Clinical trial NCT02391038: MLN0264 in Previously Treated Asian Participants With Advanced Gastrointestinal Carcinoma or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma Expressing Guanylyl Cyclase C
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Gastrointestinal Carcinoma
Gastroesophageal Junction Adenocarcinoma
Recurrent Gastric Adenocarcinoma
Recurrent Gastroesophageal Junction Adenocarcinoma
Metastatic Gastric Adenocarcinoma
Metastatic Gastroesophageal Junction Adenocarcinoma
Recurrent Gastrointestinal Carcinoma
Keywords: MLN0264
Advanced gastrointestinal carcinoma
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-03-18
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 1- Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE)
timeFrame: Phase 1: Baseline through 30 days after the last dose of study drug (approximately up to 35 weeks)
measure: Phase 1- Number of Participants Reporting One or More Serious Adverse Events (SAE)
timeFrame: Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks)
measure: Phase 1- Number of Participants Experiencing Dose-limiting Toxicities (DLTs)
timeFrame: Phase 1: Up to Cycle 1 (3 weeks)
measure: Phase 1- Number of Participants With Markedly Abnormal Laboratory Values
timeFrame: Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks)
measure: Phase 1- Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks)
measure: Phase 1- Recommended Phase 2 Dose (RP2D)
timeFrame: Phase 1: Baseline through 30 days after the last dose of study drug (Approximately up to 35 weeks)
measure: Phase 1: Cycle 1- Cmax: Maximum Observed Plasma Concentration for MLN0264
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Cmax: Maximum Observed Plasma Concentration for MLN0264
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0264
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0264
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MLN0264
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MLN0264
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: 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
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
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
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MLN0264
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MLN0264
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Cmax: Maximum Observed Serum Concentration for Total Antibody (TAb)
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Cmax: Maximum Observed Serum Concentration for TAb
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for TAb
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for TAb
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for TAb
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for TAb
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: 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
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
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 TAb
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAb
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for TAb
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Cmax: Maximum Observed Plasma Concentration for Monomethyl Auristatin E (MMAE)
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Cmax: Maximum Observed Plasma Concentration for MMAE
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MMAE
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MMAE
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MMAE
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- AUCinf: Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for MMAE
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: 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
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
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 MMAE
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 1- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MMAE
timeFrame: Day 1 of Cycle 1: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 1: Cycle 2- Ctrough: Observed Concentration Measured at the End of a Dosing Interval for MMAE
timeFrame: Day 1 of Cycle 2: predose and at multiple time points (up to 336 hours) post-dose
measure: Phase 2- Overall Response Rate
timeFrame: Baseline until end of study treatment (approximately 1 year)
Secondary outcomes:
measure: Phase 1- Number of Participants With Antitherapeutic Antibodies (ATAs)
timeFrame: Day 1 of Cycle 1, 2, 3, 4: predose
measure: Phase 1- Disease Response Based on the Investigator's Assessment
timeFrame: Phase 1: Day 21 of every other cycle (Cycle 2, 4, 6, 8) up to End of treatment (EOT) (Cycle10 or week 30)
measure: Phase 2- Percentage of Participants Who Experience at Least One TEAE
timeFrame: Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year)
measure: Phase 2- Percentage of Participants Who Experience at Least One SAE
timeFrame: Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year)
measure: Phase 2- Number of Participants With Markedly Abnormal Laboratory Values
timeFrame: Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year)
measure: Phase 2- Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Phase 2: Baseline up to 30 days after last dose of study drug (approximately 1 year)
measure: Phase 2- Progression-free Survival (PFS)
timeFrame: 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)
measure: Phase 2- Duration of Response (DOR)
timeFrame: Day 21 of every other cycle (Cycle 2, 4, 6, 8) up to EOT (approximately 1 year)
measure: Phase 2- Disease Control Rate (DCR)
timeFrame: Phase 2: Day 21 of every other cycle (Cycle 2, 4, 6, 8) up to EOT (approximately 1 year)
measure: Phase 2- Overall Survival (OS)
timeFrame: 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)
measure: Phase 2- Plasma Concentration of MLN0264
timeFrame: Day 1 of every cycle (up to 1 year): predose and at multiple time points(up to 336 hours) post-dose
measure: Phase 2- Tumor Size Reduction
timeFrame: Baseline up to approximately 1 year
measure: Phase 2- Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC)
timeFrame: Baseline up to approximately 1 year
measure: Phase 2- Number of Participants With ATA in Serum
timeFrame: Baseline up to approximately 1 year
Other outcomes:
Locations:
city: Kashiwa-shi
country: Japan
state: Chiba-Ken
city: Minato-ku
country: Japan
state: Tokyo-To
city: Seoul
country: Korea, Republic of
state: Gyeonggi-do
city: Taipei
country: Taiwan
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Director Clinical science
role: STUDY_DIRECTOR
References: