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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02202759
Recruitment Status : Terminated (Business Decision, No Safety or Efficacy Concerns)
First Posted : July 29, 2014
Results First Posted : May 15, 2017
Last Update Posted : May 15, 2017
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Tracking Information
First Submitted Date  ICMJE July 7, 2014
First Posted Date  ICMJE July 29, 2014
Results First Submitted Date  ICMJE January 13, 2017
Results First Posted Date  ICMJE May 15, 2017
Last Update Posted Date May 15, 2017
Actual Study Start Date  ICMJE August 4, 2014
Actual Primary Completion Date January 15, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 6, 2017)
Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Day 21, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 17 months) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: July 25, 2014)
Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: From 21 days, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 6 months after the enrollment of the last patient) ]
ORR is defined as the percentage of participants with a complete response (CR) or partial response (PR) 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 6, 2017)
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 10.7 months) ]
    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.
  • Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 10.7 months) ]
    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.
  • Number of Participants With Potentially Clinically Significant Vital Signs Findings [ Time Frame: Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 10.7 months) ]
    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.
  • Progression Free Survival (PFS) [ Time Frame: Time Frame: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months) ]
    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 [ Time Frame: From first documented response until disease progression (Up to 16.7 months) ]
    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 [ Time Frame: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months) ]
    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 (OS) [ Time Frame: Until death or 6 months after the last patient completes treatment-whichever occurs first (Up to 17 months) ]
    Overall survival is defined as the time in days from the date of first study drug administration to the date of death.
  • Cmax: Maximum Observed Serum Concentration for MLN0264 [ Time Frame: Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose. ]
    Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.
  • MLN0264 Serum Concentrations [ Time Frame: Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment. ]
    Blood samples were collected and sent to a laboratory to be tested for serum concentrations of MLN0264.
  • Serum Concentration of Total Antibodies (Conjugated and Unconjugated) [ Time Frame: Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment. ]
    Blood samples were collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies.
  • Serum Concentration of Monomethyl Auristatin E (MMAE) [ Time Frame: Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment. ]
    Blood samples were collected and sent to a laboratory to be tested for MMAE.
  • Number of Participants With Reduction From Baseline in Tumor Size [ Time Frame: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months) ]
    The number of participants with the best percentage of tumor reduction from baseline in the sum of the diameter was calculated.
  • Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC) [ Time Frame: Approximately 20 months ]
    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.
  • Number of Participants With Antitherapeutic Antibodies (ATA) [ Time Frame: Pre-dose of each 21 day cycle and 30 days after last dose of study medication (Up to 10.7 months) ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 25, 2014)
  • Number of Participants With Adverse Events (AEs) [ Time Frame: From the first dose through 30 days after the last dose of study medication (Up to 13 months) ]
    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. Serious adverse event (SAE) means 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.
  • Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings [ Time Frame: Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 13 months)] ]
    Participants with at least one post-baseline potentially clinically significant serum chemistry, hematology, coagulation or urinalysis result.
  • Number of Participants With Potentially Clinically Significant Vital Signs Findings [ Time Frame: Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 13 months) ]
    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.
  • Progression Free Survival (PFS) [ Time Frame: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (approximately 18 months) ]
    PFS is defined as the time from the date of first study drug administration to the date of first documentation of disease progression or death.
  • Duration of Response [ Time Frame: From first documented response until disease progression (Up to 18 months) ]
    Duration of response is defined as the time from the date of first documentation of a confirmed response to the date of first documentation of disease progression.
  • Disease Control Rate [ Time Frame: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Approximately 18 months) ]
    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. 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.
  • Overall Survival (OS) [ Time Frame: : Until death or 6 months after the last patient completes treatment-whichever occurs first ]
    Overall survival is defined as the time from the date of first study drug administration to the date of death.
  • Cmax: Maximum Observed Serum Concentration for MLN0264 [ Time Frame: Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose. ]
    Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.
  • Serum Concentration Conjugated and Unconjugated Total Antibody [ Time Frame: Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose. ]
    Blood samples will be collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies.
  • Serum Concentration of Monomethyl Auristatin E (MMAE) [ Time Frame: Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose. ]
    Blood samples will be collected and sent to a laboratory to be tested for MMAE.
  • Change from Baseline in Tumor Size [ Time Frame: Day 21 of each 21-day cycle, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Approximately 18 months) ]
    The best percentage of tumor reduction from baseline in the sum of the diameter will be calculated.
  • Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC) [ Time Frame: From pre-screening through end of study (approximately 20 months) ]
    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 is required to obtain archival tumor specimens for GCC expression assessment prior to screening.
  • Assessment of Antitherapeutic Antibodies (ATA) [ Time Frame: Pre-dose of each 21 day cycle and 30 days after last dose of study medication (Up to 13 months) ]
    Blood samples will be collected to assess the immunogenicity of MLN026 (ATA development) using a laboratory test. Neutralizing ATA assessment will be performed for ATA-positive samples only.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of MLN0264 in Participants With Cancer of the Stomach or Gastroesophageal Junction
Official Title  ICMJE 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)
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Adenocarcinoma of the Stomach
  • Gastroesophageal Junction Expressing Guanylyl Cyclase C
Intervention  ICMJE Drug: MLN0264
MLN0264 IV infusion
Study Arms  ICMJE Experimental: 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.
Intervention: Drug: MLN0264
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 6, 2017)
38
Original Estimated Enrollment  ICMJE
 (submitted: July 25, 2014)
81
Actual Study Completion Date  ICMJE January 15, 2016
Actual Primary Completion Date January 15, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female participants 18 years of age or older when written informed consent is obtained.
  2. Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the stomach or gastroesophageal junction with immunohistochemistry (IHC) evidence of guanylyl cyclase C (GCC) expression indicated by an H-score of 10 or greater.
  3. Treatment with 1 or more prior chemotherapies for advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
  4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. All scans and x-rays used to document measurable disease must be done within 28 days before enrollment (ascites and bone lesions are not considered measureable disease).
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before enrollment.
  6. Female participants who:

    • Are postmenopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

    Male participants, even if surgically sterilized (ie, status postvasectomy), who:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
  7. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
  8. Adequate organ and hematological function as evidenced by the following laboratory values within 14 days before enrollment:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
    • Platelet count ≥ 100 x 10^9/L
    • Hemoglobin ≥ 9 g/dL
    • Activated partial thromboplastin time (aPTT) ≤ 1.5 x the upper limit of the normal range (ULN) per institutional laboratory normal range
    • International normalized ratio (INR) ≤ 1.5 x ULN
    • Serum creatinine ≤ 1.5 x ULN
    • Total bilirubin ≤ 1.5 x ULN
    • Albumin ≥ 3g/dL
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
    • Serum lipase ≤ 3 x ULN and serum amylase within the normal range
  9. 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.
  10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

  1. Radiotherapy within 4 weeks before enrollment.
  2. Concurrent treatment or treatment within 4 weeks of study entry with any other investigational agent or chemotherapy.
  3. Female participants who are lactating and breastfeeding or have a positive pregnancy test during the Screening period.
  4. Uncontrolled, clinically significant, symptomatic cardiovascular disease within 6 months before enrollment, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication.
  5. 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 before starting study drug.
  6. Participants with electrocardiogram (ECG) abnormalities considered by the investigator to be clinically significant, or repeated baseline prolongation of the rate-corrected QT interval (QTc).
  7. Ongoing or clinically significant active infection as judged by the investigator.
  8. Signs of peripheral neuropathy (PN) ≥ NCI CTCAE Grade 2.
  9. Concomitant chemotherapy, hormonal therapy, immunotherapy, or any other form of cancer treatment.
  10. Use of strong cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks before the first dose of study drug.
  11. Any preexisting medical condition of sufficient severity to prevent full compliance with the study.
  12. History of or current neoplasm other than gastric adenocarcinoma, except for curatively treated nonmelanoma skin cancer or in situ carcinoma of the cervix uteri.
  13. Known diagnosis of human immunodeficiency virus (HIV) infection (testing is not mandatory).
  14. Symptomatic brain metastases.
  15. Ongoing anticoagulant therapy (eg, aspirin, coumadin, heparin).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02202759
Other Study ID Numbers  ICMJE C26002
U1111-1155-9023 ( Other Identifier: WHO )
2014-000804-88 ( EudraCT Number )
REec-2014-1176 ( Registry Identifier: REec )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Takeda ( Millennium Pharmaceuticals, Inc. )
Study Sponsor  ICMJE Millennium Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.
PRS Account Takeda
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP