| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously Untreated, Metastatic Pancreatic Adenocarcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033599 |
| E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
| E.1.2 | System Organ Class | 100000004864 |
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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 study is divided into two parts:
Part 1:
• To evaluate the safety and tolerability of nal-IRI + 5FU/LV + oxaliplatin
• To characterize dose-limiting toxicities (DLTs) associated with nal-IRI + 5FU/LV + oxaliplatin and determine the Part 2 dose of the triplet combination
Part 2:
• To assess the efficacy of nal-IRI-containing regimens in first-line metastatic pancreatic cancer patients compared to nab-paclitaxel + gemcitabine using progression-free survival (PFS) |
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| E.2.2 | Secondary objectives of the trial |
Part 1:
• To characterize the pharmacokinetics (PK) of nal-IRI in combination with 5-FU and oxaliplatin
Part 2:
• To assess efficacy of each nal-IRI-containing regimen relative to nab-paclitaxel + gemcitabine using overall survival (OS), and objective response rate (ORR; CR + PR, per RECIST v1.1)
• To assess tumor marker CA19-9 response in each nal-IRI-containing regimen relative to nab-paclitaxel + gemcitabine
• To assess health-related quality of life (HRQL) using the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (EORTC-QLQ-C30) and European Quality of Life Questionnaire (EQ-5D-5L) in each arm
• To compare the safety and adverse event profile between the treatment arms
• To assess the potential for QTcF prolongation with nal-IRI treatment |
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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 |
QTc Substudy
The objective of the QTc substudy is to evaluate the potential of QTcF prolongation with nal-IRI treatment. |
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| E.3 | Principal inclusion criteria |
a) Pathologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting.
Part 1: unresectable, locally advanced or metastatic disease is allowed, diagnosed within 6 weeks prior to enrollment
Part 2: must have metastatic disease diagnosed within 6 weeks prior to randomization; locally advanced disease is not allowed
b) Measurable or non-measurable disease as defined by RECIST v1.1
c) ECOG performance status of 0 or 1
d) Adequate biological parameters as evidenced by the following blood counts:
ANC > 1,500 cells/μl without the use of hematopoietic growth factors,
Platelet count > 100,000 cells/μl, and
Hemoglobin > 9 g/dL
e) Adequate hepatic function as evidenced by:
Serum total bilirubin ≤ ULN (biliary drainage is allowed for biliary obstruction), and AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN is acceptable if liver metastases are present)
f) Adequate renal function as evidenced by serum creatinine ≤ 1.5 x ULN, and calculated clearance ≥60 mL/min/1.73 m2 for patients with serum creatinine levels above or below the institutional normal value. Actual body weight should be used for calculating creatinine clearance using the Cockcroft-Gault Equation (CreatClear = Sex * ((140 - Age) / (SerumCreat)) * (Weight / 72); for patients with body mass index (BMI) >30 kg/m2, lean body weight should be used instead.
g) ECG without any clinically significant findings
h) Recovered from the effects of any prior surgery or radiotherapy
i) ≥ 18 years of age
j) Agreeable to submit unstained archived tumor tissue for analysis, if available
k) Able to understand and provide an informed consent |
|
| E.4 | Principal exclusion criteria |
Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy, chemotherapy or investigational therapy (note: placement of biliary stent is allowed)
b) Prior treatment of pancreatic cancer with cytotoxic doses of chemotherapy (patients receiving prior treatment with chemotherapy as a radiation sensitizer are eligible if ≥ 6 months has elapsed from completion of therapy)
c) Uncontrolled CNS metastases (patients who require steroids should be on a stable or decreasing dose)
d) Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, diarrhea > grade 1, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, or partial bowel obstruction
e) History of any second malignancy in the last 3 years; patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 3 years.
f) Known hypersensitivity to any of the components of nal-IRI, other liposomal products, or any components of 5-FU, leucovorin or oxaliplatin
g) Known hypersensitivity to any of the components of nab-paclitaxel or gemcitabine (Part 2 only)
h) Concurrent illnesses that would be a relative contraindication to trial participation such as active cardiac or liver disease, including:
Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion
NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
Known historical or active infection with HIV, hepatitis B, or hepatitis C
i) Active infection or 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), which in the investigator’s opinion might compromise the patient’s participation in the trial or affect the study outcome
j) Use of strong CYP3A4 inhibitors or inducers, or presence of any other contraindications for irinotecan
k) Presence of any contraindications for 5-FU, leucovorin, or oxaliplatin
l) Use of strong CYP2C8 inhibitors or inducers, or presence of any other contraindications for nab-paclitaxel or gemcitabine (Part 2 only)1
m) Any other medical or social condition deemed by the Investigator to be likely to interfere with a patient’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results
n) Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test. Both male and female patients of reproductive potential must agree to use a highly effective method of birth control, during the study and for 6 months following the last dose of study drug. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: Assessments for safety will include all treated patients and will be based on adverse events, laboratory data, and study treatment related dose-limiting toxicities. Patients who discontinue prior to completion of Cycle 1 due to events that are not related to study treatment toxicity will not be considered in the assessment for DLT, and will be replaced for the purposes of DLT evaluation. Plasma samples will be analyzed for the concentration of nal-IRI (irinotecan) and its metabolites (SN-38 and SN-38G) in order to derive PK parameters of nal-IRI when given in combination with other anticancer therapies. PK parameters of the combination therapies (5-FU and oxaliplatin) will also be analyzed to evaluate any drug interactions with nal-IRI.
Part 2:
The primary endpoint is progression free survival, which will be assessed in all 3 study arms. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1:
Dose limiting toxicities (DLTs) will be evaluated during the first cycle of treatment (i.e. 28 days per cycle; or 14 days after the 2nd dose of study treatment if there is a treatment delay).
Part 2:
A primary analysis will be conducted when there are at least 70 PFS events for each comparison to the control arm. |
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| E.5.2 | Secondary end point(s) |
Part 2:
The secondary endpoints related to efficacy will include overall survival and objective response (CR or PR, per RECIST, v 1.1). Achievement of a 20%/50%/90% or greater decrease in CA19-9 levels compared to baseline (at 8, 16, and 24 weeks post-treatment and overall) will also be assessed, along with a quality of life assessment (EORTC-QLQ-C30 and EQ-5D-5L). QTcF prolongation will be assessed in the Arm 2 (nal-IRI+5-FU/LV) in patients with PK and QTcF measurements.
Translational / Exploratory:
Archived tumor tissue (if available) and blood samples will be collected and analyzed for biomarkers (Parts 1 and 2). Samples will be used to explore potential markers of sensitivity and resistance to irinotecan, including, but not limited to, the following: DNA damage repair pathways (e.g. Topo1, BRCA1/2, and SLFN11), growth factor pathways (IGF1 and EGFR family receptors and ligands), and factors involved in CPT-11 conversion to SN-38 (e.g. macrophage content and CES activity). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| A subsequent analysis for PFS and other endpoints will be performed when PFS events have occurred in at least 120 (i.e. 80% of randomized patients) patients. |
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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 | No |
| 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) | 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 | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| New Zealand |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
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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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| Patients will be treated until disease progression (radiologic or clinical deterioration) per RECIST v1.1, intolerable toxicity, or at the discretion of the treating physician. A follow up clinic visit is required approximately 30 days after last dose of study treatment to complete the final safety assessments. Subsequently, patients will be followed for survival once every 2 months via telephone, email, or clinic visit until death or study closure, whichever occurs first. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned days | 17 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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