E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Gastric, Gastroesophageal Junction, or Distal Esophageal Adenocarcinoma |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063916 |
E.1.2 | Term | Metastatic gastric cancer |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066354 |
E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
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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 |
To estimate the treatment effect as measured by progression free survival (PFS) of subjects receiving AMG 386 (at 2 doses) in combination with CX relative to CX/placebo |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of the combination regimen of AMG 386 with CX - To estimate other measures of treatment effect (objective response rate, duration of response, overall survival, time to progression and time to response) - To evaluate the pharmacokinetics of AMG 386 when used in combination with CX - To estimate the immunogenicity as assessed by the incidence of anti-AMG 386 antibody formation - To estimate the impact of AMG 386 on cancer-related symptoms based on patient reported outcomes using the QLQ-STO22 |
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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 |
A pharmacokinetics substudy for cisplatin and capecitabine is described in the protocol. No subjects from the EU will be enrolled in this substudy. |
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E.3 | Principal inclusion criteria |
Disease Related • Histologically or cytologically confirmed adenocarcinoma of the stomach, gastroesophageal junction or distal esophagus with metastatic disease. All scans and x-rays used to document measurable or non-measurable disease must be done within 28 days prior to randomization • Measurable or non-measurable disease per modified RECIST (Response Evaluation Criteria in Solid Tumor) Guidelines
Demographic • 18 years of age or older at the time the written informed consent is obtained • Subjects of child-bearing potential and sexually active must use an accepted and effective non-hormonal method of contraception (ie, double barrier method [eg, condom plus diaphragm]) from signing the informed consent through 6 months following last administration of study drug
General • Able to tolerate intravenous infusions • Able to swallow oral medication • ECOG performance status of 0 or 1 (within 14 days prior to randomization) • Subject plans to begin protocol directed therapy within 7 days of randomization
Laboratory Adequate organ and hematological function as evidenced by the following laboratory studies within 14 days prior to randomization: • Hematological function, as follows: o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L o Platelet count ≥ 75 x 109/L and ≤ 850 x 109/L o Hemoglobin ≥ 9 g/dL o PTT and INR ≤ ULN • Renal function, as follows: o Creatinine clearance ≥ 60 mL/min - Investigators may calculate creatinine clearance by either Cockcroft-Gault formula or 24 hour urine creatinine clearance. Creatinine clearance (mL/min) = (140–age) x actual body weight (kg) (x 0.85 for females) 72 x serum creatinine (mg/dL) • Hepatic function, as follows: o Total bilirubin ≤ 1.5 x ULN o SGOT (AST) and SGPT (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present) |
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E.4 | Principal exclusion criteria |
Disease Related • Prior chemotherapy for metastatic disease (1st line) • Less than 12 months have elapsed from completion of previous adjuvant or neoadjuvant chemotherapy or chemoradiotherapy • Subjects with persistant gastric outlet obstruction, complete dysphagia or feeding jejunostomy • Current or prior history of central nervous system metastases • History of bleeding diathesis or clinically significant bleeding within 14 days prior to randomization • Major surgical procedure within 28 days prior to randomization • Minor surgical procedure, placement of access device, or fine needle aspiration within 7 days prior to first dose • Prior malignancy (other than in situ cervical cancer, or basal cell cancer of the skin) unless treated with curative intent and without evidence of disease for ≥ 3 years prior to randomization • Clinically significant cardiovascular diseases within 12 months prior to randomization, 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 • Presence of clinically significant non-healing wound, ulcer or fracture as judged by the investigator • Ongoing or clinically significant active infection as judged by the investigator • Known hypersensitivity to bacterial proteins, or any of the drugs required in this study • Known peripheral neuropathy ≥ Grade 1 • Known dihydropyrimidine dehydrogenase deficiency • Known hypersensitivity to 5-FU/capecitabine • Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B surface antigen • Known active or chronic hepatitis
Medications • Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1 or TIE-2 including, but not limited to, AMG 386, XL880, XL820 • Treatment with immune modulators such as cyclosporine or tacrolimus within 30 days prior to randomization • Treatment with sorivudine or its chemically related analogues such as brivudine • Anticoagulants (other than aspirin) including *coumarin-type anticoagulants (other than low dose prophylaxis for central venous catheters ≤ 1mg/day) or heparin (except for low molecular weight heparin for prophylaxis against central venous catheter thrombosis) within 7 days prior to randomization
* Coumarin-type anticoagulants may be used in subjects receiving capecitabine with an increased frequency of INR and PTT monitoring.
General • Any condition which in the investigator’s opinion makes the subject unsuitable for study participation • Not yet completed at least 30 days since ending other investigational device/drug trial(s), or subject is receiving other investigational treatments • Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding • Previously enrolled into this study • Inability to comply with protocol and/or not available for follow-up assessments |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary: PFS: defined as time from date of randomization to date of disease progression (per the modified RECIST criteria) or death. Subjects not meeting the criteria for progression by the analysis data cutoff date will be censored at their last evaluable disease assessment date.
Secondary: • Incidence of Adverse Events (AEs) and significant laboratory changes from baseline • Objective Response Rate (ORR): the incidence of either confirmed Complete Response (CR) or confirmed Partial Response (PR) per the modified RECIST criteria. A confirmed CR requires two assessments of CR at least 28 days apart. Two assessments at least 28 days apart of either CR or PR are required for a determination of PR. Subjects who do not meet the criteria for confirmed response by the database cutoff date are considered to be non-responders • Duration of Response (DOR): (only calculated for those subjects who respond) time from first confirmed objective response to disease progression (per the modified RECIST criteria). Subjects who do not meet the criteria for progression or who die by the database cutoff date for analysis are censored at their last evaluable disease assessment date • Overall Survival (OS): time from date of randomization to date of death. Subjects still alive at the database cutoff date for analysis are censored at their last contact date • Time to Progression (TTP): time from date of randomization to date of disease progression per the modified RECIST criteria. Subjects who do not meet the criteria for progression by the database cutoff date for analysis will be censored at their last evaluable disease assessment date • Time to response: time from randomization date to date of first response for confirmed responders. Subjects with a best response of SD by the database cutoff date for analysis are censored at their last evaluable disease assessment date. Non-responders with a best response of PD will be censored at the maximum time to a first confirmed response among all responders • Pharmacokinetics parameters of AMG 386 when used in combination with CX • Incidence of anti-AMG 386 antibody formation • Change in cancer-related symptoms as assessed with the QLQ-STO22 |
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
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 | No |
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.8.3 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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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The end of study is when all subjects have completed the treatment period or long-term follow-up (maximum 48 months from the date the last subject is randomized), whichever is later. |
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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 | |
E.8.9.1 | In the Member State concerned months | 61 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 61 |