Clinical Trials List
Protocol NumberMM-111-13-02-04
NCT Number(ClinicalTrials.gov Identfier)NCT01774851
2013-07-01 - 2015-01-31
Phase II
Terminated3
Study ended1
ICD-10C15.9
Malignant neoplasm of esophagus, unspecified
ICD-10C15.5
Malignant neoplasm of lower third of esophagus
ICD-10C16.9
Malignant neoplasm of stomach, unspecified
Randomized, Open Label, Phase 2 Study of MM-111 and Paclitaxel with or without Trastuzumab in Patients with ‘Traditional’ and ‘Non-Traditional’ HER2 Expressing Carcinomas of the Distal Esophagus, Gastroesophageal (GE) Junction and Stomach Who Have Failed Front Line Metastatic or Locally Advanced Therapy
-
Trial Applicant
Syneos Health
-
Sponsor
Merrimack Pharmaceuticals
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- 馬政仁 Division of Gastroenterological Surgery
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Rheun-Chuan Lee Division of Radiology
- Ming-Huang Chen Division of Hematology & Oncology
- Chung-Pin Li Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Chen-Yuan Lin Division of Hematology & Oncology
- Chang-Fang Chiu Division of Hematology & Oncology
- 林柏翰 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
2 Study ended
Co-Principal Investigator
- Hui-Jen Tsai Division of Hematology & Oncology
- Yan-Shen Shan Division of Hematology & Oncology
- Nai-Jung Chiang Division of Hematology & Oncology
- Chia-Jui Yen Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Carcinomas of the Distal Esophagus, Gastroesophageal (GE) Junction and Stomach
Objectives
Traditional HER2 Group 1:
Patients who are HER2 3+ by IHC
OR
Patients who are HER2 2+ by IHC and HER2 gene amplified by FISH or CISH.
This patient population is typically eligible to receive trastuzumab in the front-line
setting. Trastuzumab and paclitaxel will be administered to all patients (both
trastuzumab exposed and naïve) in the second-line setting and they will be
randomized between the following treatment arms:
o Paclitaxel plus trastuzumab plus MM-111 (experimental)
o Paclitaxel plus trastuzumab (comparator)
Non-Traditional HER2 Group 2:
Patients who are HER2 2+ by IHC and HER2 gene non-amplified by FISH or
CISH. This patient population is typically not treated with trastuzumab. These
patients will be randomized between the following treatment arms:
o Paclitaxel plus MM-111 (experimental)
o Paclitaxel (comparator)
Secondary: The secondary objectives of the study are:
To compare the following measures between the two treatment arms within each group:
Overall Survival (OS)
Time to treatment failure (TTF)
Objective response rate
Duration of Response (DOR)
Safety Profiles
Health-Related Quality of Life (HRQOL) scores
To evaluate the following in treatment arm regimens that include MM-111:
Pharmacokinetic (PK) profile and pharmacodynamic activity of MM-111 in distal
esophageal, GE junction, and gastric carcinoma
Immunogenicity of MM-111 when administered in combination with paclitaxel
with/without trastuzumab
Exploratory: The exploratory objectives are:
To correlate expression of a pre-specified biomarker panel reflective of human
epidermal growth factor receptor 2 (HER2), human epidermal growth factor
receptor 3 (HER3) and heregulin related signaling activity
(1) between archived tumor tissue and pre-treatment tumor biopsies and
(2) with clinical outcome (correlation between PFS and other clinical efficacy
criteria with expression of the biomarker panel) within each treatment arm.
Additional biomarkers may also be explored in tissue, plasma and serum.
Test Drug
MM-111
Active Ingredient
MM-111
Dosage Form
vial
Dosage
250
Endpoints
The primary PFS efficacy comparison in the Traditional HER2 Group is between
experimental arm (paclitaxel+ trastuzumab + MM-111) and comparator arm (paclitaxel + trastuzumab). The primary PFS efficacy comparison in the Non-Traditional HER2 Group is between experimental arm (paclitaxel + MM-111) and comparator arm (paclitaxel).
The secondary efficacy objectives are to assess the antitumor activity of each treatment arm as evidenced by overall survival (OS), the time to treatment failure (TTF), Objective Response Rate, Duration of Response (DOR) and safety profiles and health-related quality of life scores.
These data will be analysed using RECIST v1.1.
Safety: Safety analyses will be performed using all the patients who receive at least one infusion of any of the study drugs. TEAEs will be presented by treatment arm, by patient, using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade and by Medical Dictionary for Regulatory Activity (MedDRA) system organ class (SOC) and preferred term. Separate listings will be presented for total TEAEs, serious adverse events (SAEs), TEAEs related to MM-111, and Grade 3/4 TEAEs. Generated patient listings of clinically significant safety data will be reviewed on a regular basis by the Sponsor to help identify any evolving safety concerns. Subsequently, any safety concerns will be escalated to the Data Safety Monitory Board (DSMB) for each quarterly meeting.
Laboratory data will be presented by treatment arm and by study visit. Abnormal laboratory values will be assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, where possible. When appropriate, investigators are expected to identify laboratory data as ‘clinically significant’ to aid in Sponsor review and safety reporting. Evaluation of QTc will be based upon Fridericia’s correction (QTcF) method and CTCAE criteria will be applied to the QTcF values.
Pharmacokinetics: The PK parameters will include minimum and maximum serum
concentration (Cmax and Cmin) and time to Cmax (Tmax) The method used for analysis is Electrochemiluminescent Assay (ECL) Method. Briefly, MM-111 in serum samples is captured by HER2 adsorbed onto a 96-well microtiter plate. The captured MM-111 is detected by addition of HER3 conjugated to a Sulfo-Tag signal molecule. Signal from the HER2-MM-111-HER3-Sulfo-Tag complex is then generated by an electrochemiluminescent reaction and measured on a Meso Scale Discovery (MSD) Sector Imager 2400 instrument.
The amount of signal (light) produced is proportional to the concentration of MM-111 in the sampleBiomarker Assessment: Archived tumor tissue biopsies are mandatory for all patients participating in this study. Pre-treatment biopsies are mandatory for the first 30 patients in each treatment group (i.e. for the first sixty patients) and optional thereafter. On-treatment biopsies and biopsies at the time of progression are optional. Tumor tissue samples will be obtained from patients to determine expression of a pre-specified biomarker panel reflective of HER2 and HER3 signaling activity. Correlative biomarker analyses will be performed on all
tumor tissue measurements.
experimental arm (paclitaxel+ trastuzumab + MM-111) and comparator arm (paclitaxel + trastuzumab). The primary PFS efficacy comparison in the Non-Traditional HER2 Group is between experimental arm (paclitaxel + MM-111) and comparator arm (paclitaxel).
The secondary efficacy objectives are to assess the antitumor activity of each treatment arm as evidenced by overall survival (OS), the time to treatment failure (TTF), Objective Response Rate, Duration of Response (DOR) and safety profiles and health-related quality of life scores.
These data will be analysed using RECIST v1.1.
Safety: Safety analyses will be performed using all the patients who receive at least one infusion of any of the study drugs. TEAEs will be presented by treatment arm, by patient, using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade and by Medical Dictionary for Regulatory Activity (MedDRA) system organ class (SOC) and preferred term. Separate listings will be presented for total TEAEs, serious adverse events (SAEs), TEAEs related to MM-111, and Grade 3/4 TEAEs. Generated patient listings of clinically significant safety data will be reviewed on a regular basis by the Sponsor to help identify any evolving safety concerns. Subsequently, any safety concerns will be escalated to the Data Safety Monitory Board (DSMB) for each quarterly meeting.
Laboratory data will be presented by treatment arm and by study visit. Abnormal laboratory values will be assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, where possible. When appropriate, investigators are expected to identify laboratory data as ‘clinically significant’ to aid in Sponsor review and safety reporting. Evaluation of QTc will be based upon Fridericia’s correction (QTcF) method and CTCAE criteria will be applied to the QTcF values.
Pharmacokinetics: The PK parameters will include minimum and maximum serum
concentration (Cmax and Cmin) and time to Cmax (Tmax) The method used for analysis is Electrochemiluminescent Assay (ECL) Method. Briefly, MM-111 in serum samples is captured by HER2 adsorbed onto a 96-well microtiter plate. The captured MM-111 is detected by addition of HER3 conjugated to a Sulfo-Tag signal molecule. Signal from the HER2-MM-111-HER3-Sulfo-Tag complex is then generated by an electrochemiluminescent reaction and measured on a Meso Scale Discovery (MSD) Sector Imager 2400 instrument.
The amount of signal (light) produced is proportional to the concentration of MM-111 in the sampleBiomarker Assessment: Archived tumor tissue biopsies are mandatory for all patients participating in this study. Pre-treatment biopsies are mandatory for the first 30 patients in each treatment group (i.e. for the first sixty patients) and optional thereafter. On-treatment biopsies and biopsies at the time of progression are optional. Tumor tissue samples will be obtained from patients to determine expression of a pre-specified biomarker panel reflective of HER2 and HER3 signaling activity. Correlative biomarker analyses will be performed on all
tumor tissue measurements.
Inclution Criteria
Patients will be qualified for study participation based on the following inclusion criteria:
Patients must have documentation of histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the distal esophagus, GE junction or stomach
Patients must have documentation of histologically or cytologically confirmed HER2 expression as follows:
o Traditional HER2 Group 1: Patients who are HER2 3+ by IHC OR
HER 2 2+ by IHC and HER2 gene amplified by FISH or CISH
o Non-Traditional HER2 Group 2: Patients who are HER2 2+ by IHC and HER2 gene nonamplified by FISH or CISH
For Traditional HER2 Group 1
o Patients must have received one prior systemic therapy for metastatic disease, which must be a standard fluoropyrimidine/platinum-based frontline therapy given with or without trastuzumab
Non-Traditional HER2 Group 2
o Patients must have received one prior systemic therapy for metastatic disease which must be a standard fluoropyrimidine/platinum-based frontline therapy given without trastuzumab
Patients must be ≥18 years of age
Patients or their legal representatives must be able to understand and sign an informedconsent
Patients should have evaluable or measurable disease ≥1 cm per RECIST 1.1
Patients must have ECOG PS of 0, 1, or 2
Patients must have adequate hematologic status as evidenced by:
o Absolute neutrophil count (ANC) ≥1500 cells/mm3
o Platelet count ≥100,000 platelets/mm3
o Hemoglobin ≥9 g/dL
Patients must have adequate hepatic function as evidenced by:
o Serum total bilirubin ≤1.5 × the upper limit of normal (ULN)
o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase ≤2.5 x ULN (5 × ULN is acceptable if liver metastases are present)
Patients must have adequate renal function as evidenced by:
o Serum creatinine ≤1.5 × ULN or calculated clearance 60 mL/min/1.73 m2 for
patients with creatinine levels above institutional normal
Patients must be recovered from the effects of any prior surgery, radiotherapy or other antineoplastic therapy. NCI CTCAE v.4.0 up to grade 1 is acceptable for patients with preexisting peripheral neuropathy
Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 60 days following the last dose of assigned study drug(s)
Patients must have an archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue sample
Patients must be willing and able to undergo a pre-treatment biopsy (this applies to the first 30 patients in each treatment group i.e. 30 for Traditional HER2 and 30 for Non-Traditional HER2)
Patients must have documentation of histologically or cytologically confirmed metastatic or locally advanced adenocarcinoma of the distal esophagus, GE junction or stomach
Patients must have documentation of histologically or cytologically confirmed HER2 expression as follows:
o Traditional HER2 Group 1: Patients who are HER2 3+ by IHC OR
HER 2 2+ by IHC and HER2 gene amplified by FISH or CISH
o Non-Traditional HER2 Group 2: Patients who are HER2 2+ by IHC and HER2 gene nonamplified by FISH or CISH
For Traditional HER2 Group 1
o Patients must have received one prior systemic therapy for metastatic disease, which must be a standard fluoropyrimidine/platinum-based frontline therapy given with or without trastuzumab
Non-Traditional HER2 Group 2
o Patients must have received one prior systemic therapy for metastatic disease which must be a standard fluoropyrimidine/platinum-based frontline therapy given without trastuzumab
Patients must be ≥18 years of age
Patients or their legal representatives must be able to understand and sign an informedconsent
Patients should have evaluable or measurable disease ≥1 cm per RECIST 1.1
Patients must have ECOG PS of 0, 1, or 2
Patients must have adequate hematologic status as evidenced by:
o Absolute neutrophil count (ANC) ≥1500 cells/mm3
o Platelet count ≥100,000 platelets/mm3
o Hemoglobin ≥9 g/dL
Patients must have adequate hepatic function as evidenced by:
o Serum total bilirubin ≤1.5 × the upper limit of normal (ULN)
o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase ≤2.5 x ULN (5 × ULN is acceptable if liver metastases are present)
Patients must have adequate renal function as evidenced by:
o Serum creatinine ≤1.5 × ULN or calculated clearance 60 mL/min/1.73 m2 for
patients with creatinine levels above institutional normal
Patients must be recovered from the effects of any prior surgery, radiotherapy or other antineoplastic therapy. NCI CTCAE v.4.0 up to grade 1 is acceptable for patients with preexisting peripheral neuropathy
Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 60 days following the last dose of assigned study drug(s)
Patients must have an archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue sample
Patients must be willing and able to undergo a pre-treatment biopsy (this applies to the first 30 patients in each treatment group i.e. 30 for Traditional HER2 and 30 for Non-Traditional HER2)
Exclusion Criteria
Patients will be disqualified from study participation based on the following exclusion criteria:
Patients for whom potentially curative antineoplastic therapy is available
Patients who previously received paclitaxel or other taxane treatment in the frontline or locally advanced setting
Patients who are pregnant or lactating
Patients with an active infection or with an unexplained fever >38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, patients with tumor fever may be enrolled)
Patients with known brain metastasis
Patients with known hypersensitivity to any of the components of MM-111 or who have had hypersensitivity reactions to fully human monoclonal antibodies
Patients with a known history of hypersensitivity to paclitaxel or other drugs formulated in Cremophor® EL, unless a patient has been de-sensitized in accordance with institutional guidelines
Patients with a known history of hypersensitivity to trastuzumab or any of its components (for group 1 only)
Patients who have received other recent anti-tumor therapy. This includes the following:
o Investigational therapy administered within the 28 days prior to the first scheduled day of dosing MM-111
Dosing within <28 days since receiving investigational therapy is acceptable once
a time interval equal to at least five half-lives of the investigational agent has
passed
Patients in the Traditional HER2 group already receiving trastuzumab do not
require a wash-out period from trastuzumab (for group 1 only)
o Any standard chemotherapy or radiation or other therapy within 14 days prior to the
first scheduled dose of MM-111
o Patients who have not recovered from clinically significant effects of any prior
surgery, radiotherapy or any other antineoplastic therapies. Patients with a known peripheral neuropathy must present with a grade 1 severity or less according to NCI
CTCAE 4.0
Patients with active or prior history of New York Heart Association (NYHA) congestive
heart failure or left ventricular ejection fraction (LVEF) <50%
History of myocardial infarction within 12 months of enrollment
Uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg)
Known angina pectoris requiring medication
Known clinically significant heart valve disease
Known history of high-risk arrhythmias requiring medical attention (chronic stable well controlled atrial fibrillation is permissible)
Active gastrointestinal bleeding
Patients who have received prior maximum cumulative anthracycline doses:
o Doxorubicin or liposomal doxorubicin doses >360 mg/m2
o Mitoxantrone >120 mg/m2 and idarubicin >90 mg/m2
o Epirubicin doses higher than 720 mg/m2
o Other (e.g., liposomal doxorubicin or other anthracycline equivalent of 360 mg/m2 of doxorubicin)
o If more than 1 anthracycline has been used, the cumulative dose must not exceed the equivalent of 360mg/m2 of doxorubicin
Patients with known human immunodeficiency virus (HIV). Patients with Hepatitis B surface antigen (carriers) may be enrolled but must receive nucleoside/nucleotide analogue or other suitable treatment for Hepatitis B per institutional guidelines
Patients with any other medical or psychological condition, deemed by the investigator to likely interfere with a patient’s ability to sign informed consent or cooperate and participate in the study, or interfere with the interpretation of the study results
Patients for whom potentially curative antineoplastic therapy is available
Patients who previously received paclitaxel or other taxane treatment in the frontline or locally advanced setting
Patients who are pregnant or lactating
Patients with an active infection or with an unexplained fever >38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, patients with tumor fever may be enrolled)
Patients with known brain metastasis
Patients with known hypersensitivity to any of the components of MM-111 or who have had hypersensitivity reactions to fully human monoclonal antibodies
Patients with a known history of hypersensitivity to paclitaxel or other drugs formulated in Cremophor® EL, unless a patient has been de-sensitized in accordance with institutional guidelines
Patients with a known history of hypersensitivity to trastuzumab or any of its components (for group 1 only)
Patients who have received other recent anti-tumor therapy. This includes the following:
o Investigational therapy administered within the 28 days prior to the first scheduled day of dosing MM-111
Dosing within <28 days since receiving investigational therapy is acceptable once
a time interval equal to at least five half-lives of the investigational agent has
passed
Patients in the Traditional HER2 group already receiving trastuzumab do not
require a wash-out period from trastuzumab (for group 1 only)
o Any standard chemotherapy or radiation or other therapy within 14 days prior to the
first scheduled dose of MM-111
o Patients who have not recovered from clinically significant effects of any prior
surgery, radiotherapy or any other antineoplastic therapies. Patients with a known peripheral neuropathy must present with a grade 1 severity or less according to NCI
CTCAE 4.0
Patients with active or prior history of New York Heart Association (NYHA) congestive
heart failure or left ventricular ejection fraction (LVEF) <50%
History of myocardial infarction within 12 months of enrollment
Uncontrolled hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg)
Known angina pectoris requiring medication
Known clinically significant heart valve disease
Known history of high-risk arrhythmias requiring medical attention (chronic stable well controlled atrial fibrillation is permissible)
Active gastrointestinal bleeding
Patients who have received prior maximum cumulative anthracycline doses:
o Doxorubicin or liposomal doxorubicin doses >360 mg/m2
o Mitoxantrone >120 mg/m2 and idarubicin >90 mg/m2
o Epirubicin doses higher than 720 mg/m2
o Other (e.g., liposomal doxorubicin or other anthracycline equivalent of 360 mg/m2 of doxorubicin)
o If more than 1 anthracycline has been used, the cumulative dose must not exceed the equivalent of 360mg/m2 of doxorubicin
Patients with known human immunodeficiency virus (HIV). Patients with Hepatitis B surface antigen (carriers) may be enrolled but must receive nucleoside/nucleotide analogue or other suitable treatment for Hepatitis B per institutional guidelines
Patients with any other medical or psychological condition, deemed by the investigator to likely interfere with a patient’s ability to sign informed consent or cooperate and participate in the study, or interfere with the interpretation of the study results
The Estimated Number of Participants
-
Taiwan
40 participants
-
Global
180 participants
