Melanoma
Conditions
Brief summary
This study will evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma.
Detailed description
The study is divided into 2 stages. Stage I of the study is completed when 22 patients with measurable disease have been enrolled and completed ORR evaluation. If the number of responders in Stage I is more than 3, another 16 patients may be enrolled to Stage II.
Interventions
DRUGAtezolizumab
Atezolizumab 1200 mg will be administered intravenously every 3 weeks.
DRUGBevacizumab
Bevacizumab 7.5 mg/kg will be administered intravenously every 3 weeks.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed unresectable locally advanced(stage III) or metastatic(Stage IV) mucosal melanoma * May have received prior systemic treatment or treatment naive at enrollment * Measurable disease per RECIST v1.1 * ECOG Performance Status of 0-1 * Life expectancy \>= 12 weeks * Adequate hematologic and end-organ function * Negative HIV test at screening * Negative hepatitis B surface antigen test at screening * Negative hepatitis B core antibody at screening, or positive total HBcAb test followed by quantitative hepatitis B virus DNA\<500 IU/mL at screening. * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening * 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 contraceptive measures, and agreement to refrain from donating sperm
Exclusion criteria
* Symptomatic or actively progressing central nervous system (CNS) metastases * History of leptomeningeal disease * Uncontrolled tumor-related pain * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Uncontrolled or symptomatic hypercalcemia * Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: 1) Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. 2) Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. 3) Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only are eligible for the study provided all of following conditions are met: (i) Rash must cover \< 10% of body surface area (ii) Disease is well controlled at baseline and requires only low-potency topical corticosteroids (iii) No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * Active tuberculosis * Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina * History of malignancy other than melanoma within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer * Prior allogeneic stem cell or solid organ transplantation * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications * Current treatment with anti-viral therapy for HBV * Current, recent (within 28 days prior to initiation of study treatment) or planned treatment with any other investigational agent or participation in another clinical study with anti-cancer therapeutic intent * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab, 6 months after the final dose of bevacizumab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) in the Full Analysis Set Analysis Population | Up to approximately 32 months | ORR was defined as the percentage of participants with a complete response (CR) defined as disappearance of all target lesions, or partial response (PR) defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR, on two consecutive occasions \>= 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to approximately 32 months | PFS was defined as the time from the date of first treatment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1. |
| Overall Survival (OS) | Up to approximately 32 months | Overall survival was defined as the time from the date of first treatment to death from any cause. |
| Duration of Objective Response (DOR) | Up to approximately 32 months | DOR was defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 |
| Disease Control Rate (DCR) | Up to approximately 32 months | DCR was defined as the sum of a complete or partial response or stable disease rates as determined by the investigator according to RECIST v1.1. |
| Percentage of Participants With Adverse Events | From the first study drug to the data cutoff date: 31 August 2022 (up to approximately 32 months) | The percentage of participants who experienced an Adverse Event (AE) or Serious Adverse Event (SAE). Incidence, nature, and severity of Adverse Events (AE), are reported per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0). |
Countries
China
Participant flow
Recruitment details
This study was conducted at 3 centers in China.
Pre-assignment details
There were 20 participants who died during the follow-up period who were recorded as study completed as per the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Atezolizumab + Bevacizumab Participants received 1200 mg atezolizumab by intravenous infusion every 3 weeks and/or 7.5 mg/kg bevacizumab by intravenous infusion every 3 weeks until unacceptable toxicity or loss of clinical benefit as determined by the investigator. Participants who transiently withheld or permanently discontinued either atezolizumab or bevacizumab may continue on single-agent therapy as long as the participants were experiencing clinical benefit in the opinion of the investigator. | 43 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
Baseline characteristics
| Characteristic | Atezolizumab + Bevacizumab |
|---|---|
| Age, Continuous | 61.0 Years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 43 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 20 / 43 |
| other Total, other adverse events | 34 / 43 |
| serious Total, serious adverse events | 9 / 43 |
Outcome results
Primary
Objective Response Rate (ORR) in the Full Analysis Set Analysis Population
ORR was defined as the percentage of participants with a complete response (CR) defined as disappearance of all target lesions, or partial response (PR) defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR, on two consecutive occasions \>= 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).
Time frame: Up to approximately 32 months
Population: Full Analysis Set (FAS) is defined as all enrolled participants who receive any amount of study treatment and evaluable for efficacy endpoints.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Bevacizumab | Objective Response Rate (ORR) in the Full Analysis Set Analysis Population | 45.0 Percentage of participants |
Secondary
Disease Control Rate (DCR)
DCR was defined as the sum of a complete or partial response or stable disease rates as determined by the investigator according to RECIST v1.1.
Time frame: Up to approximately 32 months
Population: Full Analysis Set (FAS) was defined as all enrolled participants who receive any amount of study treatment and evaluable for efficacy endpoints.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atezolizumab + Bevacizumab | Disease Control Rate (DCR) | 65.0 Percentage of Participants |
Secondary
Duration of Objective Response (DOR)
DOR was defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
Time frame: Up to approximately 32 months
Population: Only responders (CR/PR) assessed by investigator were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Bevacizumab | Duration of Objective Response (DOR) | 12.42 Months |
Secondary
Overall Survival (OS)
Overall survival was defined as the time from the date of first treatment to death from any cause.
Time frame: Up to approximately 32 months
Population: Full Analysis Set (FAS) was defined as all enrolled participants who receive any amount of study treatment and evaluable for efficacy endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Bevacizumab | Overall Survival (OS) | 24.77 Months |
Secondary
Percentage of Participants With Adverse Events
The percentage of participants who experienced an Adverse Event (AE) or Serious Adverse Event (SAE). Incidence, nature, and severity of Adverse Events (AE), are reported per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0).
Time frame: From the first study drug to the data cutoff date: 31 August 2022 (up to approximately 32 months)
Population: Safety analysis set is defined as all enrolled participants who receive any amount of least one dose of any study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage of participants with at least 1 AE | 95.3 Percentage of participants |
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage of participants with at least one Grade 3-5 AE | 25.6 Percentage of participants |
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage of participants with at least one AE by worst grade - Grade 1 | 41.9 Percentage of participants |
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage of participants with at least one AE by worst grade - Grade 2 | 27.9 Percentage of participants |
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage of participants with at least one AE by worst grade - Grade 3 | 23.3 Percentage of participants |
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage of participants with at least one AE by worst grade - Grade 4 | 0 Percentage of participants |
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage of participants with at least one AE by worst grade - Grade 5 | 2.3 Percentage of participants |
| Atezolizumab + Bevacizumab | Percentage of Participants With Adverse Events | Percentage with at least one SAE | 20.9 Percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time from the date of first treatment to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.
Time frame: Up to approximately 32 months
Population: Full Analysis Set (FAS) is defined as all enrolled participants who receive any amount of study treatment and evaluable for efficacy endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Atezolizumab + Bevacizumab | Progression-Free Survival (PFS) | 8.21 Months |