Symptoms and General Pathology

All Conditions

Neoplasms

Digestive System Diseases

Rare Diseases

Recurrence

Adenocarcinoma

Stomach Neoplasms

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Stomach Cancer

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.

MLN0264

Medical Director Clinical Science

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.

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.

A Study of MLN0264 in Participants With Cancer of the Stomach or Gastroesophageal Junction

A Phase 2 Trial of MLN0264 in Previously Treated Patients With Metastatic or Recurrent Adenocarcinoma of the Stomach or Gastroesophageal Junction Expressing Guanylyl Cyclase C (GCC)

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.

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.

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.

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.

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 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 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 is defined as the time in days from the date of first study drug administration to the date of death.

Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.

Blood samples were collected and sent to a laboratory to be tested for serum concentrations of MLN0264.

Blood samples were collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies.

Blood samples were collected and sent to a laboratory to be tested for MMAE.

The number of participants with the best percentage of tumor reduction from baseline in the sum of the diameter was calculated.

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.

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.

Millennium Pharmaceuticals, Inc.

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.

MLN0264 1.8 mg/kg

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 Low)

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 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 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 1.8 mg/kg (GCC High)

Total

Age, Continuous

Sex: Female, Male

Hispanic or Latino

Not Hispanic or Latino

Not Reported

Race/Ethnicity, Customized

White

Black or African American

Asian

Belgium

United States

United Kingdom

Spain

Region of Enrollment

Height

Weight

Body Surface Area

Safety population included all participants who received any amount of MLN0264.

Medical Director

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.

Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

SAEs

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

Chemistry

Hematology

Coagulation

Urinalysis

Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings

Number of Participants With Potentially Clinically Significant Vital Signs Findings

Progression Free Survival (PFS)

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

Disease Control Rate

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 (OS)

Cmax was not a pre-specified secondary outcome measure. No data was collected.

Cmax: Maximum Observed Serum Concentration for MLN0264

Cycle 1 Day 1, Pre-Dose (n=37)

Cycle 1 Day 1, 10 Minutes Post-Dose (n=37)

Cycle 1 Day 1, 4 Hours Post-Dose (n=38)

Cycle 1 Day 3, 48 Hours Post-Dose (n=35)

Cycle 1 Day 4, 72 Hours Post-Dose (n=35)

Cycle 1 Day 8, 168 Hours Post-Dose (n=38)

Cycle 1 Day 15, 336 Hours Post-Dose (n=36)

Cycle 2 Day 1, Pre-Dose (n=36)

Cycle 2 Day 1, 10 Minutes Post-Dose (n=36)

Cycle 2 Day 1, 4 Hours Post-Dose (n=36)

Cycle 2 Day 3, 48 Hours Post-Dose (n=36)

Cycle 2 Day 4, 72 Hours Post-Dose (n=33)

Cycle 2 Day 8, 168 Hours Post-Dose (n=35)

Cycle 2 Day 15, 336 Hours Post-Dose (n=36)

Cycle 3 Day 1, Pre-Dose (n=19)

Cycle 3 Day 1, 10 Minutes Post-Dose (n=19)

Cycle 3 Day 1, 4 Hours Post-Dose (n=19)

Cycle 3 Day 3, 48 Hours Post-Dose (n=14)

Cycle 3 Day 4, 72 Hours Post-Dose (n=15)

Cycle 3 Day 8, 168 Hours Post-Dose (n=18)

Cycle 3 Day 15, 336 Hours Post-Dose (n=18)

Cycle 4 Day 1, Pre-Dose (n=16)

Cycle 4 Day 1, 10 Minutes Post-Dose (n=15)

Cycle 5 Day 1, Pre-Dose (n=7)

Cycle 5 Day 1, 10 Minutes Post-Dose (n=7)

Cycle 6 Day 1, Pre-Dose (n=8)

Cycle 6 Day 1, 10 Minutes Post-Dose (n=8)

Cycle 6 Day 4, 72 Hours Post-Dose (n=7)

Cycle 6 Day 8, 168 Hours Post-Dose (n=6)

Cycle 7 Day 1, Pre-Dose (n=3)

Cycle 7 Day 1, 10 Minutes Post-Dose (n=3)

Cycle 8 Day 1, Pre-Dose (n=3)

Cycle 8 Day 1, 10 Minute Post-Dose (n=3)

Cycle 9 Day 1, Pre-Dose (n=2)

Cycle 9 Day 1, 10 Minutes Post-Dose (n=2)

Cycle 11 Day 1, Pre-Dose (n=1)

Cycle 11 Day 1, 10 Minutes Post-Dose (n=1)

Cycle 12 Day 1, Pre-Dose (n=1)

Cycle 12 Day 1, 10 Minutes Post-Dose (n=1)

Cycle 13 Day 1, Pre-Dose (n=1)

Cycle 13 Day 1, 10 Minutes Post-Dose (n=1)

Cycle 14 Day 1, Pre-Dose (n=1)

Cycle 14 Day 1, 10 Minutes Post-Dose (n=1)

End of Treatment (n=26)

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.

MLN0264 Serum Concentrations

Cycle 2 Day 1, 10 Minutes Post-Dose (n=35)

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.

Serum Concentration of Total Antibodies (Conjugated and Unconjugated)

Cycle 3 Day 1, 10 Minutes Post-Dose (n=18)

Cycle 3 Day 15, 336 Hours Post-Dose (n=17)

Cycle 6 Day 1, 10 Minutes Post-Dose (n=7)

End of Treatment (n=25)

Serum Concentration of Monomethyl Auristatin E (MMAE)

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.

Spots Global Cancer Trial Database for gastroesophageal junction expressing guanylyl cyclase c