Biliary Tract Cancer
Conditions
Brief summary
This study will evaluate the efficacy and safety of atezolizumab with bevacizumab in combination with cisplatin and gemcitabine(CisGem), compared with atezolizumab in combination with CisGem, in participants with advanced biliary tract cancer (BTC) who have not received prior systemic therapy. Treatment will consist of a chemotherapy combination phase followed by a cancer immunotherapy (CIT)/placebo phase.
Interventions
DRUGAtezolizumab
Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.
DRUGBevacizumab
Bevacizumab will be administered at a dose of 15 mg/kg intravenously on Day 1 of each 21-day cycle after atezolizumab.
OTHERPlacebo
Placebo matching bevacizumab will be administered intravenously on Day 1 of each 21-day cycle after atezolizumab.
DRUGCisplatin
Cisplatin will be administered intravenously at a dose of 25 mg/m\^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.
DRUGGemcitabine
Gemcitabine will be administered intravenously at a dose of 1000 mg/m\^2 on Days 1 and 8 of each 21-day cycle for Cycles 1-8.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Considered to be eligible to receive platinum-based chemotherapy, in the investigator's judgment * Documentation of recurrent/metastatic or locally advanced unresectable disease based on computed tomography (CT) or magnetic resonance imaging (MRI) scans * Histologically or cytologically confirmed diagnosis of iCCA, eCCA, or GBC * No prior systemic therapy for advanced BTC * At least one measurable untreated lesion (per RECIST v1.1) * Adequate biliary drainage with no evidence of ongoing infection * Eastern Cooperative Oncology Group Performance Status of 0 or 1 * Life expectancy of \> 3 months * Adequate hematologic and end-organ function * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm
Exclusion criteria
* Recurrent disease \<=6 months after curative surgery or \<= 6 months after the completion of adjuvant therapy * Prior local regional therapy such as radioembolization * Combined or mixed hepatocellular/cholangiocarcinoma * Clinically significant hepatic encephalopathy within the 12 months prior to Day 1 of Cycle 1 * National Cancer Institute Common Terminoogy Criteria for Adverse Events Grade \>= 2 peripheral neuropathy * Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to Day 1 of Cycle 1 * Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezolizumab or within 6 months after the final dose of bevacizumab, cisplatin or gemcitabine * Active or history of autoimmune disease or immune deficiency * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan * History of malignancy other than BTC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death * Symptomatic, untreated, or actively progressing CNS metastases * For patients with lung metastases, if one of the following criteria applies: Large, centrally located pulmonary metastases; Clear tumor infiltration into the thoracic great vessels seen on imaging; Clear cavitation of pulmonary lesions seen on imaging * Active tuberculosis * Co-infection with HBV and HCV * Treatment with systemic immunostimulatory agents or immunosuppressive medication * Inadequately controlled arterial hypertension * History of hypertensive crisis or hypertensive encephalopathy * Significant vascular disease * Evidence of bleeding diathesis or significant coagulopathy * Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture * Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID) * Preexisting renal impairment, myelosuppression, or hearing impairment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months) | PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Objective Response Rate (ORR) | Randomization up to approximately 14 months | Confirmed ORR is defined as the proportion of participants with Complete Response (CR) or Partial Response (PR) on two consecutive occasions \>=4 weeks apart, as determined by the investigator according to RECIST v1.1. |
| Duration of Response (DOR) | First occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months) | DOR is defined as the time from the first occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first). |
| Disease Control Rate (DCR) | Randomization up to approximately 14 months | DCR is defined as the proportion of participants with a CR or a PR on two consecutive occasions \>= 4 weeks apart or SD with a minimum duration of 9weeks, as determined by the investigator according to RECIST v1.1 |
| Time to Confirmed Deterioration (TTCD) | Randomization to the first clinically meaningful deterioration (up to approximately 14 months) | TTCD in patient-reported physical functioning, role functioning, and quality of life, as measured by the respective scales of the EORTC QLQ-C30 and/or EORTC IL77, and defined as the time from randomization to the first clinically meaningful deterioration that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks. |
| Overall Survival (OS) | Randomization to death from any cause (up to approximately 23 months) | OS is defined as the time from randomization to death from any cause. |
| Serum Concentration of Atezolizumab | Pre-Dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and Post Dose Day 1 of Cycle 1 (cycle length=21 days) | Serum concentration of atezolizumab at specified timepoints. |
| Prevalence of ADAs to Atezolizumab | Baseline | — |
| Incidence of ADAs to Atezolizumab | At pre-defined intervals from administration of study drug up to approximately 14 months | — |
| Percentage of Participants With at Least One Adverse Event | Treatment start up to approximately 30 months. | Percentage of participants with at least one adverse event. |
Countries
China, Hong Kong, Italy, Poland, Russia, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study is considered Completed because all pre-planned study activities and analyses have been performed. Participants are ongoing treatment on a roll over study.
Participants by arm
| Arm | Count |
|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) \*Cycle is 21 days. Cisplatin is administered on Days 1 and 8 of each 21 day cycle for cycles 1-8. | 83 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) \*Cycle is 21 days. Cisplatin is administered on Days 1 and 8 of each 21 day cycle for cycles 1-8. | 79 |
| Total | 162 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 51 | 49 |
| Overall Study | Progressive Disease | 1 | 0 |
| Overall Study | Study Terminated By Sponsor | 28 | 24 |
| Overall Study | Symptomatic Deterioration | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 5 |
Baseline characteristics
| Characteristic | Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Total | Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) |
|---|---|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 9.9 | 61.3 Years STANDARD_DEVIATION 10 | 63.0 Years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 160 Participants | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 37 Participants | 72 Participants | 35 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 41 Participants | 87 Participants | 46 Participants |
| Sex: Female, Male Female | 30 Participants | 75 Participants | 45 Participants |
| Sex: Female, Male Male | 49 Participants | 87 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 51 / 83 | 49 / 79 |
| other Total, other adverse events | 81 / 81 | 77 / 78 |
| serious Total, serious adverse events | 43 / 81 | 36 / 78 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)
Time frame: Randomization to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months)
Population: Analysis was performed on the Intent-to-treat (ITT) population, defined as all randomized participants, regardless of whether they received the assigned treatment or not, were included for analyses with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Progression Free Survival (PFS) | 7.92 Months |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Progression Free Survival (PFS) | 8.35 Months |
Comparison: Stratified analysis. Stratification factors are: Location of primary tumor (iCCA vs.~eCCA vs. GBC), Geographic region (Asia vs. Rest of the World).95% CI: [0.51, 1.14]Regression, Cox
Secondary
Confirmed Objective Response Rate (ORR)
Confirmed ORR is defined as the proportion of participants with Complete Response (CR) or Partial Response (PR) on two consecutive occasions \>=4 weeks apart, as determined by the investigator according to RECIST v1.1.
Time frame: Randomization up to approximately 14 months
Population: Analysis was performed on the Intent-to-treat (ITT) population, defined as all randomized participants, regardless of whether they received the assigned treatment or not, were included for analyses with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Confirmed Objective Response Rate (ORR) | 25.3 Percentage of participants |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Confirmed Objective Response Rate (ORR) | 24.1 Percentage of participants |
Secondary
Disease Control Rate (DCR)
DCR is defined as the proportion of participants with a CR or a PR on two consecutive occasions \>= 4 weeks apart or SD with a minimum duration of 9weeks, as determined by the investigator according to RECIST v1.1
Time frame: Randomization up to approximately 14 months
Population: Analysis was performed on the Intent-to-treat (ITT) population, defined as all randomized participants, regardless of whether they received the assigned treatment or not, were included for analyses with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Disease Control Rate (DCR) | 75.9 Percentage of participants |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Disease Control Rate (DCR) | 78.5 Percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time from the first occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first).
Time frame: First occurrence of a confirmed objective response to disease progression as determined by the investigator according to RECIST v1.1 or death from any cause (whichever occurs first)(up to approximately 14 months)
Population: Analysis was performed on the Intent-to-treat (ITT) population, defined as all randomized participants, regardless of whether they received the assigned treatment or not, were included for analyses with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Duration of Response (DOR) | 5.78 Months |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Duration of Response (DOR) | NA Months |
Secondary
Incidence of ADAs to Atezolizumab
Time frame: At pre-defined intervals from administration of study drug up to approximately 14 months
Population: The immunogenicity analysis population consist of all participants with at least 1 postbaseline ADA assessment. Participants are grouped according to treatment received. No data were collected because the study was discontinued before any measurements were completed.
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to death from any cause.
Time frame: Randomization to death from any cause (up to approximately 23 months)
Population: Analysis was performed on the Intent-to-treat (ITT) population, defined as all randomized participants, regardless of whether they received the assigned treatment or not, were included for analyses with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Overall Survival (OS) | 14.59 Months |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Overall Survival (OS) | 14.85 Months |
Comparison: Stratified analysis. Stratification factors are: Location of primary tumor (iCCA vs.~eCCA vs. GBC), Geographic region (Asia vs. Rest of the World).p-value: 0.885795% CI: [0.64, 1.47]Log Rank
Secondary
Percentage of Participants With at Least One Adverse Event
Percentage of participants with at least one adverse event.
Time frame: Treatment start up to approximately 30 months.
Population: Safety analyses will be performed on the safety-evaluable population, which is defined as all randomized participants who receive any amount of any component of protocol treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Percentage of Participants With at Least One Adverse Event | 100 Percentage of participants |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Percentage of Participants With at Least One Adverse Event | 100 Percentage of participants |
Secondary
Prevalence of ADAs to Atezolizumab
Time frame: Baseline
Population: The immunogenicity analysis population consist of all participants with at least 1 postbaseline ADA assessment. Participants are grouped according to treatment received. No data were collected because the study was discontinued before any measurements were completed.
Secondary
Serum Concentration of Atezolizumab
Serum concentration of atezolizumab at specified timepoints.
Time frame: Pre-Dose on Day 1 of Cycles 1, 2, 3, 4, 8, 12, and 16, and Post Dose Day 1 of Cycle 1 (cycle length=21 days)
Population: The PK analysis population consisted of all participants with at least 1 PK assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 12 Day 1 Pre-Dose | 210 μg/ mL | Standard Deviation 76.4 |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 8 Day 1 Pre-Dose | 200 μg/ mL | Standard Deviation 100 |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 1 Day 1 Pre-Dose | NA μg/ mL | — |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 1 Day 1 Post Dose | 411 μg/ mL | Standard Deviation 73.8 |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 2 Day 1 Pre-Dose | 79.4 μg/ mL | Standard Deviation 46.1 |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 3 Day 1 Pre-Dose | 118 μg/ mL | Standard Deviation 41.4 |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 4 Day 1 Pre-Dose | 155 μg/ mL | Standard Deviation 50.6 |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 16 Day 1 Pre-Dose | 174 μg/ mL | Standard Deviation 64.9 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 16 Day 1 Pre-Dose | 230 μg/ mL | Standard Deviation 71.6 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 12 Day 1 Pre-Dose | 223 μg/ mL | Standard Deviation 103 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 2 Day 1 Pre-Dose | 85.0 μg/ mL | Standard Deviation 71.7 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 8 Day 1 Pre-Dose | 224 μg/ mL | Standard Deviation 126 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 4 Day 1 Pre-Dose | 153 μg/ mL | Standard Deviation 74.8 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 1 Day 1 Pre-Dose | NA μg/ mL | — |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 3 Day 1 Pre-Dose | 129 μg/ mL | Standard Deviation 83.5 |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Serum Concentration of Atezolizumab | Cycle 1 Day 1 Post Dose | 416 μg/ mL | Standard Deviation 173 |
Secondary
Time to Confirmed Deterioration (TTCD)
TTCD in patient-reported physical functioning, role functioning, and quality of life, as measured by the respective scales of the EORTC QLQ-C30 and/or EORTC IL77, and defined as the time from randomization to the first clinically meaningful deterioration that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks.
Time frame: Randomization to the first clinically meaningful deterioration (up to approximately 14 months)
Population: Analysis was performed on the Intent-to-treat (ITT) population, defined as all randomized participants, regardless of whether they received the assigned treatment or not, were included for analyses with participants grouped according to the treatment assigned at randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Time to Confirmed Deterioration (TTCD) | Quality of Life | 6.28 Months |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Time to Confirmed Deterioration (TTCD) | Physical Function Scale | 3.29 Months |
| Arm B: Atezo+PBO+CisGem (Cycle*1-8), Followed by Atezo+PBO (Cycle*9 and Beyond) | Time to Confirmed Deterioration (TTCD) | Role Function Scale | 3.52 Months |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Time to Confirmed Deterioration (TTCD) | Quality of Life | 2.79 Months |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Time to Confirmed Deterioration (TTCD) | Physical Function Scale | 6.21 Months |
| Arm A: Atezo+Bev+CisGem (Cycle*1-8), Followed by Atezo+Bev (Cycle*9 and Beyond) | Time to Confirmed Deterioration (TTCD) | Role Function Scale | 4.24 Months |
Comparison: Quality of Life95% CI: [0.93, 2.63]Regression, Cox
Comparison: Physical Function Scale95% CI: [0.48, 1.36]Regression, Cox
Comparison: Role Function Scale95% CI: [0.68, 1.85]Regression, Cox