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.
