| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced MET-Positive Gastric, Lower Esophageal or Gastroesophageal Junction Adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
Lower Esophageal and Gastroesophageal Junction Adenocarcinoma
Gastric Cancer
|
|
| 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 | LLT |
| E.1.2 | Classification code | 10066354 |
| E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10017761 |
| E.1.2 | Term | Gastric cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10017766 |
| E.1.2 | Term | Gastric cancer stage IV NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10017765 |
| E.1.2 | Term | Gastric cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| To determine if the treatment of rilotumumab in combination with ECX significantly improves overall survival (OS) as compared with rilotumumab-placebo in combination with ECX in subjects with unresectable locally advanced or metastatic MET-positive gastric or GEJ adenocarcinoma. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary
To evaluate progression-free survival (PFS), survival rate at 12 months, time to progression (TTP), objective response rate (ORR), disease control rate (DCR), duration of response, time to response (TTR), safety and immunogenicity, rilotumumab and ECX
pharmacokinetic (PK) parameters. To evaluate the impact of MET expression levels on efficacy. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic substudy
If subjects sign the additional optional pharmacokinetic informed
consent, subjects at selected sites will participate in rilotumumab and ECX intensive PK (IPK) sampling until approximately 12 evaluable subjects per arm have been identified. A detailed example of dosing and PK sampling schedule for those subjects can be found in Appendix A of the protocol.
Pharmacogenetic substudy
If the subject consents to the optional pharmacogenetic portion of this study, DNA analyses may be performed. These optional pharmacogenetic analyses focus on inherited genetic variations to evaluate their possible correlation to the disease and/or responsiveness to the therapies used in this study. No additional blood or tumor samples will be collected for this part of the study, however DNA will be extracted from the blood and/or tumor samples collected for the biomarker development studies. |
|
| E.3 | Principal inclusion criteria |
Inclusion Criteria
Disease Related
• Pathologically confirmed unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma; adenocarcinomas of the distal esophagus within 5 cm of the GEJ are eligible
• ECOG performance status (0 or 1)
• Tumor MET-positive by IHC (≥ 25% tumor membrane staining as defined by an investigational use only MET IHC assay) by protocol-specified centralized testing
• Formalin fixed paraffin-embedded (FFPE) tumor tissue submission required
• Evaluable (measurable or non-measurable) disease by RECIST 1.1 criteria
Demographic
• Men or women ≥ 18 years of age
Ethical
• Before any study-specific procedure, the appropriate written informed consent must be obtained (Section 11.1)
Laboratory
• Adequate organ function as evidenced by the following laboratory studies within 28 days prior to randomization:
- Hemoglobin ≥ 9 g/dL
- Absolute neutrophil count ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Creatinine clearance ≥ 60mL/minute (calculated or measured)
- Aspartate aminotransferase (AST) and alanine amino transferase (ALT) ≤ 2.5 x ULN or AST and ALT ≤ 5.0 x ULN if liver metastases are present
- Total bilirubin ≤ 1.5x ULN
General
• Able to tolerate infusions and take oral medications
|
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria
Disease Related
• HER2-overexpressing locally advanced or metastatic gastric or GEJ adenocarcinoma. Subjects whose tumor HER2 expression status is not known must submit tumor samples for HER2 testing
• Previous systemic therapy (including chemotherapy, biologic, immunotherapy, or investigational therapy) for locally advanced or metastatic gastric or GEJ or lower esophageal (within 5 cm of GEJ) adenocarcinoma Less than 6 months have elapsed from completion of prior neoadjuvant or adjuvant chemotherapy or chemoradiotherapy to randomization
• Previous treatment with anthracyclines exceeds total cumulative dose of epirubicin of 400 mg/m2 (or equivalent thereof, if a different anthracycline has been administered in the past)
• Subjects with ongoing toxicities from palliative radiotherapy, or who have undergone radiotherapy to the only site of known disease, or received palliative radiation ≤ 14 days prior to randomization. Subjects who received palliative
radiotherapy are otherwise eligible.
• Squamous cell histology
• Subjects with resectable disease or suitable for definitive chemoradiation
• Plans for surgical resection or definitive chemoradiation based on response to protocol therapy
• Subjects who have persistent gastric outlet obstruction, complete dysphagia or are dependent upon jejunostomy for feeding
• Known central nervous system metastases
• Clinically significant upper gastro-intestinal bleeding < 30 days prior to randomization
Other Medical Conditions
• Left ventricular ejection fraction (LVEF) < 50% as determined by either multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)
• Documented myocardial infarction or unstable/uncontrolled cardiac disease (eg, unstable angina, severe arrhythmias, congestive heart failure [New York Heart Association (NYHA) > Class II]) within 6 months before randomization (Appendix E)
• Presence of peripheral edema > grade 1
• Arterial thrombosis or vascular ischemic events, such as transient ischemic attack, cerebral infarction, within six months prior to randomization
• Subjects with venous thromboembolic events (including deep vein thrombosis or pulmonary emboli) within 6 months prior to randomization
• Serious or non-healing wound
• Known positive HepBsAg (indicative of acute or chronic Hepatitis B) or detectable Hepatitis C virus (indicative of active Hepatitis C), known positive test for HIV
• Known peripheral neuropathy > grade 1
• Known dihydropyrimidine dehydrogenase deficiency (DPD)
• History of any medical condition including cardiovascular disease or chronic obstructive pulmonary disease (COPD), that in the opinion of the investigator, may increase the risks associated with study participation or study treatments or may interfere with the conduct of the study or interpretation of study resultsMajor surgical procedure ≤ 30 days before randomization or not yet recovered from prior major surgery. Major surgery is defined within this protocol as any surgical procedure that involves general anesthesia and a significant incision (ie, larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy)
• Minor surgery (eg, catheter or gastrostomy tube placement) ≤14 days before randomization or not yet recovered from prior minor surgery. Placement of central venous access device, fine needle aspiration, thoracentesis, endoscopic biliary stent or paracentesis ≥ 1 day before randomization is acceptable
Medications or Other Treatments
• Prior treatment with inhibitors of the MET pathway
• Recent infection requiring a course of systemic anti-infectives that was administered within 7 days before randomization (with the exception of uncomplicated urinary tract infection)
• Treatment with therapeutic anti-coagulation within 6 months of randomization. Prophylaxis against central venous catheter thrombosis is allowed with prophylactic doses of low molecular weight heparin (per local prescribing information guidelines)
• Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s) at time of randomization, or subject is receiving other investigational agent(s)
General
• Subject is pregnant or breast feeding, or might become pregnant within 6 months after the last dose of protocol-required therapy
• Woman of childbearing potential and is not willing to use 2 highly effective methods of contraception while receiving protocol-required therapy and for an additional 6 months after the last dose of protocol-required therapy.
• Male who has a female partner of childbearing potential, and is not willing to use a highly effective birth control method while receiving protocol-required therapy and for at least an additional 6 months after the last dose of protocol required therapy.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints:
The primary endpoint is overall survival (OS).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Assuming an approximate average enrollment rate of 6 subjects per month in the first month and 28 subjects per month therefore with an accrual period of approximately 28 months and a dropout rate of 5% per year, the event goal in the FAS is expected to be achieved approximately 30 months after the first subject is enrolled if the study enrolls 600 subjects. The primary analysis in the subgroup is planned when approximately 280 OS events have been observed in that set. This is expected to be acheived approximately 40 months after the first subject is randomized. |
|
| E.5.2 | Secondary end point(s) |
•PFS, defined as the time from the date of randomization to either disease progression (as per RECIST 1.1) or death
• Survival rate at 12 months, defined as the K-M estimate of the proportion of subjects alive at the corresponding time point
• TTP, defined as time from the date of randomization to disease progression (per RECIST 1.1)
• ORR, defined as the incidence rate of either CR or PR per RECIST 1.1 criteria.
• DCR, defined as the incidence rate of either a CR, PR or SD per RECIST 1.1. The stable disease classification requires subjects to have a response of stable disease ≥ 11 weeks after the date of the first dose of rilotumumab
• Duration of response, defined as time from the date of first response (PR or CR) to disease progression (per RECIST 1.1) or death
• TTR, defined as time from the date of randomization to either a CR or PR per RECIST 1.1 criteria
• OS within tertiles of MET expression levels
• Incidence of subject adverse events, laboratory abnormalities and immunogenicity
• Rilotumumab dose exposure, dose intensity and PK parameters
• ECX dose exposure, dose intensity and PK parameters in a subset of subjects |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All of the secondary endpoints will be analysed at the same time as the primary endpoint. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Health-related quality of life |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 120 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Mexico |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
Primary Completion: the time when the last subject is assessed or receives an intervention for the purposes of final data collection for the primary analysis.
End of Trial: the time when the last subject is assessed or receives an intervention for evaluation in the study. This will be the later of the final analysis or when the last subject discontinues all protocol therapy and has had the opportunity to complete the safety follow-up visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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