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Phase 1: MLN0264 1.2 milligram per kilogram (mg/kg) starting dose, Intravenous (IV), on Day 1 of 3 week cycles, for up to 1 year or until disease progression or unacceptable toxicity. Dosage of MLN0264 will be increased to 1.5 mg/kg then 1.8 mg/kg using a 3 + 3 dose escalation design to determine a maximum tolerated dose (MTD) and/or recommended Phase 2 Dose (RP2D).

Phase 2: MLN0264, IV, on Day 1 of 3 week cycles, for up to 1 year or until disease progression or unacceptable toxicity. Dosage for this phase will be determined from results of Phase 1 MTD/RP2D.

MLN0264

Medical Director Clinical science

The purpose of this study is to evaluate the effects of MLN0264 in previously treated Asian participants with Advanced Gastrointestinal (GI) Carcinoma (Phase 1) or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma (Phase 2) Expressing Guanylyl Cyclase C (GCC).

The drug being tested in this study is called MLN0264. This drug is being evaluated to check the effects on previously treated Asian individuals with Advanced GI Carcinoma (Phase 1) or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma (Phase 2). The study will enroll approximately 95 participants.

In Phase 1, approximately 14 Asian participants with GI malignancies will be enrolled in 3 planned dose cohorts according to the traditional 3 + 3 dose escalation scheme. The starting dose will be 1.2 mg/kg of MLN0264 administered IV on Day 1 of 3-week cycles for up to 1 year or until disease progression or unacceptable toxicity occurs. Dose escalation will take place until Phase 2 recommended dose is determined.

In Phase 2, eligible Asian participants with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction will be enrolled. Participants must have failed at least 2 lines of prior anticancer therapy for advanced or metastatic disease. Disease recurrence within 6 months of the last dose of post-surgical adjuvant chemotherapy counts as 1 line of prior anticancer therapy for advanced disease.

This multi-center trial will be conducted in Japan, Korea and Taiwan. The overall time to participate in this study is up to 3 years.

MLN0264 in Previously Treated Asian Participants With Advanced Gastrointestinal Carcinoma or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma Expressing Guanylyl Cyclase C

A Phase 1/2 Trial of MLN0264 in Previously Treated Asian Patients With Advanced Gastrointestinal (GI) Carcinoma (Phase 1) or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma (Phase 2) Expressing Guanylyl Cyclase C (GCC)

Toxicity evaluated as per NationalCancerInstituteCommonTerminologyCriteria for AEs (NCI CTCAE),version 4.03.DLT=any event related to MLN0264:Grade 4 neutropenia(absolute neutrophil count\[ANC\]less than\[\<\]500 cells/millimeter\[mm\]\^3); \>=Grade 3 neutropenia with fever/infection;Grade 4 thrombocytopenia(platelets \<25,000/mm\^3)/requires platelet transfusion(with/without hemorrhage);Grade 3/greater thrombocytopenia with clinically meaningful bleeding;Anemia requiring blood transfusion;\>=Grade 3 nausea/emesis occurring despite using optimal anti-emetic prophylaxis;\>=Grade 3 diarrhea despite optimal supportive care measures;any other \>=Grade 3 nonhematologic toxicity except brief(\<1 week)Grade 3 fatigue;Inability to start next therapy cycle greater than (\>)2 weeks due to delayed treatment and adequate recovery of MLN0264-related hematologic or nonhematologic toxicity;other\>= Grade 2 MLN0264-related nonhematologic toxicity which requires dose reduction or discontinuation of therapy.

The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. Laboratory assessment includes serum chemistry, hematology, urine analysis and coagulation.

Vital signs include body temperature (oral or tympanic measurement), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (beats per minute \[bpm\]).

RP2D is maximum tolerated dose(MTD) in study Phase1.MTD was highest dose of MLN0264 given at which \<=1 of 6 participants experienced DLTduring Cycle1 of Phase1.DLT=any event related to MLN0264:Grade 4 neutropenia ANC less than\<500 cells mm\^3;\>=Grade 3 neutropenia with fever/infection;Grade 4 thrombocytopenia(platelets \<25,000/mm\^3)/requires platelet transfusion(with/without hemorrhage);Grade 3/greater thrombocytopenia with clinically meaningful bleeding;Anemia requiring blood transfusion;\>=Grade 3 nausea/emesis occurring despite using optimal anti-emetic prophylaxis;\>=Grade 3 diarrhea despite optimal supportive care measures;any other \>=Grade 3 nonhematologic toxicity except brief(\<1 week)Grade 3 fatigue;Inability to start next therapy cycle\>2 weeks due to delayed treatment and adequate recovery of MLN0264-related hematologic or nonhematologic toxicity;other\>= Grade 2 MLN0264-related nonhematologic toxicity which requires dose reduction or discontinuation of therapy.

ORR is the percentage of participants with complete response \[CR\] + partial response \[PR\]) based on modified Response Evaluation Criteria in Solid Tumors (RECIST). Overall response rate (CR + PR) based on modified RECIST version 1.1 guidelines. CR: Disappearance of all target lesions and PR: at least a 30 percentage (%) decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total representative of all involved organs were identified as target lesions at baseline. Target lesions were selected on the basis of size (longest lesions) and suitability for reproducible repeated measurements.

Blood samples was collected predose to evaluate ATA. Data was collected only for limited period due to early termination of the study.

Disease response was based on the investigator's assessment using the modified RECIST version 1.1 guidelines. Evaluation of target lesions included CR (Disappearance of all target lesions),PR(at least a 30% decrease in the sum of the LD of target lesions),Progressive disease (PD:at least a 20% increase in the sum of the LD of target lesions, taking the smallest sum LD recorded as reference since the treatment started or the appearance of one or more new lesions) and Stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD).Evaluation of Non target Lesions included CR (disappearance of all non target lesions and normalization of tumor marker level), Incomplete response/SD (Persistence of 1 or more non target lesions and/or maintenance of tumor marker level above the normal limits) and PD(Appearance of 1 or more new lesions and/or unequivocal progression of existing non target lesions).

PFS is defined as the time from the date of first study drug administration to the date of first documentation of progressive disease or death. For a participant who has not progressed and is last known to be alive, PFS was censored at the last response assessment that was stable disease or better. PD:at least a 20% increase in the sum of the LD of target lesions, taking the smallest sum LD recorded as reference since the treatment started or the appearance of one or more new lesions.

DOR is defined as the time from the date of first documentation of a confirmed response to the date of first documentation of Progressive Disease (PD). Responders without documentation of PD were censored at the last response assessment that was stable disease or better. CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD and PD:at least a 20% increase in the sum of the LD of target lesions, taking the smallest sum LD recorded as reference since the treatment started or the appearance of one or more new lesions.

DCR is defined as Complete Response (CR) rate + Partial Response (PR) rate + stable disease (SD) rate with a minimum of 12 weeks' duration. Duration of SD is defined as the time from the date of first study drug administration to the date of first documentation of disease progression for participants who achieved SD as the best overall response. CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; PD:at least a 20% increase in the sum of the LD of target lesions, taking the smallest sum LD recorded as reference since the treatment started or the appearance of one or more new lesions) and SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

OS is defined as the time from the date of first study drug administration to the date of death. Participants without documentation of death at the time of analysis were censored at the date when they were last known to be alive.

For each participant, the best percentage of tumor reduction from baseline in the sum of the diameter was calculated.

The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors. The score is obtained by the formula: 3 \* percentage of strongly staining nuclei + 2 \* percentage of moderately staining nuclei + percentage of weakly staining nuclei, giving a range of 0 to 300. The 600 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

Blood samples were to be collected predose to evaluate ATA.

Millennium Pharmaceuticals, Inc.

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Participants who either received MLN0264 1.2 mg/kg as starting dose, or 1.5 mg/kg, or 1.8 mg/kg infusion, intravenously over 30 minutes, on Day 1 of every 3 week cycle of Phase 1, for up to 1 year or until disease progression or unacceptable toxicity.

Phase 1: All Participants

Between 45 to 78 years

Age, Customized

Sex: Female, Male

Race (NIH/OMB)

Japan

Taiwan

Korea, Republic of

Region of Enrollment

Colon cancer

Rectal cancer

Gastric cancer

Lymphovascular invasion

Invasive ductal carcinoma of the pancreas

Moderately differentiated ductal adenocarcinoma

Adenocarcinoma not otherwise specified

Tubular adenocarcinoma

Moderately differentiated and descending colon

Histological classification included moderately differentiated adenocarcinoma (colon and rectal cancer); intestinal type adenocarcinoma (gastric cancer); adenocarcinoma with lymphovascular invasion; invasive ductal carcinoma of the pancreas, moderately differentiated ductal adenocarcinoma, adenocarcinoma not otherwise specified, tubular adenocarcinoma, and moderately differentiated adenocarcinoma of the transverse and descending colon.

Histological classification

Participants With Prior Medical Condition

With Surgical History

Without Surgical History

Participants With Surgical History

Participants With Prior Anticancer Therapy

With prior radiation therapy

Without prior radiation therapy

Participants With Prior Radiation Therapy

ECOG performance status is used to assess how the disease affects the daily living abilities of the participant. It ranges on the scale from 0-5 (0= normal activity; 1= symptoms but ambulatory; 2= in bed for less than (\<) 50 percent (%) of the time; 3= in bed for greater than (\>) 50% of the time; 4= 100% bedridden; 5= dead.

Eastern Cooperative Oncology Group (ECOG) Therapy

Safety population included all participants who received any amount of study drug.

Medical Director

Safety population includes all participants who received any amount of study drug.

Phase 1- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE)

Phase 1- Number of Participants Reporting One or More Serious Adverse Events (SAE)

The DLT-Evaluable population included all participants who either experienced DLT during Cycle 1 or received their scheduled Cycle 1 dose and completed all study procedures in Cycle 1 without DLT.

Phase 1- Number of Participants Experiencing Dose-limiting Toxicities (DLTs)

Serum Chemistry

Hematology

Urinalysis

Coagulation

Phase 1- Number of Participants With Markedly Abnormal Laboratory Values

Phase 1- Number of Participants With Clinically Significant Change From Baseline in Vital Signs

Phase 1- Recommended Phase 2 Dose (RP2D)

MLN0264 1.2 mg/kg, infusion, intravenously over 30 minutes, on Day 1 of every 3 week cycle during the Phase 1, for up to 1 year or until disease progression or unacceptable toxicity

Phase 1: MLN0264 1.2 mg/kg

MLN0264 1.5 mg/kg, infusion, intravenously over 30 minutes, on Day 1 of every 3 week cycle during the Phase 1, for up to 1 year or until disease progression or unacceptable toxicity

Phase 1: MLN0264 1.5 mg/kg

MLN0264 1.8 mg/kg, infusion, intravenously, over 30 minutes on Day 1 of every 3 week cycle during the Phase 1, for up to 1 year or until disease progression or unacceptable toxicity

Phase 1: MLN0264 1.8 mg/kg

The Pharmacokinetic (PK) evaluable population included all participants who received greater than or equal to (\>=1) dose of MLN0264 and had sufficient MLN0264 concentration time data to permit reliable estimation of MLN0264 exposure.

Phase 1: Cycle 1- Cmax: Maximum Observed Plasma Concentration for MLN0264

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MLN0264 concentration time data to permit reliable estimation of MLN0264 exposure where Cycle 2 Day 1 PK assessment were available.

Phase 1: Cycle 2- Cmax: Maximum Observed Plasma Concentration for MLN0264

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MLN0264 concentration time data to permit reliable estimation of MLN0264 exposure.

Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0264

Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0264

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MLN0264 concentration time data to permit reliable estimation of MLN0264 exposure where Cycle 1 Day 1 PK assessment were available.

Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MLN0264

Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MLN0264

Phase 1: Cycle 1- AUCint: Area Under the Serum/Plasma Concentration-time Curve From Time 0 to End of the 21-day Dosing Interval (AUCint) for MLN0264

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MLN0264 concentration time data to permit reliable estimation of MLN0264 exposure where Cycle 2 Day 1 PK assessment were available. Data is not reported for MLN0264 1.2 mg/kg arm as none of the participants had data evaluable for this measure.

Phase 1: Cycle 2- AUCint: Area Under the Serum/Plasma Concentration-time Curve From Time 0 to End of the 21-day Dosing Interval (AUCint) for MLN0264

Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MLN0264

Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MLN0264

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient TAb concentration time data to permit reliable estimation of the PK parameters.

Phase 1: Cycle 1- Cmax: Maximum Observed Serum Concentration for Total Antibody (TAb)

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient TAb concentration time data to permit reliable estimation of the PK parameters where Cycle 2 Day 1 PK assessment were available.

Phase 1: Cycle 2- Cmax: Maximum Observed Serum Concentration for TAb

Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for TAb

Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for TAb

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient TAb concentration time data to permit reliable estimation of the PK parameters where Cycle 1 Day 1 PK assessment were available.

Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for TAb

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient TAb concentration time data to permit reliable estimation of the PK parameters where Cycle 2 Day1 PK assessment were available. Data is not reported for MLN0264 1.2 mg/kg arm because none of the participants had data evaluable for this measure.

Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for TAb

Phase 1: Cycle 1- AUCint: Area Under the Serum/Plasma Concentration-time Curve From Time 0 to End of the 21-day Dosing Interval (AUCint) for TAb

Phase 1: Cycle 2- AUCint: Area Under the Serum/Plasma Concentration-time Curve From Time 0 to End of the 21-day Dosing Interval (AUCint) for TAb

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient TAb concentration time data to permit reliable estimation of the PK parameters where Cycle 1 Day1 PK assessment were available. Data is not reported for MLN0264 1.2 mg/kg arm because none of the participants had data evaluable for this measure.

Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAb

Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAb

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MMAE concentration time data to permit reliable estimation of the PK parameters.

Phase 1: Cycle 1- Cmax: Maximum Observed Plasma Concentration for Monomethyl Auristatin E (MMAE)

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MMAE concentration time data to permit reliable estimation of the PK parameters where Cycle 2 Day 1 PK assessment were available.

Phase 1: Cycle 2- Cmax: Maximum Observed Plasma Concentration for MMAE

Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MMAE

Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MMAE

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MMAE concentration time data to permit reliable estimation of the PK parameters where Cycle 1 Day 1 PK assessment were available.

Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MMAE

The PK evaluable population included all participants who received \>=1 dose of MLN0264 and had sufficient MMAE concentration time data to permit reliable estimation of the PK parameters where Cycle2 Day1 PK assessment were available. Data is not reported for MLN0264 1.2 mg/kg arm because none of the participants had data evaluable for this measure.

Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MMAE

Phase 1: Cycle 1- AUCint: Area Under the Serum/Plasma Concentration-time Curve From Time 0 to End of the 21-day Dosing Interval (AUCint) for MMAE

Phase 1: Cycle 2- AUCint: Area Under the Serum/Plasma Concentration-time Curve From Time 0 to End of the 21-day Dosing Interval (AUCint) for MMAE

Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MMAE

Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MMAE

MLN0264, infusion was planned to be administered intravenously on Day 1 of every 3 week cycle for up to 1 year or until disease progression or unacceptable toxicity during Phase 2. Dosage for this phase was to be determined from results of Phase 1 MTD/RP2D.

Phase 2: All Participants

Data was not reported for this measure as Phase 2 was not initiated, due to study termination during the dose-escalation portion of phase 1 consistent with the findings that preliminary PK and overall clinical data demonstrated compelling similarity between Western and Asian participant populations.

Phase 2- Overall Response Rate

Phase 1- Number of Participants With Antitherapeutic Antibodies (ATAs)

The Response-Evaluable population is defined as all participants with measurable disease who receive at least 1 dose of MLN0264 and have at least 1 post baseline response assessment.

Phase 1- Disease Response Based on the Investigator's Assessment

Phase 2- Percentage of Participants Who Experience at Least One TEAE

Phase 2- Percentage of Participants Who Experience at Least One SAE

Phase 2- Number of Participants With Markedly Abnormal Laboratory Values

Phase 2- Number of Participants With Clinically Significant Change From Baseline in Vital Signs

Phase 2- Progression-free Survival (PFS)

Phase 2- Duration of Response (DOR)

Phase 2- Disease Control Rate (DCR)

Phase 2- Overall Survival (OS)

Phase 2- Plasma Concentration of MLN0264

Phase 2- Tumor Size Reduction

MLN0264, injection, intravenously on Day 1 of 3 week cycles of Phase 2, until disease progression or unacceptable toxicity. Dosage for this phase was determined from results of Phase 1 MTD/RP2D.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
MLN0264 in Previously Treated Asian Participants With Advanced Gastrointestinal Carcinoma or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma Expressing Guanylyl Cyclase C	NCT02391038	Advanced Gastro... Gastroesophagea... Recurrent Gastr... Recurrent Gastr... Metastatic Gast... Metastatic Gast... Recurrent Gastr...	MLN0264	18 Years -	Takeda
MLN0264 in Previously Treated Asian Participants With Advanced Gastrointestinal Carcinoma or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma Expressing Guanylyl Cyclase C	NCT02391038	Advanced Gastro... Gastroesophagea... Recurrent Gastr... Recurrent Gastr... Metastatic Gast... Metastatic Gast... Recurrent Gastr...	MLN0264	18 Years -	Takeda

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