Abstract OT3-02-03: IMMUNe mOdulation in early stage estrogen receptor positive breast cancer treated with neoADjuvant Avelumab, Palbociclib, and Tamoxifen: The ImmunoADAPT study (NCT03573648)
Authors: Santa-Maria CA , Wang C , Cimino-Mathews A , Roussos-Torres E , Connolly RM , Wolff AC , Jaffee EM , Stearns V 
Published: May 2019

Abstract
Background:
While some patients with early stage endocrine receptor positive (ER+) breast cancer experience excellent prognosis, a subset of patients with more aggressive phenotypes still have a high rate of recurrence despite optimal adjuvant endocrine therapy and chemotherapy, thus novel therapies are needed for patients with high risk disease.
Although immune checkpoint blockade has shown significant benefit in numerous types of cancer, initial reports demonstrate low response rates to single agent programmed cell death ligand 1 (PD-L1) inhibition in ER+ breast cancer. Inhibitors of cyclin dependent kinases (CDK) 4 and 6 in combination with endocrine therapy are highly active in breast cancer, and recently have been demonstrated to recruit immune cells, and increase PD-L1 on tumor cells in preclinical models. Increased tumor infiltrating lymphocytes (TILs) has been observed with neoadjuvant treatment with CDK4/6 inhibitors in patients with ER+ breast cancer. We thus hypothesize that the addition of palbociclib (CDK4/6 inhibitor) will improve responses to avelumab (PD-L1) inhibitor in patients with high risk ER+ breast cancer.
Trial Design:
Eligible participants are those stage II or III ER+HER2- breast cancer (T2N0 must have ≥grade 2, T1N+ must have at least a 1.5cm breast primary). Patients will undergo a baseline MRI and biopsy, start tamoxifen +/- palbociclib for 1 cycle (1 cycle =28 days), and then undergo a repeat MRI and biopsy. Avelumab will be added to both arms in cycle 2. Patients will be treated for 3 cycles of avelumab with tamoxifen +/- palbociclib (thus 4 cycles total, including run-in without avelumab). Patients will be treated as long as there is no evidence of progression and therapy is tolerated, and then undergo MRI and surgery. The primary objective is to determine the clinical complete response (cCR) rate by MRI. Secondary objectives include evaluation of TILs (H&E), CD8 and FOXP3 by immunohistochemistry (IHC), T cell receptor (TCR) repertoire (TCR sequencing), multiplex gene expression panel (Nanostring), and multiplex IHC. Changes in these immune biomarkers will be assessed to determine differential immunophenotypic effects of palbociclib, and correlated to cCR in each arm.
The sample size of this pilot study is determined by primary analysis on the cCR rate. We hypothesize that the addition of palbociclib to tamoxifen will result in an increase rate of cCR in patients receiving avelumab. We hypothesize that the addition of avelumab will increase the response rate to palbociclib and tamoxifen by 30%. We thus estimate that a total of 40 evaluable patients (20 to each arm) will provide close to 80% power to detect a difference on cCR rates of 10% vs 40% at two-sided alpha level 10%. We will evaluate and compare cCR rates between arms by conducting Fisher's Exact test and reporting the estimated proportions together with their exact confidence intervals. Logistic regression analysis will also be conducted to explore the association between cCR and immune biomarkers.
This study has received IRB approval and is open as of Summer 2018.
Citation Format: Santa-Maria CA, Wang C, Cimino-Mathews A, Roussos-Torres E, Connolly RM, Wolff AC, Jaffee EM, Stearns V. IMMUNe mOdulation in early stage estrogen receptor positive breast cancer treated with neoADjuvant Avelumab, Palbociclib, and Tamoxifen: The ImmunoADAPT study (NCT03573648) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-03.