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Background MDM2/MDMX proteins are frequently elevated in hormone receptor-positive (ER+) breast cancer. We sought to determine the antitumor efficacy of the combination of ALRN-6924, a dual inhibitor of MDM2/MDMX, with chemotherapy in ER+ breast cancer models. Methods Three hundred two cell lines representing multiple tumor types were screened to confirm the role of TP53 status in ALRN-6924 efficacy. ER+ breast cancer cell lines (MCF-7 and ZR-75-1) were used to investigate the antitumor efficacy of ALRN-6924 combination. In vitro cell proliferation, cell cycle, and apoptosis assays were performed. Xenograft tumor volumes were measured, and reverse-phase protein array (RPPA), immunohistochemistry (IHC), and TUNEL assay of tumor tissues were performed to evaluate the in vivo pharmacodynamic effects of ALRN-6924 with paclitaxel. Results ALRN-6924 was active in wild-type TP53 (WT-TP53) cancer cell lines, but not mutant TP53. On ER+ breast cancer cell lines, it was synergistic in vitro and had enhanced in vivo antitumor activity with both paclitaxel and eribulin. Flow cytometry revealed signs of mitotic crisis in all treatment groups; however, S phase was only decreased in MCF-7 single agent and combinatorial ALRN-6924 arms. RPPA and IHC demonstrated an increase in p21 expression in both combinatorial and single agent ALRN-6924 in vivo treatment groups. Apoptotic assays revealed a significantly enhanced in vivo apoptotic rate in ALRN-6924 combined with paclitaxel treatment arm compared to either single agent. Conclusion The significant synergy observed with ALRN-6924 in combination with chemotherapeutic agents supports further evaluation in patients with hormone receptor-positive breast cancer.

Background Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors. Methods We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0). Results Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade ≥ 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease ≥ 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1–10). Conclusions The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center

Background ADP-A2M10 SPEAR T-cells are genetically engineered autologous T-cells that express a high affinity MAGE-A10-specific T-cell receptor targeting MAGE-A10+tumors in the context of HLA A*02. This trial is no longer enrolling (NCT02989064). Methods This ADP-A2M10 dose escalation trial utilized a modified 3+3 design to evaluate safety and antitumor activity. Patients (pts) with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial cancer (UC) were enrolled. Pts were HLA A*02+ with tumors expressing MAGE A10. Pts underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Eligible pts underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered at Dose Level (DL) 1 = 0.1 × 109, DL2 = >1.2 - 6×109, and Expansion = 1.2–15×109 transduced cells. Results As of January 10, 2020, 10 pts (8 male and 2 female) with HNSCC (4), melanoma (3), and UC (3) cancers were treated. Three pts each were treated at DL1 and DL2 and 4 pts were treated in Expansion. The most frequently reported adverse events ≥ Grade 3 were lymphopenia (10 pts), neutropenia (10), anemia (8), leukopenia (7), and thrombocytopenia (5). Two pts reported CRS (1 Grade 1, 1 Grade 3) with resolution. Responses included: 3 pts - stable disease, 5 pts – progressive disease, 1 pt – not evaluable, and 1 pt too early to determine. ADP-A2M10 SPEAR T-cells were detectable in peripheral blood from pts at each dose level and in tumor tissues from several pts at Expansion. Conclusions There was no evidence of on- or off-target toxicity. Given the minimal antitumor activity and the discovery that MAGE-A10 expression frequently overlaps with MAGE-A4 expression, the clinical program has closed. Several trials with SPEAR T-cells targeting MAGE-A4 are ongoing (https://bit.ly/35htsZK). Trial Registration NCT02989064 Ethics Approval The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. All the patients provided written informed consent before study entry.

Patients with cancer are more vulnerable to COVID-19 infection with higher risk of severe symptoms and death.