Trainee-Led Quality Improvement Project to Improve Fertility Preservation Counseling for Patients With Cancer.

Purpose: Oncofertility counseling regarding the reproductive risks associated with cancer therapy is essential for quality cancer care. We aimed to increase the rate of oncofertility counseling for patients of reproductive age (18-40 years) with cancer who were initiating systemic therapy at the Johns Hopkins Cancer Center from a baseline rate of 37% (25 of 68, June 2019-January 2020) to 70% by February 2021.

Methods: We formed an interprofessional, multidisciplinary team as part of the ASCO Quality Training Program.

An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients.

A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer.

Background: Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single-agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole-cell, granulocyte-macrophage colony-stimulating factor -secreting cellular immunotherapy that induces T-cell immunity against tumor-associated antigens and has previously been studied in combination with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells.

Methods: We conducted a single-arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC.

Immune-Related Adverse Events Requiring Hospitalization: Spectrum of Toxicity, Treatment, and Outcomes.

Purpose: Immune checkpoint inhibitors (ICIs) cause immune-related adverse events (irAEs). The proportion of patients who are hospitalized for irAEs and their spectrum, management, and outcomes are not well described.

Methods: We report the proportion of hospitalized patients in an academic center who were treated with ICIs from May to December 2017.

Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.

Background: Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC).

Patients And Methods: In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM).

Effects of the leucovorin shortage: Pilot study investigating cost, efficacy, and toxicity comparison of low fixed-dose versus body surface area-adjusted leucovorin dosing in patients with resectable colon or metastatic colorectal cancer.

Purpose As a result of the leucovorin shortage, we switched from BSA-adjusted to low fixed-dose leucovorin in patients with colon cancer receiving fluorouracil-containing therapy. Methods A retrospective, pilot study of adults receiving intravenous leucovorin as part of a fluorouracil-containing treatment was conducted including individuals with stage II or III colon or newly diagnosed metastatic colorectal cancer. One low fixed-dose (leucovorin 50 mg) patient was matched by the investigator to one BSA-adjusted (leucovorin 200-500 mg/m/dose) patient on disease stage and age.

Phase 1 Study of ABT-751 in Combination With CAPIRI (Capecitabine and Irinotecan) and Bevacizumab in Patients With Advanced Colorectal Cancer.

ABT-751 is an orally bioavailable sulfonamide with antimitotic properties. A nonrandomized phase 1 dose-escalation study of ABT-751 in combination with CAPIRI (capecitabine and irinotecan) and bevacizumab was conducted to define the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics in patients with advanced colorectal cancer. Patients were treated with ABT-751 daily for 7 days (alone) and then began 21-day cycles of treatment with ABT-751 daily and capecitabine twice daily for 14 days plus irinotecan on day 1 intravenously.

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

Background: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade.

Methods: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency.

Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind, randomised phase 2 study.

Background: Dysregulation of the hepatocyte growth factor (HGF)/MET pathway promotes tumour growth and metastasis. Rilotumumab is a fully human, monoclonal antibody that neutralises HGF. We aimed to assess the safety, efficacy, biomarkers, and pharmacokinetics of rilotumumab combined with epirubicin, cisplatin, and capecitabine (ECX) in patients with advanced gastric or oesophagogastric junction cancer.

Interventions for preventing neuropathy caused by cisplatin and related compounds.

Background: Cisplatin and several related antineoplastic drugs used to treat many types of solid tumours are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought.

Objectives: To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs.

Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases.

Background: Molecular biomarkers offer the potential for refining prognostic determinants in patients undergoing cancer surgery. Among patients with colorectal cancer, KRAS and BRAF are important biomarkers, but their role in patients undergoing surgical therapy for liver metastases is unknown. In this study, the incidence and prognostic significance of KRAS and BRAF mutations were determined in patients undergoing surgical therapy of colorectal liver metastases (CRLM).

Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer.

Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg.

Phase 2 study of erlotinib combined with adjuvant chemoradiation and chemotherapy in patients with resectable pancreatic cancer.

Purpose: Long-term survival rates for patients with resected pancreatic ductal adenocarcinoma (PDAC) have stagnated at 20% for more than a decade, demonstrating the need to develop novel adjuvant therapies. Gemcitabine-erlotinib therapy has demonstrated a survival benefit for patients with metastatic PDAC. Here we report the first phase 2 study of erlotinib in combination with adjuvant chemoradiation and chemotherapy for resected PDAC.

Randomized phase III multi-institutional study of TNFerade biologic with fluorouracil and radiotherapy for locally advanced pancreatic cancer: final results.

Purpose: TNFerade biologic is a novel means of delivering tumor necrosis factor alpha to tumor cells by gene transfer. We herein report final results of the largest randomized phase III trial performed to date among patients with locally advanced pancreatic cancer (LAPC) and the first to test gene transfer against this malignancy.

Patients And Methods: In all, 304 patients were randomly assigned 2:1 to standard of care plus TNFerade (SOC + TNFerade) versus standard of care alone (SOC).

Phase I pharmacokinetic and pharmacodynamic study of cetuximab, irinotecan and sorafenib in advanced colorectal cancer.

Background This phase Ib study was designed to determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of irinotecan and cetuximab with sorafenib. Secondary objectives included characterizing the pharmacokinetics and pharmacodynamics and evaluating preliminary antitumor activity in patients with advanced colorectal cancer (CRC). Methods Patients with metastatic, pretreated CRC were treated at five dose levels.

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.

A multicenter analysis of GTX chemotherapy in patients with locally advanced and metastatic pancreatic adenocarcinoma.

Purpose: Studies treating adenocarcinoma of the pancreas with gemcitabine alone or in combination with a doublet have demonstrated modest improvements in survival. Recent reports have suggested that using the triple-drug regimen FOLFIRINOX can substantially extend survival in patients with metastatic disease. We were interested in determining the clinical benefit of another three-drug regimen of gemcitabine, docetaxel and capecitabine (GTX) in patients with advanced pancreatic adenocarcinoma.

Interventions for preventing neuropathy caused by cisplatin and related compounds.

Background: Cisplatin and several related antineoplastic agents used to treat many types of solid tumors are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought.

Objectives: To examine the efficacy of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related agents.

Phase I trial of oxaliplatin, infusional 5-fluorouracil, and leucovorin (FOLFOX4) with erlotinib and bevacizumab in colorectal cancer.

Rationale: This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.

Patients And Methods: Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously.

A tolerability and pharmacokinetic study of adjuvant erlotinib and capecitabine with concurrent radiation in resected pancreatic cancer.

Background: Erlotinib is approved for the treatment of advanced pancreas cancer. We conducted a prospective trial to determine the safety profile and recommended phase 2 dose of erlotinib and capecitabine given concurrently with intensity-modulated radiation therapy (IMRT) in resected pancreatic cancer patients. The pharmacokinetic profile of this combination was also evaluated.

Thymidylate synthase (TYMS) enhancer region genotype-directed phase II trial of oral capecitabine for 2nd line treatment of advanced pancreatic cancer.

Purpose: The primary aim of this study was to characterize the 6-month overall survival and toxicity associated with second-line capecitabine treatment of advanced pancreatic cancer patients harboring the TYMS *2/*2 allele. The secondary aim was to analyze the response rate and pharmacokinetics of capecitabine-based therapy in this patient population. Lastly, TYMS, ATM and RecQ1 single nucleotide polymorphism were analyzed relative to overall survival in patients screened for study participation.

A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors.

Purpose: This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.

Experimental Design: Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded.