Kelly K. Curtis

Neoadjuvant chemoradiation compared to neoadjuvant radiation alone and surgery alone for Stage II and III soft tissue sarcoma of the extremities.

BackgroundNeoadjuvant chemoradiation (NCR) prior to resection of extremity soft tissue sarcoma (STS) has been studied, but data are limited. We present outcomes with NCR using a variety of chemotherapy regimens compared to neoadjuvant radiation without chemotherapy (NR) and surgery alone (SA).MethodsWe conducted a retrospective chart review of 112 cases.ResultsTreatments included SA (36 patients), NCR (39 patients), and NR (37 patients). NCR did not improve the rate of margin-negative resections over SA or NR. Loco-regional relapse-free survival, distant metastases-free survival, and overall survival (OS) were not different among the treatment groups. Patients with relapsed disease (OR 11.6; p = 0.01), and tumor size greater than 5 cm (OR 9.4; p = 0.01) were more likely to have a loco-regional recurrence on logistic regression analysis. Significantly increased OS was found among NCR-treated patients with tumors greater than 5 cm compared to SA (3 year OS 69 vs. 40%; p = 0.03). Wound complication rates were higher after NCR compared to SA (50 vs. 11%; p = 0.003) but not compared to NR (p = 0.36). Wet desquamation was the most common adverse event of NCR.ConclusionsNCR and NR are acceptable strategies for patients with STS. NCR is well-tolerated, but not clearly superior to NR.

Anaemia following initiation of androgen deprivation therapy for metastatic prostate cancer: a retrospective chart review.

Objective. Haemoglobin levels often decline into the anaemic range with androgen deprivation therapy (ADT). We conducted a chart review of patients receiving ADT for metastatic prostate cancer to assess anaemia-related symptoms. Methods. 135 stage IV prostate cancer cases were reviewed for treatment type; haemoglobin values before and after treatment; and symptoms of anaemia. Mean haemoglobin levels before and after for all treatment forms, for leuprolide alone, and for combination leuprolide/bicalutamide were calculated and evaluated for significant differences. The numbers of patients developing symptoms were recorded and the effects of specific therapies evaluated. Results. For all ADT treated patients, mean haemoglobin declined by −1.11 g/dL (p < .0001). Leuprolide-alone treated patients had a mean decline of −1.66 g/dL (p < 0.0001). Leuprolide and bicalutamide combination treatment caused a mean decline of −0.78 g/dL (p = 0.0426). 16 of 43 patients had anemia symptoms. Contingency analysis with Fishers exact test shows patients receiving leuprolide therapy alone versus other forms of ADT were significantly less likely to have symptoms (χ2 = 0.0190). Conclusions. The present study confirms that ADT results in a significant drop in haemoglobin levels into the anaemic range. A number of patients become symptomatic from this change. Practitioners should monitor haemoglobin levels, and treat symptomatic patients.

Transoral laser microsurgery followed by radiation therapy for oropharyngeal tumors: The mayo clinic arizona experience

The purpose of this study was to report the treatment outcomes of patients with advanced oropharyngeal cancer treated with transoral laser microsurgery (TLM) followed by radiation therapy (RT) at Mayo Clinic in Arizona.

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway. Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50–1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1. Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade ≥3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n = 4) and fatigue (n = 3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration–time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors). Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. Clin Cancer Res; 21(5); 1002–9. ©2014 AACR.

The impact of concomitant medication use on patient eligibility for phase I cancer clinical trials.

Concomitant medication (CM) use may result in Phase I cancer clinical trial ineligibility due to concern for potential CM-investigational drug interactions or alteration of investigational drug absorption. Few studies have examined the impact of CM use on trial eligibility. Methods: We reviewed records of 274 patients on Phase I trials at a single academic institution. Demographics, CM identities and classes, CM discontinuation, reasons, and incidence of CM substitution were recorded. CM-investigational drug cytochrome P450 (CYP) enzyme interactions were documented. Statistical analysis was performed using descriptive statistics. Results: 273 of 274 patients (99.6%, 95% confidence interval [CI] 98.9-100%) took CM, with a median of 8 CM per patient (range 0 - 42). CM discontinuation occurred in 67 cases (25%, 95% CI 19-30%). The most common CM classes discontinued were herbal (17 cases, 25%, 95% CI 16-37%) and proton pump inhibitors (15 cases, 22%, 95% CI 12-32%). CM discontinuation reasons were: protocol prohibition (32 cases, 48%, 95% CI 36-60%); potential CM-investigational drug interaction (25 cases, 37%, 95% CI 26-49%); other (10 cases, 15%, 95% CI 6-23%). A potential CM-investigational drug CYP interaction was noted in 122 cases (45%, 95% CI 39-50%). CM potentially weakly decreased investigational drug metabolism in 52 cases (43%, 95% CI 34-51%), and potentially strongly decreased investigational drug metabolism in 17 cases (14%, 95% CI 8-20%). Investigational drug potentially weakly decreased CM metabolism in 39 cases (32%, 95% CI 24-40%), and potentially strongly decreased CM metabolism in 28 cases (23%, 95% CI 15-30%). CM substitution occurred in 36/67 cases (54%, 95% CI 41-66%) where CM were discontinued to allow for eventual participation in clinical trials. Overall in 2 cases (0.7%, 95% CI 0.1-2.6%), patients were protocol ineligible because CM could not be discontinued or substituted. Conclusions: This study highlights the high prevalence of concomitant medication use among cancer patients enrolled in phase I clinical trials. Most patients did meet trial eligibility criteria with careful substitution and discontinuation of CM. The most common reason for discontinuation of CM was protocol prohibition. The most common medications discontinued were herbal, proton pump inhibitors, selective serotonin reuptake inhibitor anti-depressants, and non-steroidal anti-inflammatory drugs.

Past approaches and future directions for targeting tumor hypoxia in squamous cell carcinomas of the head and neck

Recurrent squamous cell carcinoma of the head and neck (SCCHN) carries a poor prognosis. Tumor hypoxia (TH) has been implicated as one of many factors contributing to SCCHN recurrence. TH leads to radiation resistance by reversing radiation-induced DNA damage. Effective strategies to overcome TH may improve outcomes in patients with SCCHN. We searched the English literature on PubMed and reviewed the reference sections of key articles related to TH (publications spanning from the early 1900s to the present). We summarized the underlying theory of TH in SCCHN, methods for quantifying it, and the numerous therapies developed to modulate it. We included articles that set the foundation of TH as a theory and the most relevant articles published within the last 15 years related to TH quantification and therapeutic targeting. Despite extensive research, targeting TH in SCCHN has not become a part of routine clinical practice in North America, and we analyze the pitfalls in hypoxia research that have led to this failure. We propose that future studies should test a combined approach of targeting the immune system in addition to cellular pathways rendered aberrant in TH and should include development of novel surrogate markers of TH and/or TH imaging.

A phase I study to characterize the safety, tolerability, and pharmacokinetics of topotecan at 4 mg/m2 administered weekly as a 30-minute intravenous infusion in patients with cancer.

Topotecan pharmacokinetics at higher infusion rates (4 mg/m2 over 30 minutes) have not been studied. The authors report a pharmacokinetics and safety study of this dose in advanced cancer patients. Sixteen patients were given a 4‐mg/m2 topotecan infusion intravenously (IV) over 30 minutes weekly for 3 weeks, repeated every 28 days. Pharmacokinetics were determined after the first dose. Plasma concentrations of total topotecan were measured to derive CL, Vss, Cmax, tmax, t1/2, AUC0‐t, and AUC0–∞. Plasma total topotecan concentrations decreased biexponentially, with a mean CL value of 20.6 L/h, Vss value of 101 L, and t1/2 value of 5.0 h. Nine significant adverse events (all hematologic) were topotecan related. Grade 3 or less adverse events included anemia, thrombocytopenia, leukopenia, and fatigue. Pharmacokinetics of the 4‐mg/m2 infusion of topotecan over 30 minutes are comparable to findings from studies of lower and higher doses. Toxicities are similar to previous reports.

Trends in oncology trials termination due to toxicity over a period of 16 years.

2535Background: Pre-clinical studies may not fully determine the safety profile of an investigational agent resulting in the need to terminate studies due to safety concerns. Additionally, the deve...

Abstract A088: Evolution of the use of nonrandomized (NRCT) versus randomized (RCT) phase 2 trial designs preceding phase 3 registration trials for oncology drugs approved from 2004-2016

Background: In oncology drug development, prior to conduct of phase 3 registration trials, phase 2 RCTs have been conducted in many instances to provide initial evidence of a statistically significant effect on patient outcomes. However, the high antitumor activity of recent novel agents observed at early phases of development may obviate the need to demonstrate clinical activity of a drug via an RCT in hase 2. Our objective was to identify differences in the frequency with which NRCT or RCT designs were used in the phase 2 setting for oncology drugs approved from 2004-2016. Methods: We identified all hematology/oncology drugs approved by the United States Food and Drug Administration (FDA) from 2004-2016. We then searched Citeline® Trialtrove database and clinicaltrials.gov to identify the phase of trial leading to registration as well as any stand-alone phase 2 studies conducted with these agents either before or as the registration trial. For agents with phase 2 studies conducted prior to registration, we analyzed the phase 2 trial design (NRCT or RCT) and primary endpoint, and categorized by year of approval and drug type [nonimmunologic/targeted drug (NIO), immunologic drug (IO) or chemotherapeutic drug (CT)]. We then calculated percentages of RCT or NRCT by year and drug type to detect changes in frequency of trial design over time. Results: A total of 102 FDA-approved agents across 29 oncology indications were evaluated. Phases of trials leading to approval were: phase 1 (n = 2); phase 1/2 (n = 5); phase 2 (n = 35); phase 3 (n = 60). Among 77 FDA-approved agents with a stand-alone phase 2 study conducted prior to registration, drug types were: 15 CT, 50 NIO, and 12 IO. 24 agents were approved from 2004-2010, while 53 were approved from 2011-2016 (of those, 18 in 2015-2016). Of the phase 2 studies conducted prior to registration, 13 were RCT and 64 were NRCT. Primary endpoints in these phase 2 studies were: ORR (n = 57), OS or PFS (n = 8), major cytogenetic response (n = 5), TTP (n = 2), or other (n = 5). Approximately 50% of RCT (7/13) evaluated time to event endpoints such as OS, PFS, or TTP; however, for NRCT, only 5% (3/64) used a survival-time endpoint; 81% (52/64) of NRCT used ORR for primary endpoint. With regard to type of oncology drug, no specific trend in NRCT vs. RCT was observed: 86% (43/50) of NIO drugs used NRCT in phase 2; 75% (9/12) of IO drugs used NRCT in phase 2; and 80% (12/15) of CT drugs used NRCT in phase 2. For drugs approved 2004-2010, NRCT were used in phase 2 for 79% of agents (19/24 agents), and from 2011-2016, NRCT were used in phase 2 for 85 % of agents (45/53). Among NIO approved from 2004-2010, 67% of agents (10/15) used NRCT in phase 2, but from 2011-2016, 94% (33/35) used NRCT in phase 2. From 2010-2016, 82% (9/11) of IO drugs approved used NRCT in phase 2, and 82% (9/11) used ORR as a primary endpoint. Conclusions: From 2004-2016, a vast majority of FDA-approved oncology drugs used NRCT design in the phase 2 setting. The percentage of NRCT in phase 2 for approved drugs has increased in recent years, especially for approved NIO drugs. Most phase 2 NRCT for approved drugs used a primary endpoint other than survival, such as ORR. As novel oncology drugs targeting the right population enter clinical trials, demonstrating statistical improvements in survival in a phase 2 RCT is less frequently pursued prior to conduct of registration trials. Citation Format: Kelly K. Curtis, Laura Vidal Boixader, Jozsef Palatka, Liat Vidal, Nicholas Kenny, Keren R. Moss. Evolution of the use of nonrandomized (NRCT) versus randomized (RCT) phase 2 trial designs preceding phase 3 registration trials for oncology drugs approved from 2004-2016 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A088.

Mucosal Sparing Radiation Therapy in Resected Oropharyngeal Cancer

Purpose: To report the outcomes of patients with favorable risk oropharyngeal cancer that underwent adjuvant radiation therapy with omission of the primary site from the clinical target volume (CTV). Material/Methods: A retrospective study of 40 patients treated with transoral surgery (TOS) followed by neck only radiation using intensity modulated radiation therapy (IMRT) with exclusion of the primary site. For all patients, a CTV of the primary surgical bed was contoured to obtain the estimated incidental dose to the primary site. Results: Median follow-up was 51 months (range, 13-155 months). The median radiation therapy (RT) dose to the neck was 6000 cGy (range, 5400-6400 cGy). The mean incidental dose to the primary tonsillar site was 4320 cGy (SD ± 480 cGy) and to the primary base of tongue site was 4060 cGy (SD ± 420 cGy). There were no local failures and only 1 regional failure, resulting in 97.5% locoregional control rate at 4 years. Two patients developed distant metastases, without evidence of locoregional recurrence, for a 4-year overall survival rate of 97%. Conclusions: Our analysis suggests that mucosal sparing RT after TOS in favorable risk oropharyngeal cancer patients may provide comparable oncologic and improved functional outcomes compared to conventional treatment in selected patients.