LP-118 is a novel B-cell lymphoma 2 / extra-large inhibitor that demonstrates efficacy in models of venetoclax-resistant chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) respond well to initial treatment with the Bcell lymphoma 2 (BCL2) inhibitor venetoclax. Upon relapse, they often retain sensitivity to BCL2 targeting, but durability of response remains a concern. We hypothesize that targeting both BCL2 and B-cell lymphoma-extra large (BCLXL) will be a successful strategy to treat CLL, including for patients who relapse on venetoclax.

CSF1 receptor inhibition of tenosynovial giant cell tumor using novel disease-specific MRI measures of tumor burden.

Monitoring treatment of tenosynovial giant cell tumor (TGCT) is complicated by the irregular shape and asymmetrical growth of the tumor. We compared responses to pexidartinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with those by tumor volume score (TVS) and modified RECIST (m-RECIST).

Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT.

Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity.

Patients And Methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO).

Multi-omic molecular profiling guide's efficacious treatment selection in refractory metastatic breast cancer: a prospective phase II clinical trial.

This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi-omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.

Phase I Study of Alvocidib Followed by 7+3 (Cytarabine + Daunorubicin) in Newly Diagnosed Acute Myeloid Leukemia.

Purpose: Alvocidib is a cyclin-dependent kinase 9 inhibitor leading to downregulation of the antiapoptotic BCL-2 family member, MCL-1. Alvocidib has shown clinical activity in a timed sequential regimen with cytarabine and mitoxantrone in relapsed/refractory and newly diagnosed acute myeloid leukemia (AML) but has not been studied in combination with traditional 7+3 induction therapy.

Patients And Methods: A multiinstitutional phase I dose-escalation study of alvocidib on days 1-3 followed by 7+3 (cytarabine 100 mg/m/day i.

Safety and Pharmacokinetics of Bendamustine Rapid-Infusion Formulation.

Bendamustine hydrochloride (BDM) is approved in the United States to treat chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin lymphoma. The first formulation marketed in the United States (original BDM) was a lyophilized product requiring reconstitution prior to dilution to the final admixture. A liquid formulation of BDM was subsequently introduced that did not require reconstitution before dilution.

Enrichment of PI3K-AKT-mTOR Pathway Activation in Hepatic Metastases from Breast Cancer.

Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K-AKT-mTOR pathway is associated with specific sites of breast cancer metastasis. Next-generation sequencing-based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K-AKT-mTOR axis in 32 pretreated breast cancer metastases.

Patient-reported Symptoms of Tenosynovial Giant Cell Tumors.

Purpose: Tenosynovial giant cell tumor (TGCT), a rare locally aggressive neoplasm of the synovium of joints and tendon sheaths, is associated with joint destruction, inflammation, pain, and swelling, in part due to colony-stimulating factor 1 receptor-bearing macrophages recruited to the tumor by genetic elevation of colony-stimulating factor 1 activity. The most common treatment is surgery, although promising pharmacologic treatments are in development. Patient-reported outcome (PRO) instruments are critical end points in demonstrating the clinical relevance of standard oncologic outcome measures and the overall impact of novel pharmacologic therapies in nonmalignant neoplastic conditions such as TGCT.

Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.

Background: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R).

Methods: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation.

A pilot study utilizing multi-omic molecular profiling to find potential targets and select individualized treatments for patients with previously treated metastatic breast cancer.

The primary objective was to determine if multi-omic molecular profiling (MMP) informed selection of approved cancer treatments could change the clinical course of disease for patients with previously treated metastatic breast cancer (MBC) (i.e., produce a growth modulation index (GMI) ≥1.

Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4.

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 75% (9/12) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors.

Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.

A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors.

Introduction: TRC102 potentiates the activity of cancer therapies that induce base excision repair (BER) including antimetabolite and alkylating agents. TRC102 rapidly and covalently binds to apurinic/apyrimidinic (AP) sites generated during BER, and TRC102-bound DNA causes topoisomerase II-dependent irreversible strand breaks and apoptosis. This study assessed the safety, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of TRC102 alone and in combination with pemetrexed.

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

Purpose: This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters.

Experimental Design: This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed.

Molecular Characterization of a Patient's Small Cell Carcinoma of the Ovary of the Hypercalcemic Type.

Small cell carcinoma of the ovary of the hypercalcemic type (SCCOHT) is a very rare tumor type that mainly affects young women. We report a 21-year old woman with SCCOHT. The patient initially presented with stage T3AN1MX disease and treated with surgery.

Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma.

Background: Metastatic melanoma is an incurable disease with an average survival of less than one year. Talabostat is a novel dipeptidyl peptidase inhibitor with immunostimulatory properties.

Methods: This phase II, open label, single arm study was conducted to evaluate the safety and efficacy of 75-100 mg/m2 cisplatin combined with 300-400 mcg talabostat bid for 6, 21-day cycles.

Systemic therapy for gastric cancer and adenocarcinoma of the gastroesophageal junction: present status and future directions.

Gastric cancer is a major worldwide problem and is a leading cause of death. The incidence of distal gastric cancer is declining; however, there has been a rapid rise in the incidence of adenocarcinoma of the gastroesophageal junction, which is a more aggressive entity. Combination chemotherapy has significant activity in the treatment of both of these diseases, improving overall survival and quality of life.

Phase 1 study of escalating-dose OncoGel (ReGel/paclitaxel) depot injection, a controlled-release formulation of paclitaxel, for local management of superficial solid tumor lesions.

OncoGel is a novel depot formulation of paclitaxel designed for intralesional injection with a sustained paclitaxel delivery over approximately 6 weeks from a single administration. This phase 1 study was designed to characterize the toxicity, pharmacokinetics and preliminary antitumor activity associated with OncoGel administered directly into solid tumors. OncoGel was injected into 18 superficially accessible advanced solid cancerous lesions among 16 adult patients for whom no curative therapy was available.

Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer.

Purpose: The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of docetaxel and cyclophosphamide (TC) in metastatic breast cancer (MBC) showed promise in MBC. In 1997, we initiated a randomized adjuvant trial of TC compared with standard-dose AC with a primary end point of disease-free survival (DFS).