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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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)

Conditions
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Advanced Gastrointestinal Carcinoma, Gastroesophageal Junction Adenocarcinoma, Recurrent Gastric Adenocarcinoma, Recurrent Gastroesophageal Junction Adenocarcinoma, Metastatic Gastric Adenocarcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma, Recurrent Gastrointestinal Carcinoma

Intervention / Treatment
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* Drug: MLN0264


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has Diagnosis of GI carcinoma with Immunohistochemistry/ Immunohistochemical (IHC) evidence of expression of GCC protein (H-score of 10 or greater), for which standard treatment is no longer effective or does not offer curative or life-prolonging potential. Has completed prior chemotherapy, immunotherapy or radiation therapy at least 4 weeks prior to enrollment (except for Avastin [bevacizumab] for which at least 8 weeks from its last administration should elapse prior to enrollment). Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the stomach or gastroesophageal junction with IHC evidence of expression of GCC indicated by an H-score of 10 or greater. Has completed prior chemotherapy, immunotherapy or radiation therapy at least 4 weeks prior to enrollment. Has measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Has Eastern Cooperative Oncology Group performance status of 0 or 1 (within 14 days prior to enrollment). Females must be 1-year postmenopausal, or even if surgically sterile, agree to use other acceptable forms of birth control. Has adequate organ and hematological function. Has 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 Exclusion Criteria: Has Concurrent treatment or treatment within 4 weeks of study entry with any other investigational agent. Female participants who are in the lactation period, even if they discontinue breastfeeding, or have a positive pregnancy test during the Screening period. Has uncontrolled, clinically significant, symptomatic cardiovascular disease within 6 months prior to enrollment. Has 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 prior to starting study drug. Participants with electrocardiogram (ECG) abnormalities considered by the investigator to be clinically -significant, or repeated baseline prolongation of the rate-corrected QT interval millisecond (msec) of electrocardiograph (QTc). Ongoing or clinically significant active infection. Has signs of peripheral neuropathy. Concomitant chemotherapy, hormonal therapy, immunotherapy, or any other form of cancer treatment. Use of strong cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks before the first dose of study drug. Has any preexisting medical condition of sufficient severity to prevent full compliance with the study. Has past or concurrent history of neoplasm other than GI carcinoma (phase 1) or gastric adenocarcinoma (phase 2), except for curatively treated nonmelanoma skin cancer or in situ carcinoma of the cervix uteri. Known diagnosis of human immunodeficiency virus (HIV) infection. Has asymptomatic brain metastases. Has an alcohol or substance abuse disorder. Has positive test for hepatitis B surface antigen. History of hypersensitivity to any ingredient of MLN0264.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN0264<br>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. | Drug: MLN0264<br>* MLN0264 IV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) |  | Phase 1: Baseline through 30 days after the last dose of study drug (approximately up to 35 weeks) | 
| Phase 1- Number of Participants Reporting One or More Serious Adverse Events (SAE) |  | Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks) | 
| Phase 1- Number of Participants Experiencing Dose-limiting Toxicities (DLTs) | 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. | Phase 1: Up to Cycle 1 (3 weeks) | 
| Phase 1- Number of Participants With Markedly Abnormal Laboratory Values | 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. | Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks) | 
| Phase 1- Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 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]). | Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks) | 
| Phase 1- Recommended Phase 2 Dose (RP2D) | 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. | Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks) | 
| Phase 1: Cycle 1- Cmax: Maximum Observed Plasma Concentration for MLN0264 |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Cmax: Maximum Observed Plasma Concentration for MLN0264 |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0264 |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0264 |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MLN0264 |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MLN0264 |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| 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 |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| 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 |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MLN0264 |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MLN0264 |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Cmax: Maximum Observed Serum Concentration for Total Antibody (TAb) |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Cmax: Maximum Observed Serum Concentration for TAb |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for TAb |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for TAb |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for TAb |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for TAb |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| 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 |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| 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 |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAb |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAb |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Cmax: Maximum Observed Plasma Concentration for Monomethyl Auristatin E (MMAE) |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Cmax: Maximum Observed Plasma Concentration for MMAE |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MMAE |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MMAE |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MMAE |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MMAE |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| 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 |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| 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 |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MMAE |  | Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MMAE |  | Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose | 
| Phase 2- Overall Response Rate | 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. | Baseline until end of study treatment (approximately 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1- Number of Participants With Antitherapeutic Antibodies (ATAs) | Blood samples was collected predose to evaluate ATA. Data was collected only for limited period due to early termination of the study. | Day 1 of Cycle 1, 2, 3, 4: predose | 
| Phase 1- Disease Response Based on the Investigator's Assessment | 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). | Phase 1: Day 21 of every other cycle (Cycle 2, 4, 6, 8) up to End of treatment (EOT) (Cycle10 or week 30) | 
| Phase 2- Percentage of Participants Who Experience at Least One TEAE |  | Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year) | 
| Phase 2- Percentage of Participants Who Experience at Least One SAE |  | Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year) | 
| Phase 2- Number of Participants With Markedly Abnormal Laboratory Values | 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. | Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year) | 
| Phase 2- Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 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]). | Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year) | 
| Phase 2- Progression-free Survival (PFS) | 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. | Baseline up to EOT, thereafter every 12 weeks until the occurrence of PD, the start of subsequent antineoplastic therapy, or 6 months after discontinuation from treatment, whichever occurs first (total duration of assessment up to 1.5 years) | 
| Phase 2- Duration of Response (DOR) | 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. | Day 21 of every other cycle (Cycle 2, 4, 6, 8) up to EOT (approximately 1 year) | 
| Phase 2- Disease Control Rate (DCR) | 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. | Phase 2: Day 21 of every other cycle (Cycle 2, 4, 6, 8) up to EOT (approximately 1 year) | 
| Phase 2- Overall Survival (OS) | 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. | Baseline up to EOT thereafter every 12 weeks until death or the start of subsequent antineoplastic therapy, or 6 months after discontinuation from treatment, whichever occurs first (total duration of assessment up to 1.5 years) | 
| Phase 2- Plasma Concentration of MLN0264 |  | Day 1 of every cycle (up to 1 year): predose and at multiple time points(up to 336 hours) post-dose | 
| Phase 2- Tumor Size Reduction | For each participant, the best percentage of tumor reduction from baseline in the sum of the diameter was calculated. | Baseline up to approximately 1 year | 
| Phase 2- Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC) | 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 | Baseline up to approximately 1 year | 
| Phase 2- Number of Participants With ATA in Serum | Blood samples were to be collected predose to evaluate ATA. | Baseline up to approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MLN0264, Advanced gastrointestinal carcinoma