| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically or cytologically confirmed advanced pancreatic adenocarcinoma that is metastatic. |
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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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033610 |
| E.1.2 | Term | Pancreatic carcinoma 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 |
To compare the following endpoints for napabucasin in combination with weekly paclitaxel and low-dose gemcitabine (Arm 1) versus standard of care treatment options (Arm 2) in patients with metastatic pancreatic adenocarcinoma following chemotherapy failure:
Phase II part of the study:
Progression free survival (PFS)
Safety
Phase III part of the study:
Overall survival (OS)
Note: Overall survival will not be assessed in Phase II part of this study. Phase II patients will be pooled with Phase III patients for Phase III assessment of OS.
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| E.2.2 | Secondary objectives of the trial |
To compare the following endpoints for napabucasin in combination with weekly paclitaxel and low-dose gemcitabine (Arm 1) versus standard of care treatment options (Arm 2) in patients with pancreatic adenocarcinoma following chemotherapy failure:
Phase II part of the study:
Disease control rate (DCR)
Objective response rate (ORR)
Phase III part of the study:
PFS
ORR and DCR
OS, PFS, ORR and DCR in the predefined biomarker-positive sub-population
Safety
Quality of life (QoL)
Note: Phase II patients will be pooled with Phase III patients for the Phase III assessment of secondary endpoints
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written, signed consent for trial participation must be obtained from the patient appropriately in accordance with applicable ICH guidelines and local and regulatory requirements prior to the performance of any study specific procedure.
2. Must have histologically or cytologically confirmed advanced pancreatic adenocarcinoma that is metastatic. The definitive diagnosis of metastatic pancreatic adenocarcinoma will be made by integrating the histopathological/cytological data within the context of the clinical and radiographic findings. Patients with islet cell neoplasms and rare subtypes of pancreatic adenocarcinoma are excluded.
3. Must have failed at least one line of chemotherapy, including but not limited to:
• A gemcitabine-containing regimen (i.e. single-agent or in combination)
• FOLFIRINOX or mFOLFIRINOX
Patients who relapsed during or within 6 months of last dose of the regimens listed above in the adjuvant or neoadjuvant setting may be enrolled.
4. Must have one or more metastatic tumors evaluable by CT scan with contrast (or MRI, if patient is allergic to CT contrast media) per RECIST 1.1. Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all sites of disease must be performed within 14 days prior to randomization. Qualifying scans performed as part of standard of care prior to patient signature of the study informed consent will be acceptable as baseline scanning as long as scanning is performed ≤ 14 days prior to randomization.
5. Must have ECOG Performance Status of 0 or 1, assessed within 14 days prior to randomization. Two observers qualified to perform assessment of the performance status will be required to perform this assessment. If discrepant, the one with the most deteriorated performance status will be considered true.
6. Must have life-expectancy of > 12 weeks.
7. Must be ≥ 18 years of age.
8. For male or female patients of child producing potential: must agree to use contraception or take measures to avoid pregnancy during the study and for 180 days after the final dose of the chemotherapy or for 30 days for female patients and for 90 days for male patients, after the final napabucasin dose if chemotherapy were not administered.
9. Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 3 days prior to randomization. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of human chorionic gonadotropin (HCG).
10. Patient has adequate biological parameters as demonstrated by the following blood counts at baseline (obtained ≤ 14 days prior to randomization:
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
• Platelet count ≥ 100,000/mm3 (100 × 109/L).
• Hemoglobin (Hgb) ≥ 9 g/dL.
11. Patient has the following blood chemistry levels at baseline (obtained ≤ 14 days prior to randomization:
• AST (SGOT) and ALT (SGPT) ≤ 2.5 × institutional upper limit of normal (ULN) [5 ×ULN in presence of liver metastases]
• Total bilirubin ≤ 1.5 × institutional ULN. If total bilirubin is > ULN, it must be non-rising for at least 3 days.
• Serum creatinine within normal limits or calculated clearance > 60 mL/min/1.73 m2 for patients with serum creatinine levels above or below the institutional normal value.
12. Patient not on anticoagulation has acceptable coagulation studies (obtained ≤ 14 days prior to randomization as demonstrated by prothrombin time (PT) and partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) below or within normal limits (+15%).
13. Patient has no clinically significant abnormalities on urinalysis results (obtained ≤ 14 days prior to randomization.
14. Patient must have adequate nutritional status with Body Mass Index (BMI) ≥ 18 kg/m2 and body weight of ≥ 40 kg with serum albumin ≥ 3 g/dL.
15. Patients requiring biliary stent placement must have biliary stent placed ≥ 7 days prior to screening.
16. Pain symptoms should be stable (of tolerable Grade 2 or less).
17. Only patients with available archival tumor tissue must consent to provision of, and Investigator(s) must confirm access to and agree to submit a representative formalin fixed paraffin block of tumor tissue in order that the specific correlative marker assays proscribed in this protocol may be conducted.
18. Patients must be accessible for treatment and follow-up.
19. The patient is not receiving therapy in a concurrent clinical study and the patient agrees not to participate in other interventional clinical studies during their participation in this trial while on study treatment.
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| E.4 | Principal exclusion criteria |
1. Anti-cancer chemotherapy, radiotherapy, biologic therapy or immunotherapy/immunomodulating treatment (for non-cancer related treatment) administered two weeks prior to the first planned dose of study medication. Investigational agents administered within four weeks of first planned dose of study medication. An exception is made for oral fluoropyrimidines (e.g. capecitabine, S-1), where a minimum of 10 days since last dose must be observed prior to the first planned dose of study medication.
2. Patients with any unresolved lingering toxicity > Grade 2 from prior treatment will be excluded.
3. Patients received prior chemotherapy only in the adjuvant or neoadjuvant setting, with progression occurring > 6 months of completion of therapy or resection with curative intent, respectively.
4. Patient who were intolerant to prior taxane treatment.
5. Patient has experienced a decline in ECOG performance status between baseline visit and within 3 days prior to randomization.
6. Patient has a ≥ 20% decrease in serum albumin level between baseline visit and within 3 days prior to randomization.
7. Patient has a ≥ 10% decrease in weight between baseline visit and within 3 days prior to randomization.
8. Major surgery within 4 weeks prior to randomization.
9. Patients with any known brain or leptomeningeal metastases are excluded, even if treated.
10. Patients with clinically significant pleural effusion or ascites.
11. Women who are pregnant or breastfeeding.
12. Patients with gastrointestinal disorder(s) which could significantly impede the absorption of an oral agent.
13. Prior treatment with napabucasin or participation in a clinical trial evaluating napabucasin.
14. Unable or unwilling to swallow napabucasin capsules daily.
15. Patient who has smoked cigarettes/tobacco within 28 days prior to randomization or plan to use these products while on study treatment.
16. Uncontrolled inter-current illness.
17. Known hypersensitivity to gemcitabine, taxanes or any of their excipients.
18. Neurosensory neuropathy ≥ grade 2 at baseline.
19. Uncontrolled chronic diarrhea ≥ grade 2 at baseline.
20. Patients being treated with any coumarins.
21. Patients with active, uncontrolled bacterial, viral or fungal infection(s) requiring systemic therapy.
22. Patients with a history of other malignancies.
23. Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
24. Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase II Part of the Study:
Progression Free Survival (PFS) and Safety in the general study population.
Phase III Part of the Study:
Overall Survival (OS) in the general study population.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase II Part of the Study:
PFS will be assessed when 70 events occur in Phase II part of the study. PFS is defined as the time interval between the date of randomization and the date of objective disease progression or death, whichever occurs first.
Phase III Part of the Study:
The 204th event will trigger the final analysis. It is estimated that 204 events will be required to detect an increase of median OS from 4.3 to 6.8 months (HR 0.63) which would be observed by randomizing 230 patients over 10 months with a follow-up period of 20 months.
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| E.5.2 | Secondary end point(s) |
Phase II Part of the Study:
• Disease control rate (DCR) in the general study population
• Objective response rate (ORR) in the general study population
Phase III Part of the Study:
• PFS in the general study population
• ORR and DCR in the general study population
• OS, PFS, ORR and DCR in the predefined biomarker positive population*
• Safety
• Quality of Life
*Biomarker-positive sub-population is defined as those patients with nuclear β-catenin and/or phospho-STAT3 positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to protocol for further information. |
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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 | 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) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| A choice of standard of care therapies selected by the Investigator. |
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| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Canada |
| China |
| Belgium |
| France |
| Italy |
| Spain |
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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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| The primary endpoint is Overall Survival (OS) in the general population and the predefined biomarker positive subpopulation. Patients who are still alive at the time of the final analysis, or who have become lost to follow-up will become censored on the date the patient was known to be alive. |
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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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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