A Phase II Trial of Atezolizumab (Anti-PDL1) With Carboplatin in Patients With Metastatic Triple Negative Breast Cancer
Overview
- Phase
- Phase 2
- Intervention
- Atezolizumab
- Conditions
- Triple Negative Breast Cancer
- Sponsor
- Vanderbilt-Ingram Cancer Center
- Enrollment
- 106
- Locations
- 6
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This randomized phase II trial studies how well carboplatin with or without atezolizumab works in treating patients with stage IV triple negative breast cancer. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving carboplatin with atezolizumab may work better in treating patients with stage IV triple negative breast cancer
Detailed Description
Primary objective: To evaluate the efficacy, as measured by progression free survival (PFS) of carboplatin + atezolizumab (using irRECIST) versus carboplatin alone (using RECIST) in patients with triple negative metastatic breast cancer Secondary objectives: * To determine overall response rate. * To evaluate the efficacy, as measured by clinical benefit rate, of carboplatin + atezolizumab (using irRECIST) versus carboplatin (using RECIST) alone in patients with triple negative metastatic breast cancer. Clinical benefit rate is defined as complete response plus partial response plus stable disease for 6 months. * To determine the duration of response for patients achieving a partial or complete response. * To evaluate the overall survival (OS) of carboplatin + atezolizumab versus carboplatin alone in patients with triple negative metastatic breast cancer. TERTIARY OBJECTIVES: * To perform the following correlative studies from biopsies taken at baseline: 1. Tumor infiltrating lymphocyte frequency and phenotype (TILs) at baseline 2. PD-L1 expression from the baseline pre-treatment tissue and at progression lesion, performed by IHC (SP142 clone) 3. HER2 (IHC, FISH) and ER/PR levels (IHC) from a metastatic site 4. Perform RNA-seq to determine non-synonymous mutation burden in expressed genes and gene expression to assign a triple negative subtype at baseline for correlations with clinic outcome 5. Immune phenotyping (IHC) for markers of T cell subsets and activation (CD4, CD8, FoxP3, CD25, Glut1) and exhaustion (PD1, CTLA4) and test feasibility of flow cytometric analyses to include additional markers * To assess the effect of BRCA mutations on response to the study drugs * To evaluate the effect of steroids on the efficacy of atezolizumab To assess the prognostic effects of TILs on PFS and CBR in patients receiving atezolizumab
Investigators
Vandana Abramson
Principal Investigator
Vanderbilt-Ingram Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Patients must provide informed written consent
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- •Clinical stage IV ER, PR, HER2 negative invasive mammary carcinoma, previously documented by histological analysis and that meets the following criteria:
- •HER2 negativity is defined as any of the following by local laboratory assessment: In-situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 \< 2.0 or single probe average HER2 gene copy number \< 4 signals/cell), or IHC 0 or IHC 1+ (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the protocol chair to establish eligibility of the patient)
- •ER and PR negativity are defined as =\< 5% of cells expressing hormonal receptors via IHC analysis
- •Willing to undergo biopsy of a metastatic lesion (in patients with reasonably accessible metastatic lesions such as chest wall, skin, subcutaneous tissue, lymph nodes, bones, peripheral lung, and liver metastases)
- •Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension by RECIST criteria version (v)1.1
- •Zero or one prior chemotherapy regimens for metastatic disease
- •No prior treatment with carboplatin
- •Absolute neutrophil count (ANC) \>= 1500/mm\^3 (without granulocyte colony-stimulating factor \[G-CSF\] support within 2 weeks prior to cycle 1, day 1)
Exclusion Criteria
- •CANCER-SPECIFIC EXCLUSION CRITERIA
- •Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for \> 2 weeks prior to randomization
- •Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases, provided all of the following criteria are met: measurable disease outside the CNS, only supratentorial metastases allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord), no evidence of progression or hemorrhage after completion of CNS-directed therapy, no ongoing requirement for dexamethasone as therapy for CNS disease (anticonvulsants at a stable dose are allowed), no stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization
- •Leptomeningeal disease
- •Uncontrolled tumor-related pain: patients requiring narcotic pain medication must be on a stable regimen at registration; symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization; patients should be recovered from the effects of radiation; there is no required minimum recovery period; asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to randomization
- •Uncontrolled hypercalcemia (\> 1.5 mmol/L ionized calcium or calcium \> 12 mg/dL or corrected serum calcium \> upper limit of normal \[ULN\]) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy; patients who are receiving denosumab must discontinue denosumab use and replace it with a bisphosphonate instead while on study; patients receiving a bisphosphonate for skeletal metastases are not excluded and can continue treatment
- •Malignancies other than triple negative breast cancer (TNBC) within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer)
- •Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, hormonal therapy, biological therapy) other than the ones specified in the protocol; any other investigational drugs should be discontinued 2 weeks prior to the first dose of study medication
- •GENERAL MEDICAL EXCLUSION CRITERIA
- •Women only: pregnancy or lactation
Arms & Interventions
Arm 1 (atezolizumab, carboplatin)
Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Arm 1 (atezolizumab, carboplatin)
Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Carboplatin
Arm 1 (atezolizumab, carboplatin)
Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker
Arm 1 (atezolizumab, carboplatin)
Patients receive atezolizumab IV over 30-60 minutes and carboplatin IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: Quality-of-Life Assessment
Arm 2 (atezolizumab, carboplatin)
Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression.
Intervention: Atezolizumab
Arm 2 (atezolizumab, carboplatin)
Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression.
Intervention: Carboplatin
Arm 2 (atezolizumab, carboplatin)
Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression.
Intervention: Laboratory Biomarker
Arm 2 (atezolizumab, carboplatin)
Patients receive carboplatin as in Arm 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may cross-over to Arm 1 upon disease progression.
Intervention: Quality-of-Life Assessment
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: Up to 3 years.
The PFS is defined as the time from the first day of treatment to the first observation of disease progression (RECIST V1.1) or death of any cause. Those without events were censored at the last follow up. The median PFS time will be estimated using the Kaplan-Meier method with 95% confidence intervals.
Secondary Outcomes
- Overall Survival (OS)(Up to 3 years.)
- Duration of Response (DOR)(Up to 3 years)
- Clinical Benefit Rate (CBR)(Up to 3 years)
- Overall Response Rate (ORR)(Up to 3 years)