This phase I/II trial studies the side effects and best dose of idasanutlin when given together with atezolizumab, and to see how well atezolizumab and cobimetinib or idasanutlin work in treating participants with stage IV estrogen-receptor positive (ER+) breast cancer, or ER+ breast cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib and idasanutlin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib or atezolizumab with idasanutlin may work better in treating participants with estrogen-receptor positive breast cancer.
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of atezolizumab and idasanutlin in patients with estrogen receptor positive (ER+) metastatic breast cancer (mBC) (Phase I). II. To determine the anti-tumor effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II). SECONDARY OBJECTIVES: I. To determine the anti-tumor duration of effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II). II. To determine the safety and tolerability of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II). EXPLORATORY OBJECTIVES: I. To evaluate if CD8+ T cells are enhanced in the tumor with either MEK or MDM2 inhibition (Phase II). II. To evaluate if MHC-I/II and/or PD-L1 expression is enhanced with MEK inhibition (Phase II). III. To evaluate if T cell chemotractants (CCL5, CXCL9,10,11,13) are upregulated upon MDM2 antagonism (Phase II). IV. To determine if baseline or changes in PDL1 expression, MHC expression, presence of tumor infiltrating lymphocytes, neoantigen expression/ mutation burden (using ribonucleic acid \[RNA\]-and whole exome sequencing), CCL5, CXCL9, CXCL10, CXCL11, and CXCL13 correlate with clinical outcome (Phase II). V. To determine if immunological activity of MEK inhibition can be tracked noninvasively using Zr\^89-atezolizumab (Phase II). OUTLINE: This is a phase 1, dose-escalation study of idasanutlin followed by a phase II study. Participants are assigned to 1 of 2 arms. ARM I: Participants with TP53 gene mutation receive atezolizumab intravenously (IV) over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Participants without TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and idasanutlin PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed for 28 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
Number of Participants With a Dose Limiting Toxicity (DLT) (Phase I)
Assessment of DLT for the patients in the atezolizumab and idasanutiln arm of the study
Time frame: At 28 days
Maximum Tolerated Dose (Phase I)
Assessment of MTD for the atezolizumab and idasanutiln combination arm of the study
Time frame: At 28 days
Recommended Phase II Dose (Phase I)
Assessment of recommended phase II dose for the atezolizumab and idasanutiln combination arm of the study
Time frame: At 28 days
Overall Response Rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST]1.1) (Phase II)
Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER \+ breast cancer by measure the rate (%) of complete and partial responses seen in patients with measurable disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 28 days after completion of study treatment, for a total of 2 years
Clinical Benefit Rate (CBR) (Phase II)
Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER \+ breast cancer by measure the rate (%) of complete and partial responses + stability of disease at 6 months seen in patients with measurable disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: At 6 months
Immune Related Response Criteria (irRC) (Phase II)
Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER \+ breast cancer by measure the rate (%) of immune-related complete and partial responses seen in patients with measurable disease
Time frame: Up to 28 days after completion of study treatment, for a total of 2 years
Progression-free Survival (PFS) (Phase II) in Days
Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER \+ breast cancer by measuring the interval (in months) between treatment initiation and disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1).
Time frame: At 12 months
Overall Survival (OS) (Phase II) in Days
Assessment of clinical impact (anti-tumor effect) of the combination of atezolizumab and cobimetinib or idasanutiln in patients with metastatic ER \+ breast cancer by measuring the interval (in months) between treatment initiation and death from any cause
Time frame: At 12 months
Number of Adverse Events (Phase II)
Assessment of adverse events throughout the phase II study
Time frame: Up to 28 days after completion of study treatment, for a total of 2 years
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