Hepatocellular Carcinoma (HCC)
Conditions
Brief summary
The purpose of this clinical research study is to learn if BMS-582664 can shrink or slow the growth of advanced liver cancer. The safety of this treatment will also be studied.
Interventions
DRUGbrivanib (active)
Tablet, Oral, Brivanib 800 mg, once daily, until progression
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of hepatocellular carcinoma (HCC) ≥ 2cm based on: * Biopsy OR * Radiological evidence of HCC by contrast-enhanced CT scan or contrast-enhanced AND * Blood test positive for Hepatitis B or C AND * Alpha fetoprotein above \> 400 mg/L * Not appropriate for curative surgery * Screening Blood Pressure \<150/100 mmHg, Left Ventricular Ejection Fraction (LVEF) \>50%
Exclusion criteria
* Heart Attack within 12 months, uncontrolled chest pain within 6 months * Ascites resistant to diuretic medication therapy * Portal-systemic encephalopathy * Portal hypertension with bleeding esophageal or gastric varices within the past 2 months * Deficiency of sodium in the blood with sodium \< 125 mEq/L * Subjects with serious non-healing wounds, ulcers or bone fractures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Rate at 6 Months Per Independent Response Review Committee (IRRC) in Cohort A | From first dose up to approximately 6 months after first dose | The percent of participants who have not progressed or died prior to 6 months from the date of their first dose. Participants who have neither progressed nor died but had their last tumor assessment prior to 6 months will not be categorized as progression free and will not be included. Tumor response was measured by the IRRC using mWHO criteria. Progression is defined as a 25% or more increase in the sum of all index lesion areas taking as reference the smallest sum recorded at or following baseline. |
| The Number of Participants Experiencing Adverse Events (AEs) | From first dose up to 30 days post last dose (up to approximately 34 months) | An Adverse Event (AE) is defined as any new untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have to have a causal relationship with this treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival for Participants With No Prior Systemic Therapy | From first dose to the date of death (up to approximately 34 months) | The time (in months) from first dosing until the date of death. For those participants who have not died, survival duration will be censored at the last date the participant was known to be alive. |
| Overall Survival for Participants With One Prior Angiogenesis Inhibitor Therapy | From first dose to the date of death (up to approximately 34 months) | The time (in months) from first dosing until the date of death. For those participants who have not died, survival duration will be censored at the last date the participant was known to be alive. |
| Progression Free Survival (PFS) Per Independent Response Review Committee (IRRC) | From first dose to the date of the first documented progression (up to approximately 34 months) | The time (in months) from first dosing date to the date of progression per IRRC. Participants who die without a reported prior progression will be considered to have progressed on their date of death (as found in the BMS clinical database). Participants who did not progress or die will be censored on the date of their last tumor assessment. Participants who have only baseline tumor assessment will be censored on the first dosing date. Progression is defined as a 25% or more increase in the sum of all index lesion areas taking as reference the smallest sum recorded at or following baseline. |
| Tumor Response Rate Per Independent Response Review Committee (IRRC) | From first dose to the date of the first documented response (up to approximately 34 months) | The percent of participants whose best overall response is a partial response (PR) or complete response (CR). Tumor measurements by CT/ MRI of the chest, abdomen and pelvis will be obtained at pre-treatment (within 28 days prior to the start of treatment) and every 6 weeks. Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later. |
| Duration of Response Per Independent Response Review Committee (IRRC) | From first dose to the date of documented progressive disease or death (up to approximately 34 months) | Duration of response will be computed as from time measurement criteria are met for PR or CR until the date of documented progressive disease or death. Participants who neither relapse nor die will be censored on the date of their last tumor assessment. Progression is defined as a 25% or more increase in the sum of all index lesion areas taking as reference the smallest sum recorded at or following baseline. Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later. |
| Change From Baseline to End of Treatment in FHSI-8 Total Score | Baseline and end of treatment (up to approximately 33 months) | FHSI-8 (Functional Assessment of Cancer Therapy, Hepatobiliary, Symptom Index) was used to assess HCC-related symptoms. The FHSI-8 includes eight items representing HCC-related symptoms; each symptom is rated by participants on a scale of from 0 to 4. The FHSI-8 total score ranges in value from 0 to 32, with higher scores representing fewer symptoms and lower scores representing more symptoms. |
| Time to Response Per Independent Response Review Committee (IRRC) | From first dose to the date of the first documented response (up to approximately 34 months) | The time from the first dose of study therapy until measurement criteria are first met for Partial response (PR) or complete response (CR), whichever is recorded first. Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later. |
| Disease Control Rate Per Independent Response Review Committee (IRRC) | From first dose to the date of the first documented response (up to approximately 34 months) | The percent of participants whose best response is a partial response (PR), complete response (CR) or stable disease (SD). Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later. Stable Disease (SD): A decrease of 50% or more or an increase of 25% or more in the sum of all index lesion areas compared to baseline cannot be established. There can be no appearance of new lesions. Documentation must occur 6 weeks (42 days) or more from the baseline determination. |
Countries
France, Hong Kong, Malaysia, Philippines, Singapore, South Korea, Taiwan, United States
Participant flow
Pre-assignment details
Cohort D data collection is not in scope of the planned primary and secondary endpoints per protocol amendment 07. Participants who are randomized into the doxorubicin arm and cross-over to brivanib prior to or after this amendment will not be included as treated participants in Arm A, B, or C.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Brivanib 800 mg QD) Participants with no prior systemic therapy receive brivanib (800 mg) daily (QD). | 55 |
| Group B (Brivanib 800 mg QD) Participants with one prior regimen of angiogenesis inhibitor therapy treated with brivanib (800 mg) daily (QD). | 46 |
| Group C (400 mg BID) Participants with one prior regimen of angiogenesis inhibitor therapy treated with brivanib (400 mg) twice daily (BID). | 22 |
| Cohort D: Doxorubicin All participants who received at least 1 dose of doxorubicin prior to Protocol Amendment 7. Participants treated with doxorubicin from the original protocol were allowed to cross-over to recieve brivanib alaninate after unequivocal disease progression (no cross-over was allowed for toxicity alone) providing they still met the eligibility criteria and had recovered from doxorubicin toxicities. | 14 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse event unrelated to study drug | 2 | 2 | 0 | 1 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Disease progression | 37 | 36 | 16 | 11 |
| Overall Study | Participant request to discontinue study treatment | 1 | 0 | 1 | 0 |
| Overall Study | Participant withdrew consent | 3 | 1 | 0 | 0 |
| Overall Study | Study drug toxicity | 11 | 7 | 5 | 2 |
Baseline characteristics
| Characteristic | Group A (Brivanib 800 mg QD) | Group B (Brivanib 800 mg QD) | Group C (400 mg BID) | Cohort D: Doxorubicin | Total |
|---|---|---|---|---|---|
| Age, Customized < 65 | 41 Participants | 34 Participants | 13 Participants | 9 Participants | 97 Participants |
| Age, Customized >= 65 | 14 Participants | 12 Participants | 9 Participants | 5 Participants | 40 Participants |
| Race/Ethnicity, Customized Asian Other | 5 Participants | 3 Participants | 2 Participants | 1 Participants | 11 Participants |
| Race/Ethnicity, Customized Black/ African American | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Chinese | 11 Participants | 5 Participants | 0 Participants | 1 Participants | 17 Participants |
| Race/Ethnicity, Customized Korean | 18 Participants | 23 Participants | 15 Participants | 7 Participants | 63 Participants |
| Race/Ethnicity, Customized Malaysian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian/ Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 18 Participants | 12 Participants | 4 Participants | 5 Participants | 39 Participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 3 Participants | 1 Participants | 23 Participants |
| Sex: Female, Male Male | 49 Participants | 33 Participants | 19 Participants | 13 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 39 / 55 | 37 / 46 | 13 / 22 | 4 / 14 | 3 / 6 |
| other Total, other adverse events | 54 / 55 | 45 / 46 | 22 / 22 | 14 / 14 | 6 / 6 |
| serious Total, serious adverse events | 24 / 55 | 17 / 46 | 5 / 22 | 5 / 14 | 5 / 6 |
Outcome results
Primary
Progression Free Survival (PFS) Rate at 6 Months Per Independent Response Review Committee (IRRC) in Cohort A
The percent of participants who have not progressed or died prior to 6 months from the date of their first dose. Participants who have neither progressed nor died but had their last tumor assessment prior to 6 months will not be categorized as progression free and will not be included. Tumor response was measured by the IRRC using mWHO criteria. Progression is defined as a 25% or more increase in the sum of all index lesion areas taking as reference the smallest sum recorded at or following baseline.
Time frame: From first dose up to approximately 6 months after first dose
Population: All treated participants with no prior systemic therapy (Pre-specified in Group A participants only).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Progression Free Survival (PFS) Rate at 6 Months Per Independent Response Review Committee (IRRC) in Cohort A | 22.4 Percent of participants |
Primary
The Number of Participants Experiencing Adverse Events (AEs)
An Adverse Event (AE) is defined as any new untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have to have a causal relationship with this treatment.
Time frame: From first dose up to 30 days post last dose (up to approximately 34 months)
Population: Pre-specified for all treated participants in group A, B, and C only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | The Number of Participants Experiencing Adverse Events (AEs) | 54 Participants |
| Group B (Brivanib 800 mg QD) | The Number of Participants Experiencing Adverse Events (AEs) | 46 Participants |
| Group C (400 mg BID) | The Number of Participants Experiencing Adverse Events (AEs) | 22 Participants |
Secondary
Change From Baseline to End of Treatment in FHSI-8 Total Score
FHSI-8 (Functional Assessment of Cancer Therapy, Hepatobiliary, Symptom Index) was used to assess HCC-related symptoms. The FHSI-8 includes eight items representing HCC-related symptoms; each symptom is rated by participants on a scale of from 0 to 4. The FHSI-8 total score ranges in value from 0 to 32, with higher scores representing fewer symptoms and lower scores representing more symptoms.
Time frame: Baseline and end of treatment (up to approximately 33 months)
Population: Pre-specified for all treated participants in group A, B, and C only with baseline and end of treatment measurements
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (Brivanib 800 mg QD) | Change From Baseline to End of Treatment in FHSI-8 Total Score | -4.01 Change from baseline in FSHI-8 score | Standard Deviation 8.37 |
| Group B (Brivanib 800 mg QD) | Change From Baseline to End of Treatment in FHSI-8 Total Score | -2.40 Change from baseline in FSHI-8 score | Standard Deviation 4.72 |
| Group C (400 mg BID) | Change From Baseline to End of Treatment in FHSI-8 Total Score | -1.06 Change from baseline in FSHI-8 score | Standard Deviation 6.98 |
Secondary
Disease Control Rate Per Independent Response Review Committee (IRRC)
The percent of participants whose best response is a partial response (PR), complete response (CR) or stable disease (SD). Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later. Stable Disease (SD): A decrease of 50% or more or an increase of 25% or more in the sum of all index lesion areas compared to baseline cannot be established. There can be no appearance of new lesions. Documentation must occur 6 weeks (42 days) or more from the baseline determination.
Time frame: From first dose to the date of the first documented response (up to approximately 34 months)
Population: Pre-specified for all treated participants in group A, B, and C only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Disease Control Rate Per Independent Response Review Committee (IRRC) | 50.9 Percent of participants |
| Group B (Brivanib 800 mg QD) | Disease Control Rate Per Independent Response Review Committee (IRRC) | 45.7 Percent of participants |
| Group C (400 mg BID) | Disease Control Rate Per Independent Response Review Committee (IRRC) | 54.5 Percent of participants |
Secondary
Duration of Response Per Independent Response Review Committee (IRRC)
Duration of response will be computed as from time measurement criteria are met for PR or CR until the date of documented progressive disease or death. Participants who neither relapse nor die will be censored on the date of their last tumor assessment. Progression is defined as a 25% or more increase in the sum of all index lesion areas taking as reference the smallest sum recorded at or following baseline. Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later.
Time frame: From first dose to the date of documented progressive disease or death (up to approximately 34 months)
Population: Pre-specified for all treated participants in group A, B, and C only whose best response is either PR or CR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Duration of Response Per Independent Response Review Committee (IRRC) | 2.9 Months |
| Group B (Brivanib 800 mg QD) | Duration of Response Per Independent Response Review Committee (IRRC) | 4.2 Months |
Secondary
Overall Survival for Participants With No Prior Systemic Therapy
The time (in months) from first dosing until the date of death. For those participants who have not died, survival duration will be censored at the last date the participant was known to be alive.
Time frame: From first dose to the date of death (up to approximately 34 months)
Population: Pre-specified for all treated participants in group A only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Overall Survival for Participants With No Prior Systemic Therapy | 9.95 Months |
Secondary
Overall Survival for Participants With One Prior Angiogenesis Inhibitor Therapy
The time (in months) from first dosing until the date of death. For those participants who have not died, survival duration will be censored at the last date the participant was known to be alive.
Time frame: From first dose to the date of death (up to approximately 34 months)
Population: Pre-specified for all treated participants in group B and C only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Overall Survival for Participants With One Prior Angiogenesis Inhibitor Therapy | 9.79 Months |
| Group B (Brivanib 800 mg QD) | Overall Survival for Participants With One Prior Angiogenesis Inhibitor Therapy | 8.25 Months |
Secondary
Progression Free Survival (PFS) Per Independent Response Review Committee (IRRC)
The time (in months) from first dosing date to the date of progression per IRRC. Participants who die without a reported prior progression will be considered to have progressed on their date of death (as found in the BMS clinical database). Participants who did not progress or die will be censored on the date of their last tumor assessment. Participants who have only baseline tumor assessment will be censored on the first dosing date. Progression is defined as a 25% or more increase in the sum of all index lesion areas taking as reference the smallest sum recorded at or following baseline.
Time frame: From first dose to the date of the first documented progression (up to approximately 34 months)
Population: Pre-specified for all treated participants in group A, B, and C only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Progression Free Survival (PFS) Per Independent Response Review Committee (IRRC) | 2.69 Months |
| Group B (Brivanib 800 mg QD) | Progression Free Survival (PFS) Per Independent Response Review Committee (IRRC) | 2.0 Months |
| Group C (400 mg BID) | Progression Free Survival (PFS) Per Independent Response Review Committee (IRRC) | 2.96 Months |
Secondary
Time to Response Per Independent Response Review Committee (IRRC)
The time from the first dose of study therapy until measurement criteria are first met for Partial response (PR) or complete response (CR), whichever is recorded first. Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later.
Time frame: From first dose to the date of the first documented response (up to approximately 34 months)
Population: Pre-specified for all treated participants in group A, B, and C only whose best response is either PR or CR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Time to Response Per Independent Response Review Committee (IRRC) | 10.4 Months |
| Group B (Brivanib 800 mg QD) | Time to Response Per Independent Response Review Committee (IRRC) | 1.4 Months |
Secondary
Tumor Response Rate Per Independent Response Review Committee (IRRC)
The percent of participants whose best overall response is a partial response (PR) or complete response (CR). Tumor measurements by CT/ MRI of the chest, abdomen and pelvis will be obtained at pre-treatment (within 28 days prior to the start of treatment) and every 6 weeks. Complete Response (CR): Disappearance of all known disease. Must be confirmed 4 or more weeks later. Partial Response (PR): A 50% or more decrease in the sum of all index lesion areas compared to the baseline sum and no unequivocal progression of existing non-index lesions. In addition, there can be no appearance of new lesions. Must be confirmed 4 or more weeks later.
Time frame: From first dose to the date of the first documented response (up to approximately 34 months)
Population: Pre-specified for all treated participants in group A, B, and C only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Brivanib 800 mg QD) | Tumor Response Rate Per Independent Response Review Committee (IRRC) | 7.3 Percent of participants |
| Group B (Brivanib 800 mg QD) | Tumor Response Rate Per Independent Response Review Committee (IRRC) | 4.3 Percent of participants |
| Group C (400 mg BID) | Tumor Response Rate Per Independent Response Review Committee (IRRC) | 0.0 Percent of participants |