E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or metastatic adenocarcinoma of the pancreas in patients that have failed or are intolerant to first-line chemotherapy |
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E.1.1.1 | Medical condition in easily understood language |
Advanced pancreatic cancer |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033607 |
E.1.2 | Term | Pancreatic cancer recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
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 | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033605 |
E.1.2 | Term | Pancreatic cancer metastatic |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10033604 |
E.1.2 | Term | Pancreatic cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•To evaluate and compare the OS of subjects with advanced or metastatic adenocarcinoma of the pancreas when treated with ruxolitinib in combination with capecitabine versus capecitabine alone. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate and compare the efficacy of the 2 treatment groups with respect to PFS.
•To evaluate and compare the efficacy of the 2 treatment groups with respect to overall tumor response and duration of response.
•To evaluate and compare the safety and tolerability of ruxolitinib in combination with capecitabine versus capecitabine alone.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female, 18 years or older.
• Histologically or cytologically confirmed adenocarcinoma of the pancreas.
• Advanced adenocarcinoma of the pancreas that is inoperable or metastatic.
• mGPS of 1 or 2 as defined below:
− mGPS of 1: C-reactive protein (CRP) > 10 mg/L and albumin ≥ 35 g/L
− mGPS of 2: CRP > 10 mg/L and albumin < 35 g/L
• Received 1 prior chemotherapy regimen for advanced or metastatic disease (not including neoadjuvant and/or adjuvant therapy).
− Use of a fluoropyrimidine-containing regimen (eg, FOLFIRNOX, FOLFOX, CapeOx, chemoradiation, etc) in the first-line setting is permitted provided the subject discontinued treatment for reasons other than disease progression and the subject received ≤ 8 weeks of therapy. Subjects who received single-agent capecitabine as first-line therapy are not eligible.
− Neoadjuvant regimens will be considered first-line therapy if the subject has disease progression during treatment. Adjuvant regimens will be considered first-line therapy if the subject has disease progression during treatment or ≤ 6 months after the last dose.
− There is no restriction on the use of fluoropyrimidine-containing regimens in the neoadjuvant or adjuvant setting.
− History of palliative radiotherapy to disease sites is allowed provided there are other sites of disease or subsequent progression of the disease in the radiation field, and ≥ 4 weeks have elapsed since the completion of radiotherapy and all treatment-related toxicities have resolved or are at a new stable baseline.
• Able to tolerate and benefit from therapy as evidenced by:
− Absolute neutrophil count ≥ 1.5 × 109/L with white blood cell count < 20 × 109/L.
− Platelets ≥ 75 × 109/L.
− Hemoglobin ≥ 9 g/dL (transfusions are permitted to achieve baseline hemoglobin level).
− Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN); or ≤ 5 × ULN in the presence of liver metastases.
− Total bilirubin ≤ 1.5 × ULN; if total bilirubin is > 1.5 × ULN then direct bilirubin must be ≤ 1.5 × ULN (use of biliary stent to achieve bilirubin levels is permitted).
− Alkaline phosphatase < 3 × ULN.
− Lactate dehydrogenase (LDH) < 3 × ULN in the absence of hemolysis.
− Creatinine clearance ≥ 50 mL/min measured or calculated by Cockroft-Gault equation.
− ECOG performance status 0 to 2.
− Body mass index (BMI) > 16 kg/m2.
− Absence of significant concurrent, uncontrolled medical condition including, but not limited to renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, cerebral, or psychiatric disease.
− Able to swallow and retain oral medication.
• ≥ 2 weeks elapsed from the completion of previous treatment regimen and subjects must have recovered or be at a new stable baseline from any related toxicities.
• Radiographically measurable or evaluable disease (based on local evaluation), per RECIST (v1.1). |
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E.4 | Principal exclusion criteria |
• Received more than 1 prior regimen (eg, chemotherapy, biologic, targeted, immune, investigational therapies alone or in combination) for advanced or metastatic disease.
• Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment.
• Known brain or central nervous system metastases or history of uncontrolled seizures.
• Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, and arrhythmia requiring therapy.
• Ongoing radiation therapy or radiation therapy administered within 30 days of enrollment.
• Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization).
• Subjects who participated in any other study in which receipt of an investigational study drug occurred within 28 days or 5 half-lives (whichever is longer) prior to the first dose.
• Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval.
• Recent (≤ 3 months) history or ongoing partial or complete bowel obstruction, unless surgically corrected.
• Prior severe reaction to fluoropyrimidines, known DPD deficiency, or other known hypersensitivity to active substances, including fluorouracil (5-FU), or ruxolitinib, or any of their excipients.
• Known history of human immunodeficiency virus infection.
• Active hepatitis B or C infection that requires treatment.
• Unwilling to be transfused with blood components.
• Prior treatment with a JAK inhibitor for any indication. |
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E.5 End points |
E.5.1 | Primary end point(s) |
•Overall survival as determined from the date of randomization until death due to any cause. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary variable is OS, defined as number of days from randomization to death. |
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E.5.2 | Secondary end point(s) |
• Progression-free survival defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per RECIST (v1.1), or death due to any cause, if sooner.
• Restricted mean survival time (RMST) estimated over the interval between the date of randomization and 12 months (365 days); if the last death in either treatment group is prior to study Day 365, then the earlier of the death in the placebo or the death in the ruxolitinib treatment group, truncated to the last full 30-day incremented prior the earlier death, will be used as the end of the RMST estimation interval in both groups.
• Objective response rate and duration of response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment.
• Safety and tolerability of the treatment regimens through assessment of adverse events and changes in safety assessments including laboratory parameters. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression-free survival, defined as the number of days from randomization to the earlier of death or disease progression by RECIST v1.1 criteria as assessed by the investigator. |
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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 | 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) | 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 | 4 |
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 | 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 |
Argentina |
Brazil |
Chile |
Colombia |
European Union |
Israel |
Mexico |
Peru |
Switzerland |
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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There is no predefined EOT.
After discontinuation of study treatment, all subjects will remain in the follow-up phase of the study for the collection of subsequent anticancer therapies and survival |
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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 | 9 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |