E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced adenocarcinoma of the pancreas |
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E.1.1.1 | Medical condition in easily understood language |
Adenocarcinoma Pancreas
Locally Advanced
Unresectable
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033606 |
E.1.2 | Term | Pancreatic cancer non-resectable |
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 |
To estimate the relative treatment effect of AMG 479 in combination with
gemcitabine compared to placebo in combination with gemcitabine as measured by the hazard ratio for progression-free survival (PFS) in subjects with locally advanced adenocarcinoma of the pancreas |
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E.2.2 | Secondary objectives of the trial |
To evaluate overall survival (OS)
To evaluate the PFS and OS rates at 3, 6, 9, 12, 18, & 24 months
To evaluate objective response rate, time to progression, duration of response and disease control rate (partial response [PR] + complete response [CR] + stable disease [SD]) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
To evaluate subject incidence of adverse events, significant laboratory abnormalities & immunogenicity
To evaluate AMG 479 dose intensity, dose exposure and pharmacokinetic (PK) parameters & to evaluate relationships between AMG 479 exposure measures & selected safety and efficacy measures
To evaluate gemcitabine dose intensity & dose exposure
To evaluate patient reported outcomes as measured by the FACT Hepatobiliary Questionnaire – Hepatobiliary subscale (FACT-Hep HS)
To evaluate outcomes (PFS & OS) with respect to biomarker enrichment status defined by an analysis of serum biomarkers in metastatic pancreatic cancer (Study 20060540)
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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 |
If the subject signs the additional optional pharmacogenetic informed consent, DNA will be used for exploratory pharmacogenetic analyses. These analyses differ from the above blood and tumor analyses
because they focus on evaluation of the different heritable gene forms in DNA that may influence the different responses subjects have to a study treatment. The goals of exploratory studies include the use of genetic markers to help in the investigation of cancer and to identify persons who may have the best possible response to AMG 479. To study the effects of human heritable genetic variation on investigational product response, we plan to conduct exploratory pharmacogenetic studies as an optional part of this study. No additional blood samples will be collected for this part of the study; however, for those subjects that consent to participate in optional PG studies, DNA will be extracted from the cell pellet left-over after biomarker plasma preparation. |
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E.3 | Principal inclusion criteria |
Disease Related
Subjects must have histologically or cytologically confirmed locally advanced adenocarcinoma of the pancreas that is unresectable, per institutional practice
Radiologically measurable and/or non-measurable disease as defined by
RECIST version 1.1 Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
Demographic
Men or women ≥ 18 years of age
Ethical
Before any protocol specified procedure is performed, the appropriate approved written informed consent must be obtained by the subject or the subject’s legally acceptable representative
Laboratory
Adequate organ function as evidenced by the following laboratory studies within 14 days before randomization:
Hemoglobin ≥ 9 g/dL
Absolute neutrophil count ≥ 1.5 x 109/L
Platelet count ≥ 100 x 109/L (and no platelet transfusion within 14 days prior to the performance of the platelet count)
Partial thromboplastin (aPTT or PTT) ≤ 1.3 x upper limit of normal (ULN) and international normalization ratio (INR) ≤ 1.5, unless subject is on anti-coagulation therapy. Subjects on therapeutic anti-coagulation are eligible if there is no bleeding and they are on a stable dose of anticoagulation therapy (eg, warfarin with an INR of 2 to 3 within 7 days before randomization)
Calculated creatinine clearance ≥ 40 mL/minute calculated by Cockcroft-Gault formula
Amylase ≤ 2.0 x ULN
Blood glucose level ≤ 160 mg/dL (8.9 mmol/L). Subjects with a non-fasting blood glucose > 160 mg/dL (8.9 mmol/L) must have a fasting blood glucose ≤ 160 mg/dL (8.9 mmol/L) in order to be eligible
Total bilirubin ≤ 2.0 x ULN
Aspartate aminotransferase (AST) and alanine amino transferase
(ALT) ≤ 2.5 x ULN
General
Plan to begin protocol specified therapy within 7 days of randomization
Plan to be treated on protocol specified therapy until disease progression, withdrawal of consent or intolerable toxicity |
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E.4 | Principal exclusion criteria |
Disease Related
Islet cell, acinar cell carcinoma, non-adenocarcinoma, (eg, lymphoma,
sarcoma, etc), adenocarcinoma originating from biliary tree or
cystadenocarcinoma
Early (stage I) or metastatic (stage IV) disease
External biliary drain
Any prior or synchronous malignancy, except:
• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years prior to randomization and felt to be at low risk for recurrence by the treating physician
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Prostatic intraepithelial neoplasia without evidence of prostate cancer
Other Medical Conditions
Documented myocardial infarction or unstable/uncontrolled cardiac disease (eg, unstable angina, congestive heart failure [New York Heart Association(NYHA) > Class II]) within 6 months before randomization
History of any medical condition that in the opinion of the investigator, may increase the risks associated with study participation or protocol specified therapy or may interfere with the conduct of the study or interpretation of study results
Major surgical procedure within 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 surgical procedures within 7 days before randomization or not yet
recovered from prior minor surgery; although placement of central venous access device, fine needle aspiration or endoscopic biliary stent ≥ 1 day before randomization is acceptable
Known positive test for human immunodeficiency virus or hepatitis C or acute or chronic hepatitis B infection
Any co-morbid disease that would increase the risk of toxicity
Medications or Other Treatments
Currently treated or previously treated with biologic, small molecule,
immunotherapy, chemotherapy (ie, including gemcitabine), or other agents for pancreatic cancer
Currently treated or previously treated with radiotherapy, or chemoradiotherapy for pancreatic cancer
Recent infection requiring a course of systemic anti-infectives that was
completed within 7 days before randomization (with the exception of
uncomplicated urinary tract infection)
General
Subject is continuing to receive other investigational agent(s) or subject has not yet completed at least 30 days (before randomization) since ending other investigational device or drug study(s)
Subject of child-bearing potential is evidently pregnant (eg, positive human chorionic gonadotropin test) or is breast feeding
Woman or man with partner of childbearing potential not consenting to use adequate contraceptive precautions ie, double barrier contraceptive methods (eg diaphragm plus condom), or abstinence, during the course of protocol specified therapy and for 6 months after the last dose of protocol specified therapy for women and men (including sperm donation)
Subject has known sensitivity to any of the products to be administered during the study
Subject was previously randomized into this study
Subject will not be available for protocol required study visits or procedures, to the best of the subject and investigator’s knowledge
Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is progression-free survival (PFS). This is defined as the time from randomization to progression (per RECIST version 1.1) or death. Subjects who are alive and do not have documented disease progression per RECIST version 1.1 by the analysis data cut-off date or are lost to follow up will be censored at the last evaluable tumor assessment date. Subjects who withdraw consent to participate in the study will be censored on the date of their last evaluable tumor assessment date prior to withdrawal. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This is defined as the time from randomization to progression (per RECIST version 1.1) or death. |
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E.5.2 | Secondary end point(s) |
• Overall survival (OS)
• PFS and OS rates at the timepoints of 3, 6, 9, 12, 18, and 24 months.
• Objective Response Rate. This is defined as the incidence rate of either a complete response (CR) or partial response (PR) per RECIST version 1.1. The RECIST version 1.1 does not require a confirmatory image in a randomized study
• Time to disease progression (TTP) for a subject is defined as time from the date of randomization to disease progression (per RECIST v1.1)
• Duration of response as defined as time from the date of first response (PR or CR) to disease progression (per RECIST v1.1) or death
• Disease Control Rate as defined as the incidence rate of either a complete response (CR), or partial response (PR), or stable disease (SD) per RECIST version 1.1
• Incidence of subject adverse events, laboratory abnormalities and
immunogenicity
• AMG 479 dose intensity, dose exposure and pharmacokinetic (PK) parameters
• Gemcitabine dose intensity and dose exposure
• Relationship between AMG 479 exposure measures and selected safety and efficacy measures
• The area under the curve for the hepatobiliary symptoms subscale as measured by the FACT-Hep HS |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3, 6, 9, 12, 18, and 24 months |
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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 | Yes |
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 | Yes |
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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Austria |
Belgium |
Czech Republic |
Denmark |
Germany |
Hungary |
Korea, Republic of |
Poland |
Portugal |
Russian Federation |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
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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 will be the later of the Primary Completion or when the last subject discontinues all protocol therapy and has had the opportunity to complete the safety follow-up visit. The Primary Completion is the final analysis is estimated to be 24 months after the date the last subject is randomized; however, the final analysis may occur earlier if all subjects who are under active observation (ie, have not withdrawn full consent and have a last contact date within 14 weeks) have died. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |