This phase II trial studies how well the combination of avelumab with liposomal doxorubicin with or without binimetinib, or the combination of avelumab with sacituzumab govitecan works in treating patients with triple negative breast cancer that is stage IV or is not able to be removed by surgery (unresectable) and has come back (recurrent). Immunotherapy with checkpoint inhibitors like avelumab require activation of the patient's immune system. This trial includes a two week induction or lead-in of medications that can stimulate the immune system. It is our hope that this induction will improve the response to immunotherapy with avelumab. One treatment, sacituzumab Govitecan, is a monoclonal antibody called sacituzumab linked to a chemotherapy drug called SN-38. Sacituzumab govitecan is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of tumor cells, known as Tumor-associated calcium signal transducer 2 (TROP2) receptors, and delivers SN-38 to kill them. Another treatment, liposomal doxorubicin, is a form of the anticancer drug doxorubicin that is contained in very tiny, fat-like particles. It may have fewer side effects and work better than doxorubicin, and may enhance factors associated with immune response. The third medication is called binimetinib, which may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, and may help activate the immune system. It is not yet known whether giving avelumab in combination with liposomal doxorubicin with or without binimetinib, or the combination of avelumab with sacituzumab govitecan will work better in treating patients with triple negative breast cancer.
OUTLINE: Patients are randomized to 1 of 3 active arms. The three previous study arms are closed to further accrual. ARM A: Patients receive binimetinib orally (PO) twice daily (BID) for a lead-in period of 15 days in the absence of disease progression or unacceptable toxicity. Patients then receive binimetinib PO BID on days 1-28, avelumab intravenously (IV) over 60 minutes on days 1 and 15, and liposomal doxorubicin IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive sacituzumab govitecan IV on days -15 for a lead-in period in the absence of disease progression or unacceptable toxicity. Patients then receive sacituzumab govitecan day 8 and day 15 of Cycle (C) 1; day 1, 8, and 21 of C2; day 1, 15 and 21 of C3; day 8 and 15 of C4, and the schedule continues with two weeks on, one week off for 21-day cycles which repeat in the absence of disease progression or unacceptable toxicity. Participants also receive avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive liposomal doxorubicin IV over 60 minutes on day -15 for a lead-in period of 15 days in the absence of disease progression or unacceptable toxicity. Patients then receive liposomal doxorubicin IV over 60 minutes on day 15 and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 6 months for a minimum of 1 year. Participants will be followed every 3 months after experiencing disease progression to assess for survival/anti-cancer therapy status until death or 1 year after Cycle 1 Day 1. PRIMARY OBJECTIVE: I. Anti-tumor effect of avelumab in combination with different therapeutic agents explored in the sub-protocols of the trial. SECONDARY OBJECTIVES: I. Additional anti-tumor effects. II. Safety and tolerability of avelumab in combination with different therapeutic agents explored in the sub-protocols of the trial. III. Patient reported outcomes (PRO) between baseline and cycle 3 day 1 across arms. IV. Longitudinal trends in PRO outcomes across treatment arms. V. Differences in PRO outcomes for patients who respond compared to those who do not respond. CORRELATIVE OBJECTIVES: I. To determine the therapeutic predictive role of the following on clinical outcome as well as changes with induction therapy with either liposomal doxorubicin or targeted agents: 1. PD-L1 expression and immune 'hot-spots'. 2. Tumor infiltrating lymphocyte (TIL)s, and Cluster of differentiation 8 (CD8) and Cluster of differentiation 4 (CD4) positivity in TIL. 3. Human leukocyte antigen (HLA)-A (MHC-I) and HLA-DR (MHC-II), FoxP3, OX40 and OX40L, phosphatase and tensin homologue (PTEN), and MYC expression. 4. Number/levels of expressed predicted class I and class II neoantigens, central memory T-cells and T-cells. 5. Expression of effector/regulatory immune gene, innate PD-1 resistance signature (IPRES), and B cell, T cell, and/or macrophage signatures. 6. Basal or claudin-low molecular subtypes. 7. T cell receptor (TCR) clonality in the tumor and peripheral blood. 8. Genomic mutational burden. II. To determine if circulating tumor deoxyribonucleic acid (DNA) (ctDNA) results will discriminate pseudo-progression from true progression. III. To determine if certain genomic alterations detected in tumor tissue or ctDNA are potentially associated with resistance to the tested drug combinations. IV. To correlate the composition of the pretreatment microbiome with response and secondary endpoints in each arm of the trial. OUTLINE: Patients are randomized to 1 of 3 arms. ARM A: Patients receive binimetinib orally (PO) twice daily (BID) for a lead-in period of 15 days in the absence of disease progression or unacceptable toxicity. Patients then receive binimetinib PO BID on days 1-28, avelumab intravenously (IV) over 60 minutes on days 1 and 15, and liposomal doxorubicin IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive sacituzumab govitecan IV on days -15 and -8 as a lead-in period in the absence of disease progression or unacceptable toxicity. Patients then receive sacituzumab govitecan IV on days 1 and 8 and avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive liposomal doxorubicin IV over 60 minutes on day -15. Patients then receive liposomal doxorubicin IV over 60 minutes on day 15 and every 4 weeks thereafter. Patients also receive avelumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, then every 6 months for a minimum of 1 year.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
145
Given IV
Given IV
Given PO
Given IV
Given IV
Given IV
O'Neal Comprehensive Cancer Center
Birmingham, Alabama, United States
University of California, San Francisco
San Francisco, California, United States
Georgetown University
Washington D.C., District of Columbia, United States
University of Chicago Medicine Comprehensive Cancer Center
Evergreen Park, Illinois, United States
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
Baltimore, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Mayo Clinic
Rochester, Minnesota, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States
Duke Cancer Institute
Durham, North Carolina, United States
Abramson Cancer Center, University of Pennsylvania
Philadelphia, Pennsylvania, United States
...and 2 more locations
Best Overall Response Rate (BORR)
BORR is defined as the percentage of patients achieving complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and will be reported for each arm along with 95% two-sided confidence intervals.
Time frame: From treatment initiation until disease progression, an estimated average of 1 year
Overall Response Rate (ORR)
ORR is defined as the percentage of patients achieving complete response (CR) or partial response (PR) assessed by Immune-Related RECIST (iRECIST) and will be reported by arm with 95% two-sided confidence intervals
Time frame: From treatment initiation until disease progression, an estimated average of 1 year
Clinical Benefit Rate (CBR)
CBR is defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) using RECIST version 1.1 at 6 months and will be reported by arm with 95% two-sided confidence intervals
Time frame: 6 months
Median Progression-free Survival (PFS)
The median duration of progression-free survival in weeks by arm will be estimated using the Kaplan-Meier method with censoring used as needed. Median time to event and corresponding confidence intervals will be reported.
Time frame: From treatment initiation until disease progression, an estimated average of 1 year
Median Overall Survival (OS)
OS is defined as the time from treatment initiation until disease progression or death, whichever comes first and will be reported by arm with 95% two-sided confidence intervals .
Time frame: 12 months
Percentage of participants with treatment-related adverse events
An unacceptable toxicity is defined as any unexpected and clinically relevant drug-related grade 3 toxicity, or any drug-related grade 4-5 adverse event within the first cycle of therapy assessed via National Cancer Institute CTCAE version 5 criteria. Safety will be evaluated by estimating the percentage of patients who experience a clinically relevant toxicity (both patient and physician reported) for each arm with 95% two-sided confidence intervals.
Time frame: Up to 30 days after completion of study treatment, approximately 13 months
Change in Quality of Life at 8 Weeks Assessed by Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Measure
Will be measured the PROMIS Global Short Form. Change scores will be compared across treatment arms using one way analysis of variance (ANOVA) with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn's adjustment for multiple comparisons.
Time frame: Baseline up to 8 weeks
Change in Quality of Life Over Treatment Duration Assessed by PROMIS Global Health Measure
Will be measured the PROMIS Global Short Form. Change scores will be compared across treatment arms using one way analysis of variance (ANOVA) with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn's adjustment for multiple comparisons.
Time frame: From baseline until the date disease progression is first observed, an estimated average of 1 year
Change in Symptoms (Self-Reported Toxicities) at 8 Weeks Assessed by Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE)
Will be measured by the PRO-CTCAE criteria . The data will be presented descriptively using summary statistics and graphical representations across time points. Will assess symptom burden using Likert scores. Each attribute will be presented descriptively using summary statistics and graphical representations across time points.
Time frame: Baseline up to 8 weeks
Change in Symptoms (Self-Reported Toxicities) Over Treatment Duration Assessed by PRO-CTCAE
Will be measured by the PRO-CTCAE criteria . The data will be presented descriptively using summary statistics and graphical representations across time points. Will assess symptom burden using Likert scores. Each attribute will be presented descriptively using summary statistics and graphical representations across time points.
Time frame: From baseline until the date disease progression is first observed, an estimated average of 1 year
Change in Ability to Participate in Social Roles and Activities at 8 Weeks Assessed by PROMIS
The data will be presented descriptively using summary statistics and graphical representations across time points. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.
Time frame: Baseline up to 8 weeks
Change in Ability to Participate in Social Roles and Activities Over Treatment Duration Assessed by PROMIS
The data will be presented descriptively using summary statistics and graphical representations across time points. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.
Time frame: From baseline until the date disease progression is first observed, an estimated average of 1 year
Change in Treatment Satisfaction at 8 Weeks Assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM)
Will be assessed by TSQM Questionnaire. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.
Time frame: Baseline up to 8 weeks
Change in Treatment Satisfaction Over Treatment Duration Assessed by the TSQM
Will be assessed by TSQM Questionnaire. Change scores will be compared across treatment arms using one way ANOVA with Bonferroni adjustment for post-hoc multiple comparisons. In the instance that distributional assumptions are not valid, Kruskal-Wallis one-way ANOVA will be used with Dunn?s adjustment for multiple comparisons.
Time frame: From baseline until the date disease progression is first observed, an estimated average of 1 year
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