bluuebunny/crossref_metadata_2025 huggingface dataset:
Minocycline to reduce cancer pain in patients with multiple myeloma: A phase II randomized trial.
Authors: Wang Xin Shelley , Cleeland Charles S. , Shi Qiuling , Prasad Seema , Bokhari Raza H , Orlowski Robert
Published: September 2018

10100

Background: Patients with multiple myeloma (MM) experience substantial pain that may be from disease and/or post autologous stem cell transplant condition, and exacerbated by maintenance therapy. Minocycline is a readily available, low-cost antibiotic with anti-inflammatory properties. We conducted a phase II randomized, double-blinded, placebo controlled clinical trial to investigate the effect of minocycline in reducing patient-reported symptoms during maintenance therapy. Methods: Adults with MM scheduled for maintenance therapy at a single-institution were consented and randomized to receive either minocycline (100 mg twice daily) or placebo over the first 3 cycles maintenance therapy. Feasibility, toxicity, and patient-reported outcome data were prospectively collected. The MD Anderson Symptom Inventory-MM (0–10 scale) was used to assess pain and other symptoms weekly during 3 months trial. The longitudinal analysis for pain was compared between the minocycline and control groups to examine minocycline’s efficacy. Results: From April 2013 to Aug 2016, 88 patients were enrolled and 69 (78%) were evaluable: 33 were randomized to minocycline and 36 to placebo. There were no grade 3+ study medication-related adverse events. The worst 5 symptoms on MDASI-core during the trial were fatigue, pain, numbness/tinging, drowsiness, and disturbed sleep, followed by two MM module item bone aches and muscle weakness. Demographic and disease characteristics were not significantly different between groups. Longitudinal modelling of revealed a significant reduction on pain in minocycline group than placebo group (time and treatment group interaction, estimate=-0.068, P=.003). The favorite pain reduction in minocycline group vs placebo arm was represented by a moderate effect size (Cohen’s d =0.48). Conclusions: Minocycline during maintenance therapy for MM was feasible, had a low toxicity profile, and yielded a statistically significant positive signal on pain reduction. These preliminary results are encouraging and warrant a Phase III trial to test its efficacy. Clinical trial information: NCT01793051.
Phase II study of the effect of the topical corticosteroid fluocinonide in patients on endocrine therapy for breast cancer or breast cancer prevention with symptoms of vaginal dryness and dyspareunia.
Authors: Hobbs Evthokia A. , Lethert Kristine , Nauman Deirdre J. , Bucher Jenna , Latour Emile , Mori Motomi , Chui Stephen Y. , Kemmer Kathleen A.
Published: September 2018

10105

Background: Gynecologic symptoms and sexual dysfunction from endocrine therapy are troublesome side effects for a significant number of patients. This study explored amelioration of vaginal dryness and dyspareunia with fluocinonide cream, a strong topical corticosteroid. Methods: A single-arm, open-label phase II trial of topical fluocinonide 0.05% cream to improve vaginal symptoms in women on endocrine therapy in the adjuvant setting for early stage breast cancer was performed. Patients with vaginal symptoms applied topical vaginal fluocinonide 0.05% cream twice a day for two weeks then once daily for two weeks. Patients were assessed for symptoms by weekly completion of the Mayo/North Central Cancer Treatment Group Patient Pretreatment Questionnaire. The primary outcome was a change from baseline in patient-reported effects of vaginal dryness and dyspareunia on a scale from 0 (no symptoms) to 4 (very severe symptoms) from time of enrollment and at 4 weeks. Secondary outcomes were decrease in vaginal itching and total vaginal index score. Comparisons were made with Wilcoxon sign rank test with 2.5% significance level. Results: Thirty-four women were accrued. At 4 weeks compared with baseline, vaginal dryness improved from a median score of 2 (moderate symptoms) to 0 (no symptoms) ( P < .001) and dyspareunia from 3 (severe symptoms) compared with 1 (mild symptoms) ( P = .002). Percentage of patients who had > 2 point improvement in vaginal dryness and dyspareunia was 69.0% and 75% respectively. Secondary analysis showed decrease in vaginal itching score from 1 to 0 ( P = .001) and vaginal index score of 6 to 1 ( P = .002). Twenty-one patients experienced low-grade toxicities which were mostly limited to skin irritation. Conclusions: Fluocinonide 0.05% cream improves vaginal dryness and dyspareunia experienced by women receiving endocrine therapy and has the potential to improve quality of life of cancer survivors and compliance of endocrine therapy. Clinical trial information: NCT00297011.
The impact of caregiver’s role preference on decisional conflicts and psychiatric distresses in decision making to help caregiver’s disclosure of terminal disease status.
Authors: Yoo Shin Hye , Yun Young Ho , Kim Kyoung-Nam , Lee Jung Lim , PARK Jeanno , Choi Youn Seon , Lim Yeun Keun , Kim Samyong , Jeong Hyun Sik , Kang Jung Hun , Oh Ho-Suk , Park Jichan , Kim Si-Young , Song Hong-Suk , Lee Keun Seok , Heo Dae Seog , Hong Young Seon
Published: September 2018

10106

Background: A decision aid (DA) increases knowledge, decreases decisional conflicts and regrets and improves post-decision satisfaction, emotional distress. However, few DA trials have revealed whether decisional role preferences have an impact on patient-reported outcomes by decision making. The objective of this study was to investigate the impact of caregiver’s decisional role preference on decisional conflicts and psychiatric distresses in decision making. Methods: 406 of 444 caregivers of terminally ill cancer patients enrolled onto a previous trial determining the efficacy of the decision aid about disclosure of terminal disease status were included in this analysis. The analysis outcomes were change score of decisional conflicts using the Decision Conflict Scale (DCS) and depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) at 1 and 3 months from baseline. Participants were divided into 4 groups: active caregiver who received DA (active-DA), active caregiver in control group (active-control), passive caregiver who received DA (passive-DA), and passive caregiver in control group (passive-control). Linear mixed model was conducted to find out the impact of caregiver’s decisional role preference on the DCS and the HADS. Results: Among 406 caregivers, 137 (33.7%) showed active role preference, and 269 (66.3%) showed passive role preference. In post-hoc analysis of adjusted differences of change scores between passive-DA and active-DA groups, non-significant differences were observed in DCS. However, at 3 months, change scores of HADS depression subscale increased as 4.43 (95% confidence interval (CI), 0.78-8.07; P< 0.007; effect size (ES) 0.71) and those of HADS anxiety subscales increased as 4.14 (95% CI, 0.37-7.91; P= 0.021; ES 0.61) in passive-DA group than in active-DA group, showing moderate to large difference. Conclusions: These findings suggest that information about decision making might be provided with tailored format for how much individual wish to involve in decision making.
Biomarker to cost-effectively harness the technical prowess of palliative radiation: Neutrophil lymphocyte ratio (NLR) and overall survival following palliative radiotherapy in an unselected real-world population of all tumor sites.
Authors: Sundar Santhanam , Price James , Clarke Kirsty , Wolfe Thomas , Thurairasa D , Shawcroft Ewan
Published: September 2018

10111

Background: Single fraction radiotherapy (RT) is standard of care for palliation of pain from bone metastases (ASTRO IJROBP 2011 79:965). But costly, complex, multi-fraction RT is quite often used for palliation of symptoms from various organs. Health care costs are burgeoning (ASCO JCO 2012 30: 1715). Costs can be constrained by judiciously reducing use of unnecessary multi-fraction RT in pts with limited life expectancy. But radiation oncologists’ ability to predict survival is inaccurate. (Chow IJROBP 2005 61:870). Hence we assessed clinical utility of Neutrophil Lymphocyte ratio (NLR) - a routinely available biomarker. Methods: 233 patients (pts) undergoing palliative RT over a 3 month at Nottingham University Hospital. Predominant Tumour SITES: Lung 28% Breast 13% Prostate 13% Colorectal 9% Gastro-Oesophageal 5% Myeloma 5% Bladder 5%. Predominant HISTOLOGY: Adenocarcinoma 61% Squamous Cell 14%. NLR available for 158 pts. Results: A NLR of 4.5 was highly predictive of 90-day mortality & overall survival in an unselected real world population. (Table). No survival benefit seen for multi-fraction RT over single fraction RT across all tumour sites. On survival analysis by Cox regression, increased NLR was significant with a hazard ratio of 2.2 (95% CI 1.3 to 3.7) whereas total radiation dose, use of multiple fractions , age, serum haemoglobin, serum albumin & histology were not significant. Conclusions: In palliative care of advanced cancer, for pts with high NLR (>4.5), Single fraction RT should be the standard of care for palliation of symptoms. [Table: see text]
Safety and efficacy of same-day administration of pegfilgrastim in patients (pts) receiving chemotherapy for gastrointestinal (GI) malignancies.
Authors: Matera Robert M. , Relias Valerie , Saif Wasif M.
Published: September 2018

10112

Background: Pegfilgrastim is typically administered 24 hours after chemotherapy per package insert; however some pts are unable or unwilling to return for this additional visit due to work or transportation especially with regimens consisting of infusional 5-FU. Same-day dosing eliminates need for this additional visit. Results from prior studies in other tumor types are inconclusive as few support same-day dosing whereas others show inferiority. Purpose of our study was to determine safety and efficacy of administering pegfilgrastim on same day as chemotherapy in pts with GI malignancies. Methods: A single-institution retrospective review was conducted of pts with GI malignancies who received chemotherapy and same-day pegfilgrastim (6 mg) within 1 hour of completion of chemotherapy from Jan 2014 through Jan 2017. Decision to administer pegfilgrastim was based on NCCN or ASCO recommendations. As per institutional guidelines, pts were counseled on risks of same-day pegfilgrastim prior to its administration. Data was collected on demographics, clinic notes and complete blood counts. Analyses included neutropenia, febrile neutropenia, hospitalization, use of antibiotics or bone pain. Results: A total of 536 chemotherapy cycles in 69 pts were analyzed. Median age was 60 years (range 32-87) with 46% of pts ≥ 65. Pts had an average of 4 risk factors for febrile neutropenia: advanced disease, gender, age > 65 and chemotherapy regimen. Most common malignancy was colon (48%), pancreas (17%) and gastric (17%). Most commonly used regimens included mFOLFOX6 (42%), FOLFIRINOX (23%) and FOLFIRI (12%). Median absolute neutrophil count nadir for all cycles was 4538/uL (range: 1160-25168). Grade 1 and 2 neutropenia developed in 6 of 536 (1%) cycles. Bone pain reported in 3 pts (4%). There were no episodes of grade 3 or 4 neutropenia or febrile neutropenia. None had dose reductions, chemotherapy delays, hospitalizations, or antibiotic use due to neutropenia. Conclusions: We believe our study is the first in GI malignancies to report that same-day pegfilgrastim administration may be as effective and safe as next-day administration, benefiting pts and might reduce costs.
Anticipative monitoring to improve chemotherapy induced nausea.
Authors: Elaidi Reza , Oudard Stephane , Aboudagga Hail , Thibault Constance , Waechter Lorraine , Stevens Jerome , Bonan Brigitte , Scotte Florian
Published: September 2018

10120

Background: The PROCHE [Programme for optimisation of the chemotherapy network] initiative is an innovative oncology-monitoring program designed to reduce patient waiting time and chemotherapy wastage, ultimately improving patient care. Methods: Primary objective was to evaluate the incidence of nausea reported by grade (NCI-CTC AE: from 0 to 4) from 2008 to 2016. Association was quantified using Mantel-Haenszel khi2 and exact p-values. Secondary objective compared the 2009-2016 patients with the control patients of 2008 period. Results: Between Oct 2008 and Oct 2016, 3012 patients participated in the program, representing 36 803 questionnaires completed over the whole period. Nausea was, clinically and statistically, significantly improved during the whole follow-up period with a decrease of grade 3-4 from 0.6% to 0.08% and a decrease of grade 1-2 from 29.3% to 8.2%. The already adapted nausea management in 2008 with 70% of questionnaires reported no nausea improved to 92% in 2016, with a 10% improvement the year after program initiation. As MASCC propose to change guidelines with an improvement above 10%, such an organization may impact new recommendations. Conclusions: Anticipating anti-cancer treatment adaptation and prevention, following guidelines and using adapted antiemetics, explain these positive results. The PROCHE initiative improves chemotherapy induced nausea. [Table: see text]
Advanced cancer patients' self-reported perception of timeliness of their referral to outpatient supportive/palliative care and their survival data.
Authors: Wong Angelique , Hui David , Epner Margeaux , Balankari Vishidha Reddy , De la Cruz Vera J , Frisbee-Hume Susan , Cantu Hilda , Perez Zapata Kresnier , Liu Diane D , Williams Janet L. , Bruera Eduardo
Published: September 2018

10121

Background: Palliative Care referral is often thought to be delayed as judged by health professionals and caregivers. However, no studies have ever examined patients’ perception of timeliness of referral. The primary objective of this study was to determine patients’ perception of the timeliness of their own referral to an outpatient palliative care clinic. We also examined the association between perceived timeliness and actual timing of referral. Methods: In this prospective survey, patients with advanced cancer were asked to rate their perceived timeliness of referral using a 5-point Likert scale ranging from much too early to much too late within 7-35 days after their first consultation visit at Supportive Care Center. They were also asked when they felt referral to Supportive Care should occur along 4 points in their disease trajectory. Actual timing of referral was assessed based on survival from the timing of completion of the survey. Results: 200 advanced cancer patients were surveyed. Median age was 64, 111 (55%) were female, and 35 (18%), 32 (16%) and 26 (13%) had gastrointestinal, lung and breast cancer, respectively. The median overall survival was 8.5 months. 144 (72%) patients perceived their referral was “just in time,” 42 (21%) felt it was “late/much too late,” and 14 (7%) felt it was much “too early/early.” 76/193 (39%) felt the referral should occur at the time of diagnosis of cancer, 32 (17%) when they start first-line chemotherapy, 46 (24%) at diagnosis of recurrent disease, 14 (7%) when there are no further treatment options, and 4 (2%) reported never. We found no significant difference in survival among patients who reported their referral was early, just in time, and late (median 9.8 vs. 8.3 vs. 9.0 months, P=0.43). Conclusions: Patients with advanced cancer were referred to our outpatient Supportive Care clinic a median of 8.5 months before death. A vast majority of patients perceived the timing of referral was appropriate, and many agreed that referral should occur early in the disease trajectory. The lack of association between perceived timeliness of referral and survival may be related to the ceiling effect and the small number of patients who felt their referral was late.
Evaluation of RAD1901, a novel investigational, selective estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast cancer.
Authors: Bardia Aditya , Kabos Peter , Elledge Richard , Wang Dannie , Shen Jinshan , Garner Fiona , O'Neill Alison , Kaklamani Virginia G.
Published: September 2018

1014

Background: The treatment of advanced ER+ breast cancer remains a clinical challenge with the majority of patients eventually progressing due to resistance to endocrine therapy. RAD1901 is a novel, nonsteroidal, oral SERD that has demonstrated dose dependent degradation of ER, and ER regulated genes in preclinical studies. In multiple in vivo patient derived xenograft models of breast cancer, including those harboring ESR1 mutations, RAD1901 demonstrated significant antitumor activity. Methods: In a phase-1 Study RAD1901-005 (ClinicalTrials.gov ID: NCT02338349), patients with advanced ER+ breast cancer were enrolled in dose escalation cohorts, followed by a safety expansion cohort. Key inclusion criteria include postmenopausal women aged 18 years or older, with advanced ER+, HER2- breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and > 6 months of prior endocrine therapy. ESR1 mutation status was determined from circulating tumor DNA (ctDNA) samples. Clinical outcomes were evaluated based on RECIST v1.1 criteria. Results: As of January 25, 2017, total of 39 patients were enrolled at the 400 mg qd dose. Patients were heavily pre-treated (median lines of prior therapy = 3), with 38% and 41% having previously received fulvestrant and palbociclib/CDK4/6 inhibitor, respectively. RAD1901 was generally well-tolerated, with the most common adverse events being low grade nausea (Grade 3/4 = 0%) and dyspepsia (Grade 3/4 = 0%). ESR1 mutations, including D538G, Y537S/N/C, L536H/P/R, S436P and E380Q, were detected at baseline in 44% of patients and dynamic changes in the allele frequency of ESR1 mutations were observed in response to treatment. Confirmed partial responses were observed in patients with ESR1 mutations, and those who had previously received fulvestrant and palbociclib. Conclusions: RAD1901 has demonstrated evidence of single agent activity, with confirmed partial responses in heavily pre-treated patients with advanced ER+ breast cancer, including those with ESR1 mutations, warranting additional clinical development. Clinical trial information: NCT02338349.
Predicting sensitivity to palbociclib with early circulating tumor DNA dynamics in the PALOMA-3 trial.
Authors: O'Leary Ben , Hrebien Sarah , Morden James P , Beaney Matthew , Liu Yuan , Bartlett Cynthia Huang , Koehler Maria , Cristofanilli Massimo , Garcia-Murillas Isaac , Bliss Judith , Turner Nicholas C.
Published: September 2018

1018

Background: Palbociclib improves progression free survival (PFS) in patients with advanced, hormone receptor positive, HER2-negative breast cancer. There are currently no biomarkers to predict sensitivity to palbociclib. We investigated if early circulating tumour DNA (ctDNA) dynamics could predict clinical outcome on palbociclib (Palbo) and fulvestrant (F) in the PALOMA-3 trial. Methods: Plasma samples were prospectively collected in PALOMA-3 for ctDNA analysis at baseline, cycle 1 day 15 (D15) and end of treatment (EOT), and were screened for PIK3CA and ESR1 mutations using digital PCR. The primary objective was to assess whether early dynamic changes in PIK3CA mutations would predict PFS in patients treated with Palbo + F. Suppression of PIK3CA ctDNA levels below an optimised cut-off at cycle 1 D15, relative to baseline levels, was termed a ‘circulating DNA ratio (CDR) response. Results: PIK3CA mutations were identified in 22.0% (100/455) of screened baseline samples with 52 of these randomised to Palbo + F and having matched D15 samples. Patients on Palbo + F with a CDR response had a median PFS of 11.2 months (95%CI 11.1 – undefined) whereas patients on Palbo + F without a CDR response had a median PFS of 4.1 months (95%CI 3.6 – 5.5) (HR for no CDR response 4.92, 95% CI 1.98 – 12.26, p = 0.0002). Overall, Palbo + F suppressed D15 PIK3CA ctDNA levels to a greater extent than placebo + F (p<0.0001). ESR1 mutations were identified in 25.6% (114/445) of screened baseline samples, 65 having matched D15 samples. ESR1 mutations showed greater ctDNA suppression than PIK3CA mutations, and were more frequently undetectable at EOT (25.8% ESR1 undetectable 8/31, v 2.6% for PIK3CA, 1/38, p=0.004). Clearance of ESR1 mutation at EOT was associated with early loss of ESR1at D15 (p = 0.027). Conclusions: Early circulating tumor DNA assessment may predict sensitivity to palbociclib and fulvestrant, and if validated by further analysis may allow treatment to be adapted prior to progression. ESR1 mutations are frequently lost after treatment with palbociclib and fulvestrant.
Health-related quality of life (HRQoL) of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with ribociclib + letrozole: Results from MONALEESA-2.
Authors: Verma Sunil , O'Shaughnessy Joyce , Burris Howard A. , Campone Mario , Alba Emilio , Chandiwana David , Manson Stephanie , Sutradhar Santosh C. , Monaco Mauricio , Janni Wolfgang
Published: September 2018

1020

Background: In the MONALEESA-2 trial, ribociclib + letrozole significantly improved progression-free survival (PFS) and showed higher overall response rates vs letrozole alone in HR+, HER2– ABC. To place these clinical results in the context of patient experience, here we present key patient-reported outcomes (PROs) including HRQoL. Methods: 668 patients were randomized (1:1); 334 each to the ribociclib + letrozole and placebo + letrozole arms. PROs were evaluated during treatment and at progression using the EORTC QLQ-C30, QLQ-BR23, and EQ-5D-5L questionnaires. Changes from baseline in all subscales were analyzed using a linear mixed-effect model and time to 10% deterioration was compared between treatment arms using the stratified log-rank test. Results: Questionnaire compliance rates were high (≥90%). During treatment, HRQoL (global health status/QoL score) was maintained and similar in both treatment arms. At progression/end of treatment, HRQoL worsened numerically in both arms. Time to definitive 10% deterioration of HRQoL was similar between treatment groups, slightly favoring the ribociclib + letrozole arm (hazard ratio: 0.89; 95% confidence interval: 0.67–1.18). No statistically or clinically relevant differences were observed for key symptoms using EORTC QLQ-C30 including fatigue, nausea, and vomiting. There was a clinically relevant ( > 5 points) improvement in pain from baseline to post-baseline (up to Cycle 15) in the ribociclib + letrozole arm while there was only mild improvement ( < 5 points) observed in the placebo + letrozole arm. Conclusions: In addition to significantly improving PFS, ribociclib + letrozole maintains HRQoL when compared with letrozole + placebo. A numerical trend was observed favoring ribociclib + letrozole for pain reduction. Clinical trial information: NCT01958021.
Burden of out-of-pocket spending among high-deductible health plan members with metastatic breast cancer.
Authors: Leopold Christine , Wagner Anita K. , Zhang Fang , Lu Christine , Earle Craig , Nekhlyudov Larissa , Ross-Degnan Dennis , Wharam James Frank
Published: September 2018

1029

Background: 50% of workers have high-deductible health plans (HDHP) that require major outofpocket (OOP) spending for cancerrelated care. The OOP burden among patients with advanced cancer in HDHPs is unknown. Our objective was to estimate OOP spending for women with metastatic breast cancer (mbc) stratified by health plan type. Methods: Our data source was administrative health insurance claims and enrollment data of members insured though a large national health plan. We included 7142 women age 25-64 with mbc who had at least 6 months enrollment before the diagnosis and at least 12 months followup. We used a time series design and plotted OOP spending stratified by HDHP vs low-deductible plan. Primary outcome measures included: (1) 20042012 calendar trends in total annual OOP spending, (2) monthly total OOP spending in the 6 months before and 24 months after women were diagnosed with mbc, and (3) monthly total OOP spending in the last 6 months of life. Plots were adjusted for age, socioeconomic status, race/ethnicity, and US region of residence, and we then conducted linear regression to assess for statistical significance of trends. Results: In 2004, average annual OOP spending for women with mbc cancer in low-deductible health plans was $1196.2 and increased to $2570 in 2012, a yearly increase of $159.2 (113.2205.2). For women in HDHP average OOP spending in 2004 amounted to $2648 and increased to $3736.4 in 2012, representing an annual increase of $160.4 per year (105.4215.4) Average OOP spending per person month peaked in the month of diagnosis to $1633.8 for women in HDHPs and to $643 among low-deductible plan members. Average OOP spending in the last 6 months of life were $285.7 per person month among low-plan ($1714.2 per 6 months) and $607.3 among HDHP ($3644 per 6 months). Conclusions: To our knowledge, this is the first analysis to estimate OOP spending for women with mbc accounting for enrollment in HDHPs versus low-deductible plans. We found that OOP spending is increasing over time and is high in the last 6 months of life. HDHP members with mbc faced much higher OOP spending than women in traditional plans across all analyses. Findings raise concerns that HDHPs could worsen access to mbc treatments.
Safety of trastuzumab emtansine (T-DM1) in HER2-positive advanced breast cancer (BC) patients (pts): Primary results from KAMILLA study cohort 1.
Authors: Barrios Carlos H. , Wuerstlein Rachel , Anton Antonio , Delaloge Suzette , Montemurro Filippo , Bonneterre Jacques , Quenel-Tueux Nathalie , Linn Sabine C. , Button Peter , Lindegger Nicolas , Ellis Paul Anthony
Published: September 2018

1033

Background: KAMILLA is a single-arm, open-label, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC from 278 sites in 40 countries. We report the primary analysis of the first study cohort (N = 2003). Methods: Pts with HER2-positive, locally advanced or metastatic BC (locally confirmed) with progression after prior treatment with chemotherapy and a HER2-directed agent for metastatic BC or within 6 mo of completing adjuvant therapy were enrolled. Pts received T-DM1 3.6 mg/kg every 3 wks until unacceptable toxicity, withdrawal, or disease progression. The primary outcome was safety. Results: A total of 2002 pts were treated (median age 55 yrs, range, 26–88). Most pts had a baseline ECOG score of 0 (n = 1110, 55.4%) or 1 (n = 775, 38.7%), and 1232 (61.5%) had ER and/or PR positive tumors. Median time since initial BC diagnosis was 5 yrs (range, 0–53). Most pts had received ≥2 prior lines of therapy (0–1 prior lines: 29.7%; ≥2: 66.0%); 1855 (92.8%) received prior targeted therapy in the locally advanced/metastatic setting. Median T-DM1 exposure was 5.6 mo (range, 0–46). Adverse events (AEs) were reported in 93.0% (n = 1862). Serious AEs occurred in 21.3% (n = 427), most commonly vomiting (17, 0.8%), pneumonia (16, 0.8%), anemia (13, 0.6%), and pyrexia (13, 0.6%). Grade ≥3 AEs occurred in 40.8% (n = 816), most commonly anemia (60, 3.0%), thrombocytopenia (55, 2.7%), and fatigue (50, 2.5%). Additional AEs of grade ≥3 (multiple individual items grouped) were thrombocytopenia/platelet count decrease (74, 3.7%), hepatic disorders (139, 6.9%), and hemorrhage (46, 2.3%). Grade 5 AEs occurred in 2.2% (n = 45). Treatment discontinuation was most often due to disease progression (1495, 78.1%). Median progression-free survival was 8.3 (95% CI: 8.0–9.7), 6.5 (5.6–8.0), 5.9 (5.6–8.1), 5.6 (5.0–5.9), and 5.6 (5.4–6.6) mo in pts with 0–1, 2, 3, 4, and 5+ prior lines of therapy. Median overall survival was 27.2 mo (95% CI: 25.5–28.7). Conclusions: KAMILLA isthe largest (to date) cohort of T-DM1 treated pts and these data are consistent with safety and efficacy seen in prior randomized studies, thereby supporting T-DM1 as therapy for previously treated HER2-positive advanced BC pts. Clinical trial information: NCT01702571.
A phase II study of eribulin mesylate in combination with trastuzumab and pertuzumab in patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC).
Authors: Luis Ines Maria Vaz Duarte , Guo Hao , Barry William Thomas , Krop Ian E. , Wagle Nikhil , Lowe Alarice , Gore Danielle , Andrews Chelsea , Osmani Wafa , Isakoff Steven J. , Tung Nadine M. , Winer Eric P. , Lin Nancy U. , Freedman Rachel A.
Published: September 2018

1034

Background: As a single agent, eribulin is an active agent among MBC pts. In the first-line setting, pertuzumab improves progression free and overall survival when added to trastuzumab and chemotherapy (CT); however there are limited data in the second line or beyond. The primary aim of this study was to evaluate the activity of eribulin in combination with trastuzumab and pertuzumab in pts with HER2+ MBC whose cancers are refractory to trastuzumab containing regimens. Safety and toxicity were examined and correlative studies are also planned. Methods: Single center, single-arm, phase II, 2 cohorts study planned to enroll up to 81 pts. The studied combination would be of clinical interest if the true overall response rate (ORR) was 40% among those without prior pertuzumab exposure (Cohort A) and 30% among those with prior pertuzumab exposure (Cohort B). The trial was stopped prematurely due to low accrual. Prior to the start of the phase II study, a run-in established dose of eribulin with standard dose of trastuzumab and pertuzumab (1.4mg/m2 days 1, 8 /21 days). Results: Of 32 pts enrolled, 6 were in the run-in, 19 in Cohort A and 7 in Cohort B. Most pts were heavily pre-treated (median [range] lines of CT for metastatic disease, run-in: 4[2-11], cohort A: 2.5 [0-7], cohort B: 3[1-8]). In cohort A, 5 pts had partial responses (ORR = 26% [95% CI 9-51%]), 1 (5%) experienced stable disease (SD) lasting ≥ 6 months and 11 (58%) had a SD lasting < 6 months. In cohort B, the ORR was 0% [95% CI 0-41%]), 1(14%) experienced SD lasting ≥ 6 months and 5 (75%) had a SD lasting < 6 months. The combination was well tolerated, most adverse events (AE) were mild to moderate. Hematologic toxicity was the most frequent grade 3-4 AE. Analyses looking at tissue genomic markers and cell free DNA will be presented. Conclusions: We observed modest activity of the treatment combination in those without prior pertuzumab exposure but limited activity in unselected pts with HER2+ MBC. The study was limited by small sample size. Correlative studies may help us to understand resistance and response to eribulin with anti-HER2 therapy and the interplay between CT and targeted therapy. Clinical trial information: NCT01912963.
Predictors of prolonged benefit from palbociclib (PAL) plus fulvestrant (F) in women with endocrine-resistant hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer (ABC) in PALOMA-3.
Authors: Cristofanilli Massimo , DeMichele Angela , Giorgetti Carla , Slamon Dennis J. , Im Seock-Ah , Masuda Norikazu , Verma Shailendra , Loi Sherene , Colleoni Marco , Theall Kathy Puyana , Huang Xin , Bartlett Cynthia Huang , Turner Nicholas C.
Published: September 2018

1050

Background: PAL+F improved progression-free survival (PFS) over F + placebo (P) in patients (pts) with endocrine-resistant HR+/HER2– ABC. We examined factors predictive of long-term benefit on PAL+F. Methods: Pre/postmenopausal pts with HR+/HER2– ABC that progressed on prior endocrine therapy (ET) were randomized 2:1 to PAL (125 mg/d oral [3 wk on, 1 wk off]) + F (500 mg) or P+F. Characteristics of pts with prolonged benefit (treatment [tx] duration ≥18 mo for PAL+F; ≥12 mo for P+F based on median PFS and tx duration) were compared with the intent-to-treat (ITT) population. Results: PAL+F improved PFS vs P+F (11.2 vs 4.6 mo; hazard ratio, 0.50). By Aug 2016, 138 pts had long-term benefit: 100/347 (29%) pts on PAL+F received tx for ≥18 mo, including 70 (20%) who received > 2 y (26–39 cycles). In contrast, 38/174 (22%) pts on P+F received ≥12 mo of tx; only 16 (9%) received > 2 y (27–38 cycles). No apparent differences in baseline characteristics of pts with long-term benefit were observed between groups except that a greater proportion of those on P+F had a single site of disease involvement (40% PAL+F vs 63% P+F). Pts with long-term benefit on PAL+F had lower rates of visceral disease (42% vs 60%), liver metastases (18% vs 40%), and ≥3 disease sites (27% vs 39%) at baseline vs the ITT population; no difference in sensitivity to prior ET was observed (84% vs 79%). Objective response rate (ORR) was higher among pts with prolonged benefit on PAL+F vs ITT (36% vs 26%). Conclusions: PAL+F is associated with prolonged benefit in about a third of pts treated with the combination in PALOMA-3. These pts achieve higher ORR compared to other study pts and the benefit is independent of baseline site and number of metastatic recurrences and prior endocrine sensitivity. Benefit from F alone is less prolonged and appears limited to those with 1 site of disease involvement. The analysis confirms the efficacy of PAL+F in HR+ ABC with visceral recurrence. Biomarker analyses are ongoing in pts with long-term benefit to understand molecular features predictive of tx sensitivity. Funding: Pfizer. Clinical trial information: NCT01942135.
A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.
Authors: Fangusaro Jason R. , Onar-Thomas Arzu , Young-Poussaint Tina , Wu Shengjie , Ligon Azra H , Lindeman Neal Ian , Banerjee Anuradha , Packer Roger , Kilburn Lindsay B. , Pollack Ian , Jakacki Regina , Qaddoumi Ibrahim A. , Fisher Paul Graham , Dhall Girish , Baxter Patricia Ann , Kreissman Susan G. , Doyle L. Austin , Smith Malcolm A. , Dunkel Ira J. , Fouladi Maryam ,   Pediatric Brain Tumor Consortium
Published: September 2018

10504

Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.
ACNS1221: A phase II study for the treatment of non metastatic desmoplastic medulloblastoma in children less than 4 years of age—A report from the Children Oncology Group.
Authors: Lafay-Cousin Lucie , Bouffet Eric , Onar-Thomas Arzu , Billups Catherine A , Hawkins Cynthia , Eberhart Charles , Horbinski Craig , Robinson Giles W. , Strother Douglas R. , Heier Linda , Souweidane Mark M. , Fouladi Maryam , Gajjar Amar J. ,   Children Oncology Group
Published: September 2018

10505

Background: Nodular desmoplastic medulloblastoma and medulloblastoma with extensive nodularity (ND/MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. Methods: We prospectively conducted a single-arm multicenter trial of conventional chemotherapy for non-metastatic ND/MBEN, based on a modified HIT SKK2000 regimen excluding the use of intraventricular methotrexate (MTX) injection, with the aim to achieve a similar outcome with reduced treatment related neurotoxicity. The design required 37 patients and targeted a 2-year PFS of ≥ 90%. Secondary objectives included evaluation of feasibility of timely central pathology review, prospective evaluation of the cohort’s molecular profile and neurocognitive outcomes. Results: Between 12/2013 and 07/2016, 26 patients were enrolled, including 16 males and 10 females, diagnosed at a median age of 19.7 months (7.1-42.9 months). Four patients had residual disease at baseline. There were 19 ND and 7 MBEN medulloblastoma, confirmed by central pathology review. All cases were reviewed within 10 days by at least 2 of the 3 neuropathologists. The study was closed early following interim analysis due to a higher than expected relapse rate. At last follow-up, 7 patients had relapsed (3 local, 2 distant and 2 combined) at a median time of 9.7 months from diagnosis (range, 9.5-13.7 months). One patient subsequently died of disease. The current median follow-up for the 25 survivors is 1 year (range, 0.2-1.9 years) and the 1 year PFS rate is 66.2% (SE 12.2%). Based on the currently available information, older age (p = 0.07) and ND histology (p = 0.009) appear to be associated with worse PFS. To date none of the patients with MBEN histology have relapsed. Conclusions: The proposed modified regimen of chemotherapy without intraventricular MTX failed to achieve the desirable 2 y PFS of 90%, leading to premature closure of the study. Ongoing molecular characterization of the cohort may help uncover patients who may still benefit from this regimen. Clinical trial information: NCT02017964.
Biomarkers of brain injury and neurologic outcomes in children treated with chemotherapy for acute lymphoblastic leukemia (ALL).
Authors: Cheung Yin Ting , Khan Raja B. , Liu Wei , Brinkman Tara M. , Edelmann Michelle N. , Reddick Wilburn E. , Pei Deqing , Panoskaltsis-Mortari Angela , Srivastava Deokumar , Cheng Cheng , Robison Leslie L. , Hudson Melissa M. , Pui Ching-Hon , Krull Kevin R.
Published: September 2018

10521

Background: Little is known about neurotoxic mechanisms associated with chemotherapy in children with ALL. Cerebrospinal fluid (CSF) biomarkers of brain injury may provide insight into this process. Methods: 235 patients (51% male; mean [SD] age diagnosed 6.8 [4.7] years) treated on a chemotherapy only protocol provided CSF samples following diagnosis and through consolidation. CSF was assayed for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF], total-Tau [T-Tau]) and astrogliosis (glial fibrillary acidic protein [GFAP]). Leukoencephalopathy was evaluated by brain MRI’s during therapy. At ≥5 years post-diagnosis, 138 (70%) of the 198 still eligible survivors (without relapse and unrelated neurologic injury) completed neurocognitive testing and brain diffusion tensor imaging of white matter integrity at age 13.6 [4.6] years. Log-binomial and general linear models were used to examine whether biomarker changes from baseline through consolidation were related to serum methotrexate exposure, acute leukoencephalopathy, and long-term brain outcomes. Results: NGF and T-Tau increased from baseline to consolidation ( P's < 0.001), while MBP and GFAP were elevated at baseline and remained so through consolidation. The number of intrathecal injections (methotrexate, hydrocortisone, cytarabine) was positively correlated with NGF increase at consolidation ( P= 0.005). Increases in GFAP (RR 1.2; 95% CI [1.0 – 1.4]), MBP (RR 1.1 [1.0 – 1.1]) and T-Tau (RR 1.8 [1.1 – 2.8]) were related to higher risk for acute leukoencephalopathy, and higher diffusivity in frontal lobe white matter at ≥5 years post-diagnosis ( P’s < 0.05). Increase in T-Tau at consolidation was associated with worse long-term sustained attention ( P= 0.03), and visual- ( P= 0.04) and visual-motor ( P= 0.02) processing speed. Conclusions: Glial injury, which is evident at diagnosis, may be related to leukemia and methotrexate exposure. Neuronal injury is associated with intrathecal chemotherapy and long-term neurocognitive and brain imaging outcomes. Monitoring CSF biomarkers may be useful in identifying individuals at risk for poor neurological outcomes.
Cardiac effects of chimeric antigen receptor (CAR) T-cell therapy in children.
Authors: Burstein Danielle S. , Maude Shannon L. , Grupp Stephan A. , Griffis Heather , Rossano Joseph W. , Lin Kimberly Y.
Published: September 2018

10531

Background: Treatment with CAR T-cells targeting CD19 for pediatric leukemia has demonstrated significant efficacy with the principal toxicity being cytokine release syndrome (CRS). However, the cardiac effects related to CAR T-cell therapy have not been systematically evaluated. Methods: A retrospective chart review was performed on a large cohort who received CAR T-cell therapy from April 2012 through September 2016. Baseline oncologic and cardiac characteristics were recorded. Cardiomyopathy was defined as an ejection fraction < 55%, shortening fraction < 28%, or diastolic dysfunction. Primary outcome was cardiac event, defined as need for inotropic support or echocardiographic decline in function. Descriptive and univariate analyses were performed. Results: 93 patients were included [55% male, mean age 11.8 yrs (range 1.7-27.1)]; 98% had B cell ALL. Prior to treatment, 15% had cardiomyopathy and 1 patient had single ventricle Fontan palliation. Cardiac events occurred in 34 (36%) with mean onset 4.8 days (range 1-9) after CAR T-cell infusion, of whom 12 (35%) had abnormal systolic or diastolic function on echocardiogram and 6 (18%) required milrinone for cardiac support. 21 (22%) patients had CRS requiring tocilizumab and vasoactive infusions; there were no cardiac-related deaths. Factors associated with cardiac events included higher pre-treatment blast % on bone marrow biopsy [OR 10.45 (95% CI 3.87-28.22) for blast > 10%; p < 0.001] but not cardiomyopathy (p = 0.356), total body irradiation (p = 0.717) or anthracycline dose (p = 0.711). At discharge, 7 (7.5%) patients had worse cardiac function than at baseline, but only 2 (2%) had persistent cardiac dysfunction by 6 months post-infusion. Pre-treatment factors were not associated with persistent dysfunction. Conclusions: This is the first study to describe the cardiac effects of CAR T-cell therapy in children. CAR T-cell therapy appears to be safe, even in patients with cardiomyopathy. Although one-third experienced a cardiac event, persistent cardiac dysfunction is rare. Children with a pre-treatment blast > 10% were most at risk for cardiac events, a finding that may help identify patients who warrant close observation and early intervention with pressor support.
Clinical outcomes of adolescents and young adults (AYA) with advanced solid tumors participating in phase I trials.
Authors: Sundar Raghav , McVeigh Terri Patricia , Petruckevitch Ann , Diamantis Nikolaos , Ang Joo Ern , Chenard-Poirier Maxime , Collins Dearbhaile Catherine , Lim Joline Si Jing , Ameratunga Malaka , Khan Khurum Hayat , Kaye Stanley B. , Banerji Udai , Lopez Juanita Suzanne , De Bono Johann S. , Van Der Graaf Winette T.A.
Published: September 2018

10536

Background: AYA cancer patients are relatively under-represented in clinical trials, with no published data regarding their outcomes in phase I studies. Trials utilizing novel therapeutic agents are often considered in these patients, due to their tendency to have good organ reserve, and ability to tolerate additional lines of therapy. This study describes the experience of AYA patients with advanced solid tumors treated in a specialized drug development unit. Methods: Patient characteristics and clinical outcomes of AYA patients (defined as age 15 to 39 years at time of initial cancer diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, United Kingdom, between 2002 and 2016, were captured and analyzed from case and trial records. Results: From a database of 2631 patients treated on phase I trials, 219 AYA patients (8%) were identified. Major tumor types included gynaecological cancer (24%), sarcoma (18%), gastrointestinal (16%) and breast cancer (11%). Patients had a median of 3 previous lines of systemic chemotherapy (range 0 – 6), and 19% participated in 2 or more phase I studies. Twenty (9%) had a known hereditary cancer syndrome (most commonly BRCA), 27% had a family history (FH) of cancer, 15% no FH and 49% no FH documented. Molecular characterization of tumors (n = 45) identified mutations most commonly in p53 (33%) , PI3KCA (18%) and KRAS (9%) . Major trial categories included DNA damage repair (16%), PI3K (16%) and anti-angiogenesis (15%) agents. Grade 3/4 toxicities were experienced in 25% of patients (10% hematological). Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median progression free survival was 2.3 months (95% CI: 1.9 to 2.8), median OS was 7.6 months (95% CI: 6.3 to 9.5), and 2-year OS was 11%. Of patients with responses, 35% were matched to phase I trials based on germline or somatic genetic aberrations. Conclusions: A sub-group of AYA patients with advanced solid tumors derive considerable benefit from participating in trials involving novel therapeutics. Future research must focus on predictive biomarkers and molecular profiling to identify those that would benefit from novel therapies.