Aerosolized Azacytidine as Epigenetic Priming for Bintrafusp Alfa-Mediated Immune Checkpoint Blockade in Patients With Unresectable Pulmonary Metastases From Sarcomas, Germ Cell Tumors, or Epithelial Malignancies

Background: While malignancies of diverse histologies express a variety of cancer-testis antigens (CTAs), immune responses to these proteins appear uncommon in cancer patients due to low-level, heterogeneous antigen expression, as well as local and systemic immunosuppression. CTAs such as NY-ESO-1 and MAGE-A3 can be up-regulated in tumor cells of various histologies, but not in normal cells, by DNA demethylating agents such as decitabine (DAC) and azacytidine (AZA). Up-regulation of these CTAs facilitates CTL-mediated lysis of tumor cells. Clinical trials have demonstrated impressive regressions of tumors expressing NY-ESO-1 following adoptive immunotherapy targeting this CTA. In addition to shared CTAs, unique neoantigens are major targets for immune eradication of cancer cells. DNA demethylating agents not only up-regulate cancer-testis (CT) genes but also induce expression of endogenous retroviruses (ERV) which further augments immunogenicity of cancer cells. Additionally, DNA demethylating agents enhance antigen processing and presentation by cancer cells, and inhibit activity of myeloid derived suppressor cells (MDSC), thereby increasing the efficacy of immune checkpoint inhibitors in murine tumor models. Despite these provocative preclinical results, epigenetic priming for immune checkpoint blockade has yet to be translated to humans due to systemic toxicities and pharmacokinetic/pharmacodynamic limitations that prevent optimal dosing of DNA demethylating agents. One potential strategy to enhance delivery of DNA demethylating agents to pulmonary malignancies while minimizing systemic toxicities is to administer these drugs by inhalation techniques. Preclinical studies have demonstrated that aerosolized AZA mediates epigenetic activation of gene expression in orthotopic lung cancers, and significantly prolongs survival of mice bearing these tumors without systemic toxicities. Conceivably, inhaled AZA may help to prime pulmonary malignancies for immune checkpoint blockade. In this study, the optimal dose of inhaled AZA will be established in patients with unresectable pulmonary metastases who are receiving the dual immune checkpoint inhibitor-TGF-Beta trap, Bintrafusp alfa (M7824). This trial is intended to establish the rationale for further evaluation of inhalational epigenetic priming regimens in combination with immune checkpoint inhibitors or adoptive cell transfer regimens in patients with locally advanced pulmonary malignancies. Objectives: Phase I component: To determine pharmacokinetics, toxicities, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of aerosolized AZA in patients receiving Bintrafusp alfa for unresectable pulmonary metastases Phase II component: To determine frequency of intrathoracic clinical responses in these patients following administration of aerosolized AZA at the RP2D and Bintrafusp alfa. Both components: To determine safety of aerosolized AZA and Bintrafusp alfa in patients with unresectable pulmonary metastases. Eligibility Criteria: Patients with histologically or cytologically proven, unresectable pulmonary metastases from sarcomas, melanomas, germ cell tumors, or epithelial malignancies (except lung or kidney cancers) who have received first line standard of care treatment for their metastatic disease. Measurable disease by RECIST Patients are eligible irrespective of intratumoral PD-L1 expression. Patients with prior treatment with an immune checkpoint inhibitor and DNA demethylating agents may be eligible for study provided they did not experience serious immune adverse events that required discontinuation of the drug, and more than three weeks have elapsed since treatment Patients greater than or equal to 18 years; ECOG performance status of 0-1 without evidence of unstable or decompensated myocardial disease; adequate pulmonary reserve evidenced by FEV1 greater than or equal to 60% predicted, FEV1/FVC ratio greater than or equal to 60%, and adjusted DLCO greater than or equal to 60% predicted; pCO2 less than or equal to 45 mm Hg and pO2 greater than or equal to 60 mm Hg on room air ABG Adequate renal, hepatic and hematopoietic function Design: Subjects will receive aerosolized AZA on three consecutive days (i.e.; Days 1, 2, and 3, or Days 3, 4, 5) of a 21-day cycle. Three cycles constitute one course of treatment. Bintrafusp alfa will be administered at a fixed dose of 2400 mg. During Phase I, Bintrafusp alfa will be administered on Day 13 (i.e., once every 3 weeks, one week after AZA) of each cycle starting from Cycle 2 of Course 1 (i.e., no Bintrafusp alfa in the first cycle of Course 1). During Phase II, Bintrafusp alfa will be administered the day after the last AZA treatment, during Week 1 of each treatment cycle. The dose of AZA will be escalated during Phase I using a 3+3 design with no intrapatient dose escalation. The dose of AZA will be sequentially increased to maximize intra-tumoral DNMT1 depletion while avoiding Grade 3 or greater pulmonary or systemic toxicities attributable to this agent during the first cycle of therapy. Treatment evaluation will be three weeks +/- one week following completion of each course of therapy. Once the RP2D of aerosolized AZA has been defined, that dose level will be expanded to a total of 9 patients to determine response rates at the RP2D using a Simon two stage design for Phase II trials. Approximately 42 patients will be accrued to this trial.