NCI Grade Research Articles

Development and regulatory approval of a new systemic targeted therapy for advanced hepatocellular carcinoma.

613 Background: There are no commercially available devices for the treatment of patients with advanced hepatocellular carcinoma who have failed 1st line and 2nd line therapy. We have identified tumor-specific modulation frequencies in patients with advanced hepatocellular carcinoma. We exposed patients to radiofrequency electromagnetic fields, which are amplitude-modulated from 0.1 Hz to 100 kHz and measured changes in pulse pressure. Frequencies eliciting measurable changes in pulse pressure were selected as tumor-specific frequencies. Methods: Treatment is administered to patients with advanced hepatocellular carcinoma by means of a battery-operated portable device emitting 27 MHz radiofrequency electromagnetic fields, which are amplitude-modulated at hepatocellular carcinoma frequencies. The device is connected to a coaxial cable ending with a spoon-shaped antenna placed on the anterior part of the patient's tongue during treatment. Treatment is administered three times a day for one hour. Results: A total of 69 patients with advanced hepatocellular carcinoma received treatment with the TheraBionic device until progression or death. The median overall survival of patients who received treatment with the TheraBionic device after failing 1st line and 2nd line therapy was 9.15 (95% CI 1.6-34.8) months and the median overall survival of Child-Pugh A patients was 9.5 months, which are comparatively longer than the 7.8 months pooled estimated medians of the placebo arms of 11 randomized 1st line and 2nd line placebo-controlled studies assessing the safety and efficacy of new agents for the treatment of Child-Pugh A advanced HCC (Llovet, Montal et al., J Hepatol 2019). We also analyzed the survival of patients who had received two lines of systemic therapy and did not receive any additional cancer treatment while and after receiving treatment with the TheraBionic device. The median OS of these patients was 9.8 months and the median OS of the Child-Pugh A patients was 17.2 months, which are comparatively longer than the 7.74 months pooled estimated medians of the placebo arms of the above cited 11 randomized studies. To assess unknown device-related adverse events, we assessed patient reported symptoms using the same scale in the SHARP and Asian Pacific Sorafenib studies. The incidence of any grade adverse events among Child-Pugh A who received treatment with the TheraBionic device was not different from the Placebo group of the SHARP and Asian Pacific Sorafenib studies. There were no NCI Grade 2, 3 or 4 toxicities. One patient developed grade 1 mucositis and one patient developed grade 1 fatigue. Conclusions: The data presented here provide reasonable assurance of safety and probable benefit in patients with advanced hepatocellular carcinoma who have failed 1st line and 2nd line therapy: https://www.fda.gov/medical-devices/recently-approved-devices/therabionic-p1-h220001 .

Actionable tests and treatments for patients with gastrointestinal cancers and historically short median survival times.

Patients have difficult unmet needs when standard chemotherapy produces a median survival of less than 1 year or many patients will experience severe toxicities. Blood tests can predict their survival. Analyses evaluate predictive blood tests to identify patients who often survive 1 and 2 years. A four-test model includes: albumin, absolute neutrophil count, neutrophil-lymphocyte ratio, and lymphocyte-monocyte ratio. Individual tests include: alkaline phosphatase, lymphocytes, white blood count, platelet count, and hemoglobin. Eligible patients have advanced: resistant 3rd line colorectal, and both resistant and new pancreatic and intrahepatic bile duct cancers. Eligibility characteristics include: biopsy-proven, measurable metastatic disease, NCI grade 0-2 blood tests, Karnofsky Score 100-50, and any adult age. Drugs are given at 1/4-1/3 of their standard dosages biweekly: gemcitabine, irinotecan, fluorouracil, leucovorin, and day 2 oxaliplatin every 2 weeks. In case of progression, Docetaxel is added (except colon cancer), with or without Mitomycin C, and next cetuximab (except pancreatic and KRAS BRAF mutation cancers). Bevacizumab is substituted for cetuximab in case of another progression or ineligibility. Consent was written and conforms with Helsinki, IRB, and FDA criteria (FDA #119005). Median survival is 14.5 months. Of 205 patients, 60% survive 12, and 37% survive 24 months (95% CI ± 8%). Survival is > 24, 13, and 3.8 months for patients with 0, 1-2, and 3-4 unfavorable tests, respectively. Individual "favorable and unfavorable" tests predict long and short survival. Neither age nor prior therapy discernibly affects survival. Net rates of clinically significant toxicities are less than 5%. Treatments reproduce predictable, greater than 12 and 24-month chances of survival for the aged and for patients with drug-resistant tumors. Evaluation of blood tests may change practice, expand eligibility, and personalize treatments. Findings support investigation of drug combinations and novel dosages to reverse resistance and improve safety.

PATTERNS OF ORAL MUCOSITIS IN ADVANCED OSCC PATIENTS MANAGED WITH PROPHYLACTIC PHOTOBIOMODULATION THERAPY – INSIGHTS FOR FUTURE PROTOCOL DEVELOPMENT

<h3>Background</h3> Photobiomodulation therapy (PBMT) is recommended for the prevention of radiation-induced oral mucositis (OM) in head and neck patients. It is unclear to what extent the delivered PBMT therapy effectively provides an adequate uniform dose to the at-risk tissues. <h3>Objective</h3> To characterize oral sites affected by radiation-induced OM and its clinicopathologic outcomes in oral squamous cell carcinoma (OSCC) patients subjected to prophylactic PBMT. <h3>Methods</h3> The site distribution of OM, OM grading (NCI, Version 4.0), OM-related pain (visual analog scale), analgesic protocol (WHO), and use of enteral nutrition were evaluated weekly during treatment for OSCC patients with prophylactic PBMT. Data analysis was performed using descriptive statistics. <h3>Results</h3> One hundred forty-five OSCC patients were included. The most frequently affected sites by OM included lateral tongue (44.1%) and buccal mucosa (37.2%). Keratinized oral mucosae sites, including the tongue dorsum (6.21%) and retromolar trigone (8.3%), were also affected. Peak OM scores were observed at weeks 5, 6 and 7, with severe OM (NCI grades 3 and 4) rates of 11%, 20%, and 25%, respectively. The cumulative occurrence of severe OM was 23%, which developed as early as week 3 and as late as week 7. The highest mean value of OM-related pain (2.7) was observed in the sixth week, and 13.8% of the patients required feeding support. <h3>Conclusions</h3> Compared to previously published studies that did not provide PBMT, OM, pain and analgesia and tube feeding use reduction was seen. Keratinized surfaces should also be included in the prophylactic PBMT for OM aiming to reduce severe OM.

Patterns of oral mucositis in advanced oral squamous cell carcinoma patients managed with prophylactic photobiomodulation therapy-insights for future protocol development.

To characterize oral sites affected by radiation-induced oral mucositis (OM) and related clinical outcomes in oral cancer patients subjected to prophylactic photobiomodulation therapy (PBMT). This study included advanced oral squamous cell carcinoma (OSCC) patients treated with prophylactic PBMT for OM. The site distribution of OM, OM grading (CTCAE NCI, Version 4.0, 2010), OM-related pain (VAS), analgesic protocol (WHO Analgesic Ladder), and use of enteral nutrition were evaluated weekly during treatment. Data analysis was performed using descriptive statistics expressed as median values and percentages. A total of 145 OSCC patients were included. OM most frequently affected the lateral border of the tongue (44.1%), buccal mucosa (37.2%), and labial mucosa (33.8%). Keratinized oral mucosa sites, including the tongue dorsum (6.21%), retromolar trigone (8.3%), and hard palate (2.76%), were less frequently affected. Peak OM scores were observed at weeks 5, 6, and 7, with severe OM (NCI grades 3 and 4) rates of 11%, 20%, and 25%, respectively. The cumulative occurrence of severe OM was 23%, which developed as early as week 3 and as late as week 7. The highest mean value of OM-related pain (2.7) was observed at the sixth week, and 13.8% of the patients required feeding support. This study showed, compared with studies that did not provide PBMT, reduced severity of mucositis, reduced pain and analgesic use, and reduced tube feeding in patients treated with PBMT. OM involving keratinized and non-keratinized surfaces should be included in the prophylactic PBMT to reduce severe OM in future studies.

Fatigue design of cast iron components with surface discontinuities

Surface discontinuities are unavoidable properties of production castings, and have fundamental effect on in-service reliability. In the current study a multiaxial probabilistic fatigue analysis model has been developed for the description of local (e.g.: notches or surface defects) and structural gradient (e.g: bending) effects on crack initiation life. Identification of the model parameters and the validation has been done on the ferrite-pearlitic NCI grade EN GJS 500-7. The survival probability type simulation results are proven to be highly accurate with 5% average, and 11% maximum prediction error. In theory, the model might be able to assess the effect of arbitrarily complex defects on the fatigue strength, which is to be investigated in the future.

Prophylactic use of antidiarrheal agents to control diarrhea associated with lapatinib therapy in breast cancer patients.

205 Background: Lapatinib causes diarrhea in about 40-50% of patients treated with it for HER-2 positive breast cancer. It is the major dose and treatment limiting toxicity of lapatinib. Methods: This is a retrospective review of a cohort of patients treated with lapatinib for HER2 positive breast cancer at the Kirklin clinic at the University of Alabama at Birmingham from January 1, 2009 through September 30, 2013. Loperamide 2-8mg before lapatinib dose was recommended for prophylaxis in patients who developed clinically significant diarrhea. Additional doses of loperamide were used if needed. Results: 44 eligible patients were identified, 7 had stage IA, 10 had IIA, 7 had IIB, 5 had IIIA, 5 had IIIB and 6 had stage IV disease. Median age was 52 years (28-72 years) with 75% Caucasians. Starting dose of lapatinib was 1000mg oral daily. Overall 33 patients experienced diarrhea. 14 had NCI grade I, 5 had grade II, 10 had grade III and 3 had grade IV diarrhea. Other side effects encountered included rash, nausea, vomiting, LFT elevation, fatigue and allergic reaction. 17/33 patients received prophylactic loperamide. Median treatment duration with lapatinib for all patients was 6 months, range 1-60 months for patients receiving prophylactic loperamide and 1-22 months for others. 12/17 patients who received prophylactic loperamide had early improvement in diarrhea to NCI grade I or less vs. 4/16 for others. 5/17 patients who received prophylactic antidiarrheals required dose reduction due to diarrhea vs. 8/16 for others. Grade III and IV diarrhea was more common in standard treatment patients (8 vs. 5). 14 patients did not complete expected treatment duration, 5 due to diarrhea, all of whom had not received prophylactic antidiarrheals. Conclusions: Our study suggests that the use of prophylactic antidiarrheal treatment with lapatinib is possibly an effective strategy in getting patient to their therapy goals without interruptions or dose adjustments. The discontinuation rate and dose reduction rate in our population is lower than previously reported. Larger prospective studies will be of interest to evaluate this strategy further. Similar strategy could be applied to other agents causing diarrhea.

Confocal Microscopy Is Useful for Detection of Bortezomib Related Neuropathy (BOR-PN) in Multiple Myeloma (MM) Patients (PTS)

Abstract Background: Bortezomib-related painful sensory peripheral neuropathy (Bor-PN) represents the main dose-limiting toxicity of Bor. Cornea is the most innervated tissue in human body, with the highest density of small sensitive fibers, which are the main target of Bor-PN. Corneal confocal microscopy is a rapid, noninvasive, clinical examination technique that quantifies small nerve fiber damage and is already used for early identification of neural damage in course of diabetic sensory PN. Aims: To evaluate the possible role of confocal microscopy for identification and monitoring of corneal sub-basal neural plexus damage in Multiple Myeloma (MM) patients (pts) treated with Bor and to correlate confocal microscopy findings with Bor-PN. Patients and Methods: Patients underwent corneal examination with corneal confocal microscope (Confoscan 4). Corneal sub-basal fibers were evaluated in terms of the following morphometric measurements used as sign of neural damage: nerve fiber length, nerve fiber number, beadings number, tortuosity (according to Oliveira scale and Nidek index). The study was approved by local ethic committee, all patients signed informed consent before confocal microscopy evaluation. Twenty-six MM pts treated with Bor entered the study and were compared with 20 healthy controls. Control group morphometric findings were similar to data on healthy population reported in the literature. At time of confocal assessment among MM group there were 20 MM pts (77%) under active bor treatment, 6 pts were off bor-therapy (23%), clinically evident PN (NCI grade ≤2) was reported in 10 pts (38.5%). Results: MM pts and healthy controls were well matched as far as median age and sex. Compared to healthy controls, MM pts showed: I) a significant reduction in terms of length and number of corneal fibers (median length 552 μm in MM vs 1223.5 μm in control p&lt;0.001; median number 4/field vs 7/field p&lt;0.001) II) a higher grade of fiber tortuosity with both methods (1.8 vs 0.5 according to Oliveira scale, p&lt;0.001; 4 vs 2 according to Nidek index p&lt;0.001) III) a significant reduced number of beadings (40.8/mm vs 68/mm, p&lt;0.001). Finally, we found a trend for sign of increased neural damage in terms of length reduction and tortuosity of corneal fibers in MM pts with clinically evident Bor-PN when compared with pts asymptomatic for Bor-PN, these differences were not statistically significant maybe due to the limited number of pts evaluable (median fiber length 524.7 vs 557.5, p&lt;0.416; grade of fiber tortuosity 2 vs 1.5 according to Oliveira scale, p&lt;0.493; 4.3 vs 3.9 according to Nidek index, p&lt;0.247 respectively in MM pts with vs without bor-PN) Conclusions: Confocal microscopy can be a useful tool for detection of Bortezomib induced neural damage in MM patients. Prospective studies are needed to evaluate if it could help physicians in detecting neural damage in advance with respect to the emergence of clinically evident Bor-PN. Disclosures No relevant conflicts of interest to declare.

A nomogram for predicting serious complications in patients with solid tumors and apparently stable febrile neutropenia: Prospective data on 781 consecutive episodes from the FINITE study.

165 Background: An accurate estimate of the likelihood of serious complications in patients with otherwise apparently stable febrile neutropenia (FN) may assist in decision-making regarding individualized therapy. Our group has developed a prognostic score for predicting complications in patients with solid tumors and apparently stable episodes called CISNE (Clinical Index for Stable Febrile Neutropenia). The purpose of this study is to present a nomogram based on the previously mentioned index in a broader dataset of patients. Methods: FINITE is a prospective and multicenter study which aims to investigate prognostic factors and outcomes of FN episodes with clinical stability at first assessment, defined as events without acute organ dysfunction, vital signs abnormalities or major infections. We performed a nomogram based on the CISNE score which includes the following prognostic variables: ECOG PS≥2, chronic obstructive pulmonary disease, cardiovascular disease, mucositis NCI grade ≥2, monocytes &lt;200/mm3 and stress-induced hyperglycemia. A calibration plot was used to analyze the accuracy of this multivariate nomogram. Results: From October 2012 to December 2013, 781 patients with apparently stable FN were recruited in 21 Spanish hospitals. The rate of infection-related complications and death was 15.6% (95% confidence interval [CI], 12.9-18.6%) and 1.7% (95% CI, 0.98%-3.01%). A nomogram was designed according to the CISNE score. The area under the ROC curve was 0.836 (95% CI, 0.808-0.861). The observed and predicted probabilities also matched closely. Conclusions: Our group has developed a user-friendly nomogram for predicting complications in patients with apparently stable FN. This nomogram may be particularly useful to prevent premature discharges of cancer patients starting inpatient management.

P3-20-4 - Ischemic Colitis After Docetaxel-Based Chemotherapy in a Breast Cancer Patient

Abstract Background: In patients with malignancies, ischemic colitis sometimes occurs as complications of chemotherapy. Here we present a case of severe ischemic colitis in a patient treated with docetaxel-based chemotherapy. Case report: A woman aged 67 years old was treated with 75mg/m2 docetaxel and 600mg/m2 cyclophosphamide as adjuvant chemotherapy for right breast cancer. On the day 7 of first chemotherapy, she got constipated and noticed red blood per rectum. On the day 10, she visited our institute with shock state, having a fever and lower abdominal pain. Computed tomography of the abdomen revealed nonspecific distension and wall edema of the transverse colon. Laboratory findings showed NCI grade 4 neutropenia and an elevation of C-reactive protein to 27.0 mg/dl. She was immediately admitted to the intensive care unit and treated with broad-spectrum antibiotics, vasopressor agent and G-CSF. A colonoscopy was conducted and it showed longitudinal ulcer of the transverse colon and scattered redness of whole colon, consistent with ischemic colitis. She recovered 10 days later after hospitalization and could be discharged. Discussion: There are some reports that docetaxel-based regimen can be associated with ischemic colitis. In some cases it induces perforation of the bowel wall or septic shock, such as our case. If we use docetaxel-based regimen, the potential risk of ischemic colitis should be considered.

Prognostic Evaluation of Clinically Stable Febrile Neutropenia: Prospective Data from 921 Patients from the Finite Study

ABSTRACT Aim: In the present study, we aimed to assess the prognostic factors and outcomes of apparently stable febrile neutropenia (ASFN) episodes. Methods: FINITE is a prospective, multicenter study to assess prognostic factors and patterns of care in patients with ASFN defined by the absence of hemodynamic instability, acute organ failure, specific sources of infection (e.g. pneumonia) or inability to take oral medication. We used a binary logistic regression model with bootstrap resampling to identify prognostic factors for serious complications in stable patients. Results: From Sep/12 to Mar/14, 921 patients with ASFN were included from 24 centers. The rates of serious complicatios and mortality were:14.6% (95%CI, 12.5 to 17%) and 2.1% (95%CI, 1.4 to 3.3%). Signifficant clinical and microbiological differences were observed in patients with or without complications. In the multivariate analysis, nine variables were independent risk factors for serious complications: European Cooperative Oncology Group performance status >1, cardiovascular disease, chronic obstructive pulmonary disease, mucositis NCI grade >1, monocytes Multivariate and bootstrap analysis of risk factors for serious complications Parameter Coeff. OR 95% CI p-value ECOG ≥2 1.39 4 1.33-3.37 0.001 Cardiovascular disease 0.81 2.2 1.15-4.47 0.01 COPD 1.01 2.7 1.68-6.77 0.001 Mucositis ≥2 1.08 2.9 1.78-4.96 0.001 Monocytes 0.99 2.6 1.66-4.96 0.001 Lymphocytes 450/mm3 0.85 2.3 1.45-4.1 0.002 Rigors 0.75 2.1 1.33-3.37 0.002 Previous treatment with corticoids 0.71 2 1.05-3.95 0.02 Malnutrition 1.20 3.3 1.68-6.46 0.01 Conclusions: This study identified risk factors for serious complications in patients with solid cancers and ASFN episodes, with potential implications on individualized therapy. Disclosure: All authors have declared no conflicts of interest.

Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer

Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC). Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity. Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred. The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group. NCT00499603.

Sorafenib induced Hand Foot Skin Rash in FLT3 ITD mutated Acute Myeloid leukemia- A case report and review of literature

Sorafenib is a novel small molecule multiple kinase inhibitor which has been used for metastatic renal cancer, hepatocellular cancer. Sorafenib induced skin rash has been discussed as a side effect in trials in both, FLT3 wild type and mutated acute myeloid leukemia (AML), as monotherapy or as combination with other chemotherapeutic agents. We describe a patient with FLT 3 ITD mutated AML, who was started on adjunctive Sorafenib therapy. Skin reactions manifested as NCI Grade III palmoplantar erythrodysesthesia (PPE), requiring drug discontinuation. Several pathogenic mechanisms have been implicated in Sorafenib induced skin reactions, but none has been conclusively proven. While treatment options are varied for early stage skin reactions, drug discontinuation remains the only possible therapy presently for severe grade skin reaction.

Abstract P2-15-02: Trastuzumab treatment of early breast cancer: Long-term results from a prospective observation study, including a large cohort of elderly patients

Abstract Purpose: Trastuzumab (T; Roche) is part of the standard treatment in patients (pts) of any age with early stage, HER2+ breast cancer, in addition to (neo)adjuvant chemotherapy (CT) and locoregional treatment. After its registration in Germany in 2006, this prospective observation study was started in order to assess the generalizability of the results from the randomized studies, specifically with respect to elderly age cohorts. Methods: 4027 pts were enrolled between 2006 and 2012. 87 were non-eligible due to M1 and/or negative HER2 status. There were no restrictions for recruitment with respect to age or concomitant/sequential adjuvant medication. The long-term relapse/survival status of pts was retrieved by fax forms collected once a year. Safety assessment was limited to the treatment period. Data base cut-off was May 2013. Results: Among the 3940 evaluable pts, there were 1013 elderly pts (EP) ≥ 65 years (y) of age (26%). This contrasts to the pivotal studies, e.g. with a proportion of only 6% beyond 65 y in the NSABP B-31 and NCCTG N9831 studies. The rate of EP steadily increased during the period from 2006 to 2009, remaining stable thereafter. More than half of the pts had pT≥2, with EP more often presenting with a larger tumor (56% vs. 48%,p&amp;lt;.0001). 52% had a grade 3 tumor. Hormone receptor positivity was recorded in 63%. As to be expected, performance status was more impaired in elderly compared to younger pts (ECOG 0: 53 vs 65%,p&amp;lt;.0001). 94% received CT, 78% as adjuvant, 14% as neoadjuvant treatment (in EP only 8%), while 2% received both modalities. In the vast majority (87%), T was administered sequentially to CT, with no differences among the age cohorts. The proportion without any adjuvant CT was higher in EP (8 vs. 5%). 56% of pts were treated with adjuvant endocrine medication, 78% with irradiation. T treatment was stopped prematurely in only 9% of pts, but more often in EP (11% vs 8%, p = .014). After a follow-up period of up to a maximum of 8 y, 370 relapses were reported so far. The estimated recurrence-free survival is 94.7% (95% CI: 94-96%), 89.8% (89-91%), and 82.9% (81-85%) after 2, 3 and 5 y, respectively. Numeric results in EP are only slightly lower with 93.9 (92-96%), 89.3% (87-92%), and 81.6% (78-85%), not statistically significant (p = 0.18, HR = 1.17 [95% CI: 0.93 - 1.47]). Adverse effects with respect to cardiac function were reported in overall 153 pts (3.9%), with the majority of these cases of NCI grade 1 (39%) or 2 (38%). 23% of these events were of grade 3/4, but life-threatening in only 2 pts. Thus, the overall incidence of acute grade 3/4 cardiac function toxicity was 0.9%. In the EP subgroup the incidence across all NCI grades was only slightly increased (4.6%), but grade 3/4 cases were more common (1.6%). Conclusion: Overall, the maturing follow-up data of this observational study confirm the beneficial results from the randomized studies. In addition, the data from more than thousand pts ≥ 65 y of age show that a similar anti-tumor efficiency can be achieved in elderly pts, and suggest that minor age-related differences detected with respect to adjuvant treatment duration, aggressiveness and toxicity do not impair the long-term clinical outcome. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-15-02.

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Introduction: Use of medications for non-Food and Drug Administration (FDA) approved indications is considered "off-label". A multicenter, 24-hour snapshot study in the intensive care unit (ICU), indicates off-label use occurs with 36% of prescribed medications. Medications used for off-label indications raises concern for potential patient safety and resultant adverse drug reactions (ADRs), as the drug has not been subjected to the same scientific inquiry as medications being utilized for FDA approved indications. Medications are used commonly for off-label indications in the ICU; however, the frequency and severity of ADRs due to off-label use is unknown. Methods: This was a prospective, observational, multi-site study of adult patients admitted to medical ICUs (MICU) at two academic medical centers for a 3 month period. Upon admission of the patient to the MICU, all inpatient medications were reviewed by a pharmacist extender to determine if medications were being used for FDA approved or unapproved indications. Subsequently, newly prescribed medications for each patient were evaluated for indication every 24 hours. Patients were evaluated daily for the development of an ADR by the clinical pharmacist during patient care rounds and through electronic medical record review. When the clinical pharmacist identified a possible ADR, the ADR was assessed using 3 objective, published ADR causality instruments (Kramer, Naranjo, and Jones). Agreement between 2 of the 3 instruments for events ranking "possible" or greater, were considered an ADR. Upon completion of data collection, the culprit medications associated with ADRs evaluated by the pharmacist were matched to the medication indication list generated by independent reviewers. The severity of the ADR was classified based upon two commonly used severity scales. The National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events was used with a grade of 3-5 considered severe/life threatening. A MEDMARX classification was applied and A-D was considered "no harm", while E-I was considered "harm" to the patient. Descriptive statistics are provided and chi-square tests were utilized as appropriate Results: Overall, 13,580 medications, during 950 patient days, were evaluated with, 41.5% (5636/ 13580) being used for an off-label indication. Off-label use was categorized into 4 types: 1) non-indicated patient population (132/5636); 2) non-indicated condition (4662/5636); 3) non-indicated dose (662/5636) and 4) non-indicated route of administration (180/5636). A total of 100 ADRs per 1000 patient days were identified, with opioids and sedatives accounting for over 25% of the ADRs. A total of 44 ADRs per 1000 patient days occurred for medications used for off-label indications and 56 ADRs per 1000 patient days occurred for medications used for approved indications. There was no statistical difference in the frequency of ADRs between medications being used for FDA approved or off-label indications with 0.67 % vs 0.73%, respectively (p=0.38). Upon evaluation of ADR severity, there was no difference in the frequency of ADRs that received a NCI grade of severe/life threatening, between medications used for a FDA approved or off-label indication (17 vs 19; p=0.10). There was also no difference in the number of ADRs that resulted in a MEDMARX classification of "harm" between medications being used for FDA approved or off-label indications (31 vs 28; p=0.26). Conclusions: Off-label use occurs frequently in the ICU; however, this does not result in additional patient safety concerns based on frequency or severity of ADRs.

Phase II, Open Label, Randomized Comparative Trial Of Ondansetron Alone Versus The Combination Of Ondansetron Plus Aprepitant For The Prevention Of Nausea and Vomiting In Patients (Pts) With Hematological Malignancies Receiving Regimens Containing High Dose Cytarabine

Abstract Background Chemotherapy induced nausea and vomiting can be a significant problem for pts with acute myeloid leukemia (AML) receiving induction chemotherapy causing deterioration in quality of life. Cytarabine-containing regimens are the cornerstone for the management of AML and cytarabine is a moderate emetic risk chemotherapy agent. Combination of cytarabine with other chemotherapeutic agent can substantially worsen nausea and vomiting. Ondansetron has been used for nausea control in pts receiving chemotherapy. Aprepitant is a P/neurokinin-1 (NK1)-receptor antagonist approved for use in combination with a 5-HT3-receptor antagonist and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. We explored whether the combination of two drugs with different mechanisms of action may improve the control of nausea in pts with AML receiving cytarabine-based induction. Methods Pts with AML, high-risk MDS or CML blast phase receiving induction chemotherapy with cytarabine at a dose of ≥1 g/m2/day for at least 3 days were randomized to: Arm 1) Ondansetron 8mg IV 30 minutes before high dose cytarabine followed by ondansetron 24mg IV continuous infusion daily until 6-12 hours after the end of last chemotherapy infusion. Arm 2) Aprepitant 125mg PO plus ondansetron 8mg IV 30 minutes before high dose cytarabine followed by ondansetron 24mg IV continuous infusion daily until 6-12 hours after the end of last chemotherapy, plus aprepitant 80 mg PO daily and to continue for 1 day after last dose of chemotherapy. Pts were followed for 72 hrs post chemotherapy. A diary was used by the pts to record daily number of episodes of nausea and /or vomiting experienced during the study, as well as to record any need of extra medications for escape nausea. Complete response was defined as no emesis episodes and no use of rescue medication during the study period. Partial response was defined as ≤ 1 episode of emesis during the entire study period, no use of rescue medication during the study period, and no more than moderate nausea (NCI grade 2). Results Forty nine pts were enrolled in each arm. Fifty seven percent were men in arm 1 and 55% men in arm 2. The median age was 53yrs (ranges, 30-68) in arm 1 and 49yrs (ranges, 21-70) arm 2. Caucasians were 83% in arm 1 and 76% in arm 2. African American and Hispanics were 10 % and 6% respectively in arm 1 and 8% and 12% in arm 2. Among the population studied 96% were diagnosed with AML in each arm. MDS 2% in arm 1 and 4% in arm 2. Fourteen percent received Idarubicin with cytarabine (Ara-C) in each arm. Twenty percent in ondansetron (OND) arm and 16% in ondansetron plus aprepitant (OND+APREP) arm receive Ara-C combined with Fludarabin. Ara-C in combination with anthracycline plus nucleoside analogues was given to 49% of pts in each arm. Ten percent in arm 1 received Ara-C with anthracycline and targeted therapy, 8% in arm 2 receive similar combination. Forty two pts on OND arm and 41 pts in the OND+APREP arm were evaluable for efficacy. Patient in the OND+APREP arms achieved higher overall response rates (complete plus partial responses) as shown in Figure 1, but the difference was not statistically significant (OND 67%, OND+APREP 80%; P= 0.11). More than 75% of pts overall were free of nausea on Days 1 and 2. On days 6 and 7 higher proportion of pts in OND+APREP arm were free from nausea than OND arm. Overall 36% of pts required rescue medications, 38% in OND arm and 34% in OND+APREP arm. Among them 14% of pts required rescue more than once; 19% in the OND arm and 10% in OND+APREP arm, as shown in Figure 2. Requirement of rescue medications on Days 2 and 3 were fewer in OND+APREP arm 7% and 5% respectively compare to 21% and 16% in the ondansetron arm (P = 0.06 and P=0.07). Most common adverse events were headache and diarrhea. Twenty percent of pts in OND arm and 19% in OND+APREP arm reported to have NCI grade 2 headache (P= 0.56). Five percent of pts in ondansetron arm and 12% in ondansetron plus aprepitant arm had grade 2 diarrhea (P=0.19). Conclusions The daily assessment of emesis and nausea did not show statistically significant differences between the study arms but there was a clear trend towards better responses in ondansetron plus aprepitant arm with more overall response rates and lower use of rescue medications. Further larger studies are warranted to further define the benefits of this combination of antiemetic drugs. Disclosures: No relevant conflicts of interest to declare.

Feasibility Of Pegylated-Asparaginase (PEG-ASP) During Induction In Adults With Acute Lymphoblastic Leukaemia (ALL): Results From The UK Phase 3 Multicentre Trial UKALL 14

Abstract L- asparaginase treatment improves clinical outcomes in childhood ALL and Pegylated asparaginase (PEG-ASP) ) has become the standard of care for this patient group. By contrast, safety and efficacy data on PEG-ASP in adult ALL is limited. A key question is the impact of asparaginase associated toxicity on the delivery of multiagent chemotherapy in adult treatment regimes. UKALL14 prospectively evaluated the tolerability of PEG-ASP as part of a 5 drug induction regimen in adults with ALL between 25-65 yrs. The primary-end point of the PEG-ASP evaluation was toxicity. Here, we report on the toxicity of PEG-ASP in the first 91 subjects, after which the trial protocol was amended due to safety concerns. UKALL 14 Induction Phase 1 consisted of intravenous PEG-ASP (1000 IU/m2) on days (d) 4 and 18, Daunorubicin 60mg/m2 and Vincristine 1.4mg/m2 (2mg max) on d1,8,15 and 22, Dexamethasone 10mg/m2 d1,-4, 8-11,15-18 and a single intrathecal (IT) Methotrexate 12.5mg on d14. Patients with pre-B lineage ALL were randomized to receive Rituximab or not. Patients with Philadelphia chromosome (Ph) positive disease received continuous Imatinib 400mg escalating to 600mg daily throughout induction. Phase 2 induction comprised of cyclophosphamide 1000mg/m2 d1+ 15, Ara-C 75mg/m2 d2-5, 9-12, 16-19 + 23-26, mercaptopurine 60mg/m2 throughout and IT methotrexate d1,8,15,22. Results The median age was 47 years (25-65yrs). Overall, 80.2% (73/91) patients completed phase 1 induction. Of these 60 achieved CR, 9 did not, and 4 had missing CR data. Thirteen of the 18 patients who did not complete phase 1 induction suffered early death. The overall induction mortality was 19.8% (18/91). Sixteen deaths occurred pre phase 2 induction and 2 deaths post phase 2. The most common cause of induction death was sepsis in combination with hepatotoxicity (55.6%,10/18) followed by sepsis alone (16.7%, n= 3). Additional causes of death were bowel ischaemia in combination with hepatotoxicity (n=2), acute coronary syndrome (n=1), haemorrhage (n=1) and pancreatitis + bowel perforation (n=1). Ten of the 12 hepatotoxicity associated induction deaths had NCI Grades 3-4 hyperbilirubinaemia. The median time from last dose of PEG-ASP to induction death was 14.5 days (6-71). Taking into account the multiple risk factors contributing to hepatoxicity associated morbidity (concomitant administration of hepatotoxic drugs and sepsis itself), a PEG-ASP related cause of death was “definitely or probably” implicated in 11/18 induction deaths. Logistic regression showed that age and Ph status were independent variables predicting induction death&lt;40yrs vs ≥40yrs, odds ratio (OR) 5.27 (95% CI 1.13-24.7), p =0.035; age &lt;55yrs vs ≥55yrs OR 4.47 (1.51-13.18), p =0.007 and Ph pos vs Ph neg disease, OR 6.08 (2.01 – 18.34), p =0.001. The trial steering committee confirmed that there was no relationship to Rituximab randomization. The incidence of non-fatal PEG-ASP toxicity during induction was 36.7% (n=33).The most common toxicity was abnormal liver function test (24.5%,n=22) followed by coagulopathy (7.7%,n=7) and thrombosis (5.6%,n=5). Grade 3-4 PEG-ASP related liver dysfunction was significantly associated with older age (&lt;40 vs &gt;40, p= 0.031). Enzyme activity, assessed by MAAT, after the first PEG-ASP dose in phase 1 induction was available for a subset of patients (n=27). Nearly all patients (88.9%) achieved a therapeutic level of enzyme activity of &gt;100IU/ml 14 days after the first PEG-ASP. Conclusion Significant levels of treatment associated mortality occurred in adults treated with a PEG-ASP containing induction regimen on UKALL 14 which was strongly associated with older age and Ph pos disease. As a consequence of the toxicity the protocol was amended to omit d4 PEG-ASP for those over 40yrs. PEG-ASP was completely removed from induction treatment for Ph positive patients. Furthermore, due to the high level of sepsis related to profound myelosuppression, the daunorubicin dose was halved to 30mg /m2 on d1,8,15 and 22. One year following the amendment 123 further patients have been recruited and 8 (6.5%) induction deaths recorded. Our data indicate that whilst PEG-ASP achieves effective asparagine depletion in adult patients it is difficult to deliver safely to those over the age of 40yrs with particularly pronounced toxicity in the over 55s, and should not be started early during induction. Caution should be exercised in co-administration with Imatinib. Disclosures: Fielding: Medac: Research Funding.

Incidence of neurotoxicity and ototoxicity with cisplatin vs. non-cisplatin regimens: A meta-analysis with subgroup analyses based on renal eligibility criteria.

e15555 Background: Using glomerular filtration rate (GFR) to screen patients for trial eligibility may reduce the risk of cisplatin (CIS) associated nephrotoxicity compared to serum creatinine (SCr). The impact of using GFR or SCr on incidence of neurotoxicity and ototoxicity remains unknown. This meta-analysis compared incidence of neurotoxicity and ototoxicity among trials of solid tumors treated with CIS reporting nephrotoxicity when renal function was assessed using SCr or GFR. Methods: A PubMed literature search identified randomized trials comparing CIS to non-CIS containing chemotherapy regimens. Studies were included if performed from 1990-2010, used SCr or GFR as eligibility criteria, and reported incidence of WHO or NCI grade ≥3 nephrotoxic events. Separate analyses were performed on studies reporting grade ≥3 neurotoxic or ototoxic events. For neurotoxicity, studies comparing CIS to other neurotoxic drugs were excluded. Review articles, observational studies, phase 1 studies, non-randomized trials, studies without a comparator group, or studies not reported in English were excluded. Relative risk (RR) associated with CIS vs. non-CIS regimens was calculated and subgroup analyses were performed for studies using SCr, GFR, and either SCr or GFR for screening. Results: The literature search identified 2359 studies with 18 studies meeting all inclusion and exclusion criteria for neurotoxicity (N=3441 patients) and 9 for ototoxicity (N=2947). The RR for developing neurotoxicity was 1.27 (p=0.50) and ototoxicity was 2.32 (p=0.10) for CIS vs. non-CIS regimens. For neurotoxicity, the RR when SCr was used as eligibility criteria was 2.31 (p=0.11), 0.71 (p=0.54) when GFR was used, and 1.01 (p=0.99) when either was used. For ototoxicity, the RR for SCr was 2.33 (p=0.21) and 3.47 (p=0.20) for either. Studies using GFR reported zero ototoxic events. Conclusions: The risk of neurotoxicity and ototoxicity did not significantly change when SCr or GFR was used to screen patients. However, these analyses were performed on a subgroup of studies reporting nephrotoxicity and further research on all studies of neurotoxicity and ototoxicity is warranted.

Incidence of severe nephrotoxicity with cisplatin vs. non-cisplatin regimens: A meta-analysis with sub-group analyses based on renal eligibility criteria.

e15549 Background: Serum Creatinine (SCr) is commonly used to screen patients for eligibility in trials of the nephrotoxic drug cisplatin despite the fact that glomerular filtration rate (GFR) is known to better estimate renal function. The objective of this meta-analysis was to indirectly compare incidence of nephrotoxicity in trials using cisplatin for treatment of solid tumors when renal function was assessed using SCr or GFR for eligibility criteria. Methods: A literature search was conducted in PubMed to identify randomized trials comparing cisplatin to non-cisplatin containing chemotherapy regimens. Studies were included if they were performed from 1990-2010, used SCr or GFR as eligibility criteria, and reported incidence of WHO or NCI grade ≥3 nephrotoxic events for both treatment arms. Review articles, non-randomized trials, observational, phase I, studies without a comparator group, or not reported in English were excluded. The relative risk (RR) of grade ≥3 nephrotoxicity associated with cisplatin vs. non-cisplatin regimens was examined using inverse variance weighted fixed effects (FE) and random effects (RE) methods. Subgroup analyses of studies using SCr, GFR, and either SCr or GFR for screening were performed. Results: The literature search identified 2,359 studies, and 42 studies met all inclusion and exclusion criterion (N=9,521 patients). SCr was used as eligibility criteria in 20 studies (N=4,704), GFR was used by 9 studies (N=1,650), and either SCr or GFR was used by 13 studies (N=3,167). The overall RR for developing nephrotoxicity with cisplatin vs. non-cisplatin treatment was 1.75 (95%CI 1.18-2.58, p=0.005). Results from subgroup analyses showed the RR was 2.60 (95%CI 1.34-5.03, p=0.005) when SCr was used as eligibility criteria compared to 1.50 (95%CI 0.82-2.74, p=0.19) when GFR was used and 1.26 (95%CI 0.55-2.85, p=0.59) when either SCr or GFR was used. Results did not vary between FE and RE methods. Conclusions: Cisplatin based therapy is associated with a significant increase in severe nephrotoxicity. The risk of severe nephrotoxicity is higher in trials that utilize SCr as eligibility criteria compared to those that utilize GFR.

A randomised double-blind placebo-controlled phase II study of AGI004 for control of chemotherapy-induced diarrhoea

Background:AGI004 is a controlled-release transdermal patch preparation of mecamylamine. We conducted a randomised placebo-controlled phase II study of two dose levels of AGI004 in chemotherapy-induced diarrhoea (CID).Methods:Adult patients receiving chemotherapy who had experienced diarrhoea (NCI grade 1–2) during previous cycles of chemotherapy were eligible. In all, 64 patients were randomised to receive AGI004 4 mg then 8 mg per 24 h transdermal patch or placebo for two sequential cycles of chemotherapy. Patients' severity of diarrhoea was physician-assessed using NCI grade of diarrhoea and patient-assessed using information recorded in daily diaries of bowel movements.Results:Overall AGI004 doubled the odds of a response to treatment on the first day of chemotherapy based on physician assessment of NCI grade of diarrhoea compared with placebo (odds ratio=2.0, 90% confidence interval: 0.9–4.5) and there was a trend to improved response rates for AGI004 for the full treatment cycle although these results were not statistically significant. There was also evidence of significantly improved response rates based on patient assessment of diarrhoea both overall (P=0.05) and at the 8-mg dose level (P=0.02) compared with placebo.Conclusion:AGI004 demonstrated effectiveness in reducing chemotherapy-associated diarrhoea, with results suggesting response across multiple measurements of diarrhoea. Treatment was well tolerated with no drug-related adverse events. Further evaluation of this agent in the management of CID is warranted.

Recombinant human epidermal growth factor on oral mucositis induced by intensive chemotherapy with stem cell transplantation

Oral mucositis (OM) is one of the most common and debilitating complications in patients undergoing intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for OM induced by intensive chemotherapy followed by HSCT. Patients were randomly assigned to either the rhEGF group or placebo group. The severity of OM and self-reported quality of life (QOL) were assessed daily. A total of 58 patients were analyzed. Baseline characteristics were similar between the two groups. The incidence of NCI grade ≥ 2 OM was higher in the rhEGF group (78.6% vs. 50%, P = 0.0496). However, the duration of OM in patients with NCI grade ≥ 2 tended to be shorter in the rhEGF group (8.5 days vs. 14.5 days, P = 0.262). The QOL analysis in patients with World Health Organization (WHO) grade ≥ 3 OM showed that rhEGF significantly reduced limitations in swallowing (P = 0.039) and drinking (P = 0.042). The duration of hospitalization (P = 0.047), administration of total parenteral nutrition (P = 0.012), and the usage of opioid analgesics (P = 0.018) were significantly shorter in the rhEGF group with WHO grade ≥ 3 OM. Adverse events were mild and similar between the two groups. In conclusion, this analysis showed that rhEGF did not reduce the incidence of NCI grade ≥ 2 OM. However, the patients with WHO grade ≥ 3 OM in the rhEGF group showed better results compared to the placebo group for several secondary endpoints.