BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT)

Summary

Participation Requirements

Description

Background: Current greater than or equal to 2nd line treatments for metastatic breast cancer provide modest response rates, and modest improvement in progression-free survival but no treatments are curative. Bavarian-Nordic (BN)-Brachyury vaccine is a recombinant poxvirus vaccine against the transc...

Background: Current greater than or equal to 2nd line treatments for metastatic breast cancer provide modest response rates, and modest improvement in progression-free survival but no treatments are curative. Bavarian-Nordic (BN)-Brachyury vaccine is a recombinant poxvirus vaccine against the transcription factor brachyury, which plays an important role in the epithelial-to-mesenchymal transition in breast cancer. A recently completed phase 1 study of BN-Brachyury vaccine showed the vaccine was well tolerated and generated an immune response. M7824 is a novel bifunctional fusion protein composed of a monoclonal antibody against human PD-L1 fused to the soluble extracellular domain of human TGF-Beta receptor II (TGF-BetaRII), which functions as a TGF-Beta trap. Ado-trastuzumab emtansine (T-DM1 or Kadcyla) is an antibody drug conjugate used in second- and third- line treatment of metastatic HER2+ breast cancer (HER2+BC). T-DM1 activates ADCC, dendritic cell maturation, increases TILs, increased PD-L1 expression, and increased immunomodulatory cytokines. Entinostat is a class 1 histone deacetylase inhibitor (HDACi) which suppresses tumor initiating cells, regulatory T-cells and myeloid-derived suppressor cells (MDSCs), as well as enhances cytotoxic T-cell mediated lysis, direct natural killer (NK) lysis, NK cell activation, increases PD-L1 expression and antibody-dependent cellular cytotoxicity (ADCC). In addition, entinostat may also be able to overcome HER2 resistance. We propose a Phase 1b trial to evaluate the safety and efficacy of the stepwise combination of the BN-Brachyury vaccine, M7824, T-DM1 and entinostat in metastatic breast cancer. Arm 1 - Triple Negative Breast Cancer (TNBC); M7824 + BN-Brachyury Arm 2 - ER-/PR-/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1 Arm 3 - ER-/PR-/HER2+ Breast Cancer; M7824 + BN-Brachyury + T-DM1+ Entinostat Objectives: Primary Objectives: Arms 1-3: Overall response rate (ORR; PR+CR) Arms 1-3: Safety for each of the three combinations of agents explored in the arms Eligibility: Selected Inclusion Criteria Histologically confirmed metastatic breast cancer with appropriate IHC testing by a certified lab: For Arm 1: Triple negative breast cancer. Hormone receptor negative is defined by estrogen receptor < 10% and progesterone receptor < 10%. HER2 negative breast cancer is defined as HER2 per IHC 0 or 1+ or 2+ with negative FISH. For Arms 2 and 3: Hormone receptor negative, HER2+ breast cancer as defined by estrogen receptor < 10% and progesterone receptor < 10%. HER2 positive as per IHC 3+ or 2+ with positive FISH. Prior treatment: For Arm 1: greater than or equal to 1 prior therapy in the metastatic setting. Patients with known PD-L1 positive tumors must have received prior treatment with atezolizumab + nab-paclitaxel. Patients with ER 1-9% must have received treatment with at least two lines of endocrine treatment (SERM, AI, fulvestrant) with one prior treatment including a CDK4/6 inhibitor + endocrine therapy for their metastatic cancer and should be considered endocrine therapy resistant. For Arms 2 and 3: greater than or equal to 1 prior treatment in the metastatic setting with a taxane (docetaxel or paclitaxel), herceptin and pertuzumab. Females or males greater than or equal to 18 years old ECOG 0 or 1 Measurable metastatic disease per RECIST 1.1. For Cohort 3, Arms 2 and 3: At least one biopsiable lesion and willingness to undergo up to three research biopsies. Adequate hematopoietic, hepatic, renal and cardiac (EF greater than or equal to 50%) function. Selected Exclusion Criteria Patients who have received chemotherapy, including trastuzumab and pertuzumab in the previous 3 weeks; other investigational agents within 4 weeks or a PD-1/PD-L1 antibody within 4 weeks prior to study enrollment; radiotherapy less than or equal to 4 weeks of study entry. Symptomatic CNS metastases and leptomeningeal disease are excluded but treated brain metastases (no radiotherapy within 6 weeks) or asymptomatic brain metastasis are allowed. History of invasive malignancy less than or equal to 3 years prior to enrollment. History of congestive heart failure (CHF) as defined as NYHA class 3 or 4 or hospitalization for CHF (any NYHA class) within 6 months of trial start. Concurrent use of chronic systemic steroids except for physiologic systemic steroids for replacement defined as 10mg of prednisone or an equivalent dose. Design: This study contains three separate, single arm phase 1b trials. Arm 1 will evaluate M7824 and BN-Brachyury in patients with TNBC. If this doublet is determined to have acceptable toxicity (0-1 DLTs of the first 6 patients), up to 19 patients will be enrolled on Arm 2 in which BN-Brachyury, M7824 and T-DM1 will be evaluated in patients with advanced HR-/HER2+ BC with disease progression after treatment with THP or intolerance to THP. If this triplet is determined to have acceptable toxicity (0-1 DLTs of the first 6 patients), 19 patients will be enrolled on Arm 3 in which BN-Brachyury, entinostat, M7824 and T-DM1 will be evaluated in patients with advanced HR-/HER2+ BC with disease progression after treatment with THP or intolerance to THP. Up to 51 evaluable patients will be recruited for this study, with an accrual ceiling set at 65 patients. Trial Drugs BN-Brachyury vaccine every 3 weeks until cycle 9, then every 12 weeks: Recombinant MVA-BN-Brachyury (R2PD): 4 injections of vaccines with 1 given SC in each extremity on Day 1 of Cycles 1 and 2. Each injection of MVA-BN-Brachyury consists of 2.0 x 10(8) infectious units (Inf.U). Recombinant FPV-Brachyury: 1 injection given SC in one extremity on Day 1 of Cycles 3 and beyond. Each infection of FPV-Brachyury consists of 1.0 x 10(9) Inf.U. T-DM1 3.6mg/kg via IV infusion q3 weeks on Day 1 of each cycle. M7824 2,400mg via IV infusion q3 weeks on Day 1 of each cycle. Entinostat 5mg by mouth weekly (RP2D) administered by patient on Days 1, 8 and 15 of each cycle.

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