The roles of mutant p53 in reprogramming and inflammation in breast cancers.

Rezatapopt is an investigational small molecule p53 reactivator that binds specifically to the Y220C-mutant p53 protein without interacting with wild-type or other mutant p53 proteins. Upon binding, rezatapopt stabilizes the Y220C-mutant p53 protein in the wild-type conformation, reactivating p53 functions. The Phase 1 PYNNACLE trial assessed rezatapopt in solid tumors.

Safety and Tolerability of Berzosertib, an Ataxia-Telangiectasia-Related Inhibitor, and Veliparib, an Oral Poly (ADP-ribose) Polymerase Inhibitor, in Combination With Cisplatin in Patients With Refractory Solid Tumors.

Purpose: We conducted a phase I trial of the combination of cisplatin with the ataxia-telangiectasia-related protein kinase inhibitor berzosertib and the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib, with the objective of creating a DNA damage response (DDR)-impaired, BRCA null-like phenotype to potentiate the antitumor activity of cisplatin.

Patients And Methods: In this open label, 3 + 3 trial design, cisplatin and berzosertib were administered intravenously on day 1 (D1) and D8, and D2 and D9, respectively, together with twice-daily oral veliparib on D1-D3 and D8-D10 in 21-day cycles. Previous platinum and PARPi therapy were permitted.

Preclinical NCI-MPACT: prospective modeling of the mutation-based NCI-MPACT clinical trial therapeutic strategy in patient-derived xenograft models.

Purpose: The National Cancer Institute's Molecular Profiling-Based Assignment of Cancer Therapy (NCI-MPACT) randomized phase 2 clinical trial assessed the utility of applying tumor DNA sequencing to treatment selection. Here, we report the results of a companion preclinical study in patient-derived xenograft (PDX) models to evaluate how each tumor responded to each of the treatment regimens studied in the NCI-MPACT trial instead of simply to the specific regimen targeting the study-actionable mutation of interest (aMOI).

Methods: Fifty-one PDX models (46 with and 5 without NCI-MPACT aMOIs) were tested against both the arm that would have been assigned in the NCI-MPACT trial as well as every other study regimen: (1) veliparib plus temozolomide or (2) adavosertib plus carboplatin (targeting the DNA repair pathway); (3) everolimus (targeting the PI3K pathway); and (4) trametinib (targeting the RAS/RAF/MEK pathway).

Phase 1 studies of the indenoisoquinolines LMP776 and LMP744 in patients with solid tumors and lymphomas.

Purpose: Indenoisoquinolines are a class of topoisomerase I (TOP1) inhibitors designed to overcome clinical limitations of camptothecins. Three indenoisoquinolines (LMP400, LMP776, and LMP744) demonstrated activity in murine models and a comparative canine lymphoma study. Clinical data for LMP400 were previously reported (NCT01051635).

Response to a novel type II RAF inhibitor in diffuse leptomeningeal glioneuronal tumor with BRAF fusion.

Background: Diffuse leptomeningeal glioneuronal tumor (DL-GNT) is a rare disease which is more often diagnosed in children and adolescents than adults. Activation of the MAPK/ERK pathway is implicated in the majority of cases, and BRAF fusions are the most common genetic alteration. BRAF fusions result in dimerization and constitutive downstream MAPK/ERK activity, against which type I RAF inhibitors have limited efficacy.

A Phase I Study of Nilotinib in Combination with Paclitaxel in Patients with Advanced Solid Tumors.

Purpose: We assessed the safety, maximum tolerated dose, and recommended phase 2 dose (RP2D), efficacy, pharmacokinetics, and pharmacodynamics of the nilotinib-paclitaxel combination in 44 patients with solid tumors.

Patients And Methods: Paclitaxel was administered intravenously (days 1, 8, and 15), and nilotinib was administered twice daily orally beginning on cycle 1 day 2 (C1D2; escalation) or C1D3 (expansion) in 28-day cycles using a 3 + 3 dose escalation design. Pharmacodynamic biomarkers of drug action were assessed in paired tumor biopsies and circulating tumor cells at the RP2D.

Myeloid targeting antibodies PY159 and PY314 for platinum-resistant ovarian cancer.

Background: Novel treatment options are required in patients with platinum-resistant ovarian cancer (PROC). Myeloid-derived suppressor cells promote a hostile tumor microenvironment and are associated with worse clinical outcomes in PROC. We evaluated the safety and preliminary efficacy of PY159, an agonist antibody to Triggering receptor expressed on myeloid cells-1 (TREM1) that reprograms immunosuppressive intratumoral myeloid cells, and PY314, an antagonist antibody to Triggering receptor expressed on myeloid cells-2 (TREM2) that depletes tumor-associated macrophages, as single agents and in combination with pembrolizumab in subjects with PROC.

Nirogacestat-the pathway to approval of the first treatment for desmoid tumors, a rare disease.

Drug development for rare diseases can be long, complex, and costly. Desmoid tumors (DT), a rare type of soft-tissue tumor, are associated with substantial and debilitating burden, including disease-specific symptoms (e.g.

First-in-Human Study of 23ME-00610, an Antagonistic Antibody for Genetically Validated CD200R1 Immune Checkpoint, in Participants with Advanced Solid Malignancies.

Purpose: In this phase 1 portion of a first-in-human phase 1/2a study (NCT05199272), 23ME-00610 was evaluated in participants with advanced solid malignancies to determine its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Exploratory biomarkers were evaluated to examine potential correlates of efficacy and safety.

Patients And Methods: Eligible participants (≥18 years) were administered 23ME-00610 intravenously every 3 weeks (Q3W) using an accelerated titration design followed by a traditional 3 + 3 design, with an initial dose level of 2 mg.

Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy.

Uncovering therapeutic targets for macrophage-mediated T cell suppression and PD-L1 therapy sensitization.

Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells.

ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors.

Purpose: In preclinical models, glucocorticoid receptor (GR) signaling drives resistance to taxane chemotherapy in multiple solid tumors via upregulation of antiapoptotic pathways. ORIC-101 is a potent and selective GR antagonist that was investigated in combination with taxane chemotherapy as an anticancer regimen preclinically and in a phase 1 clinical trial.

Patients And Methods: The ability of ORIC-101 to reverse taxane resistance was assessed in cell lines and xenograft models, and a phase 1 study (NCT03928314) was conducted in patients with advanced solid tumors to determine the dose, safety, and antitumor activity of ORIC-101 with nab-paclitaxel.

Illuminating immunotherapy response via precision T cell-targeted PET imaging.

Traditionally, immunotherapy agent selection and treatment strategies are guided by biopsy-based histological information. However, biopsies are limited in that they are invasive, provide static information regarding the tumor immune microenvironment, and only sample a small part of one tumor site. The tumor microenvironment is dynamic and heterogenous.

Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology.

The effect of liver dysfunction on the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers.

Belinostat was approved in 2014 for the treatment of relapsed or refractory peripheral T-cell lymphoma, however, there was insufficient data to recommend a dose in patients with moderate to severe hepatic impairment. The purpose of this analysis was to characterize the pharmacokinetic disposition of belinostat and its five metabolites in patients with advanced cancers and varying degrees of liver dysfunction. A population pharmacokinetic model was therefore developed to describe the parent-metabolite system.

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors.

Purpose: GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors.

Patients And Methods: Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks.

Pharmacodynamic effects of the PARP inhibitor talazoparib (MDV3800, BMN 673) in patients with BRCA-mutated advanced solid tumors.

Purpose: Talazoparib is an inhibitor of the poly (ADP-ribose) polymerase (PARP) family of enzymes and is FDA-approved for patients with (suspected) deleterious germline BRCA1/2-mutated, HER2‑negative, locally advanced or metastatic breast cancer. Because knowledge of the pharmacodynamic (PD) effects of talazoparib in patients has been limited to studies of PARP enzymatic activity (PARylation) in peripheral blood mononuclear cells, we developed a study to assess tumoral PD response to talazoparib treatment (NCT01989546).

Methods: We administered single-agent talazoparib (1 mg/day) orally in 28-day cycles to adult patients with advanced solid tumors harboring (suspected) deleterious BRCA1 or BRCA2 mutations.

Combining Poly (ADP-Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges.

Better understanding of molecular drivers and dysregulated pathways has furthered the concept of precision oncology and rational drug development. The role of DNA damage response (DDR) pathways has been extensively studied in carcinogenesis and as potential therapeutic targets to improve response to chemotherapy or overcome resistance. Treatment with small molecule inhibitors of PARP has resulted in clinical response and conferred survival benefit to patients with ovarian cancer, BRCA-mutant breast cancer, HRD-deficient prostate cancer and BRCA-mutant pancreatic cancer, leading to US Food and Drug Administration (FDA) approvals.

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas.

Background: Larotrectinib, a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor, has demonstrated efficacy in adult and pediatric patients with various solid tumors harboring NTRK gene fusions. This subset analysis focuses on the efficacy and safety of larotrectinib in an expanded cohort of adult patients with TRK fusion sarcomas.

Methods: Patients (≥18 years old) with sarcomas harboring NTRK gene fusions were identified from three clinical trials.

Predicting Response of Triple-Negative Breast Cancer to Neoadjuvant Chemotherapy Using a Deep Convolutional Neural Network-Based Artificial Intelligence Tool.

Purpose: Achieving a pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved patient outcomes in triple-negative breast cancer (TNBC). Currently, there are no validated predictive biomarkers for the response to NAC in TNBC. We developed and validated a deep convolutional neural network-based artificial intelligence (AI) model to predict the response of TNBC to NAC.

Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal E regressions.

Purpose: This study aimed at characterizing indotecan population pharmacokinetics and explore the indotecan-neutropenia relationship in patients with solid tumors.

Methods: Population pharmacokinetics were assessed using nonlinear mixed-effects modeling of concentration data from two first-in-human phase 1 trials evaluating different dosing schedules of indotecan. Covariates were assessed in a stepwise manner.