A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850.

Background: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers.

Clinical outcomes and immune phenotypes associated with co-occurring mutations in non-small cell lung cancer.

Background: mutation in non-small cell lung cancer (NSCLC) is associated with worse survival as well as primary resistance to PD-1/PD-L1 targeting immunotherapy. We hypothesize that co-occurring mutations and tumor mutation burden (TMB) may impact response to therapy and prognosis.

Methods: Forty-one patients with -mutated NSCLC seen in our Thoracic oncology clinic with available next-generation sequencing tumor data were included in the analysis.

A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors.

Background: Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors.

Phase I trial of daily subcutaneous SPL-108 injections in combination with paclitaxel in patients with platinum resistant CD44+ advanced ovarian epithelial cancer.

Objective: Preclinical evidence and early clinical trials have demonstrated the activity of SPL-108, a targeted agent that inhibits CD44 mediated induction of multidrug resistance specifically to paclitaxel and platinum agents. We conducted a phase I, open label, dose escalation study of the safety and tolerability of the combination of SPL-108 with weekly paclitaxel in patients with platinum resistant CD44+ ovarian, primary peritoneal, or fallopian tube cancer.

Methods: Patients with platinum resistant histologically proven epithelial ovarian, primary peritoneal, or fallopian tube cancers and measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumours) version 1.

A phase I study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782).

Background: Inhibitors of poly(ADP-ribose) polymerase (PARP) proteins potentiate antitumor activity of platinum chemotherapy. This study sought to determine the safety and tolerability of PARP inhibitor talazoparib with carboplatin and paclitaxel.

Methods: We conducted a phase I study of talazoparib with carboplatin AUC5-6 and paclitaxel 80 mg/m  days 1, 8, 15 of 21-day cycles in patients with advanced solid tumors.

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: The Search for the Optimal Biomarker.

Triple negative breast cancer (TNBC) is a high-risk and aggressive malignancy characterized by the absence of estrogen receptors (ER) and progesterone receptors (PR) on the surface of malignant cells, and by the lack of overexpression of human epidermal growth factor 2 (HER2). It has limited therapeutic options compared to other subtypes of breast cancer. There is now a growing body of evidence on the role of immunotherapy in TNBC, however much of the data from clinical trials is conflicting and thus, challenging for clinicians to integrate the data into clinical practice.

Toxicities and Locoregional Control After External Beam Chest Wall and/or Regional Lymph Node Re-irradiation for Recurrent Breast Cancer.

Background/aim: To evaluate toxicities and clinical outcomes in breast cancer (BC) patients who underwent external beam chest wall (CW) and/or regional lymph node (LN) re-irradiation (re-RT) for locoregional recurrence (LRR).

Patients And Methods: We performed a retrospective review of our institutional database to identify BC patients diagnosed with an isolated ipsilateral CW or nodal recurrence after prior whole breast/CW irradiation.

Results: Fifteen patients met the study criteria.

A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies.

Purpose: Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C.

Methods: Objectives were to establish the maximum tolerated dose (MTD) of the combinations, characterize V pharmacokinetics (PK) in the presence and absence of C, measure PAR in peripheral blood mononuclear cells (PBMCs) and γH2AX in circulating tumor cells (CTCs).

Durable Response to PD1 Inhibitor Pembrolizumab in a Metastatic, Metaplastic Breast Cancer.

Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer. Tumor characteristics typically feature estrogen receptor, progesterone receptor, and HER2-negative, triple-negative breast cancer (TNBC), with a poorer prognosis relative to pure invasive ductal or lobular disease. Resistance to chemotherapy often leads to local recurrence and distant metastasis.

Neratinib + capecitabine sustains health-related quality of life in patients with HER2-positive metastatic breast cancer and ≥ 2 prior HER2-directed regimens.

Purpose: To characterize health-related quality of life (HRQoL) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) from the NALA phase 3 study.

Methods: In NALA (NCT01808573), patients were randomized 1:1 to neratinib + capecitabine (N + C) or lapatinib + capecitabine (L + C). HRQoL was assessed using seven prespecified scores from the European Organisation for Research and Treatment of Cancer Quality Of Life Questionnaire core module (QLQ-C30) and breast cancer-specific questionnaire (QLQ-BR23) at baseline and every 6 weeks.

Breast intraductal nanoformulations for treating ductal carcinoma in situ II: Dose de-escalation using a slow releasing/slow bioconverting prodrug strategy.

Ductal carcinoma in situ (DCIS) represents approximately 20-25% of newly diagnosed breast cancers. DCIS is treated by surgery and possibly radiotherapy. Chemotherapy is only used as adjuvant or neoadjuvant therapy but not as primary therapy.

TP63-mutation as a cause of prenatal lethal multicystic dysplastic kidneys.

Background: Ectrodactyly-ectodermal dysplasia-clefting syndrome 3 (EEC) is one of the six overlapping syndromes caused by mutations in the tumor protein p63 gene (TP63). EEC is suspected when patients have cleft hands or feet, polydactyly, and syndactyly, abnormal development of the ectodermally derived structures, and orofacial clefting. Genitourinary (GU) anomalies have been identified in patients with EEC, yet these are often under-recognized and under-reported.

A first-in-human, phase 1, dose-escalation study of ABBV-176, an antibody-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors.

ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks.

Breast intraductal nanoformulations for treating ductal carcinoma in situ I: Exploring metal-ion complexation to slow ciclopirox release, enhance mammary persistence and efficacy.

Introduction: Ductal Carcinoma In Situ (DCIS) represents a significant fraction (~20-25%) of all newly diagnosed breast cancer cases and, if left untreated, a significant fraction of patients will progress to invasive disease. Surgery is the only treatment option. Ciclopirox (CPX), an FDA-approved antifungal drug, has exhibited promising antitumor activity by down-regulating the expression of vital antiapoptotic cellular proteins and inhibiting the genetic expression of several oncogenic pathways.

Safety and enhanced immunostimulatory activity of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration.

Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201.

Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors.

Purpose: Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.

Patients And Methods: Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating genomic alterations.

Inference of Germline Mutational Status and Evaluation of Loss of Heterozygosity in High-Depth, Tumor-Only Sequencing Data.

Purpose: Inherited germline defects are implicated in up to 10% of human tumors, with particularly well-known roles in breast and ovarian cancers that harbor -mutated genes. There is also increasing evidence for the role of germline alterations in other malignancies such as colon and pancreatic cancers. Mutations in familial cancer genes can be detected by high throughput sequencing (HTS), when applied to formalin-fixed paraffin-embedded (FFPE) tumor specimens.

Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer.

Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA.

First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors.

ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors.

Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases.

Purpose: Bone marrow-derived progenitor cells, including VEGFR2 endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models.