PRIMARY OBJECTIVES:
I. To determine whether BYL719 (alpelisib) and olaparib combination therapy improves progression-free survival (PFS) compared to olaparib alone in patients with PARP-inhibitor naive metastatic HER2-negative breast cancer. (Cohort 2) II. To determine the ORR of BYL719 (alpelisib) and olaparib in patients with PARP-inhibitor-resistant HER2-negative metastatic breast cancer. (Cohort 3)
SECONDARY OBJECTIVES:
I. To determine whether BYL719 (alpelisib) and olaparib combination therapy improves objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and tolerability compared to olaparib alone in patients with PARP-inhibitor naive metastatic HER2-negative breast cancer. (Cohort 2) II. Collect tissue and provide it to the ComboMATCH Registration Protocol to assess concordance between the diagnostic tumor mutation profile generated by the Designated Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment circulating tumor deoxyribonucleic acid (ctDNA) mutation profile from plasma, as described in ComboMATCH Registration Protocol. (Cohort 2) III. To assess the clinical activity of BYL719 (alpelisib) and olaparib combination therapy as measured by progression free survival (PFS), overall survival (OS), clinical benefit rate (CBR), and tolerability in patients with PARP-inhibitor-resistant HER2 negative metastatic breast cancer. (Cohort 3) IV. Collect tissue and provide it to the ComboMATCH Registration Protocol to assess concordance between the diagnostic tumor mutation profile generated by the Designated Laboratories, the pre-treatment biopsy mutation profile, and the pre-treatment ctDNA mutation profile from plasma, as described in ComboMATCH Registration Protocol. (Cohort 3)
TRANSLATIONAL OBJECTIVES:
I. To explore the effect of PIK3CA mutations on ORR and PFS in the study population.
II. To assess correlates of response to olaparib and BYL719 (alpelisib) therapy in the study population including:
IIa. Germline and somatic mutations in DNA repair genes in blood and tumor samples from patients; IIb. DNA and ribonucleic acid (RNA) signatures, loss of heterozygosity (LOH) and other measures of tumor genomic loss and instability from unbiased sequencing of DNA and RNA from patients; IIc. Biomarkers of DNA repair defects or homologous recombination repair deficiency in tumor tissue (e.g. RAD51 nuclear foci); IId. Clinical factors (e.g. prior chemotherapy; estrogen receptor status of tumor).
OUTLINE: Patients are assigned to 1 of 3 cohorts.
COHORT 1: PARP-inhibitor naive patients are assigned to Arm A.
ARM A: Patients receive olaparib orally (PO) twice daily (BID) and alpelisib PO daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients also undergo magnetic resonance imaging (MRI), computed tomography (CT), and/or positron emission tomography (PET) scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression.
COHORT 2: PARP-inhibitor naive patients are randomized to 1 of 2 arms.
ARM B: Patients receive olaparib PO BID and alpelisib PO daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with MDS or AML. Patients also undergo MRI, CT, and/or PET scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression.
ARM C: Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with MDS or AML. Patients experiencing disease progression have the option to migrate to Cohort 3, Arm D. Patients also undergo MRI, CT, and/or PET scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression.
COHORT 3: PARP-inhibitor resistant patients are assigned to Arm D.
ARM D: Patients receive olaparib PO BID and alpelisib PO daily on days 1-28 of each cycle. Cycles repeat every 28 days for up to 5 years in the absence of disease progression, unacceptable toxicity, or bone marrow findings consistent with MDS or AML. Patients also undergo MRI, CT, and/or PET scans throughout the trial and a biopsy prior to treatment start. Patients may also undergo bone scans on study as clinically indicated. Patients have the option to also undergo blood collection throughout the trial and a second biopsy at time of disease progression.
After completion of study treatment, patients are followed every 6 months for up to 5 years from registration.
