Gastric Cancer, Gastroesophageal Junction Cancer
Conditions
Brief summary
The purpose of this study is to find out whether it is better to receive a new drug, BBI608, in addition to paclitaxel chemotherapy or better to receive paclitaxel chemotherapy alone as second line treatment for gastric and gastroesophageal junction cancer after prior first line platinum and fluoropyrimidine based chemotherapy.
Detailed description
The goal of this study is to determine if paclitaxel given together with BBI608 as second line therapy will prolong overall survival compared to paclitaxel alone. Approximately 700 patients will be randomized with histologically or cytologically confirmed metastatic gastric or gastroesophageal junction adenocarcinoma. Patients must have failed first line therapy with any platinum/fluoropyrimidine doublet. BBI608/placebo will be administered daily, paclitaxel will be administered i.v. on days 1, 8 and 15 of a 4 weekly cycle.
Interventions
DRUGBBI608
BBI608 480 mg orally two times daily (960 mg total daily dose)
DRUGPaclitaxel
Paclitaxel 80 mg/m2 I.V. infusion on Days 1, 8, and 15 of every 4-week cycle
OTHERPlacebo
Orally two times daily
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Cytologically or histologically confirmed advanced gastric or GEJ adenocarcinoma that is metastatic or locally advanced and unresectable. * Failed treatment with one regimen containing at least a platinum/fluoropyrimidine doublet for unresectable or metastatic disease.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. * Paclitaxel therapy is appropriate for the patient and is recommended by the Investigator. * 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. * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. ･≥ 18 years of age. * 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 months after the final dose of Paclitaxel or for 30 days for female patients and for 90 days for male patients, of the final BBI608/Placebo dose if Paclitaxel was not administered. * Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 5 days prior to randomization. * Alanine transaminase (ALT) ≤ 3 × institutional upper limit of normal (ULN) \[≤ 5 × ULN in presence of liver metastases\] within 14 days prior to randomization. * Hemoglobin (Hgb) ≥ 9.0 g/dL within 14 days prior to randomization. Must not have required transfusion within 1 week of baseline Hgb assessment. * Total bilirubin ≤ 1.5 × institutional ULN \[≤ 2.0 x ULN in presence of liver metastases\] within 14 days prior to randomization. * Creatinine ≤ 1.5 × institutional ULN or Creatinine Clearance \> 50 ml/min (as calculated by the Cockroft-Gault equation) within 14 days prior to randomization. * Absolute neutrophil count ≥ 1.5 x 10\^9/L within 14 days prior to randomization. * Platelet count ≥ 100 x 10\^9/L within 14 days prior to randomization. Must not have required transfusion within 1 week of baseline platelet assessment. * Other baseline laboratory evaluations must be done within 14 days prior to randomization. * Patient must consent to provision of a representative formalin fixed paraffin block of tumor tissue, if available, in order that the specific correlative marker assays may be conducted. * Patient must consent to provision of a sample of blood in order that the specific correlative marker assays may be conducted. * Patients must be accessible for treatment and follow up. * Protocol treatment is to begin within 2 working days of patient randomization. * 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. Patients participating in surveys or observational studies are eligible to participate in this study.
Exclusion criteria
* 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. * Prior taxanes in the neoadjuvant or adjuvant setting with progression occurring within 6 months of completion of taxane therapy; or any taxanes in the metastatic setting. * More than one prior chemotherapy regimen administered in the metastatic setting. * Major surgery within 4 weeks prior to randomization. * Any known symptomatic brain metastases requiring steroids. * Women who are pregnant or breastfeeding. * Gastrointestinal disorder(s) which, in the opinion of the Qualified/Principal Investigator, would significantly impede the absorption of an oral agent. * Unable or unwilling to swallow BBI608/placebo capsules daily. * Uncontrolled intercurrent illness. * Peripheral neuropathy ≥ CTCAE Grade 2 at baseline. * 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 with no evidence of disease for ≥ 3 years. * Prior treatment with BBI608. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 36 months | The primary objective of this study is to assess the effect of orally administered BBI608 plus weekly paclitaxel, in comparison to placebo plus weekly paclitaxel on the Overall Survival of patients with advanced histopathologically confirmed gastric or gastroesophageal junction adenocarcinoma who failed treatment with one platinum/fluoropyrimidine containing regimen for unresectable or metastatic disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 36 months | Defined as the time from randomization to the first objective documentation of disease progression or death due to any cause which comes first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria(RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in anon-target lesion, or the appearance of new lesions. |
| Objective Response Rate | 36 months | Objective Response Rate is defined as the percentage of patients with a documented complete response or partial response (CR + PR) based on RECIST 1.1. |
| Disease Control Rate | 36 months | Disease control Rate is defined as the percentage of patients with a documented complete response or partial response (CR + PR+SD) based on RECIST 1.1. |
| Number of Patients With Adverse Events | 36 months | All patients who have received at least one dose of BBI608/Placebo will be included in the safety analysis. The number of patients who experienced at least one adverse event is reported. |
Countries
Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Estonia, France, Germany, Hungary, Israel, Italy, Japan, Lithuania, Poland, Romania, Russia, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
714 patients were enrolled to this study from 02OCT2014 to 20SEP2017 across 204 sites in 22 countries.
Pre-assignment details
Study arm was determined at patient randomization to the study, no pre-assignment activities occurred.
Participants by arm
| Arm | Count |
|---|---|
| Napabucasin + Paclitaxel Napabucasin was administered orally, twice daily, with doses separated by 12 hours. Paclitaxel 80 mg/m2 (intravenous \[IV\]) was administered weekly, on Days 1, 8, and 15 of each 28 day study cycle. Napabucasin administration began 2 days prior to the first paclitaxel infusion in the initial run in period. | 357 |
| Placebo + Paclitaxel Placebo was administered orally, twice daily, with doses separated by 12 hours. Paclitaxel 80 mg/m2 (intravenous \[IV\]) was administered weekly, on Days 1, 8, and 15 of each 28 day study cycle. Placebo administration began 2 days prior to the first paclitaxel infusion in the initial run in period. | 357 |
| Total | 714 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 4 | 4 |
| Overall Study | Sponsor terminated study | 49 | 58 |
| Overall Study | Various Reasons | 3 | 5 |
| Overall Study | Withdrawal by Subject | 15 | 11 |
Baseline characteristics
| Characteristic | Napabucasin + Paclitaxel | Placebo + Paclitaxel | Total |
|---|---|---|---|
| Age, Continuous | 60.787 years STANDARD_DEVIATION 11.513 | 59.887 years STANDARD_DEVIATION 11.1231 | 60.337 years STANDARD_DEVIATION 11.3207 |
| BMI | 23.24 kg/m^2 STANDARD_DEVIATION 4.481 | 23.56 kg/m^2 STANDARD_DEVIATION 4.709 | 23.40 kg/m^2 STANDARD_DEVIATION 4.596 |
| ECOG 0: Fully active, able to carry on all pre-disease performance without restriction | 128 Participants | 134 Participants | 262 Participants |
| ECOG 1: Restricted in physically strenuous activity but ambulatory, can carry out light/sedentary work | 229 Participants | 223 Participants | 452 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 107 Participants | 102 Participants | 209 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 11 Participants | 22 Participants |
| Race (NIH/OMB) White | 237 Participants | 240 Participants | 477 Participants |
| Sex: Female, Male Female | 96 Participants | 103 Participants | 199 Participants |
| Sex: Female, Male Male | 261 Participants | 254 Participants | 515 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 286 / 357 | 275 / 350 |
| other Total, other adverse events | 352 / 357 | 338 / 350 |
| serious Total, serious adverse events | 125 / 357 | 101 / 350 |
Outcome results
Primary
Overall Survival
The primary objective of this study is to assess the effect of orally administered BBI608 plus weekly paclitaxel, in comparison to placebo plus weekly paclitaxel on the Overall Survival of patients with advanced histopathologically confirmed gastric or gastroesophageal junction adenocarcinoma who failed treatment with one platinum/fluoropyrimidine containing regimen for unresectable or metastatic disease.
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Napabucasin + Paclitaxel | Overall Survival | 6.93 Months |
| Placebo + Paclitaxel | Overall Survival | 7.36 Months |
p-value: 0.859695% CI: [0.86, 1.02]Log Rank
Secondary
Disease Control Rate
Disease control Rate is defined as the percentage of patients with a documented complete response or partial response (CR + PR+SD) based on RECIST 1.1.
Time frame: 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Napabucasin + Paclitaxel | Disease Control Rate | 55 Participants |
| Placebo + Paclitaxel | Disease Control Rate | 58 Participants |
p-value: 0.655595% CI: [0.66, 1.3]Cochran-Mantel-Haenszel
Secondary
Number of Patients With Adverse Events
All patients who have received at least one dose of BBI608/Placebo will be included in the safety analysis. The number of patients who experienced at least one adverse event is reported.
Time frame: 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Napabucasin + Paclitaxel | Number of Patients With Adverse Events | 352 Participants |
| Placebo + Paclitaxel | Number of Patients With Adverse Events | 338 Participants |
Secondary
Objective Response Rate
Objective Response Rate is defined as the percentage of patients with a documented complete response or partial response (CR + PR) based on RECIST 1.1.
Time frame: 36 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Napabucasin + Paclitaxel | Objective Response Rate | 16 Participants |
| Placebo + Paclitaxel | Objective Response Rate | 18 Participants |
p-value: 0.735995% CI: [0.6, 1.44]Cochran-Mantel-Haenszel
Secondary
Progression Free Survival
Defined as the time from randomization to the first objective documentation of disease progression or death due to any cause which comes first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria(RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in anon-target lesion, or the appearance of new lesions.
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Napabucasin + Paclitaxel | Progression Free Survival | 3.55 Months |
| Placebo + Paclitaxel | Progression Free Survival | 3.68 Months |
p-value: 0.902895% CI: [0.85, 1.19]Log Rank