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

Gastroesophageal Junction Adenocarcinoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02391038
• Other study ID #: C26004
• Secondary ID: U1111-1164-1438J
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: November 28, 2014
• Last updated: June 3, 2016
• Start date: January 2015
• Est. completion date: October 2015

Study information

• Verified date: June 2016
• Source: Millennium Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and WelfareKorea: Food and Drug AdministrationTaiwan: Ministry of Health and Welfare
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the effects 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).

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 Gastrointestinal (GI) Carcinoma (Phase 1) or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma (Phase 2). The study will enroll approximately 95 patients.

In Phase 1, approximately 14 Asian patients 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 patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction will be enrolled. Patients 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-centre trial will be conducted in Japan, Korea and Taiwan. The overall time to participate in this study is up to 3 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: October 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has Diagnosis of GI carcinoma with 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 least4 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 RECIST version 1.1 guidelines.

• Has Eastern Cooperative Oncology Group performance status of 0 or 1 (within 14 days prior to enrolment)

• 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 NCI CTCAE version 4.03

Exclusion Criteria:

• Has Concurrent treatment or treatment within 4 weeks of study entry with any other investigational agent

• Female patients 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 ECG abnormalities considered by the investigator to be clinically -significant, or repeated baseline prolongation of the rate-corrected QT interval (msec) of electrocardiograph the (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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adenocarcinoma
• Advanced Gastrointestinal Carcinoma
• Carcinoma
• Esophageal Neoplasms
• Gastroesophageal Junction Adenocarcinoma
• Metastatic Gastric Adenocarcinoma
• Metastatic Gastroesophageal Junction Adenocarcinoma
• Recurrent Gastric Adenocarcinoma
• Recurrent Gastroesophageal Junction Adenocarcinoma
• Recurrent Gastrointestinal Carcinoma

Intervention

Drug:
• MLN0264
MLN0264 IV.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Millennium Pharmaceuticals, Inc.

Countries where clinical trial is conducted

Japan,  Korea, Republic of,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Experiencing Adverse Events in Phase 1	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.; A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.	From the First Dose through 30 days after the Last Dose of study drug (Up to Month 18)	Yes
Primary	Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) in Phase 1	Toxicity will be evaluated according to the NCI CTCAE, Version 4.03. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with MLN0264	Up to Month 19	Yes
Primary	Number of Participants With Markedly Abnormal Laboratory Values in Phase 1	Laboratory assessments include serum chemistry, hematology, and urine analysis	From Baseline up to 30 days after last Dose (Up to Month 19)	Yes
Primary	Change From Baseline in Participant Vital Sign Measurements in Phase 1	Vital sign measurements include measurements of diastolic and systolic blood pressure, heart rate, and body temperature.	Baseline and up to Month 19	Yes
Primary	Recommended Dose for Use in Study Phase II (RP2D)	RP2D for Phase 2 will be determined from the maximum tolerated dose in Phase 1 portion of the study	From baseline up to Month 19	No
Primary	Serum concentrations of Total Antibody (conjugated and unconjugated)	Blood sampling for the determination of the serum concentrations of MLN0264 will be performed.	Day 1 Predose and post dose up to Day 15 at specified time intervals of each cycle and at the end of treatment	No
Primary	Overall response rate (ORR) of Asian patients with recurrent or metastatic GCC-positive adenocarcinoma of the stomach or gastroesophageal junction treated with MLN0264 (Phase 2)	ORR is the percentage of participants with complete response [CR] + PR) based on modified RECIST Overall response rate (complete response [CR] +partial response ( PR) based on modified RECIST version 1.1 guidelines.	Up to Month 46	No
Primary	Cmax: Maximum Observed Plasma Concentration for MLN0264	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.	Days 1-15, and 30 days following the final dose	No
Primary	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0264	Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax.	Days 1-15, and 30 days following the final dose	No
Primary	Ctrough: Trough concentration of MLN0264	Ctrough is defined as the concentration at the end of the dosage interval.	Days 1-15, and 30 days following the final dose	No
Primary	AUC(0-inf): Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for MLN0264	AUC(0-inf) is measure of area under the curve over the dosing interval (tau) (AUC(0-tau]), where tau is the length of the dosing interval in this study).	Days 1-15, and 30 days following the final dose	No
Primary	Terminal Phase Elimination Half-life (T1/2) for MLN0264	Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.	Days 1-15, and 30 days following the final dose	No
Primary	Plasma concentrations of monoethyl auristatin E (MMAE)	Blood sampling for the determination of the serum concentrations of MLN0264 will be performed.	Day 1 Predose and up to 30 days after Last Dose	No
Secondary	Presence of Antitherapeutic Antibodies (ATA) in the Serum (Phase 1)	Blood samples will be collected predose to evaluate ATA and neutralizing ATA. . Neutralizing ATA assessment will be performed for ATA-positive samples only.	Day 1 Predose and up to 30 days after Last Dose	No
Secondary	Disease response based on the investigator's assessment using the modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines (Phase 1)		Up to Month 25	No
Secondary	Percentage of Participants Experiencing Adverse Events (AEs) or Serious Adverse Events (SAEs) (Phase 2)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.; A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.	Up to Month 32	Yes
Secondary	Number of Participants With Clinically Significant Laboratory Values in Phase 2	Laboratory assessments include serum chemistry, hematology, and urine analysis	Baseline and up to Month 32	Yes
Secondary	Change From Baseline in Participant Vital Sign Measurements in Phase 2	Vital sign measurements include measurements of diastolic and systolic blood pressure, heart rate, and body temperature	Baseline and up to Month 32	Yes
Secondary	Participant Progression-Free Survival (PFS) in Phase 2	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 patient who has not progressed and is last known to be alive, PFS will be censored at the last response assessment that is stable disease or better.	Every 12 weeks starting from cycle 2 up to Month 37	No
Secondary	Duration of Response (DOR) in Phase 2	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 will be censored at the last response assessment that is stable disease or better.	Up to Month 37	No
Secondary	Disease Control Rate (DCR) in Phase 2	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 patients who achieved SD as the best overall response.	Up to Month 37	No
Secondary	Participant Overall Survival (OS) in Phase 2	Overall survival is defined as the time from the date of first study drug administration to the date of death. Patients without documentation of death at the time of analysis will be censored at the date when they were last known to be alive.	Up to Month 37	No
Secondary	Pharmacokinetics of MLN0264 (Phase 2)	For all patients in the phase 2 portion, limited (sparse) PK sampling will be performed.	Up to month 31	No
Secondary	Change From Baseline in Tumor Size (Phase 2)	For each patient, the best percentage of tumor reduction from baseline in the sum of the diameter will be calculated.	Baseline and Up to Month 37	No
Secondary	Assessment of Participant GCC H-score as assessed by immunohistochemistry (IHC) Phase 2		Baseline and up to Month 37	No