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 1 Day 8, 168 Hours Post-Dose (n=38) | 1.6795 μg/mL | Standard Deviation 0.71586 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 1 Day 15, 336 Hours Post-Dose (n=36) | 0.5778 μg/mL | Standard Deviation 0.22063 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 2 Day 1, Pre-Dose (n=36) | 0.7466 μg/mL | Standard Deviation 2.68737 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 2 Day 1, 10 Minutes Post-Dose (n=36) | 32.1622 μg/mL | Standard Deviation 9.61463 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 2 Day 1, 4 Hours Post-Dose (n=36) | 26.0278 μg/mL | Standard Deviation 9.43156 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 2 Day 3, 48 Hours Post-Dose (n=36) | 7.7186 μg/mL | Standard Deviation 2.04169 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 2 Day 4, 72 Hours Post-Dose (n=33) | 4.9140 μg/mL | Standard Deviation 1.05592 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 2 Day 8, 168 Hours Post-Dose (n=35) | 1.7813 μg/mL | Standard Deviation 0.49456 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 2 Day 15, 336 Hours Post-Dose (n=36) | 0.6959 μg/mL | Standard Deviation 0.27579 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 3 Day 4, 72 Hours Post-Dose (n=15) | 5.8887 μg/mL | Standard Deviation 3.05461 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 3 Day 8, 168 Hours Post-Dose (n=18) | 1.5078 μg/mL | Standard Deviation 0.48401 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 3 Day 15, 336 Hours Post-Dose (n=18) | 0.6807 μg/mL | Standard Deviation 0.25869 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 4 Day 1, Pre-Dose (n=16) | 0.3916 μg/mL | Standard Deviation 0.16462 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 4 Day 1, 10 Minutes Post-Dose (n=15) | 32.3427 μg/mL | Standard Deviation 8.33045 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 5 Day 1, Pre-Dose (n=7) | 0.4757 μg/mL | Standard Deviation 0.18995 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 5 Day 1, 10 Minutes Post-Dose (n=7) | 33.9286 μg/mL | Standard Deviation 7.14793 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 6 Day 1, Pre-Dose (n=8) | 0.4915 μg/mL | Standard Deviation 0.34173 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 6 Day 1, 10 Minutes Post-Dose (n=8) | 30.3850 μg/mL | Standard Deviation 7.79913 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 6 Day 8, 168 Hours Post-Dose (n=6) | 1.6910 μg/mL | Standard Deviation 0.40781 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 7 Day 1, 10 Minutes Post-Dose (n=3) | 31.0133 μg/mL | Standard Deviation 8.2343 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 8 Day 1, Pre-Dose (n=3) | 0.5677 μg/mL | Standard Deviation 0.2418 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 8 Day 1, 10 Minute Post-Dose (n=3) | 31.6467 μg/mL | Standard Deviation 8.93229 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 9 Day 1, Pre-Dose (n=2) | 0.9290 μg/mL | Standard Deviation 0.49639 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 9 Day 1, 10 Minutes Post-Dose (n=2) | 32.3500 μg/mL | Standard Deviation 6.77408 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 11 Day 1, Pre-Dose (n=1) | 0.7760 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 12 Day 1, Pre-Dose (n=1) | 0.7350 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 12 Day 1, 10 Minutes Post-Dose (n=1) | 49.8800 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 13 Day 1, Pre-Dose (n=1) | 0.8870 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 13 Day 1, 10 Minutes Post-Dose (n=1) | 41.6400 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 14 Day 1, Pre-Dose (n=1) | 1.0260 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | Cycle 14 Day 1, 10 Minutes Post-Dose (n=1) | 41.9200 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | MLN0264 Serum Concentrations | End of Treatment (n=26) | 0.3323 μg/mL | Standard Deviation 0.21216 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 8 participants |
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 15 participants |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 5 participants |
| MLN0264 1.8 mg/kg (GCC High) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 14 participants |
| MLN0264 1.8 mg/kg (GCC High) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
Secondary
Number of Participants With Antitherapeutic Antibodies (ATA)
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Antitherapeutic Antibodies (ATA) | 0 participants |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Number of Participants With Antitherapeutic Antibodies (ATA) | 3 participants |
| MLN0264 1.8 mg/kg (GCC High) | Number of Participants With Antitherapeutic Antibodies (ATA) | 1 participants |
Secondary
Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings | Chemistry | 8 participants |
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings | Hematology | 13 participants |
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings | Coagulation | 24 participants |
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings | Urinalysis | 0 participants |
Secondary
Number of Participants With Potentially Clinically Significant Vital Signs Findings
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Potentially Clinically Significant Vital Signs Findings | 0 participants |
Secondary
Number of Participants With Reduction From Baseline in Tumor Size
The number of participants with the best percentage of tumor reduction from baseline in the sum of the diameter was calculated.
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 was defined as all participants with measurable disease who receive at least 1 dose of MLN0264 and have at least 1 postbaseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Number of Participants With Reduction From Baseline in Tumor Size | 1 participants |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Number of Participants With Reduction From Baseline in Tumor Size | 2 participants |
| MLN0264 1.8 mg/kg (GCC High) | Number of Participants With Reduction From Baseline in Tumor Size | 4 participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time in days from the date of first study drug administration to the date of death.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Overall Survival (OS) | 230 days |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Overall Survival (OS) | 156 days |
| MLN0264 1.8 mg/kg (GCC High) | Overall Survival (OS) | 206 days |
Secondary
Progression Free Survival (PFS)
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | Progression Free Survival (PFS) | 40 days |
| MLN0264 1.8 mg/kg (GCC Intermediate) | Progression Free Survival (PFS) | 49 days |
| MLN0264 1.8 mg/kg (GCC High) | Progression Free Survival (PFS) | 87 days |
Secondary
Serum Concentration of Monomethyl Auristatin E (MMAE)
Blood samples were collected and sent to a laboratory to be tested for MMAE.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 3 Day 4, 72 Hours Post-Dose (n=15) | 3.638 ng/mL | Standard Deviation 1.857 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 1 Day 1, Pre-Dose (n=37) | 0.000 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 2 Day 1, Pre-Dose (n=36) | 0.116 ng/mL | Standard Deviation 0.1118 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 3 Day 1, Pre-Dose (n=19) | 0.094 ng/mL | Standard Deviation 0.124 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 3 Day 8, 168 Hours Post-Dose (n=18) | 2.135 ng/mL | Standard Deviation 1.703 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 4 Day 1, Pre-Dose (n=16) | 0.081 ng/mL | Standard Deviation 0.0865 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 5 Day 1, Pre-Dose (n=7) | 0.084 ng/mL | Standard Deviation 0.0331 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 6 Day 1, Pre-Dose (n=8) | 0.093 ng/mL | Standard Deviation 0.0654 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 7 Day 1, Pre-Dose (n=3) | 0.044 ng/mL | Standard Deviation 0.0083 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 8 Day 1, Pre-Dose (n=3) | 0.058 ng/mL | Standard Deviation 0.0103 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 9 Day 1, Pre-Dose (n=2) | 0.021 ng/mL | Standard Deviation 0.0291 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 11 Day 1, Pre-Dose (n=1) | 0.093 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 11 Day 1, 10 Minutes Post-Dose (n=1) | 0.186 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 12 Day 1, Pre-Dose (n=1) | 0.087 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 12 Day 1, 10 Minutes Post-Dose (n=1) | 0.167 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 13 Day 1, Pre-Dose (n=1) | 0.074 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 13 Day 1, 10 Minutes Post-Dose (n=1) | 0.132 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 14 Day 1, Pre-Dose (n=1) | 0.081 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | Cycle 14 Day 1, 10 Minutes Post-Dose (n=1) | 0.165 ng/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Monomethyl Auristatin E (MMAE) | End of Treatment (n=25) | 0.173 ng/mL | Standard Deviation 0.3359 |
Secondary
Serum Concentration of Total Antibodies (Conjugated and Unconjugated)
Blood samples were collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 1 Day 1, Pre-Dose (n=37) | 0.0000 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 2 Day 1, Pre-Dose (n=36) | 2.5995 μg/mL | Standard Deviation 3.79916 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 3 Day 1, Pre-Dose (n=19) | 2.5274 μg/mL | Standard Deviation 1.54088 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 3 Day 1, 4 Hours Post-Dose (n=19) | 33.2692 μg/mL | Standard Deviation 9.4253 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 4 Day 1, Pre-Dose (n=16) | 2.9082 μg/mL | Standard Deviation 1.03729 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 5 Day 1, Pre-Dose (n=7) | 3.2396 μg/mL | Standard Deviation 0.88493 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 6 Day 1, Pre-Dose (n=8) | 3.0810 μg/mL | Standard Deviation 1.29133 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 7 Day 1, Pre-Dose (n=3) | 3.3417 μg/mL | Standard Deviation 1.64015 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 8 Day 1, Pre-Dose (n=3) | 3.0573 μg/mL | Standard Deviation 1.21148 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 8 Day 1, 10 Minute Post-Dose (n=3) | 32.6333 μg/mL | Standard Deviation 5.9498 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 9 Day 1, Pre-Dose (n=2) | 3.0440 μg/mL | Standard Deviation 0.98429 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 11 Day 1, Pre-Dose (n=1) | 4.2420 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 12 Day 1, Pre-Dose (n=1) | 4.1020 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 13 Day 1, Pre-Dose (n=1) | 4.9900 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | Cycle 14 Day 1, Pre-Dose (n=1) | 5.6750 μg/mL | Standard Deviation 0 |
| MLN0264 1.8 mg/kg (GCC Low) | 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 |
| MLN0264 1.8 mg/kg (GCC Low) | Serum Concentration of Total Antibodies (Conjugated and Unconjugated) | End of Treatment (n=26) | 2.5393 μg/mL | Standard Deviation 1.32302 |