| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| This study will enroll patients with histologically or cytologically confirmed adenocarcinoma of the pancreas that is metastatic (Stage IV). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic pancreatic adenocarcinoma (PDAC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 overall survival (OS) of patients with metastatic pancreatic adenocarcinoma (PDAC) treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine (Arm 1) versus weekly nab-paclitaxel with gemcitabine (Arm 2). |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives
• To compare Progression-Free Survival (PFS) in patients with metastatic PDAC treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine
versus weekly nab-paclitaxel with gemcitabine.
• To compare Disease Control Rate (DCR) in patients with metastatic PDAC treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine versus
weekly nab-paclitaxel with gemcitabine.
• To compare Overall Response Rate (ORR) in patients with metastatic PDAC treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine versus
weekly nab-paclitaxel with gemcitabine |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| This study will enroll patients with histologically or cytologically confirmed adenocarcinoma of the pancreas that is metastatic (Stage IV). Patients with local recurrence following surgical resection will be excluded. At randomization, patients will not have received systematic chemotherapy for metastatic pancreatic adenocarcinoma previously (with a fluoropyrimidine or gemcitabine administered as a radiation sensitizer in the adjuvant setting allowed). Other inclusion criteria for all patients include: age ≥ 18 years; ECOG performance status ≤ 1; and adequate hepatic, renal, and bone-marrow function. |
|
| E.4 | Principal exclusion criteria |
-Patients with no evidence of metastatic disease as well as patients with a local recurrence following surgical resection of primary lesion.
-Patient has experienced a decline in ECOG performance status between Baseline visit and within 72 hours prior to randomization.
-Patient has a > or = 20% decrease in serum albumin level between Baseline visit and within 72 hours prior to randomization.
-Patient has a > 10% decrease in weight between baseline visit and within 72 hours prior to randomization
-Any prior anti-cancer chemotherapy, biologic or investigational therapy for PDAC.
-Major surgery within 4 weeks prior to randomization.
-Any known brain or leptomeningeal metastases are excluded, even if treated.
-Patients with clinically significant ascites or pleural effusions.
-Women who are pregnant or breastfeeding. Women should not breastfeed while taking study treatment and for 4 weeks after the last dose of BBI-608 or while undergoing treatment with nab-paclitaxel and gemcitabine and for 180 days after the last dose of nab-paclitaxel and gemcitabine.
-Gastrointestinal disorder(s) which, in the opinion of the Principal Investigator, would significantly impede the absorption of an oral agent (e.g. active Crohn’s disease, ulcerative colitis, extensive gastric and small intestine resection).
-Unable or unwilling to swallow BBI-608 capsules daily.
-Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
-Known hypersensitivity to gemcitabine, taxanes or any of their excipients, or the patient exhibits any of the events outlined in the Contraindications or Special Warnings and Precautions sections of the product or comparator SmPC or Prescribing Information. Possible hypersensitivity to BBI-608 or one of the excipients which include the azo dyes sunset yellow and allura red.
-Neurosensory neuropathy > or = grade 2 at baseline.
-Uncontrolled chronic diarrhea > or = grade 2 at baseline.
-Patients being treated with Warfarin.
-Patients with active, uncontrolled bacterial, viral or fungal infection(s) requiring systemic therapy
-Patients with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated by surgery alone or surgery plus radiotherapy with no evidence of disease continuously for > or = 5 years.
-Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
-Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol, including patients with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol. Patients planning to take a vacation for 7 or more consecutive days during the course of the study are ineligible. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary study endpoint is Overall Survival (OS), defined as the time from randomization until death from any cause. A multiplicity adjustment strategy will be applied to control the overall Type I error rate with respect to several sources of multiplicity in the trial. This multiplicity adjustment will account for the analysis of the treatment effect on the primary (OS) and key secondary (PFS, DCR, ORR) endpoints. The study is designed to have a power of 90% and a one-sided alpha of 2.5% to detect a 20% reduction in the continuous risk of death (HR 0.80, which corresponds to an increase of median survival from 8.5 to 10.63 months) in the Intention to Treat (ITT) general study population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| It is estimated that 864 events will be required to detect this reduction which would be observed by randomizing 1132 patients enrolled over 24 months with patient follow up for an additional 12 months, for total study duration of 36 months. It is anticipated that up to 5% dropout rate will occur for the entire study. |
|
| E.5.2 | Secondary end point(s) |
-All randomized patients will be included in the analysis of PFS, which is defined as the time interval between the date of randomization and the date of objective disease progression or death, whichever comes first. If neither event has been observed, then the patient will be censored at the date of the last tumor assessment. The date of disease progression is defined as the date when the criteria for objective progression are first met.
-Patients with measurable disease by RECIST 1.1 at randomization will be included in the analysis of ORR which is defined as a composite of Partial Response and Complete Response as classified according to the definitions set out below (Eisenhauer, 2009).
-Patients who have measurable disease by RECIST 1.1 at randomization will be included in the analysis of DCR which is defined as a composite of Stable Disease, Partial Response and Complete Response as classified according to the definitions set out below (Eisenhauer, 2009).
-All patients who have completed the baseline quality of life questionnaire and at least one other QoL questionnaire are evaluable. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All patients will have their BEST RESPONSE from the start of study treatment until the end of treatment. Tumor assessments will be performed every 8 weeks after randomization until objective disease progression or treatment discontinuation due to toxicity. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | Yes |
| 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 |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 102 |
| 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 |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| Taiwan |
| Ukraine |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Czechia |
|
| 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
|
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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