E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2 distal esophageal, Gastroesophageal (GE) junction or gastric carcinoma. |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the esophagus, gastroesophageal (GE) junction or stomach. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017758 |
E.1.2 | Term | Gastric cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10015362 |
E.1.2 | Term | Esophageal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10056267 |
E.1.2 | Term | Gastroesophageal cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of the study are to compare Progression Free Survival (PFS) between the experimental and comparator arm in the following defined patient populations:
•Overall Study Population
•Heregulinhigh (HRGhigh) Population, comprised of patients with HRG levels at or above the median in archived tumor tissue samples assessed centrally by RT-PCR
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
To compare PFS, Objective Response Rate (ORR), and Overall Survival
(OS) between the experimental and comparator arm in the following:
•HRGISH+ population comprised of patients with detectable HRG
levels in pre-treatment biopsies using ISH
•HRGRT-PCR+ population comprised of patients with HRG levels at or above the median in pre-treatment biopsies using RT-PCR
To compare the following measures between the two treatment arms in the overall population as well as in HRGhigh population:
•OS
•Time to treatment failure (TTF)
•ORR
•Duration of Response (DOR)
•Safety Profiles
•Health-Related Quality of Life (HRQOL) scores
To evaluate the following in the experimental arm:
•Pharmacokinetic (PK) profile of MM-111 in distal esophageal, GE
junction, and gastric carcinoma
•Immunogenicity of MM-111 when administered in combination with paclitaxel and trastuzumab
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria: To be eligible for this study, patients must meet all of the following 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 determined at any point during the course of disease as follows:
oHER2 3+ by IHC OR
oHER2 2+ by IHC and HER2 gene amplified by FISH or CISH
•Patients must have progressed in one of the following settings: oWithin 6 months of a 5FU/platinum-based neoadjuvant or adjuvant therapy OR
oFollowing prior systemic therapy for metastatic or locally advanced disease which must include a standard front-line therapy combination of at least fluoropyrimidine/platinum given with or without trastuzumab
•Patients must not have received any additional systemic therapy following progression after front-line therapy in the metastatic or locally advanced setting
•Patients must be ≥ 18 years of age
oFor patients enrolled in Taiwan, age must be ≥ 20
•Patients or their legal representatives must be able to understand and sign an informed consent
•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: oAbsolute neutrophil count (ANC) ≥1.5 x 109/L (unsupported by growth factors)
oPlatelet count ≥100 x 109/L
oHemoglobin ≥9 g/dL
•Patients must have adequate hepatic function as evidenced by: oSerum total bilirubin ≤1.5 × the upper limit of normal (ULN) oAspartate 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: oSerum creatinine ≤1.5 × ULN or calculated clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
•Patients must have recovered from the effects of any prior surgery, radiotherapy or other antineoplastic therapy to NCI CTCAE v.4.0 grade 1, baseline or less, except for alopecia
•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 6 months following the last dose of assigned study drug(s), in accordance with the
label recommendations for trastuzumab
•Patients must have an unstained, archived formalin-fixed, paraffin- embedded (FFPE) tumor tissue sample available for submission to the Sponsor (or representative)
•Patients must be willing and able to undergo a pre-treatment biopsy and have an identified lesion amenable to biopsy
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E.4 | Principal exclusion criteria |
Patients cannot meet any of the follwing criteria to be eligible for the study:
•Patients who previously received paclitaxel or other taxane treatment within (≤) the last 6 months
•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, Chinese hamster ovary cell proteins, or any other components oPatients who previously had a mild infusion reaction to trastuzumab and were later re-treated with no additional infusion reactions are allowed on study.
•Patients who have received other recent anti-tumor therapy. This includes the following:
o Investigational therapy administered within (≤) 28 days prior to the first scheduled day of dosing MM-111
o 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
o Any standard chemotherapy or radiation or other therapy within (≤)
14 days prior to the first scheduled dose of MM-111
o Patients already receiving trastuzumab do not require a wash-out period from trastuzumab, nor a trastuzumab loading dose if trastuzumab has been received within the last 4 weeks
o Patients receiving or have received palliative radiation are allowed on study
•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
o Patients with stable angina with no symptoms for > 2 years are allowed on study
•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, if deemed clinically significant by the
Investigator
•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 oDEpirubicin doses higher than 720 mg/m2
o Other (e.g., liposomal doxorubicin or other anthracycline equivalent of 360 mg/m2 of doxorubicin)
oIf 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 as likely to interfere with a patient's ability to sign informed consent or cooperate and participate in the study, or to interfere with the interpretation of the study results
•Patients with any medical history and/or systemic diseases which in the investigator's opinion may impede the study treatment
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression Free Survival (PFS) is the primary efficacy endpoint. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS is defined as the number of months from the date of randomization to the date of death or progression, whichever occurred earlier. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints that will be used to evaluate target and non-target lesion antitumor response of each treatment regimen using RECIST v1.1 criteria include:
- Overall Survival (OS)
- Time to treatment failure (TTF)
- Objective response rate
- Duration of Response (DOR)
- Safety profiles will also be analyzed
- Health-Related Quality of Life (HRQOL) scores
The following will be assessed in treatment arm regimens that include MM-111:
- Pharmacokinetic (PK) concentrations of MM-111 in distal esophageal, GE junction, and gastric carcinoma Immunogenicity of MM-111 when administered in combination with paclitaxel
with trastuzumab. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Death (i.e. overall survival)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Denmark |
France |
Korea, Republic of |
South Africa |
Spain |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Date when all subjects are deceased. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |