Gallbladder Carcinoma, Metastatic Cholangiocarcinoma, Stage III Intrahepatic Cholangiocarcinoma AJCC v8, Stage IV Intrahepatic Cholangiocarcinoma AJCC v8, Unresectable Cholangiocarcinoma
Conditions
Brief summary
This randomized phase II trial studies how well atezolizumab with or without cobimetinib works in treating patients with bile duct cancer that has spread to other places in the body (metastatic) and cannot be removed by surgery (unresectable) or gallbladder cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving atezolizumab with cobimetinib may work better at treating patients with bile duct and gallbladder cancer.
Detailed description
PRIMARY OBJECTIVE: I. To assess the progression free survival (PFS) of patients receiving atezolizumab monotherapy and cobimetinib in combination with atezolizumab for unresectable cholangiocarcinoma. SECONDARY OBJECTIVES: I. To assess the overall survival (OS) of patients receiving cobimetinib in combination with atezolizumab and atezolizumab monotherapy for unresectable cholangiocarcinoma. II. To determine the objective response rate (ORR), defined as complete plus partial response, of cobimetinib in combination with atezolizumab and atezolizumab monotherapy in patients with unresectable cholangiocarcinoma. III. To assess the safety and tolerability of cobimetinib in combination with atezolizumab and atezolizumab monotherapy in patients with unresectable cholangiocarcinoma. IV. To determine the relationship between PD-L1 expression in tumor at baseline and on treatment, and response to treatment. CORRELATIVE OBJECTIVES: I. To determine the effect of cobimetinib on CD8+ T cell infiltration in tumor. II. To determine the effect of cobimetinib on T cell subpopulations systemically and in tumor, PD-1/PD-L1 expression on tumor, and MHC 1/2 expression. III. To determine the effect of cobimetinib on markers of immune exhaustion and pro-apoptotic factors in CD8+ effector T cells. IV. To explore the effect of cobimetinib on local and systemic immune activation pathways and immune suppressive pathways through expression profiling. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples throughout the trial and undergo tumor biopsy on study. ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 and cobimetinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and collection of blood samples throughout the trial and undergo tumor biopsy on study. After completion of study treatment, patients are followed up every 3 months until death, withdrawal of consent, or study closure, whichever occurs first.
Interventions
DRUGAtezolizumab
Given IV
PROCEDUREBiopsy
Undergo tumor biopsy
PROCEDUREBiospecimen Collection
Undergo collection of blood samples
DRUGCobimetinib
Given PO
PROCEDUREComputed Tomography
Undergo CT
PROCEDUREMagnetic Resonance Imaging
Undergo MRI
Sponsors
National Cancer Institute (NCI)
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
* Pathologically confirmed metastatic or unresectable cholangiocarcinoma or gallbladder carcinoma (GBC), having received at least 1 prior line of systemic therapy, and received no more than 2 prior lines of therapy in the metastatic setting (disease recurrence =\< 6 months from the last dose of adjuvant therapy in resected patients will be considered the first line of therapy) * Includes intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC), and gallbladder carcinoma (GBC), but not ampulla of vater cancers * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) with conventional techniques or as \>= 10 mm (\>= 1 cm) with spiral CT scan, MRI, or calipers by clinical exam; assessment must be completed within 4 weeks of randomization * Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of cobimetinib in combination with atezolizumab in patients \< 18 years of age, children are excluded from this study * Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 80%) * Life expectancy of greater than 2 months * Leukocytes \>= 2,500/mcL (within 2 weeks of randomization) * Absolute neutrophil count \>= 1,500/mcL (within 2 weeks of randomization) * Platelets \>= 75,000/mcL (within 2 weeks of randomization) * Hemoglobin \>= 8 g/dL (within 2 weeks of randomization) * Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =\< 3 x ULN may be enrolled) (within 2 weeks of randomization) * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x ULN (within 2 weeks of randomization) * Creatinine clearance \>= 30 mL/min/1.73 m\^2 by Cockcroft-Gault OR creatinine \< 1.5 x ULN (within 2 weeks of randomization) * International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =\< 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose) (within 2 weeks of randomization) * Administration of atezolizumab and cobimetinib may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; women of childbearing potential must agree to use either two adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual activity (complete abstinence) prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; male patients must agree to use an adequate method of contraception, or to abstain from heterosexual activity (complete abstinence), prior to study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent * Ability to understand and the willingness to sign a written informed consent document * Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have: * A stable regimen of highly active anti-retroviral therapy (HAART) * No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections * A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests * Oxygen saturation \>= 92% on room air
Exclusion criteria
* Received chemotherapy or radiotherapy within 3 weeks prior to randomization or those who have not recovered to =\< grade 1 adverse events (other than alopecia) due to agents administered more than 3 weeks earlier; herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to randomization; for patients who received prior immunotherapy (eg anti-CTLA-4), at least five drug half-lives must have passed before the patient may enroll on this study; however, the following therapies are allowed: * Hormone-replacement therapy or oral contraceptives * Palliative radiotherapy for bone metastases \>= 2 weeks prior to randomization * Prior treatment with a MEK inhibitor or ERK inhibitor * Prior treatment with any anti-PD-1 or anti-PD-L1 antibody, prior allogeneic bone marrow transplantation, or prior solid organ transplantation * Treatment with any investigational agent within 4 weeks prior to cycle 1, day 1, or five drug half-lives (whichever is longer) * Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 6 weeks prior to cycle 1 day 1; * Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed * Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, with the following exceptions: * Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following: * Radiographic demonstration of clinical stability upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS directed therapy and the screening radiographic study * No stereotactic radiation or whole-brain radiation within 28 days prior to randomization * Screening CNS radiographic study \>= 4 weeks from completion of radiotherapy and \>= 2 weeks from discontinuation of corticosteroids * Has a known concurrent malignancy that is expected to require active treatment within two years, or may interfere with the interpretation of the efficacy and safety outcomes of this study in the opinion of the treating investigator; superficial bladder cancer, non-melanoma skin cancers, or low grade prostate cancer not requiring therapy should not exclude participation in this trial * Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies * Allergy or hypersensitivity to components of the cobimetinib formulations * History of congenital long QT syndrome or corrected QT interval (QTc) \> 450 msec within 2 weeks of randomization * Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower, as determined by echocardiogram or multi-gated acquisition (MUGA) scan within 4 weeks of randomization * Patients who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From date of randomization to time of progression or death, assessed up to 1 year | PFS within each treatment arm will be summarized descriptively and compared between groups, under the assumption of Cox proportional hazards, using the stratified log-rank test to account for tumor site. 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 a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to 1 year | Will be assessed using National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The incidence of AEs will be tabulated by subgroups of interest (e.g. grade 3 or higher, organ class, relationship to study drug). For analyses at the individual level, the highest grade and relationship to study drug will be assumed if multiple events have occurred. Toxicity will be tabulated by type and grade and will be summarized with descriptive statistics. |
| Objective Response Rate | Up to 1 year | Defined as the proportion of response evaluable subjects who have a complete response or partial response and will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Overall Survival | From date of randomization to time of death, assessed up to 1 year | Results will be summarized descriptively and compared between groups, under the assumption of proportional hazards, using the stratified log-rank test to account for tumor site. |
| Change in CD8+ Density Within the Tumor | Day 21 | Change between the pre-treatment tumor biopsy to the on-treatment biopsy collected on day 21. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With PD-L1 Expression | Up to 1 year | The number of participants with tumors expressing PD-L1 by 1 percent or more. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Atezolizumab) Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 43 |
| Arm B (Atezolizumab, Cobimetinib) Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 and cobimetinib PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 43 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Health event before starting | 1 | 0 |
| Overall Study | No longer eligible | 2 | 5 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Arm A (Atezolizumab) | Arm B (Atezolizumab, Cobimetinib) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 4 Participants | 5 Participants |
| Age, Categorical >=65 years | 10 Participants | 11 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 28 Participants | 60 Participants |
| Age, Continuous | 62 years | 63 years | 63 years |
| Body Surface Area | 1.81 meters squared (m^2) | 1.90 meters squared (m^2) | 1.89 meters squared (m^2) |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 33 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Height | 163.4 centimeter (cm) | 166.4 centimeter (cm) | 164.9 centimeter (cm) |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 2 Participants | 7 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 | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) White | 33 Participants | 37 Participants | 70 Participants |
| Region of Enrollment United States | 43 participants | 43 participants | 86 participants |
| Sex: Female, Male Female | 30 Participants | 23 Participants | 53 Participants |
| Sex: Female, Male Male | 13 Participants | 20 Participants | 33 Participants |
| Subgroup Extrahepatic cholangiocarcinoma (EHC) | 9 Participants | 9 Participants | 18 Participants |
| Subgroup Gallbladder cancer (GBC) | 12 Participants | 10 Participants | 22 Participants |
| Subgroup Intrahepatic cholangiocarcinoma (IHC) | 22 Participants | 24 Participants | 46 Participants |
| Weight | 71.5 kilogram (kg) | 78.5 kilogram (kg) | 76.9 kilogram (kg) |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 35 / 43 | 35 / 43 |
| other Total, other adverse events | 38 / 43 | 36 / 43 |
| serious Total, serious adverse events | 32 / 43 | 31 / 43 |
Outcome results
Primary
Progression Free Survival (PFS)
PFS within each treatment arm will be summarized descriptively and compared between groups, under the assumption of Cox proportional hazards, using the stratified log-rank test to account for tumor site. 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 a non-target lesion, or the appearance of new lesions.
Time frame: From date of randomization to time of progression or death, assessed up to 1 year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Atezolizumab) | Progression Free Survival (PFS) | Progression free at 1 Year after Randomization | 0 Participants |
| Arm A (Atezolizumab) | Progression Free Survival (PFS) | Progressed or Off Treatment by 1 Year after Randomization | 39 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Progression Free Survival (PFS) | Progression free at 1 Year after Randomization | 3 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Progression Free Survival (PFS) | Progressed or Off Treatment by 1 Year after Randomization | 35 Participants |
p-value: 0.02790% CI: [0.35, 0.93]Log Rank
Secondary
Change in CD8+ Density Within the Tumor
Change between the pre-treatment tumor biopsy to the on-treatment biopsy collected on day 21.
Time frame: Day 21
Population: Participants with paired high-quality biopsies (fold change pre- and post-treatment).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Atezolizumab) | Change in CD8+ Density Within the Tumor | 0.719 cells per millimeter squared | Standard Deviation 0.469 |
| Arm B (Atezolizumab, Cobimetinib) | Change in CD8+ Density Within the Tumor | 0.892 cells per millimeter squared | Standard Deviation 0.535 |
Secondary
Number of Participants With Adverse Events
Will be assessed using National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The incidence of AEs will be tabulated by subgroups of interest (e.g. grade 3 or higher, organ class, relationship to study drug). For analyses at the individual level, the highest grade and relationship to study drug will be assumed if multiple events have occurred. Toxicity will be tabulated by type and grade and will be summarized with descriptive statistics.
Time frame: Up to 1 year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Atezolizumab) | Number of Participants With Adverse Events | Grade 3 or higher adverse event considered at least possibly related to the study drug(s) | 15 Participants |
| Arm A (Atezolizumab) | Number of Participants With Adverse Events | No grade 3 or higher adverse events considered at least possibly related to the study drug(s) | 24 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Number of Participants With Adverse Events | Grade 3 or higher adverse event considered at least possibly related to the study drug(s) | 17 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Number of Participants With Adverse Events | No grade 3 or higher adverse events considered at least possibly related to the study drug(s) | 21 Participants |
p-value: 0.22Fisher Exact
Secondary
Objective Response Rate
Defined as the proportion of response evaluable subjects who have a complete response or partial response and will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 1 year
Population: Evaluable population excluded patients removed from study prior to the first radiographic evaluation time point for clinical progression or death from tumor progression.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Atezolizumab) | Objective Response Rate | Complete Response | 0 Participants |
| Arm A (Atezolizumab) | Objective Response Rate | Partial Response | 1 Participants |
| Arm A (Atezolizumab) | Objective Response Rate | Stable Disease | 10 Participants |
| Arm A (Atezolizumab) | Objective Response Rate | Clinical or Radiographic Progression | 25 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Objective Response Rate | Clinical or Radiographic Progression | 16 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Objective Response Rate | Complete Response | 0 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Objective Response Rate | Stable Disease | 13 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Objective Response Rate | Partial Response | 1 Participants |
Secondary
Overall Survival
Results will be summarized descriptively and compared between groups, under the assumption of proportional hazards, using the stratified log-rank test to account for tumor site.
Time frame: From date of randomization to time of death, assessed up to 1 year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Atezolizumab) | Overall Survival | Alive at 1 year | 9 Participants |
| Arm A (Atezolizumab) | Overall Survival | Deceased or Lost to Follow Up at 1 year | 30 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Overall Survival | Alive at 1 year | 9 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Overall Survival | Deceased or Lost to Follow Up at 1 year | 29 Participants |
p-value: 0.41Log Rank
Other Pre-specified
Number of Participants With PD-L1 Expression
The number of participants with tumors expressing PD-L1 by 1 percent or more.
Time frame: Up to 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Atezolizumab) | Number of Participants With PD-L1 Expression | 1% or more Positivity | 1 Participants |
| Arm A (Atezolizumab) | Number of Participants With PD-L1 Expression | No expression | 8 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Number of Participants With PD-L1 Expression | 1% or more Positivity | 1 Participants |
| Arm B (Atezolizumab, Cobimetinib) | Number of Participants With PD-L1 Expression | No expression | 8 Participants |