| 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 | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033599 |
| E.1.2 | Term | Pancreatic adenocarcinoma metastatic |
| 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 |
| The primary objective of this study is to evaluate the efficacy of the regimen of irinotecan liposome injection + oxaliplatin + 5 fluorouracil (5-FU)/leucovorin (LV) versus nab paclitaxel + gemcitabine in improving overall survival (OS) in subjects who have not previously received chemotherapy for metastatic adenocarcinoma of the pancreas. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are as follows:
• To evaluate progression free survival (PFS) by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1 guidelines
• To evaluate the overall response rate (ORR) according to RECIST Version 1.1 guidelines
• To evaluate the safety of this regimen in this patient population.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
(1) Subject has been informed about the nature of the study, and has agreed to participate in the study, and signed the ICF prior to participation in any study-related activities.
(2) Male or non-pregnant and non-lactating female and ≥18 years of age:
(a) Females of child-bearing potential (i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy) must test negative for pregnancy at the time of screening based on a urine or serum pregnancy test. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. Female subjects of reproductive potential must agree to use a highly effective method of birth control, during the study and for 7 months following the last dose of study medication.
(b) Male subjects must agree to use condoms during the study and for 6 months following the last dose of study medication.
(3) Histological or cytologically confirmed adenocarcinoma of the pancreas that has not been previously treated in the metastatic setting.
(4) Initial diagnosis of metastatic disease must have occurred ≤6 weeks prior to screening.
(5) Subject has one or more metastatic lesions measurable by CT scan (or MRI, if the subject is allergic to CT contrast media) according to RECIST Version 1.1 criteria.
(6) Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening and within 7 days prior to randomisation.
(7) Subject has adequate biological parameters as demonstrated by the following blood counts:
(a) Absolute neutrophil count (ANC) ≥2000/mm3 without the use of hemopoietic growth factors within the last 7 days prior to randomisation
(b) Platelet count ≥100,000/mm3
(c) Haemoglobin (Hgb) ≥9 g/dL obtained ≤14 days prior to randomisation.
(8) Adequate hepatic function as evidenced by:
(a) Serum total bilirubin ≤1.5x upper limit of normal (ULN) (biliary drainage is allowed for biliary obstruction), and
(b) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN (≤5x ULN is acceptable if liver metastases are present).
(9) Adequate renal function with a creatinine clearance (CLCR) of >30 mL/min. Actual body weight should be used for calculating CLCR using the Cockcroft Gault Equation:
CLCR (mL/min) = ((140–Age [years]) * (Weight [kg]/(Serum Creatinine [mg/dL]*72).
Multiply the result by 0.85 if the subject is female. For subjects with a body mass index (BMI) >30 kg/m2, adjusted body weight should be used instead.
(10) Electrocardiogram (ECG) without any clinically significant findings (QT interval corrected by Fridericia’s formula (QTcF) < or = 450 msec and no known arrhythmias), and per the investigator’s assessment.
(11) Adequate coagulation studies (obtained ≤14 days prior to randomisation) as demonstrated by prothrombin time and partial thromboplastin time within normal limits (≤1.5 x ULN). (Subjects on warfarin or other vitamin K antagonists should be discussed with the sponsor).
(12) Subject has no clinically significant abnormalities in urinalysis results (obtained within the last 7 days prior to randomisation), per the investigator’s assessment.
(13) Subjects infected with human immunodeficiency virus (HIV) are eligible if they meet all the following criteria:
(a) CD4 count is ≥350 cells/uL, viral load is undetectable, and not taking prohibited cytochrome (CYP)-interacting medications
(b) Probable long-term survival with HIV if cancer were not present
(c) Stable on a highly active antiretroviral therapy (HAART) regimen for ≥4 weeks and willing to adhere to their HAART regimen with minimal overlapping toxicity and drug-drug interactions with the experimental agents in this study
(d) HIV is not multi-drug resistant
(e) Taking medication and/or receiving antiretroviral therapy that does not interact or have overlapping toxicities with the study medication. |
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| E.4 | Principal exclusion criteria |
(1) Any other medical or social condition deemed by the investigator to be likely to interfere with a subject’s ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.
(2) Unwilling or unable to comply with study procedures and/or study visits.
(3) Prior treatment of pancreatic cancer in the metastatic setting with surgery, radiotherapy, chemotherapy or investigational therapy:
(a) Palliative radiotherapy is permitted
(b) Placement of biliary stent/tube is permitted.
(4) Prior treatment of pancreatic adenocarcinoma with chemotherapy in the adjuvant setting, except those where at least 12 months have elapsed since completion of the last dose and no persistent treatment-related toxicities are present.
(5) Subject has only localised advanced disease.
(6) Documented serum albumin <3 g/dL within 7 days prior to randomisation.
(7) Known history of central nervous system (CNS) metastases. (Subjects on a stable or decreasing dose of steroids and deemed clinically stable as per the investigator’s assessment are eligible).
(8) Clinically significant gastrointestinal disorder including hepatic disorders, bleeding, inflammation, occlusion, diarrhoea >Grade 1, malabsorption syndrome, ulcerative colitis, inflammatory bowel disease or partial bowel obstruction.
(9) History of any second malignancy in the last 2 years; subjects with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Subjects with a history of other malignancies are eligible if they have been continuously disease free for at least 2 years prior to screening. Subjects who have a concurrent malignancy that is clinically stable and does not require tumour-directed treatment are eligible.
(10) Known hypersensitivity to any of the components of irinotecan liposome injection, other liposomal products, or any components of 5-FU, LV or oxaliplatin.
(11) Known hypersensitivity to any of the components of nab-paclitaxel or gemcitabine.
(12) Concurrent illnesses that would be a relative contraindication to trial participation such as active cardiac or liver disease, including:
(a) Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before screening
(b) High cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year prior to screening
(c) New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
(d) Known historical or active infection with hepatitis B, or active infection with hepatitis C (note that subjects with hepatitis C who have been clinically cured, defined as persistent absence of hepatitis C ribonucleic acid (RNA) detected by polymerase chain reaction (PCR) test in serum 12 weeks after completing antiviral treatment, are eligible for this study)
(13) 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, subjects with tumour fever may be enroled)
(14) Major surgery, other than diagnostic surgery, within 4 weeks prior to randomisation.
(15) Use of strong inhibitors or inducers of CYP3A, CYP2C8 and UGT1A1 (please refer to Appendix 1). Subjects are ineligible if:
- they are unable to discontinue the use of strong inhibitors of CYP3A, CYP2C8 and UGT1A1 at least 1 week prior to randomisation
- they are unable to discontinue the use of strong CYP3A and CYP2C8 inducers at least 2 weeks prior to randomisation.
(16) There is presence of any contraindications outlined in the Contraindications or Warnings and Precautions sections of the investigator brochure (IB) for irinotecan liposome injection, or in the prescribing information for 5-FU, LV or oxaliplatin.
(17) Presence of any contraindications outlined in the Contraindications or Special Warnings and Precautions sections of the product prescribing information for nab paclitaxel or gemcitabine.
(18) Neuroendocrine or acinar pancreatic carcinoma.
(19) Subjects who, in the opinion of the investigator, have symptoms or signs suggestive of clinically unacceptable deterioration of the primary disease at the time of screening.
(20) History of systemic connective tissue disorders.
(21) History of interstitial lung disease, history of slowly progressive dyspnoea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.
(22) History of peripheral artery disease.
(23) Subjects who have received a live vaccine within 4 weeks prior to randomisation
(24) Known low or absent dihydropyrimidine dehydrogenase (DPD) activity. Where required by local regulations, testing for DPD deficiency must be performed using a validated method which is recommended by local health authorities |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the overall survival of subjects treated with irinotecan liposome injection+oxaliplatin+5 FU/LV compared to subjects treated with nab paclitaxel+gemcitabine.
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects will be followed in the study until death to assess OS time. Subjects who have terminated study medication treatment will have follow-up every 2 months to determine survival status.
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints (PFS and ORR) will only be evaluated if the primary efficacy endpoint demonstrates superiority for irinotecan liposome injection+oxaliplatin+5‑FU/LV over nab-‑paclitaxel+gemcitabine. Investigator-assessed tumour response will be used in efficacy analysis.
- Plasma concentrations of total irinotecan and SN-38 will be used to characterise their corresponding PK parameters, in co-administration with 5-FU and oxaliplatin, using a nonlinear mixed effects approach. Individual PK parameters will be estimated if warranted by the data. Oxaliplatin and/or 5-FU concentrations might be used for further PK characterisation if more investigations are required.
Graphical exploration will be performed to investigate any relationship between PK and PD endpoints. If a trend is shown, PK/PD modelling will be performed and reported separately.
- Safety will be monitored through continuous reporting of AEs and serious adverse events (SAEs), laboratory abnormalities, and incidence of subjects experiencing dose modifications (including dose reductions, dose omissions and dose delays) and/or premature discontinuation of study medication (and reason for discontinuation).
The safety evaluations include:
• AEs
• Clinical laboratory assessments
• ECG findings
• Complete physical examination including the evaluation of ECOG, vital signs, measurements and body weight.
An independent data and monitoring committee (IDMC) will be established for this study to operate as an independent expert advisory group with the primary responsibility of monitoring the safety of enroled subjects by reviewing the clinical data at scheduled time points described in the IDMC Charter, as well as on an ad hoc basis, as needed. The IDMC will additionally review the safety and efficacy of the interim analyses and make appropriate recommendations based on those results. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
These safety evaluations will be performed from ICF signature, throughout the study to 30 days after the last study treatment administration.
Subjects will have CT scan (or MRI if the subject is allergic to CT contrast media) performed every 8 weeks that will be evaluated by the investigator site using RECIST guidelines Version 1.1 for complete response, partial response, stable disease or progressive disease. |
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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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 | 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 110 |
| 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 |
| Korea, Democratic People's Republic of |
| Australia |
| Brazil |
| Canada |
| Israel |
| Russian Federation |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Portugal |
| Spain |
| Sweden |
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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
|
| Study will be considered to have ended on fulfilment of analysis requirements for endpoints and once sufficient data have been collected to adequately evaluate all endpoints, for regulatory purposes, safety and efficacy profile. The study will be completed once all subjects have discontinued the study treatment, the last subject has completed their EoT visit and at least 543 OS events have occurred in the randomised subjects |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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