Low-grade Toxicity Research Articles

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials.

Background: We review factors impacting ipilimumab-associated adverse events through the experience from National Cancer Institute (NCI)-sponsored phase I immunotherapy clinical trials.Materials and Methods: Attributable ipilimumab-related adverse events from NCI-sponsored phase I immunotherapy clinical trials were queried retrospectively by anonymized patient experience reports for observed adverse events like decreased hematological cell counts, blood electrolytes or proteins, or reduced patient performance status. The prevalence of ipilimumab-related toxicity was associated by patient to the duration of ipilimumab exposure, radiographic responses, progression-free survival, and overall survival.Results: 373 patients from 11 phase 1 ipilimumab clinical trials were analyzed. Patients experiencing at least one grade 3 or 4 adverse event associated with observed radiographic response were included. The average number of grade 3/4 adverse events in responders was 1.167 versus 0.645 in non-responders (p = 0.001). Patient performance status did not significantly impact observed toxicity grade. Pretherapy lymphocyte count or chemistries were not associated with ipilimumab-associated toxicity. The number of agents combined with ipilimumab on trial was associated with average number of grade 3/4 toxicities–ipilimumab monotherapy (0.631) versus ipilimumab + 1 agent (0.877) versus ipilimumab + 2 agents (1.408) (p = 0.014). Number of low grade (grade 1/2) toxicities was associated with duration of treatment, Pearson correlation coefficient r = 0.456 (p < 0.0001); whereas the number of high grade (grade 3/4) toxicities was not, r = 0.032 (p = 0.546).Conclusions: Ipilimumab-attributed grade 3/4 toxicity was associated with therapeutic response. The number of co-administered agents added to ipilimumab significantly raised the likelihood of toxicity. Extended duration of treatment increased the incidence of low but not high-grade toxicity.

Outcome of intensity-modulated radiation therapy-based stereotactic radiation therapy for treatment of canine nasal carcinomas.

Stereotactic radiation therapy (SRT) has emerged as a convenient definitive treatment modality in veterinary medicine, but few studies exist evaluating outcome with treatment for canine nasal tumors, and no studies report the treatment of one single tumor histotype. This retrospective, observational study evaluates toxicity, response, and survival in 17 dogs with nasal carcinomas treated with SRT. Dogs received a median of 3000 centigray in three fractions via 6-MV linear accelerator. Eighty-eight percent of patients (n=15) demonstrated clinical benefit. Of dogs with repeated CT imaging (n=10), 60% (n=6) achieved a partial response and 10% (n=1) achieved a complete response. Median progression-free survival (PFS) was 359 days. Median survival time (MST) was 563 days. Among dogs evaluable for acute toxicity, 50% (n=10) developed low grade toxicity (grade 1, n=4; grade 2, n=1). No patients developed grade 3 toxicity. 16 dogs (87%) evaluable over the long term developed signs consistent with possible late toxicity. The majority of late toxicities were mild (alopecia, hyperpigmentation, and leukotrichia n=10; ocular discharge and keratoconjunctivitis sicca n=5). Thirty-seven percent of patients (n=6) developed seven possible grade 3 late toxicities (blindness, n=3; fistula, n=1; seizures, n=3), which were difficult to distinguish from progressive disease in most patients. Of the prognostic factors evaluated (demographics, tumor stage, dosimetric data, epistaxis, facial deformity, clinical response, image-based response, nonsteroidal anti-inflammatory drugs, and chemotherapy), only clinical response was a positive prognostic factor on MST (P<.00). No factors were found to be significantly associated with PFS.

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer

SummaryBackground Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1–4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.

Percutaneous Endoscopic Gastrostomy Tube Placement in Patients with Head and Neck Cancer Treated with Radiotherapy.

Background and aimThe primary aim of our study was to evaluate percutaneous endoscopic gastrostomy (PEG) tube placement depending on body weight and body mass index in patients undergoing radiotherapy (RT) for head and neck cancer (HNC). A secondary aim was to evaluate the course of weight change following PEG placement.MethodsWe retrospectively reviewed the medical records of 186 patients with HNC undergoing radiotherapy (RT) or chemoradiotherapy (CRT) at our institution between January 2010 and August 2017. Initial weight and nutritional intake were analyzed prior to RT initiation and then followed throughout treatment until completion. Based on these data, the indication of PEG placement was determined. Medical records were also reviewed to analyze PEG-related acute toxicities.ResultsA total of 186 patients met inclusion criteria. Patients were most commonly male (n=123, 66.1%) with squamous cell carcinoma (n=164, 88.2%). Patients who had dysphagia prior to treatment initiation as well as patients with a BMI <18.5 kg/m2 needed PEG placement earlier during the treatment course. Low-grade toxicities related to PEG insertion were observed in 10.7% patients, with peristomal pain and redness adjacent to the PEG tube insertion site being most common. High-grade toxicities, such as peritonitis and organ injury, were found in 4.9% of patients.ConclusionUnderweight patients and those with preexisting dysphagia should be closely screened during RT for weight loss and decreased oral intake. For weight loss greater than 4.5% during the treatment of HNC, early PEG-tube placement should be considered. Further prospective studies are needed to confirm these findings, and delineate a scoring system for timing of PEG use (prophylactic vs reactive) as well as assess the quality of life in patients with HNC who receive PEG placement.

Pragmatic dose-escalation methods incorporating relative dose intensity assessment for molecularly targeted agents in phase I trials

The recommended phase 2 doses of molecularly targeted agents, determined by using an ordinal dose-finding method that only uses toxicity data at first cycle, may not be optimal. Some researchers have proposed the use of relative dose intensity that can account for late-onset, cumulative, and low-grade toxicities to determine the recommended phase 2 dose (RP2D). In this study, we proposed two dose escalation methods based on the observed relative dose intensities (RDIs) between the pre-specified intervals (cycles) for toxicity evaluation used in combination with DLT evaluation in the first cycle. First, we propose the modified 3+3 design that incorporates longitudinal RDI assessment. Second, we propose the sequential assessment method for longitudinal RDI (SARDI) to achieve faster dose escalation compared to that of the modified 3+3 design. Simulation studies demonstrated that the SARDI was, in many cases, superior to the ordinal and modified 3+3 designs in respect to the selection rate of true RP2D and study period. The two proposed methods could also in some cases decrease the average number of patients enrolled in the trial compared to that of the ordinary 3+3 design. Incorporation of the RDI assessment into the 3+3 design is not difficult and does not require the use of complex statistical techniques. Therefore, we believe that investigators who routinely use the 3+3 design in practice can easily use our proposed methods.

593P - Dihydropyrimidine dehydrogenase (DPD) determination prior the administration of medicines containing fluorouracil: A single Spanish hospital experience

BackgroundSevere toxicity as a result of Fluoropyrimidine treatments appears in up 30% of patients. The reduce activity of DPD is one of the main cause of severe adverse events. Up to 8% of the population have low levels of DPD, and up to 0.5% of the population completely lack the enzyme. We assessed the effect of prospective screening for the 4 most relevant variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c.2846A>T [rs67376798, D949V], c.1679T>G [rs55886062, DPYD*13, I560S], c.1236G>A [rs56038477, E412E, in haplotype B3]) and rs34743033 TYMS, on patient safety and dose individualization in daily clinical practice. MethodsWe described our experience in a Tertiary University Hospital. We reviewed 208 patients with gastrointestinal cancer who were planned to receive fluoropyrimide treatment and we did prospective genotyping for DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A and rs34743033 TYMS. Heterozygous DPD variant allele carriers received an initial dose reduction of 25% (c.2846A>T and c.1236G>A) or 50% (DPYD*2A and c.1679T>G), and DPYD wild-type patients were treated according to the current standard of care. ResultsFrom April 2017 to March 2019, 208 patients were pre-tested. 8 patients (3´8%) were heterozygous DPD variant allele carriers and 200 (96´2%) were DPD wild-type patients. Overall, fluoropyrimidine-related severe toxicity was higher in DPD variant carriers (2 [25%] of 8 patients) than in wild-type patients (70 [35%] of 200 patients). 2 patients with c.1236G>A and rs34743033 TYMS heterozygous were necessary to disrupt treatment in spite of dose reduction because of severe diarrhea. However, the other 6 heterozygous have low grade toxicity with reduction preplanned. ConclusionsLife-threatening toxicities could be presented in patients with DPD deficiency if they are treated with standar dose of fluoropyridimes. Last colorectal cancer ESMO guidelines do not recommend testing DPD deficient up front. It recommend in case of patients who experience severe toxicity, DPD levels should be tested before 5-FU is re-introduced. We suggest due to our control of potential toxicities that implementation of DPD genotype individualised dosing should be a new standard of care.Legal entity responsible for the study: Mediano Rambla. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract CT233: Treatment of neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN) with cabozantinib (XL184): A Neurofibromatosis Clinical Trials Consortium Phase II trial

Abstract Background: Cabozantinib, an oral FDA approved multi-receptor tyrosine kinase inhibitor, was tested in our preclinical mouse model of PN. After finding significant reduction of tumor number and size in cabozantinib treated versus control mice, we sought to translate these findings to a phase 2 human study. Here we report the activity of cabozantinib in adolescents and adults with NF1-associated PN. Methods: A multicenter, nonrandomized phase 2 trial (NCT02101736) of cabozantinib in subjects ≥16 years with NF1 and either progressive or clinically significant inoperable PN was performed by the NFCTC (NF-105). The primary study aim was volumetric response of the target PN determined by MRI read centrally. Cabozantinib was administered continuously for up to 24 cycles, each cycle was 28 days. The starting dose was 40 mg once daily with planned escalation to a target dose of 60 mg once daily after 2 cycles. Dose reductions for toxicity were allowed to 20 mg once daily. Partial response (PR) was defined as ≥20% reduction in tumor volume from baseline. Subjects were considered evaluable for response if they completed ≥1 cycle of therapy and had a follow-up MRI. Success was defined as ≥25% of subjects achieving and maintaining a PR after 12 cycles without significant toxicity. Investigation of the impact of cabozantinib on the PN kinome network was performed on murine samples. Results: Twenty-three subjects enrolled; 21 subjects (median age 22 years) were evaluable for toxicity (2 noted to be ineligible before receiving study drug) and 19 subjects (median age 23 years) were evaluable for response (1 subject withdrew during cycle 1 and 1 was found ineligible after starting study drug). Baseline median tumor size was 557 mL (range 57-2954 mL). Among the evaluable patients, 8 (42%) met criteria for PR by cycle 12. Median change in tumor volume was -15.2% (range +2.2% to -36.9%). No subject had PN progression on treatment; maximal tumor response was not achieved until at least 18 cycles in 6/8 responders. A significant portion of patients underwent dose reductions or discontinued cabozantinib due to low grade adverse events (AE) that impaired quality of life; however, 3 responders reduced to 20 mg maintained or improved their response at this dose. The most common AEs (any grade) in ≥10 patients included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia (PPE). Eleven grade 3 AEs occurred in 8 patients, mainly PPE (n=4) and hypertension (n=2); no grade 4 or 5 AEs occurred. Analysis of kinase activity in murine PN treated with cabozantinib showed significantly decreased activity of AXL, MERTK and MET, known cabozantinib targets, but also of DDR1 and DDR2. Conclusions: Cabozantinib demonstrates considerable clinical activity for PN with a radiographic response rate of 42%. Although there were few severe AEs, low grade toxicities impacted the willingness of many subjects to continue treatment. Quantitative kinome analysis revealed that inhibition of DDR1, DDR2, AXL, MERTK and MET might underpin the therapeutic responses seen in these patients. Lower doses of cabozantinib may be optimal for the NF1 population and still lead to therapeutic response. This trial is now enrolling a pediatric cohort of children aged 3 to 15 years. Supported by DOD Award W81XWH-12-1-0155 and Exelixis Citation Format: Chie-Schin Shih, Jaishri Blakeley, D. Wade Clapp, Amy E. Armstrong, Pam Wolters, Eva Dombi, Gary Cutter, Nicole J. Ullrich, Jeffrey Allen, Roger Packer, Stewart Goldman, David H. Gutmann, Scott Plotkin, Tena Rosser, Kent Robertson, Brigitte Widemann, Steven Rhodes, Steven Angus, Gary Johnson, Bruce Korf, Michael J. Fisher. Treatment of neurofibromatosis type 1 (NF1)-related plexiform neurofibromas (PN) with cabozantinib (XL184): A Neurofibromatosis Clinical Trials Consortium Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT233.

Prevalence of immunotherapy-related adverse events due to checkpoint inhibitors: First report in Mexico.

e14090 Background: Since 2010, immune checkpoint inhibitors (ICI) have been approved for the treatment of several neoplasms. Their immune-mediated toxicity profile, used as monotherapy (nivolumab [N], Ipilimumab [Ip], pembrolizumab [P]) or in combination (Nivolumab/Ipilimumab [N/Ip]) and their management is still being described, recently. Methods: A retrospective review of medical records, included all cancer patients treated, in our institution, with ICI from January 2014 to February 2018. Frequency, type and grade of immune related adverse events (irAE) by neoplasm, individual agent or combination were recorded. Time to first ir-AE (TTF-irAE) was estimated by Kaplan Meir Method and compared by Cox regression model. Results: 140 patients were evaluated, all in pretreated metastatic setting. Median age 65.8+/-11.8, men in 59.3%. The most frequent neoplasms treated with ICI were: lung (34%), melanoma (33%), genitourinary (17%), H&amp;NC (6%), and GI (6%). Ip alone was indicated in 11.4% cases; N, 30%; P, 54.29%; N/Ip 4.29%. Median number of cycles per drug: Ip: 3 cycles, N/Ip: 4; N: 6; and P: 4 cycles. Toxicity (G1-4) was seen in Ip: 62.5%, N/Ip: 50%, N: 40.5%, P: 31.6%, p &gt; 0.05. The most frequent irAE's were: dermatological 40%, gastrointestinal 18.3%, and endocrine 13.4%; other irAE´s were reported in: pulmonary 7.3%, ophthalmologic 6%, muscle-skeletal 6%, neurologic 2.4%, renal 1.2%, hematologic 1.2%. Severe toxicities (G3-4) were observed with N/Ip: 33.3%, P: 17.4%, Ip: 10%, N: 5.6%. TTF-ir-AE per drug: I: 1st cycle (dermatitis, pruritus, colitis), N/Ip: 2nd cycle (dermatitis, conjunctivitis), N: 3rd cycle (dermatitis, thyroiditis, colitis, hepatitis), P: 1st cycle (pruritus, neuritis, adrenalitis). Ipilimumab was an independent prognostic factor for developing severe ir-AE´s [OR = 12.8, p = 0.038], and any grade toxicity [OR = 1.9 (IC95% 0.92 - 4.1, p = 0.079)]. Conclusions: In this study, the dermatological, gastrointestinal and endocrine toxicities were the most frequent ir-AE´s, and they were observed in a low grade toxicity. The irAE´s profile is different among ICI or their combination and number of cycles administered. Ipilimumab alone or combined was associated to higher risk of severe irAEs.

Immune checkpoint inhibitor toxicity in the clinical practice setting.

e14128 Background: Immune checkpoint inhibitors (ICIs) are changing the landscape of treatment in oncology. The use of ICIs is growing rapidly as the indications for these medications broaden and new ICIs become approved. Given the rapid growth and relative infancy of the use of ICIs, much information stands to be gained on their use in the clinical practice setting, especially regarding toxicity. Methods: The primary objective of this project was to examine the incidence and severity of immune-related adverse events (irAEs), after treatment with single-agent or combination ICIs at a multi-site community cancer center. A retrospective chart review was conducted on all patients who had received ipilimumab, nivolumab, pembrolizumab, atezolizumab, or ipilimumab plus nivolumab from May 1, 2011 to June 30, 2017. Data collected included patient demographics, disease state, treatment information, preexisting autoimmune disease, previous immunotherapy, and adverse event details. The results were analyzed using descriptive statistics. Results: Data was collected on 383 patients. Dermatologic irAEs were common across single agent ICIs (overall incidence 23%). Diarrhea and/or colitis incidence was highest with CTLA-4 inhibitor ipilimumab (26% at 3 mg/kg and 22% at 10 mg/kg) versus the other monotherapy PD-1/PDL-1 inhibitors. Endocrinopathies were most common with ipilimumab 10 mg/kg (55%) and pneumonitis incidence was highest with nivolumab (6%). ICI toxicity occurred in 63% of patients with preexisting autoimmune disease versus 54% of those without a baseline autoimmune disease. Incidence of hospitalization and treatment holds due to irAEs was higher with combination therapy (57% and 66%, respectively) than with monotherapy (10% and 24%, respectively). Conclusions: Overall, there was increased incidence in ICI toxicity in patients at this oncology institution versus what has been reported in clinical trials. Patients with preexisting autoimmune diseases appeared to have mainly low-grade toxicities with slightly increased incidence of irAE compared with those without pre-existing autoimmune disease. Treatment holds and hospitalizations were higher in patients treated with combination therapy ICIs compared to monotherapy ICIs.

A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.

Prognostic and predictive factors associated with ipilimumab related adverse events: A retrospective analysis of 11 NCI sponsored ipilimumab phase I clinical trials.

86 Background: We review factors affecting ipilimumab (ipi) associated toxicity in various NCI sponsored phase I clinical trials. Methods: NCI database for NCI sponsored phase I clinical trials evaluating ipilimumab was queried for adverse effects, radiological response data, lymphocyte counts, LDH, albumin, ECOG performance status, duration of treatment and diagnosis. Only treatment related AEs were analyzed. Events repeating across consecutive cycles were treated as a single event. Duration of treatment was calculated starting from cycle 1 day 1 of the treatment. IRB approval from NCI was obtained prior to the study. Results: Data from 373 patients from 11 phase I ipilimumab clinical trials were available for analysis. Median age of the study cohort was 55 years. 68%(n = 235) were males. Number of grade 3 and 4 AEs were associated with better radiological response. Mean grade 3 and 4 AEs in CR+PR cohort was 1.167 vs 0.645 in non-responder cohort (p = 0.001). No significant differences in low or high grade AEs were noticed in study cohorts differentiated based on ECOG PS (0 vs 1/2). ECOG PS 3/4 were not included in clinical trials. Pretreatment lymphocyte count, LDH or albumin was not predictive of increased ipilimumab associated toxicity. Ipilumumab associated grade 3 and 4 toxicity was directly associated with the number of concurrently used study agents. Mean grade 3 and 4 AEs were as follows in following cohorts: ipi alone; 0.631 vs ipi+ 1 drug; 0.877 vs ipi+ 2 drugs; 1.408 (p &lt; 0.0136). Number of low grade (grade 1 and 2) toxicity was associated with duration of treatment. r = 0.456 (p &lt; 0.0001). Number of high grade (grade 3 and 4) toxicity was not associated with duration of treatment with ipilimumab. r = 0.032 (p = 0.546). Conclusions: Ipilimumab associated grade 3 and 4 toxicity predicts response to therapy and is associated with higher CR/PR. ECOG PS, pretreatment lymphocyte count, LDH and albumin levels are not associated with ipilimumab toxicity. Lastly, addition of antitumor agents to ipilimumab has potential to cause a significant increase in serious AE’s.

Abstract PD3-07: A phase II pre-surgical trial of lapatinib for the treatment of women with HER2 positive or EGFR positive ductal carcinoma in situ

Abstract Background: Estrogen receptor (ER)-negative tumors and human epidermal growth factor 2-Neu (HER2) positive breast cancers are known to be more clinically aggressive subtypes of breast cancer and account for 30% of all breast cancers. Women with HER2 + breast cancers, whether ER+ or ER -, require cytotoxic chemotherapy with a HER2-targeting agent, and often have adverse outcomes. Thus, preventive agents are needed to reduce the incidence of these subtypes of aggressive breast cancer. Lapatinib, a dual tyrosine kinase inhibitor, inhibits epidermal growth factor receptors (EGFR) and HER2 kinases and has shown to decrease breast cell proliferation in invasive breast cancer and adjacent premalignant lesions. Therefore, we conducted a multi-institutional randomized Phase II clinical trial to study the effects of the signal transduction inhibitor lapatinib in women with HER2-positive or EGFR-positive ductal carcinoma in situ (DCIS). Methods: Randomized participants received either lapatinib (750mg, 1000mg, or 1500mg) or placebo daily for 2-6 weeks prior to their surgery. After minimal accrual, the trial was later amended to lapatinib 1000mg or placebo. Pre-treatment breast tissue was obtained from initial diagnostic core biopsy and post-treatment breast tissue was obtained from surgical excision specimen. Blood was obtained prior to surgery to assess serum lapatinib level. Participants kept a daily symptom assessment log and had a cardiac assessment at baseline and prior to surgery. Patients were instructed to take drug up to and including the day before surgery. The dual primary endpoint for this study was change in proliferation in pre- versus post-treatment biopsies between the two treatment arms, as measured by Ki67 as well as toxicity assessment. Secondary endpoints included incidence of DCIS at surgery and modulation of tissue biomarker expression in growth factor receptors (EGFR, ErbB2); phosphorylated growth factor receptor (phospho-ErbB2); signal transduction markers (MAPK, phospho-MAPK); hormone receptors (ER, PR); and p27. Results:Twenty-two women (mean age: 51; range: 32-66) with HER2+ or EGFR+ DCIS were treated with lapatinib (1,000 or 1,500 mg) or placebo for 2–6 weeks prior to surgical excision. Ki67 expression was significantly decreased in the lapatinib treatment arms compared to placebo (p=0.0122). Diarrhea, fatigue, and skin reactions were notable adverse events that occurred predominately in the lapatinib arm compared to placebo. No grade 3 or 4 events related to the study drug were noted during the study. No changes were noted in cardiac function. DCIS was present in all surgical specimens in both arms. Invasive breast cancer was noted in 1 patient on lapatinib 1000mg and 3 patients on placebo. No statistically significant changes were noted in signal transduction biomarkers Conclusion:These results demonstrate the effectiveness of lapatinib in reducing proliferation in women with EGFR+ or HER2+ DCIS. Even low-grade toxicities can deter use of an agent in the prevention setting. This and the lack of a risk model for HER2+ and triple negative breast cancer make the development of larger scale clinical prevention trials of lapatinib for the prevention a challenge. Citation Format: Thomas PS, Contreras A, Pruthi S, Krontiras H, Rimawi M, Garber J, Wang T, Hilsenbeck SG, Vornik LA, Gilmer T, Friedman R, Heckman-Stoddard BM, Dunn B, Kuerer H, Brown PH. A phase II pre-surgical trial of lapatinib for the treatment of women with HER2 positive or EGFR positive ductal carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-07.

Real World Analysis of the Incidence and Impact of Hypertension and Cardiac Toxicity Associated with Carfilzomib for Patients with Multiple Myeloma

Background:Carfilzomib (CFZ) is a potent, irreversible proteasome inhibitor (PI) licenced in patients with multiple myeloma (MM) demonstrating improved progression free and overall survival (OS) to standard of care therapies. However, CFZ is also associated with hypertension (HTN) and rarely cardiac toxicity. The exact mechanism is unclear but may be due to a disturbance of endothelial nitric oxide synthase and nitric oxide. Incidence of HTN in a pooled analysis of CFZ trials (Chari et al, Blood 2018, n=2044) showed all grade (G): 18.5%, ≥G3 5.9%. There is less data in the real world setting.Methods:This was a single centre retrospective analysis of all patients treated with CFZ between 2015-2018. BP was recorded in routine nursing records prior to each CFZ infusion in triplicate at each visit 10 minutes apart and the median recorded. HTN was graded by CTCAE criteria V4 (note: G1=pre-HTN (120-139/ 80-89)) and pulmonary hypertension as mean pulmonary arterial pressure (mPAsp) >25mmHg (American College of Cardiology criteria). Baseline demographics were obtained from medical records. OS was estimated using Kaplan Meier Curves and correlative analysis by Cox regression models.Results:86 patients and 1976 consecutive BP recordings were evaluated with a mean of 23 BP assessments per patient (1-74). Demographics are shown in Table 1. 32 patients (37.2%) had prior history of HTN and 14 (16.3%) had prior cardiac co-morbidity (ischaemic heart disease, dysrhythmias and cardiac amyloidosis). Initial dosing of CFZ was 20mg/m2, increasing to 27mg/m2 (n=30 (34.9%)), 36mg/m2 (n=18 (20.9%)), 45mg/m2 (n=2 (2.3%)), 56mg/m2 (n=35 (40.7%)), 70mg/m2 weekly (n=1(1.2%)). Median time on therapy was 5.3 months (0-26) with a median of 6 (1-27) cycles.The overall incidence of all grade HTN was 60 (69.8%), predominantly G1-2 and was similar in those with and without pre-existing HTN (Chi squared test p=0.4) (Table 2). 11(13%) required intervention with anti-HTN medications for ≥G2 HTN which then returned the BP to baseline. Those treated at ≥45mg/m2 of CFZ had more episodes of HTN compared to those treated at 27-36mg/m2 (OR 3.65, 95% CI: 1.39-9.21, p<0.01) despite similar co-morbidities per group. Age >65 years was not associated with increased risk of HTN (OR 1.32, 95% CI 0.45-3.73, p=0.63) nor was ethnicity (Chi squared test p=0.1). 25 patients required treatment interruption for any cause, of which 12 were due to HTN (median 7 days (1-23)).13 patients required dose reduction for any cause, and 9(10%) required reductions due to HTN, mainly at 56mg/m2 (27 n=1(1.2%), 36 n=2(2.3%), 56 n=7(8.1%)).The planned median cumulative dose for the number of cycles received was 1264mg/m2 overall (36-5772) however, the actual median cumulative dose delivered was 784 mg/m2 (36-3248). The difference was the greatest with higher carfilzomib doses (≥56mg/m2 vs 27-45mg/m2 (Chi squared test, p<0.01)). Planned vs actual dose delivered for number of cycles of CFZ received was: 27mg/m2, 634 vs 472; 36mg/m2, 1219 vs 722; 45mg/m2, 785 vs 744; 56mg/m2, 2514 vs 1282; 70mg/m2, 1210 vs 770.15(17%) patients developed cardiac complications including pulmonary HTN n=10(12%) and cardiac failure n=8(9%). Unlike HTN, cardiac complications were not associated with CFZ dose (<36mg/m2 vs ≥36mg/m2 OR 1.2, 95% CI 0.42-3.51, p=0.75) and were not related to development of HTN (OR 2.40, 95% CI 0.80-6.60, p=0.12) or prior history of HTN (OR 1.79, 95%CI 0.53-5.50, p=0.35). 1(1.2%) death was observed in a patient due to cardiac failure and progressive disease.OS was unaffected by HTN, cardiac toxicity, pulmonary HTN or HTN related treatment delays (median OS not reached regardless of developing cardiovascular adverse events, HR 1.45 95% CI 0.39-5.37, p=0.57; median follow up 17 vs 31 months respectively).Conclusions: This real world data demonstrated a higher incidence of HTN compared to clinical trials, however most were low grade toxicities. This may be partly due to under-reporting of G1 events which may not be clinically significant. Dose reductions were more frequent at CFZ doses ≥45, leading to a reduction in total cumulative dose received. Close monitoring and early intervention for HTN is therefore required to prevent further complications and to maintain cumulative dosing. In this dataset, cardiac complications did not appear to be related to HTN. [Display omitted] DisclosuresCheesman:Celltrion: Other: Speaker Fee; Roche: Other: Advisory board. Wechalekar:Janssen: Honoraria. Rabin:Janssen: Consultancy, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Other: Travel support , Speakers Bureau; Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Yong:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Takeda: Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau. Popat:Amgen: Honoraria.

Study of Treatment-Free Remission Evaluation in Real-World Chronic Myeloid Leukemia; Cost-Effectiveness Analysis

Chronic myeloid leukemia (CML) needs taking life-long tyrosine kinase inhibitor (TKI) which arises serious toxicities such as peripheral occlusive disease and pulmonary hypertension as well as low-grade toxicities. Treatment-free remission (TFR) can make almost half CML patients achieving deep molecular response (DMR) free from TKIs. We investigated total costs of each TKI considering TFR in Korea.Total numbers of annual newly-diagnosed CML patients were adopted from national cancer registration database. TFR was defined as achieving MR4.5 and lasting for 3 years. The proportion of MR4.5 was adopted from phase III studies of imatinib (IM), nilotinib (NIL) and dasatinib (DAS). TKI management followed life-long Markov model (Fig 1). Willingness to pay (WTP)was calculated for beneficial effects of patients who have achieved TFR and taking no TKIs as 2 times of gross domestic product per capita. Cost of progression was calculated based on the study by Jabbour et al. Patients older than 79y was not included in this study because TFR benefit is not considered in this age group. Duration of treatment and TFR was calculated separately according to age groups. We assumed that taking KTI lasted life-long until median life expectancy in Korea (80.87 years).Newly diagnosed annual CML patients were 443; 9 in age 0-14, 96 in age 15-34, 125 in age 35-49, 124 in age 50-64 and 89 in age 65-79. The theoretical number of patients who have sustainable TFR was 73 in IM, 93 in DAS and 119 in NIL. TFR as person-year in IM, DAS and NIL were 1940, 2521 and 3247, respectively. TFR (person-year) was very different according to age groups because of different incidence rates; 99.9 in age 0-14, 788.7 in age 15-34, 666.1 in age 35-49, 353.8 in age 50-64 and 33.7 in age 65-79 when IM was applied. TFR (person-year) were 128.2 in age 0-14, 1014.5 in age 15-34, 861.6 in age 35-49, 464.1 in age 50-64 and 52.8 in age 65-79 when DAS was applied. TFR (person-year) were 164.9 in age 0-14, 1305.6 in age 15-34, 1109.4 in age 35-49, 598.3 in age 50-64 and 69.0 in age 65-79 when NIL was applied. WTP according to TFR was 121.3 in IM, 157.5 in DAS and 202.8 billion KW in NIL. Costs by progression were 32.8 in IM, 26.8 in DAS and 22.3 billion KW in NIL. Life-long maintenance costs for patients who did not achieved sustainable TFR without progression were 128.7 in IM, 294.2 in DAS and 327.1 billion KW in NIL. Net costs considering TFR and progression were 40.2 in IM, 163.5 in DAS and 146.6 billion KW in NIL.Nilotinib was superior to other TKIs in terms of TFR benefit and progression cost according to our life-time Markov model. However, the net cost was lowest in IM. This analysis is limited by our assumption that MR4.5 is achieved by first 5 year and there is no further additional achievement of MR4.5 because of limitation of MR4.5 rates in each TKI trial. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Skin toxicity after chest wall/breast plus level III-IV lymph nodes treatment with helical tomotherapy

Introduction: To evaluate the incidence of toxicity in breast cancer with helical tomotherapy (HT).Materials and Methods: 51 patients with breast cancer were assigned to postoperative radiotherapy by means of HT to the chest wall/breast plus draining nodes. During HT treatment, toxicity was monitored and were assessed using the Common Terminology Criteria for Adverse Events 4.0 scale.Results: Acute skin G3 toxicity observed in 1.9% cases. No acute or late G4 toxicity was observed. At a median follow-up of 21 months 2 patients have late G1 toxicity.Conclusions: HT was associated with a low incidence of low-grade skin toxicity.

Efficacy and safety of raltitrexed-based transarterial chemoembolization for colorectal cancer liver metastases.

The liver is the most common site of colorectal cancer metastases. The present study aimed to evaluate the efficacy and safety of transarterial chemoembolization (TACE) with raltitrexed and oxaliplatin for colorectal liver metastases in a prospective, multicenter, single-arm trial conducted in 12 hospitals from different areas in China. A total of 90 patients with colorectal liver metastases were enrolled and treated by TACE with raltitrexed 4 mg and oxaliplatin 100 mg, followed by embolotherapy with 50 mg oxaliplatin and 5-20 ml lipiodol, administered every 28 days for four cycles. Patients were followed up every 3 months after the treatment and up to 12 months. The primary endpoint was time to progression. For the full analysis set (FAS), the median time to progression and overall survival were 9.1 and 17.8 months, respectively. The disease control rate in FAS was 71 (78.9%). Grade 3 or 4 adverse events were reported for 24 (26.7%) out of all 90 patients. Grade 3 thrombocytopenia, transglutaminase abnormality, and decreased neutrophil were observed in eight (8.9%), six (6.7%), and five (5.6%) patients, respectively. No unexpected adverse events or toxic deaths were observed. TACE with raltitrexed plus oxaliplatin is feasible, clinically beneficial, and well tolerated with low-grade toxicity for colorectal cancer patients with liver metastases.

The DigniCap Scalp Cooling System and its use in the treatment of chemotherapy-induced alopecia.

Chemotherapy-induced alopecia remains an emotionally traumatic side effect for cancer patients that impacts the quality of life, may be protracted in duration and may influence treatment decisions. Scalp cooling has been shown to be effective in preventing chemotherapy-induced alopecia. The DigniCap Scalp Cooling System is designed to prevent hair loss by cooling the scalp to reduce the impact of chemotherapy on hair follicle cells. Recent studies have shown the safety, efficacy and low-grade toxicity of the DigniCap System with a 66.3% success rate in hair preservation (n=106) relative to 0% in a nonrandomized control group according to a prospective pivotal study. Data also support improved quality of life in several domains. Two scalp cooling devices including the DigniCap are now US FDA cleared and can be offered as a part of standard of care.

Real world survival data of a rare malignancy: Anal cancer results in HIV negative patients from Turkey.

An organ preservation approach using chemoradiotherapy has been established for anal cancer. This retrospective cohort study aimed to define the clinico-demographic characteristics and outcomes of cases of human immunodeficiency virus (HIV)-negative anal carcinoma during a period of 20 years in a single comprehensive cancer institute. This was a single-center retrospective cohort study of patients who were treated between January 1995 and January 2015. The primary outcome measures that were investigated included overall survival (OS), progression-free survival (PFS), colostomy rates, and colostomy-free survival (CFS). A total of 28 patients who were principally treated with standard 5-fluorouracil + mitomycin combination chemoradiotherapy were eligible for analysis. The 3- and 5-year PFS rates were 92.4% and 63%, respectively. The lower T stage was found to be associated with a prolonged PFS (p=0.001). The 3- and 5-year CFS rates were 84.3% and 74.9%, respectively. A longer CFS was observed with lower T stages (p=0.05). At the last follow-up, 75% of the patients with anal cancer were alive, and 71.4% of the patients were disease free. The median OS was not reached with a median follow-up of 54 months (range, 6-115 months). The 3- and 5-year OS rates were 82% and 71.1%, respectively. No late toxicity was observed during the follow-up period. The short- and long-term prognoses of HIV-negative patients with anal squamous cell carcinoma were good, and low-grade toxicity was rare, thereby demonstrating that these patients can be successfully treated in a real-life setting with favorable outcomes.

Do SABR-related toxicities for lung cancer depend on treatment delivery?

Stereotactic ablative radiation therapy for lung cancer is an advanced technique where tumours are ablated with hypofractionated radiation doses, with a high degree of accuracy. The aim of this paper is to review the available literature and to discuss the SABR-induced toxicities for lung malignancies as a function of radiation delivery technique. A Medline search was conducted to identify the appropriate literature to fulfil the aim of this review and data from all applicable papers were collated and analysed. The most common techniques of SABR delivery employ linear accelerators, CyberKnife robotic radiosurgery system, TomoTherapy and the Novalis beam surgery system. Linear accelerator-based treatments give rise to a variety of toxicities that are strongly dependent on both patient-related factors and planning/dosimetry-related factors. The limited number of studies using CyberKnife reported low grade toxicities. Grade three toxicities mainly include fatigue and chest pain, usually in less than 10% of patients. All treatment techniques presented show efficiency in SABR delivery with various toxicities which, at this stage, cannot render one technique better than the other. For more conclusive results, well-designed phase three randomised clinical trials are required with better patient selection criteria, including dose and fractionation, treatment machine and technique, along with the consistent selection of a common toxicity grading criterion.

GBOIN: A Unified Model-Assisted Phase I Trial Design Accounting for Toxicity Grades, and Binary or Continuous End Points

SummaryThe landscape of oncology drug development has recently changed with the emergence of molecularly targeted agents and immunotherapies. These new therapeutic agents appear more likely to induce multiple low or moderate grade toxicities rather than dose limiting toxicities. Various model-based dose finding designs and toxicity severity scoring systems have been proposed to account for toxicity grades, but they are difficult to implement because of the use of complicated dose–toxicity models and the requirement to refit the model at each decision of dose escalation and de-escalation. We propose a generalized Bayesian optimal interval design, gBOIN, that accommodates various existing toxicity grade scoring systems under a unified framework. As a model-assisted design, gBOIN derives its optimal decision rule on the basis of the exponential family of distributions but is carried out in a simple way as the algorithm-based design: its decision of dose escalation and de-escalation involves only a simple comparison of the sample mean of the end point with two prespecified dose escalation and de-escalation boundaries. No model fitting is needed. We show that gBOIN has the desirable finite property of coherence and a large sample property of consistency. Numerical studies show that gBOIN yields good performance that is comparable with or superior to that of some existing, more complicated model-based designs. A Web application for implementing gBOIN is freely available from http://www.trialdesign.org.