Colorectal Carcinoma
Conditions
Brief summary
The purpose of this study is to find out whether it is better to receive a new drug, BBI608, or better to receive no further treatment for colon or rectal cancer. To do this, half of the patients in this study will get BBI608 and the other half will receive a placebo (a substance that is designed not to do anything).
Detailed description
This research is being done because currently there are no approved remaining effective treatments for colon or rectal cancer. The purpose of this study is to compare the effects on colon cancer of a new drug, BBI608, and best supportive care (BSC) compared to BSC alone. BBI608 has been shown to shrink tumours in animals and has been studied in a few people and seems promising, but it is not clear if it can offer better results than the usual care which is best supportive care alone. The standard or usual treatment for this disease is treatment with drugs and other treatments that may help to make a patient feel better or may improve their quality of life. This treatment is known as best supportive care (BSC). Although patients with best supportive care can feel better for some months, the cancer usually continues to grow.
Interventions
Sponsors
Sumitomo Pharma America, Inc.
NCIC Clinical Trials Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed advanced colorectal cancer that is unresectable. * Received a prior thymidylate synthase inhibitor (e.g. 5-fluorouracil (5-FU), capecitabine, raltitrexed, UFT) for metastatic disease or as adjuvant therapy. * Received and failed an irinotecan containing regimen (i.e. single-agent or in combination) for treatment of metastatic disease, OR relapsed within 6 months of completion of an irinotecan-containing adjuvant therapy, OR have documented unsuitability for an irinotecan-containing regimen. * Received and failed an oxaliplatin-containing regimen for treatment of metastatic disease, OR relapsed within 6 months of completion of an oxaliplatin-containing adjuvant therapy OR have documented unsuitability for an oxaliplatin-containing regimen. * For patients with colorectal cancer that is K-ras wild type: Received and failed a cetuximab or panitumumab-containing regimen (i.e. single-agent or in combination) for treatment of metastatic disease OR have documented unsuitability for a cetuximab or panitumumab-containing regimen * The only remaining standard available therapy as recommended by the Investigator is best supportive care. * Must have presence of measurable disease as defined by Response Evaluation Criteria in Solid Tumours (RECIST 1.1). * Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all sites of disease done within 14 days prior to randomization. * Must have an ECOG Performance Status of 0 or 1. * Must be ≥ 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 30 days after the last Protocol treatment dose. * Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test within 72 hours prior to randomization. * 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. * Must have hemoglobin (Hgb) ≥ 80 g/L within 14 days prior to randomization. * Must have total bilirubin ≤ 1.5 × institutional ULN \[≤ 2.0 x ULN in presence of liver metastases\] within 14 days prior to randomization. * Must have creatinine ≤ 1.5 × institutional ULN or Creatinine Clearance \> 50 ml/min within 14 days prior to randomization. * Must have absolute neutrophil count ≥ 1.5 x 109/L within 14 days prior to randomization. * Must have platelet count ≥ 75 x 109/L within 14 days prior to randomization. * Other biochemistry which must be done within 14 days prior to randomization includes lactate dehydrogenase (LDH) and alkaline phosphatase. * Patient must consent to provision of, and investigator(s) must confirm access to and agree to submit at the request of the NCIC CTG Central Tumour Bank, a representative formalin fixed paraffin block of tumour tissue 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. * Patient is able (i.e. sufficiently fluent) and willing to complete the Quality of Life and Health Utilities questionnaires in one of the validated languages for the questionnaires. * Patients must be accessible for treatment and follow-up. Patients registered on this trial must be treated and followed at the participating centre. This implies there must be reasonable geographical limits placed on patients being considered for this trial. * 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 clinical studies during their participation in this trial while on study treatment.
Exclusion criteria
* Anti-cancer chemotherapy or biologic therapy within the lesser of i) 21 days, or ii) the usual cycle length of the regimen (e.g. 14 days for FOLFOX), prior to the first planned dose of BBI608/placebo. An exception is made for capecitabine and regorafenib, 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. * 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 (e.g. active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection). * Unable or unwilling to swallow BBI608/placebo capsules daily. * Uncontrolled intercurrent 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. * 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 tumours curatively treated with no evidence of disease for ≥ 5 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 month | Time from the day of randomization to death. For alive patients, overall survival was censored at the last day the patient was known alive (LKA). |
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. |
| Disease Control Rate | 36 months | Proportion of all randomized patients with a documented complete response (CR) defined as disappearance of all target lesions, partial response (PR) defined as \>=30% decrease in the sum of the longest diameter of target lesions, and stable disease (SD) defined as \<30% decrease but also \<20% increase in the sum of the longest diameter of target lesions without new lesions per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1 for target lesion. |
| Number of Patients With Adverse Events | 36 months | Number of patients with at least one adverse event as assessed by NCI CTCAE Version 3.0 criteria. |
| Change of Global Quality of Life at 8 Weeks From Baseline | 8 weeks | Change scores from baseline at time 2 (8 weeks) from baseline for the global health status/quality of life scale scores (between 0 and 100 with higher value indicating better quality of life) as derived from responses of patients to the EORTC (European Organisation for Research and Treatment of Cancer) quality of life questionnaire (QLQ-C30). |
Countries
Australia, Canada, Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BBI608 BBI608 480 mg two times daily (960 mg total daily dose)+ Best Supportive Care
BBI608
Best Supportive Care | 138 |
| Placebo Placebo two times daily + Best Supportive Care
Placebo
Best Supportive Care | 144 |
| Total | 282 |
Baseline characteristics
| Characteristic | Placebo | BBI608 | Total |
|---|---|---|---|
| Age, Continuous | 64 years | 64 years | 64 years |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 0 | 42 Participants | 37 Participants | 79 Participants |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 1 | 102 Participants | 101 Participants | 203 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 26 Participants | 60 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 107 Participants | 112 Participants | 219 Participants |
| Region of Enrollment Australia | 45 participants | 52 participants | 97 participants |
| Region of Enrollment Canada | 77 participants | 64 participants | 141 participants |
| Region of Enrollment Japan | 22 participants | 22 participants | 44 participants |
| Sex: Female, Male Female | 51 Participants | 47 Participants | 98 Participants |
| Sex: Female, Male Male | 93 Participants | 91 Participants | 184 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 127 / 136 | 130 / 144 |
| other Total, other adverse events | 134 / 136 | 137 / 144 |
| serious Total, serious adverse events | 40 / 136 | 29 / 144 |
Outcome results
Primary
Overall Survival
Time from the day of randomization to death. For alive patients, overall survival was censored at the last day the patient was known alive (LKA).
Time frame: 36 month
Population: All patients who were randomized to this study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BBI608 | Overall Survival | 4.44 Months |
| Placebo | Overall Survival | 4.76 Months |
p-value: 0.33795% CI: [0.88, 1.46]Log Rank
Secondary
Change of Global Quality of Life at 8 Weeks From Baseline
Change scores from baseline at time 2 (8 weeks) from baseline for the global health status/quality of life scale scores (between 0 and 100 with higher value indicating better quality of life) as derived from responses of patients to the EORTC (European Organisation for Research and Treatment of Cancer) quality of life questionnaire (QLQ-C30).
Time frame: 8 weeks
Population: Patients who were assessed Quality of Life at baseline and week 8 from randomization.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BBI608 | Change of Global Quality of Life at 8 Weeks From Baseline | -10.61 units on a scale | Standard Deviation 23.1 |
| Placebo | Change of Global Quality of Life at 8 Weeks From Baseline | -10.66 units on a scale | Standard Deviation 17.07 |
p-value: 0.72Wilcoxon (Mann-Whitney)
Secondary
Disease Control Rate
Proportion of all randomized patients with a documented complete response (CR) defined as disappearance of all target lesions, partial response (PR) defined as \>=30% decrease in the sum of the longest diameter of target lesions, and stable disease (SD) defined as \<30% decrease but also \<20% increase in the sum of the longest diameter of target lesions without new lesions per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1 for target lesion.
Time frame: 36 months
Population: All patients randomized to this study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BBI608 | Disease Control Rate | 17 Participants |
| Placebo | Disease Control Rate | 18 Participants |
p-value: 0.95595% CI: [0.48, 2]Cochran-Mantel-Haenszel
Secondary
Number of Patients With Adverse Events
Number of patients with at least one adverse event as assessed by NCI CTCAE Version 3.0 criteria.
Time frame: 36 months
Population: All patients who have received at least one dose of BBI608/Placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BBI608 | Number of Patients With Adverse Events | 135 Participants |
| Placebo | Number of Patients With Adverse Events | 139 Participants |
Secondary
Progression Free Survival
Defined as the time from randomization to the first objective documentation of disease progression or death due to any cause.
Time frame: 36 months
Population: All patients randomized to this study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BBI608 | Progression Free Survival | 1.82 Months |
| Placebo | Progression Free Survival | 1.82 Months |
p-value: 0.83795% CI: [0.76, 1.26]Log Rank