Colorectal Cancer Metastatic
Conditions
Brief summary
The effectiveness and safety of TheraSphere will be evaluated in patients with colorectal cancer with metastases in the liver, who are scheduled to receive second line chemotherapy. All patients receive the standard of care chemotherapy with or without the addition of TheraSphere.
Interventions
DEVICETheraSphere
yttrium 90 microspheres
Sponsors
Biocompatibles UK Ltd
Boston Scientific Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be male or female, 18 years of age or older, and of any ethnic or racial group * If primary tumor has not been resected, it must be clinically stable * Must have colorectal cancer with unresectable metastatic disease to the liver (unresectable unilobar or bilobar disease) who have disease progression in the liver with oxaliplatin or irinotecan based first line chemotherapy * Must be eligible to receive second-line standard-of-care chemotherapy with either 1) an oxaliplatin-based chemotherapy regimen, or 2) an irinotecan-based chemotherapy regimen * Must have baseline efficacy images with measurable target tumors in the liver according to RECIST 1.1 using standard imaging techniques taken within 28 days prior to randomization. Images must be taken after, or at the time of completion of first line chemotherapy * Tumor replacement \<50% of total liver volume * Current Eastern Cooperative Oncology Group (ECOG) of 0-1 through screening to first treatment on study * Will have completed the first line chemotherapy regimen at least 14 days prior to initiation of 2nd line chemotherapy under the protocol * Patient is willing to participate in the study and has signed the study informed consent * Serum creatinine ≤ 2.0 mg/dL * Serum bilirubin up to 1.2 x upper limit of normal * Albumin ≥ 3.0 g/dL * Must have neutrophil count \>1200/mm3 (1.2x109/L)
Exclusion criteria
* History of hepatic encephalopathy * Contraindications to angiography and selective visceral catheterization such as bleeding diathesis or coagulopathy that is not correctable by usual therapy of hemostatic agents (eg. closure device) * History of severe peripheral allergy or intolerance to contrast agents, narcotics, sedatives or atropine that cannot be managed medically * Presentation of pulmonary insufficiency or clinically evident chronic obstructive pulmonary disease * Cirrhosis or portal hypertension * Prior external beam radiation treatment to the liver * Prior intra-arterial liver directed therapy, including transcatheter arterial chemoembolization (TACE) or Y-90 microsphere therapy * Planned treatment with biological agents within 28 days prior to receiving TheraSphere * Planned liver directed therapy or radiation therapy * Intervention for, or compromise of, the Ampulla of Vater * Clinically evident ascites (trace ascites on imaging is acceptable) * Toxicities due to prior cancer therapy that have not resolved before the initiation of study treatment, if the Investigator determines that the continuing complication will compromise the safe treatment of the patient * Significant life-threatening extra-hepatic disease, including patients who are on dialysis, have unresolved diarrhea, have serious unresolved infections including patients who are known to be human immunodeficiency virus (HIV) positive or have acute hepatitis B virus (HBV) or hepatitis C virus (HCV) * confirmed extra-hepatic metastases. Limited indeterminate extra-hepatic lesions in the lung and/or lymph nodes are permitted (up to 5 lesions in the lung, with each individual lesion \<1 cm; any number of lymph nodes with each individual nodes \<1.5 cm) * Contraindications to the planned second line standard-of-care chemotherapy regimen * Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization, and must not be breastfeeding and must agree to use contraceptive for duration of study. * Participation in a clinical trial with an investigational therapy within 30 days prior to randomization * Co-morbid disease or condition that would place the patient at undue risk and preclude safe use of TheraSphere treatment, in the Investigator's judgment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From date of randomization until the date of first documented progression, as defined by RECIST 1:1 or date of death from any cause, whichever comes first, assessed up to a minimum of 1 year follow up or until study completion | Progression Free survival by blinded independent central review per RECIST 1.1 |
| Hepatic Progression-Free Survival (HPFS) | Time from randomization until hepatic PD by BICR per RECIST 1.1 or death, whichever occurs first, assessed up to a minimum of 1 year follow up or study completion. | Hepatic Progression Free Survival (HPFS) by blinded independant central review per RECIST 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Time from date of randomization until date of death due to any cause; patients remaining on study post progression were followed until study completion; duration of follow up could be a few months to several years depending on when event was met. | Time from randomization until date of death due to any cause as reported by study site. |
Countries
Austria, Belgium, Canada, China, France, Germany, Italy, Poland, Singapore, South Korea, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group Standard of care second-line chemotherapy plus TheraSphere
TheraSphere: yttrium 90 microspheres | 215 |
| Control Group Standard of care second-line chemotherapy with no added therapy | 213 |
| Total | 428 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Reasons | 2 | 1 |
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Discontinuation by Investigator or Sponsor for any reason | 22 | 24 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 21 | 32 |
Baseline characteristics
| Characteristic | Treatment Group | Control Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 89 Participants | 81 Participants | 170 Participants |
| Age, Categorical Between 18 and 65 years | 126 Participants | 132 Participants | 258 Participants |
| Baseline Characteristics ECOG 0 at baseline | 119 Participants | 133 Participants | 252 Participants |
| Baseline Characteristics ECOG 1 at baseline | 95 Participants | 78 Participants | 173 Participants |
| KRAS status KRAS mutant | 100 Participants | 101 Participants | 201 Participants |
| KRAS status KRAS wildtype | 115 Participants | 112 Participants | 227 Participants |
| Race/Ethnicity, Customized Asian | 25 Participants | 17 Participants | 42 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 8 Participants | 17 Participants |
| Race/Ethnicity, Customized Missing | 15 Participants | 18 Participants | 33 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White or Caucasian | 164 Participants | 169 Participants | 333 Participants |
| Region of Enrollment Austria | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Belgium | 4 participants | 0 participants | 4 participants |
| Region of Enrollment Canada | 9 participants | 6 participants | 15 participants |
| Region of Enrollment France | 15 participants | 18 participants | 33 participants |
| Region of Enrollment Germany | 10 participants | 5 participants | 15 participants |
| Region of Enrollment Hong Kong | 3 participants | 1 participants | 4 participants |
| Region of Enrollment Poland | 28 participants | 28 participants | 56 participants |
| Region of Enrollment Singapore | 5 participants | 2 participants | 7 participants |
| Region of Enrollment South Korea | 13 participants | 9 participants | 22 participants |
| Region of Enrollment Spain | 22 participants | 17 participants | 39 participants |
| Region of Enrollment United Kingdom | 52 participants | 75 participants | 127 participants |
| Region of Enrollment United States | 54 participants | 50 participants | 104 participants |
| Sex: Female, Male Female | 80 Participants | 75 Participants | 155 Participants |
| Sex: Female, Male Male | 135 Participants | 138 Participants | 273 Participants |
| Unilobar vs Bilobar disease at baseline bilobar | 176 Participants | 173 Participants | 349 Participants |
| Unilobar vs Bilobar disease at baseline unilobar | 39 Participants | 40 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 182 / 215 | 165 / 213 |
| other Total, other adverse events | 186 / 187 | 196 / 207 |
| serious Total, serious adverse events | 95 / 187 | 47 / 207 |
Outcome results
Primary
Hepatic Progression-Free Survival (HPFS)
Hepatic Progression Free Survival (HPFS) by blinded independant central review per RECIST 1.1
Time frame: Time from randomization until hepatic PD by BICR per RECIST 1.1 or death, whichever occurs first, assessed up to a minimum of 1 year follow up or study completion.
Population: Outcome measurement includes data from all subjects in the ITT.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group | Hepatic Progression-Free Survival (HPFS) | 9.1 Months |
| Control Group | Hepatic Progression-Free Survival (HPFS) | 7.2 Months |
Comparison: Analysis performed using a log-rank test.p-value: <0.000195% CI: [0.46, 0.77]Log Rank
Primary
Progression Free Survival
Progression Free survival by blinded independent central review per RECIST 1.1
Time frame: From date of randomization until the date of first documented progression, as defined by RECIST 1:1 or date of death from any cause, whichever comes first, assessed up to a minimum of 1 year follow up or until study completion
Population: Outcome measurement includes data from all subjects in the ITT.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment Group | Progression Free Survival | 8.0 Months |
| Control Group | Progression Free Survival | 7.2 Months |
Comparison: Analysis performed using a log-rank testp-value: 0.001395% CI: [0.54, 0.88]Log Rank
Secondary
Overall Survival
Time from randomization until date of death due to any cause as reported by study site.
Time frame: Time from date of randomization until date of death due to any cause; patients remaining on study post progression were followed until study completion; duration of follow up could be a few months to several years depending on when event was met.
Population: ITT: all randomized patients with patient analyzed according to the treatment group to which they were randomized
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group | Overall Survival | 14 Months |
| Control Group | Overall Survival | 14.4 Months |