| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced (metastatic or locally advanced and unresectable), gastric or gastroesophageal junction (GEJ) adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of stomach / oesophagus with spreading of disease to other parts of the body |
|
| 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 | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063916 |
| E.1.2 | Term | Metastatic gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 compare overall survival (OS) of patients with pre-treated, advanced gastric and gastro-esophageal junction (GEJ) adenocarcinoma treated with BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel. OS is defined as the time from randomization until death from any cause. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety profile of BBI608 administered daily plus weekly
paclitaxel in patients with pre-treated advanced gastric/GEJ
adenocarcinoma, with safety assessed according to the National Cancer
Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE)
version 4.0. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written, signed consent for trial participation must be obtained
2. Must have cytologically or histologically confirmed advanced gastric or GEJ adenocarcinoma that is metastatic or locally advanced and unresectable (with unresectability as defined by National Comprehensive Cancer Network Guidelines for Gastric Cancer [Version 2.2013] and Esophageal and Esophagogastric Junction Cancer [Version 2.2013]). GEJ cancers may include Siewert Class I, II or III types [Siewert 1996].
3. Must have failed treatment with one regimen containing at least a platinum/fluoropyrimidine doublet for unresectable or metastatic disease. While not mandated, concomitant treatment with an anthracycline (epirubicin or doxorubicin), or anti-HER2 therapy (trastuzumab) in this setting is allowed. Patients who have progression of disease at any point during neoadjuvant or adjuvant treatment with a platinum/fluoropyrimidine doublet or < 6 months after the last dose of neoadjuvant or adjuvant treatment may be enrolled.
Treatment failure is defined as progression of disease (clinical or radiologic) during first line treatment for unresectable or metastatic disease or ≤ 6 months after last dose of first line treatment. No additional prior lines of therapy in the metastatic setting will be allowed. A patient who has received neoadjuvant or adjuvant treatment, relapsed, and then received a platinum/fluoropyrimidine doublet as first-line treatment in the unresectable/metastatic setting would be allowed, however.
Patients who have received prior taxane therapy may be enrolled, so long as the taxane was administered in the adjuvant or neoadjuvant setting and progression occurred more than 6 months following completion of therapy. Patients who were intolerant to paclitaxel are not allowed, however.
4. Paclitaxel therapy is appropriate for the patient and is recommended by the Investigator.
5. Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all sites of disease done within 21 days prior to randomization. Patients with either measurable disease OR non-measurable evaluable disease will be eligible.
6. Must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
7. Must be ≥ 18 years of age.
8. For male or female patient of child producing potential: Must agree to use contraception or take measures to avoid pregnancy during the study and for 6 month after the final dose of Paclitaxel and for 30 days for female patients and for 90 days for male patients of the final BBI608/Placebo dose if Paclitaxel was not administered.
9. WOCBP must have a negative serum or urine pregnancy test within 5 days prior to randomization. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG.
10. Must have alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal (ULN) [≤ 5 × ULN in presence of liver metastases] within 14 days prior to randomization.
11. Must have hemoglobin (Hgb) ≥ 9.0 g/dL within 14 days prior to randomization. Must not have required transfusion within 1 week of baseline Hgb assessment.
12. Must have total bilirubin ≤ 1.5 × institutional ULN [≤ 2.0 x ULN in presence of liver metastases] within 14 days prior to randomization.
13. Must have creatinine ≤ 1.5 × institutional ULN or Creatinine Clearance > 50 ml/min (as calculated by the Cockroft-Gault equation) within 14 days prior to randomization.
14. Must have absolute neutrophil count ≥ 1.5 x 10e9/L within 14 days prior to randomization.
15. Must have platelet count ≥ 100 x 10e9/L within 14 days prior to randomization. Must not have required transfusion within 1 week of baseline platelet assessment.
16. Other baseline laboratory evaluations, listed in Section 6.0, must be done within 14 days prior to randomization.
17. Patient 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 Section 14.6 (Correlative Studies) of this protocol may be conducted. Submission of the tissue does not have to occur prior to randomization. Where it is not possible to obtain two 2 mm cores of tumor from the block, 10-30 unstained slides of representative tumor tissue are also acceptable. Where no previously resected or biopsied tumor tissue exists or is available, on the approval of the Sponsor/designated CRO, the patient may still be considered eligible for the study.
18. Patient must consent to provision of a sample of blood in order that the specific correlative marker assays proscribed in Section 14.6 (Correlative Studies) may be conducted.
19. Patients must be accessible for treatment and follow up. |
|
| E.4 | Principal exclusion criteria |
1. Anti-cancer chemotherapy or biologic therapy if administered prior to the first planned dose of BBI608/placebo within period of time equivalent to the usual cycle length of the regimen. 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 BBI608/placebo.
Radiotherapy, immunotherapy, or investigational agents within four weeks of first planned dose of BBI608/placebo, with the exception of a single dose of radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization.
2. Prior taxane therapy in the neoadjuvant or adjuvant setting with progression occurring within 6 months of completion of taxane therapy; or any taxane therapy in the metastatic setting.
3. More than one prior chemotherapy regimen administered in the metastatic setting.
4. Major surgery within 4 weeks prior to randomization.
5. Any known symptomatic brain metastases requiring steroids. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids, or on a stable dose of steroids for at least 2 weeks prior to randomization. Patients with known leptomeningeal metastases are excluded, even if treated.
6. Women who are pregnant or breastfeeding.
7. Gastrointestinal disorder(s) which, in the opinion of the Qualified/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).
8.Severe hepatic impairment as per Paclitaxel Summary of product Characteristics
9. history of severe hypersensitivy to paclitaxel or to any excipients includin macrogolglycerolricinoleate.
10 Unable or unwilling to swallow BBI608/placebo capsules daily.
11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (> class II New York Heart Association (NYHA), unstable angina pectoris (including angina symptoms at rest, new onset begun < 3 months prior, or myocardial infarction < 6 months prior), clinically significant cardiac arrhythmia requiring anti-arrhythmic therapy, significant valvular or pericardial disease, severe uncontrolled arterial hypertension, pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
12. Peripheral neuropathy ≥ CTCAE Grade 2 at baseline
13. Patients with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, and in situ cancer of the urinary bladder, or other solid tumors curatively treated with no evidence of disease for > 3 years.
14. Prior treatment with BBI608.
15. Any active disease condition which would render the protocol treatment dangerous or impair the ability of the patient to receive protocol therapy.
16. Any active condition (e.g. psychological, geographical, etc.) that does not permit compliance with the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall survival is defined as the time from randomization to death from any cause.
Evaluation occurs at the first regularly scheduled 4 week assessment at which the patient has been off study therapy for a minimum of 28 days, and every 8 weeks (56 days) thereafter. (+/- 3 days) |
|
| E.5.2 | Secondary end point(s) |
Overall Survival (OS) in the biomarker-positive population [those patients with nuclear β-catenin positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue].
Progression-Free Survival (PFS) in the General Study Population
Progression-Free Survival in the Predefined Biomarker-positive Population [those patients with nuclear β-catenin positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE)
archival tissue]
Objective Response Rate (ORR) in the General Study Population
Disease Control Rate (DCR) in the General Study Population
Safety Profile |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluations will be performed at different intervals throughout the study:
If dose delays occur for any reason on the study, other study assessments, including assessment by physician and Quality of Life questionnaires, will not be delayed, but should continue at the time indicated in the protocol from randomization. |
|
| 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 |
|
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 133 |
| 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 |
| Bulgaria |
| Canada |
| China |
| Czech Republic |
| Estonia |
| France |
| Germany |
| Hungary |
| Iceland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| The primary study endpoint is Overall Survival (OS).It is estimated that 566 events will be required which would be observed by randomizing 700 patients over 24 months and following them for an additional 12months (including up to 5% of yearly dropouts). When the required number of events for the primary endpoint has been reached, all randomized patients still alive will have continued study follow up through to their deaths. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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