Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory follicular lymphoma (CITADEL-203): a phase 2 study.

Background: Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell malignancies. This phase 2 study (CITADEL-203; NCT03126019, EudraCT 2017-001624-22) assessed efficacy and safety of parsaclisib monotherapy in patients with R/R follicular lymphoma (FL). Methods: Patients ≥18 years of age with histologically confirmed R/R FL (grade 1-3a) and prior treatment with ≥2 systemic therapies received parsaclisib 20 mg once daily (QD) for 8 weeks then parsaclisib 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg QD for 8 weeks then parsaclisib 2.5 mg QD (daily dosing group [DG]); DG was selected for further assessment. Primary endpoint was objective response rate (ORR). Findings: At data cut-off (January 15, 2021), 126 patients had been treated (WG: n = 23; DG: n = 103). ORR (95% confidence interval [CI]) was 77.7% (68.4-85.3) with a complete response rate (95% CI) of 19.4% (12.3-28.4) in DG; median (95% CI) duration of response was 14.7 months (10.4-not estimable [NE]), median progression-free survival was 15.8 months (11.0-NE), and median overall survival was not reached. The most common any-grade treatment-emergent adverse events (TEAEs) among all treated patients included diarrhoea (n = 48, 38.1%), nausea (n = 31, 24.6%), and cough (n = 28, 22.2%); the most common grade ≥3 TEAEs were diarrhoea (n = 15, 11.9%), neutropenia (n = 13, 10.3%), and colitis (n = 7, 5.6%). Dose interruption, reduction, and discontinuation from TEAEs occurred in 46.8% (n = 59), 17.5% (n = 22), and 23.8% (n = 30) of patients, respectively. Interpretation: Treatment with parsaclisib demonstrated rapid and durable responses, and a manageable safety profile in patients with R/R FL. Funding: Incyte Corporation.

A phase 1/2 study of ixazomib in place of bortezomib or carfilzomib in a subsequent line of therapy for patients with multiple myeloma refractory to their last bortezomib or carfilzomib combination regimen.

Identifying effective combination regimens is a high priority in multiple myeloma (MM), as most patients eventually become refractory to their current treatments. In this study, we investigated whether the proteasome inhibitor (PI) ixazomib could delay disease progression among patients who failed regimens containing another PI, bortezomib or carfilzomib. This phase 1/2, multicenter, open-label, nonrandomized study enrolled patients who were refractory to a previous regimen containing bortezomib or carfilzomib. Patients continued the other anti-MM drugs in the regimen at the same doses and frequencies. Patients with combination regimens with unknown maximum tolerated dose (MTD) of ixazomib were enrolled in phase 1, with ixazomib starting at 3 mg and then dose escalated to 4 mg. Patients on regimens with a known ixazomib MTD were enrolled in phase 2. Primary endpoints were overall response rate (ORR), clinical benefit rate (CBR), adverse events (AEs), and determination of maximum tolerated dose (MTD). Of the 46 patients enrolled, 39 were evaluable for efficacy. ORR and CBR were 12.8% and 17.9%, respectively. Ixazomib appeared to be well tolerated as a replacement for carfilzomib and bortezomib, with 23.9% of patients experiencing at least one grade ≥3 serious adverse event (SAE) and 37.0% experiencing at least one grade ≥3 AE. The most common grade ≥3 AEs were hyponatremia (8.7%), anemia (8.7%), dyspnea (8.7%), thrombocytopenia (6.5%), dehydration (4.3%), and pneumonia (4.3%). The results indicate that ixazomib is not an effective replacement for bortezomib or carfilzomib for patients with MM who have previously relapsed on other bortezomib/carfilzomib-containing regimens.

Oxaliplatin as a radiosensitizing agent in rectal cancer.

The efficacy of oxaliplatin monotherapy against several solid tumors and its relative lack of nephrotoxicity and myelosupression, coupled with results of the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer trial, led to a great deal of interest for the implementation of this chemotherapeutic agent in the preoperative setting for the management of adenocarcinoma of the rectum. Despite limited in-vitro and in-vivo data with regard to the radiosensitizing properties of oxaliplatin in rectal cancer, it rapidly entered phase I-III clinical trials. This study reviews the results of these trials and the current status of oxaliplatin as a radiosensitizing agent in the neoadjuvant management of rectal cancer.

Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification.

Neoantigens, which are expressed on tumor cells, are one of the main targets of an effective antitumor T-cell response. Cancer immunotherapies to target neoantigens are of growing interest and are in early human trials, but methods to identify neoantigens either require invasive or difficult-to-obtain clinical specimens, require the screening of hundreds to thousands of synthetic peptides or tandem minigenes, or are only relevant to specific human leukocyte antigen (HLA) alleles. We apply deep learning to a large (N = 74 patients) HLA peptide and genomic dataset from various human tumors to create a computational model of antigen presentation for neoantigen prediction. We show that our model, named EDGE, increases the positive predictive value of HLA antigen prediction by up to ninefold. We apply EDGE to enable identification of neoantigens and neoantigen-reactive T cells using routine clinical specimens and small numbers of synthetic peptides for most common HLA alleles. EDGE could enable an improved ability to develop neoantigen-targeted immunotherapies for cancer patients.

A rare case of signet ring cell gastric adenocarcinoma.

Although the incidence and mortality rates continue to decline in the United States, gastric cancer remains one of the leading causes of cancer mortality worldwide. Signet Ring Cell gastric cancer is a rare and distinct histological subtype. This is a case report of an individual who presented with nausea, vomiting, abdominal pain and weight loss. The patient was found to have a large, obstructing antral mass that was biopsied by esophagogastroduodenoscopy (EGD) and revealed Signet Ring Cell gastric adenocarcinoma. Preoperative staging with positron emission tomography (PET) and computed tomography (CT) scan displayed multiple pulmonary nodules felt to be consistent with sarcoidosis after transbronchial biopsy results were obtained. Patient was taken to surgery for curative resection and lymph node dissection, but peritoneal metastatic disease was found intra-operatively. Gastric carcinoma frequently requires a multi-disciplinary approach to properly diagnose, stage, and treat.

Tissue microarray constructs to predict a response to chemoradiation in rectal cancer.

PURPOSE: To identify, using tissue microarray (TMA), an immunohistochemical panel predictive of response to ionizing radiation (IR) in rectal cancer. METHODS: TMA constructs were prepared from archived stage II/III rectal tumors and matching adjacent mucosa (n=38) from patients treated with pre-operative chemoradiation. Immunohistochemistry (IHC) was performed for MIB, Cyclin E, p21, p27, p53, survivin, Bcl-2, and BAX. Immunoreactivity along with clinical variables was subjected to univariate and forward stepwise logistic regression analyses. RESULTS: Pathological complete response (pCR) was 23.9%. The number of positive lymph nodes obtained in the resected specimen was associated with pCR. Immunoreactivity for MIB (Sn 15%, Sp 65%, OR 0.33), p53 (Sn 3%, Sp 84%, OR 0.16), Bcl-2 (Sn 11%, Sp 74%, OR 0.35), and BAX (Sn 92%, Sp 80%, OR 46) was associated with pathological response (all p's<0.001). Forward stepwise logistic regression analysis demonstrated that MIB was an independent predictor of a response to chemoradiation (p=0.001). CONCLUSIONS: A combined panel of mediators of apoptosis alone or combined with clinical factors is a feasible approach that can be applied to rectal tumor biopsies to predict a response to chemoradiation. The most sensitive factor was BAX; while MIB independently predicted a response to chemoradiation.