bluuebunny/crossref_metadata_2025 huggingface dataset:
Entering a Clinical Trial: Is It Right For You?–A randomized study of the Clinical Trials Video and its impact on the informed consent process
Authors: Hitchcock-Bryan S. , Hoffner B. , Joffe S. , Powell M. , Parker C. , Wolanski A. , Eder J. P. , Shapiro G. I. , Bauer-Wu S.
Published: March 2020

9072

Background: In an effort to improve the informed consent process for subjects considering participation in a clinical trial, we created an educational video: “Entering a Clinical Trial: Is it Right for You?” In this randomized study, we assessed the effect of the video on patients’ understanding and perceptions of clinical trials. We also assessed patient satisfaction with the video and how the video impacted decision-making and patient-provider communication. Methods: We recruited 90 adults considering cancer clinical trials of whom 77 participated. After discussing the trial with the physician and reading the trial consent form, patients were randomized to receive (n=38) or not receive (n=39) the study video. Using a validated questionnaire, we interviewed subjects to assess objective understanding of the trial, our primary endpoint, and self-reported understanding of clinical trials. All subjects completed a second interview assessing secondary endpoints, including patient-provider communication, satisfaction with video, and decision-making. We used linear regression (two-sided tests) to conduct the primary analysis and the Wilcoxon rank-sum test and descriptive statistics to analyze the secondary aims. Results: Neither objective nor self-reported understanding of clinical trials differed between the two groups (Mean 86.5 vs. 87, p=0.75). 85% (61/72) indicated the video was an important source of information about clinical trials; 89% of those who watched the video with their family/friends (n=37) said the video helped loved ones better understand clinical trials; 73% indicated it helped their family accept their decision about participation. 81% (58/72) felt better prepared to discuss the trial with their physician after watching the video. Of those who found the video helpful with decision- making, 80% (21/26) were considering a trial for the first time compared with 19% (5/26) veterans who had previously participated in a clinical trial. Conclusions: The video did not measurably improve subjects’ understanding of their clinical trials. However, subjects reported that the video was an important source of information, helped them educate their families, and enhanced patient-provider communication.

No significant financial relationships to disclose.
Barriers to phase I clinical trial protocol IRB approval at KCI
Authors: Wang D. , Heath E. , Powell A. , Chaperon T. , LaGrone F. , LoRusso P.
Published: March 2020

9080

Phase I oncology clinical trials are critical in the oncology drug development process. To protect human subjects, every phase 1 protocol must be approved by an institutional review board (IRB) to assure safety before patient accrual. As the volume and complexity of phase 1 trials have increased, the amount of time spent on IRB protocol reviews have also increased for various reasons. Objectives: 1) Determine the average time spent on protocol approval by IRB at KCI/WSU; 2) Identify potential issues raised by IRB resulting in approval delays; 3) Identify the redundancies for which “standard language” implementation could facilitate future IRB applications thereby expediting approval. Methods: 96 Phase 1 research IRB applications at KCI/WSU between 8/1/2005 and 10/31/2006 were reviewed. These applications were stratified based on submission (new protocol versus amendment) and IRB approval (tabled, provisional or approved) status. Concerns frequently brought up by the IRB were identified. Results: The average and median time spent from initial submission to final approval of all 96 applications were 41.4 days and 43 days, respectively. Forty eight of 96 applications (50%) were provisionally approved from the initial review. Average and median time of obtaining final approval were 52.5 days and 52 days. Nine of 96 (9.4%) protocols were tabled with their average approval 83 days. The most common concerns raised by IRB were risks/benefit issues. These concerns were an even greater approval barrier when protocols involved specialized technologies of molecular therapeutics or complicated study designs. Regulatory policy changes issued by oversight organizations also required “real-time” updates into protocols and consent form amendments. Areas of “standard language” for future IRB applications are being compiled and will be discussed upon presentation. Conclusion: Phase 1 clinical trials are essential to anti-cancer drug development. The complicated ethical issues and science warrant an ongoing constructive collaboration of both parties. Identification of commonalities that delay IRB approval will lead to more expeditious IRB approval not only at our institution, but could also benefit other institutions.

No significant financial relationships to disclose.
Effect of pretreatment distress on daily fatigue after chemotherapy for breast cancer
Authors: Higgins S. C. , Montgomery G. H. , Bovbjerg D. H.
Published: March 2020

9090

Background: Fatigue is one of the most frequently reported and aversive side effects of cancer chemotherapy. Prospective research has found that cancer patients’ levels of emotional distress prior to treatment are predictive of other side effects (e.g., nausea), but studies of such effects on fatigue are lacking. The present study prospectively tested the hypothesis that patients’ levels of emotional distress in the clinic prior to their first treatment infusion would predict the severity of their post-infusion fatigue. Methods: Sixty Stage I (32.6%) and II (67.4%) breast cancer patients (mean age=44.5 yrs), receiving standard outpatient chemotherapy (e.g., CMF), participated. The independent variable, emotional distress, was assessed (0–100) with a visual analog scale (VAS). The dependent variable, post treatment fatigue (PTF) was assessed (0–100) over each of the subsequent 6 days using end-of-day diaries, which also included assessment of distress (0–100). To explore temporal specificity, pretreatment distress was assessed for “last night”, “this morning” and “right now.” Results: Consistent with previous reports, PTF levels peaked at day 2 and began to decline after day 3, although they remained elevated across the period (p<.026). Repeated measures analysis indicated a significant main effect of pretreatment distress “right now” on PTF (p<.009); prior distress levels were less predictive. Additional regression analyses, controlling for pretreatment fatigue and daily distress, revealed a strongly selective effect of pretreatment distress on post peak PTF on days 5 (p<.002) and 6 (p<.026). Conclusions: This study is the first to demonstrate time-specific effects of pretreatment distress on PTF. Possible mechanisms of these effects now warrant investigation, as do possible benefits of brief interventions to reduce distress immediately prior to treatment.

No significant financial relationships to disclose.
A phase III randomized controlled study comparing iron sucrose intravenously (IV) to no iron treatment of anemia in cancer patients undergoing chemotherapy and erythropoietin stimulating agent (ESA) therapy
Authors: Bellet R. E. , Ghazal H. , Flam M. , Drelichman A. , Gabrail N. , Woytowitz D. , Loesch D. , Niforos D. , Mangione A. , Anthony L. ,   Iron Sucrose Study Group
Published: March 2020

9109

Background: The effect of using IV iron sucrose in managing cancer chemotherapy-related anemia has not been previously reported. To investigate this issue, we conducted a randomized study of IV iron sucrose in patients (pts) with cancer chemotherapy-related anemia who completed 8 prior wks of ESA therapy. Methods: This prospective, multicenter, randomized, open label, Phase III clinical trial enrolled 375 pts with chemotherapy induced anemia (Hgb levels = 10.0 g/dL) and was conducted in 2 stages. During Stage I (8-wk duration), pts received treatment with fixed ESA doses (100-mcg of darbepoetin or 40,000 units epoetin wkly or 200 mcg of darbepoetin every other wk). Pts were classified as either ESA responders (= 1 g/dL increase in Hgb) or ESA non-responders with each group randomized (Stage 2) separately to receive either 12 wks of fixed doses of ESA plus up to 1,500 mg of iron sucrose (given in 3 divided doses of up to 500mg) or 12 wks of fixed doses of ESA alone. Laboratories (including iron indices and acute phase reactants), quality of life and adverse events were assessed at baseline and throughout. Results: Iron sucrose plus ESA compared to ESA alone resulted in greater mean maximum Hgb levels and greater number of pts who achieved Hgb increases = 2.0 and ≥ 3.0 g/dl in both prior ESA responders and non-responders. There was also a statistically significant improvement in fatigue and iron stores in the iron sucrose treated pts. Baseline iron status did not predict responsiveness to iron sucrose therapy. Three serious but non-life threatening iron sucrose related adverse events were observed including one case of significant, transient hypotension in a female weighing 50 kg. Conclusions: IV iron sucrose increased Hgb levels and iron stores significantly and is well tolerated in doses up to 500 mg increments in ESA treated patients with cancer chemotherapy- related anemia. IV iron sucrose should be considered in combination with erythropoietic therapy in anemic cancer patients receiving chemotherapy.

[Table: see text]
Relations between psychotherapy and survival, coping strategies and quality of life (QOL) in patients with malignant gliomas: A randomized study
Authors: Jouniaux-Delbez N. , Andronikof A. , Delattre J. , Medioni J.
Published: March 2020

9110

Background: Cognitive and behavioral psychotherapies are able to modify reactions against stress. Whether psychotherapies can improve survival, coping strategies and QOL in situations such as cancer announcement is not known. Methods: Between September 2001 and October 2003, a single center two arms study was conducted. Voluntary patients with newly diagnosed malignant gliomas were prospectively and exhaustively randomized to have psychotherapy or not. Anti-cancer therapy was unchanged. Psychotherapy was performed monthly. Coping strategies and QOL using EORTC QLQ-C30 Questionnaire were evaluated every 6 months for one year. Results: 96 patients were randomized and 81 patients (50 men, 81%) completed the study. Mean age was 50 years (range: 22–67) and 79% had a performance status = 1, 70% had glioblastomas, 51% had at least partial surgical resection of the tumor, 95% received radiotherapy and 83% had at least 1 cycle of chemotherapy. After a median follow-up of 43 months, 68 deaths (84%) were noted and median survival time was 14.1 months. Despite a trend toward improved survival, psychotherapy was not a prognosis factor of survival (p = 0.19). Coping scores at 0, 6 and 12 months were similar in the two arms and no improvements between base line scores and later scores were noted. General QOL scores at 0, 6 and 12 months were similar in the two arms. More data will be presented at the meeting, notably in good responders to psychotherapy. Conclusions: In a large non selected population of patients with newly diagnosed malignant gliomas, psychotherapy does not improve coping score or QOL and doesn't significantly change survival. Further studies are required to determine which patients can benefit of psychotherapy.

No significant financial relationships to disclose.
Patient-reported burden of mucosal injury (MUI): Comparison of clinician-rated MUI and patient-reported outcomes
Authors: Elting L. S. , Calais G. , Selva N. , Brachman D. , Kudrimoti M. , Spijkervet F. , Vera-Llonch M. , Oster G. , Keefe D. , Sonis S. T. ,   Triad BOI Head and Neck Group
Published: March 2020

9117

Background: Patient (pt) reported outcome (PROs) tools identify MUI and its impact on functional and subjective outcomes. Among outpts, PRO tools are attractive because opportunities for direct assessment are limited, but agreement between PRO tools and objective MUI measures has not been uniform. We prospectively compared an objective MUI score and 3 previously validated PRO tools. Method: The Triad Burden of Illness study is an international, 41-center, prospective study of the risk and outcomes of radiation and chemotherapy-induced MUI. At baseline and during chemoradiation therapy (CRT), pts with larynx (L), hypopharynx (H), or non-small cell lung cancers (NSCLC) completed a daily MUI symptom tool (OMDQ) and 2 weekly PRO tools (FACT-E quality of life, FACIT- Fatigue). Clinicians examined pts twice weekly and scored MUI (WHO scale). In this interim analysis, we used random effects linear regression to compare clinician and pt ratings and t-tests to compare PRO scores in pts with and without severe MUI. Result: To date, 29 pts have completed =2 paired assessments; 23 (79%) had L or H cancers. Ulcerative MUI (WHO = 2) was more common among L/H than NSCLC pts (39% vs 17%). Pt-rated MUI predicted clinician-rated MUI (p = 0.001). FACT-E and FACIT-F scores were significantly lower (worse) among pts with clinician-rated ulcerative MUI than pts without and among pts with pt-rated severe MUI symptoms (OMDQ= 2) than pts without. Differences were largest in the subscales for physical and functional wellbeing and esophageal symptom special concerns. Conclusion: PRO tools estimate the burden of CRT-induced MUI in outpts with L/H or NCSL cancers. MUI appears to be associated with significantly poorer quality of life, functional status, and symptom scores. 1- 9 p <0.01; 10p = 0.06.

[Table: see text]

[Table: see text]
Specific gene expression profiles and unique chromosomal abnormalities are associated with regressing tumors among infants with disseminated neuroblastoma
Authors: Lavarino C. , Cheung N. , de Torres C. , Domenech G. , Garcia I. , Alaminos M. , Ríos J. , Gerald W. , Kushner B. , LaQuaglia M. , Mora J.
Published: March 2020

9501

Background: Among human cancers, neuroblastoma (NB) has the highest incidence of spontaneous remission, especially among the subgroup of stage 4s NB affecting infants. Clinical distinction of stage 4s from lethal stage 4 can be difficult, but critical, since it is the basis for therapeutic decisions. The identification of biological markers that allow a precise distinction of these NB subgroups will aid accurate classification. Methods: Thirty-seven infants with NB were treated at MSKCC from 1987 to 2000. Ten stage 4s and 19 stage 4 were evaluated by allelic and gene expression analyses. Results: All stage 4s patients underwent spontaneous remission while only 69% of newly diagnosed, previously untreated stage 4 patients survived despite combined modality therapy. Among stage 4 tumors, 19/19 were near-diploid/tetraploid, 8/19 MYCN amplified, 50% had LOH at 1p36, 43% had LOH at 1p34-p31 and/or 14q and 37% had LOH at 11q and/or 1p22. Among stage 4s tumors, 7/8 were near-triploid, none MYCN-amplified and LOH was restricted to 11q. Gene expression profiling identified 233 differentially expressed genes between stage 4 and 4s tumors. 25% of these genes with increased expression in stage 4s NB mapped to 1pter-p13, with transcription level correlated with LOH and ploidy. Conclusions: These findings suggest that differential expression of subsets of genes located at specific chromosomal regions play a significant role in the biology of disseminated NB. Besides offering a biological definition of stage 4s, these expression profiles may provide new insights in the genetic control of spontaneous remission in neuroblastoma.

No significant financial relationships to disclose.
Fecundity of males after treatment for childhood cancer. A report from the Childhood Cancer Survivor Study (CCSS)
Authors: Green D. M. , Kawashima T. , Leisenring W. , Stovall M. , Donaldson S. S. , Sklar C. A. , Byrne J. , Robison L. L.
Published: March 2020

9516

Background: Determine the proportion of male (M) survivors with impaired fecundity (IF). Methods: 6,555 CCSS M participants and 1,606 M siblings (S) were classified as surgically sterile (SS) for contraceptive purpose, SS for non-contraceptive purpose, IF (ongoing attempts to become pregnant for a period of one year without success or use of medication to help achieve a pregnancy), or fecund (F). Odds ratios (OR) were estimated using logistic regression, controlling for education level, marital status, age at baseline questionnaire, race/ethnicity and smoking status. Results: M were 6–29 years from cancer diagnosis (mean-16.3 years) and 15–44 years of age at the time of study (mean-25.4 years). 331 (5.0%) M or their partners were SS, 487 (7.4%) had IF and 5,737 (87.5%) were F. The OR (95% confidence interval (CI)) for being F was 0.66 (95% CI, 0.54–0.80) (p<0.0001) compared to F MS. Among M, the OR for IF was 2.60 (95% CI, 1.97–3.42) (p<0.0001) compared to F MS. The OR for IF was increased among those with a testicular (T) radiation dose (RD) of 0.1–499 cGy (OR=1.42; 95% CI 1.07–1.89; p=0.015), 500–599 cGy (OR=3.16; 95% CI 1.48–6.72; p=0.0028), 600–1,499 cGy (OR=2.53; 95% CI 1.26–5.09; p=0.009) and ≥ 2,400 cGy (OR=3.04; 95% CI 1.39–6.64; p=0.0054), pituitary (P) RD of 0.1–499 cGy (OR=1.89; 95% CI 1.41–2.55; p<0.0001), CCNU (OR=2.14; 95% CI 1.25–3.66; p=0.0054), cyclophosphamide (OR=1.56;95% CI 1.23–1.97; p=0.0002), nitrogen mustard (OR=2.88;95% CI 2.08- 4.00; p<0.0001), procarbazine (OR=2.97; 95% CI 2.24–3.93; p<0.0001), vinblastine (OR=2.07;95% CI 1.41–3.04; p=0.00022), vincristine (OR=1.90; 95% CI 1.45–2.49; p<0.0001) and melphalan (OR=2.43; 95% CI 1.09–5.43; p=0.03). The OR for IF increased with increasing alkylating agent score (AAS) (1st tertile OR=1.70; 95% CI 1.19–2.43; p=0.0035; 2nd tertile OR=2.63; 95% CI 1.82–3.81; p<0.0001; 3rd tertile OR=3.42; 95% CI 2.41–4.86; p<0.0001). Multivariate analysis demonstrated that the combination of P ≥ 500 cGy and T ≥ 500 cGy (OR= 2.65; 95% CI 1.44–4.86; p=0.0017) and increasing AAS (1st tertile OR=1.56; 95% CI 1.04–2.34; p=0.031; 2nd tertile OR= 2.22; 95% CI 1.43–3.44; p=0.00036; 3rd tertile OR=2.72;95% CI 1.74–4.25; p<0.0001) were associated with IF. Conclusions: M have IF due in part to TRD and PRD and increasing AAS.

No significant financial relationships to disclose.
Long-term cardiac outcomes following low-dose anthracycline exposure
Authors: Wright J. A. , Reimold S. , Turoff A. , Brooks S. , Huet B. , Eshelman D. , Winick N. , Oeffinger K.
Published: March 2020

9519

Background: Pediatric cancer survivors treated with moderate-high dose (=250mg/m2) anthracycline therapy are known to be at risk for cardiac toxicity. It remains unclear what cardiac risk exists for survivors who received a low dose (<250mg/m2) therapy. Methods: Cardiac MRI and maximal VO2max testing were performed on young adult survivors of childhood acute lymphoblastic leukemia (ALL). MRI measurements included ejection fraction (EF), left ventricular (LV) mass, end diastolic volume (EDV), end systolic volume (ESV), and concentricity (LV mass/EDV). Survivors who were treated with low dose anthracycline (< 250mg/m2) were compared to those without anthracycline exposure. Spearman correlations and multivariable linear regression were used to examine the relationship between anthracycline dose and measures of cardiac function and cardiorespiratory fitness. Results: Sixty-seven survivors (mean age 23.9 ±5 years) participated, including 39 (58.2%) females. The mean interval from cancer diagnosis to study was 17.4 ± 6.6 years. The number of participants by cumulative anthracycline dose were 19 (28.4%) with no exposure, 28 (41.8%) with doses of 1–249mg/m2, and 20 (29.8%) with doses of =250mg/m2. When adjusted for age and race, there was not a significant difference in the cardiac MRI outcomes and VO2max levels between participants who received 1- 249mg/m2 of anthracycline versus those without anthracycline exposure. Conclusions: With continued use of anthracyclines at cumulative low doses, particularly in ALL standard risk trials, it is important to determine if there is a long-term cardiotoxicity. With a mean follow-up of 17 years, our data support the safety of low cumulative dose anthracycline.

[Table: see text]

No significant financial relationships to disclose.
Role of fractalkine (CX3CL1) rich neuroblastoma microenvironments for ganglioside GD2 directed immunotherapy
Authors: Lode H. N. , Zeng Y. , Fest S. , Gaedicke G.
Published: March 2020

9521

Background: Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form. Methods: We found that FKN is expressed in >90% of 68 neuroblastoma (NB) samples as determined by cDNA microarray analysis. FKN expression was inversely correlated with MYCN amplification, suggesting a higher expression of FKN in MYCN non amplified tumors. We characterized the effect of FKN in the neuroblastoma microenvironment in a mouse model. We demonstrate that FKN released from NB cells mediate migration and adhesion of CD4+-, CD8+- and NK- cells and subsequent secretion of IFN-γ, in vitro and in vivo. However, the presence of FKN in NB microenvironments did not result in significant anti-NB activity. Results: Targeting of IL-2 into the NB microenvironment using anti-ganglioside GD2 antibody cytokine fusion proteins (ch14.18-IL-2) is currently under clinical evaluation. We investigated a the role of FKN in this context. For this purpose, IL-2 was targeted to GD2 positive NB microenvironments secreting FKN. Only mice bearing FKN and IL2 enriched NB microenvironments exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases, in contrast to controls with only FKN or IL-2 enriched NB. This effect was specific since a non-specific antibody-IL-2 fusion protein ch225-IL-2 was ineffective. The mechanisms involved included NK-cell activation by targeted IL-2 into FKN rich NB as indicated by the enhancement of NK-cell mediated lysis using YAC-1 cells as targeted cells. The depletion of NK cells in vivo inhibited the therapeutic effect. Furthermore, co-culture of NXS2-FKN cells and NK cells in vitro induced the expression of IFN-γ by NK cells. However, the depletion of CD8+ T-cells in vivo abrogated the therapeutic effect, and these effector cells showed the highest cytolytic activity against NXS2 target cells in vitro. Finally, only the FKN and IL-2 enriched NB microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. Conclusions: In conclusion our data suggest that targeted IL-2 therapy of FKN rich NB associated with MYCN non-amplified tumors may result in T-cell mediated immune responses.

No significant financial relationships to disclose.
Adapting molecular inversion probe (MIP) technology for allele quantification in childhood leukemia
Authors: Schiffman J. D. , Welch K. M. , Davis R. , Dahl G. V. , Lacayo N. J. , Faham M. , Ford J. M. , Ji H.
Published: March 2020

9530

Background: Leukemia accounts for ∼40% of newly diagnosed pediatric malignancies, and relapsed leukemia is the leading cause of death in childhood cancer. Genomic instability events contribute to neoplastic development and have been used to classify and risk stratify non-leukemic adult and pediatric tumors. Analyzing leukemic blasts for gene copy changes with advanced molecular techniques could prove useful in further risk stratifying and developing new treatment strategies for pediatric leukemia. Methods: Molecular Inversion Probes (MIPs) analyze genetic target sequences in parallel with high specificity and sensitivity at the highest genomic resolution, and were originally designed for single nucleotide genotyping. The MIP assay was adapted to analyze both gene copy number and loss of heterozygosity (LOH) events in pediatric leukemia samples (pre-B ALL, T-ALL, AML). DNA was extracted (100 ng) from paired bone marrow (diagnosis) and peripheral blood (remission) samples (n = 40). The MIP assay was run with a customized Affymetrix 20K Cancer Panel (representing oncogenes, tumor suppressor, DNA repair, cell growth, and metabolism genes). Gene copy number changes were identified by comparing probe signal intensity between leukemia samples and normal cell-lines. LOH events were determined by identifying genotype changes between matched leukemic and remission samples. Results: Each sample had unique patterns of multiple gene copy changes and LOH events distributed across all chromosomes. Additionally, samples were found to have overlapping copy number changes and LOH regardless of leukemia type. AML samples had fewer LOH events and could be separated by unsupervised clustering from the other leukemia samples. Conclusions: MIPs represent novel genotyping technology that can be adapted for gene copy analysis of childhood leukemia. Unique and distinguishing signatures of allelic imbalance can be determined between ALL and AML clinical samples using MIP technology. The unexpected overlap of LOH and deleted genes may represent a common molecular mechanism that requires further investigation.

No significant financial relationships to disclose.
Age, tumor grade, and mitosis-karyorrhexis index (MKI) are independently predictive of outcome in neuroblastoma (NB)
Authors: London W. B. , Shimada H. , d'Amore E. , Peuchmar M. , Hero B. , Faldum A. , Machin D. , Mosseri V. , Iehara T. , Pearson A. , Cohn S. L.
Published: March 2020

9558

Background: NB is a rare pediatric malignancy (USA incidence 1:100,000), and treatment is tailored according to risk. NB patients (pts) in the Children's Oncology Group are stratified to low, intermediate or high risk according to age at diagnosis, stage of disease, MYCN status, histopathology, and tumor cell ploidy. The International NB Pathologic Classification (INPC) uses age at diagnosis to classify tumors as Favorable or Unfavorable histology. This results in duplication of the prognostic contribution of age when both age and INPC, with other factors, are used to assign risk groups or build multivariable models of prognostic factors. To eliminate the confounding contribution of age and INPC, and determine if tumor pathology is predictive of outcome independent of age, we performed multivariable modeling using the underlying pathologic components of INPC. Methods: Using the largest cohort of NB pts ever assembled (n=11,054; 1980–2002; international), 1,860 pts with known age, INPC, diagnosis, tumor grade of differentiation, MKI, and outcome were identified. Half were selected at random (reserving the other half for validation) for analysis. A Cox multivariable model was used to perform survival tree regression to identify factors statistically significantly (p<0.05) prognostic of event-free (relapse, progression, secondary malignancy, death) survival (EFS). Factors tested were age, diagnosis, grade, and MKI. Results: Age (<547 v. ≥547 days) was the most significant factor (p<0.0001). Within pts <547 days, no factors were significantly prognostic. Within pts ≥547 days, stroma-poor NB and nodular (composite) ganglioNB was associated with significantly lower EFS than intermixed ganglioNB and ganglioneuroma, maturing (p<0.0001). Pts were further stratified within the latter diagnoses by MKI (Low/Intermediate v. High) (p=0.0016). These results were validated in the other half of the cohort. Conclusions: Histologic features of NB tumors are predictive of outcome. To remove confounding of the prognostic contribution of age, the underlying histologic features of the tumor (diagnosis, MKI, grade) should be used instead of INPC class to assign pts to risk groups or identify prognostic factors with multivariable models.

No significant financial relationships to disclose.
Safety, pharmacokinetics, and efficacy of palonosetron in pediatric patients: A multicenter, stratified, double-blind, phase 3, randomized study
Authors: Kadota R. , Shen V. , Messinger Y.
Published: March 2020

9570

Background: A single intravenous (IV) dose of palonosetron (PALO) 0.25 mg is used in the prevention of acute chemotherapy-induced nausea and vomiting (CINV) after highly (HEC) and moderately emetogenic chemotherapy (MEC) and in the prevention of delayed CINV after MEC. Since younger age is a risk factor that increases the likelihood of CINV, we conducted this study to explore the safety, pharmacokinetics (PK) and efficacy of PALO in pediatric patients receiving MEC (32% of patients) or HEC (68%). Methods: Sixty pediatric patients in 2 age strata, ages 2–11 and 12–17 years, were randomized to receive a single IV dose of PALO 3 mcg/kg (max total dose = 0.25 mg) or 10 mcg/kg (max total dose = 0.75 mg), with no concomitant antiemetics prior to MEC or HEC. The same doses were used in 12 additional younger patients (age range: 28 days - 23 months) treated in an open-label fashion. Safety, assessed as incidence of adverse events (AEs), was the primary between-group analysis endpoint. Plasma concentrations, PK parameters and efficacy (up to 24 hours after chemotherapy) were assessed descriptively for both PALO doses in each age group. Results: Only 3 AEs, 2 (pyrexia and pruritus) in the 3 mcg/kg dose group (5.7%) and 1 (pain) in the 10 mcg/kg group (2.7%), were judged possibly related to study medication by the investigators, and none of them were severe or led to study discontinuation. No cardiac safety issues were identified; vital signs and laboratory data did not raise any safety concerns for the administration of either dose of PALO. Systemic exposure (AUC) to PALO increased with increasing dose across all age groups (AUC0–8: 22.17–33.25 ng*h/mL at 3 mcg/kg dose; 49.85–75.1 ng*h/mL at 10 mcg/kg dose). Clearance and volume of distribution increased in correlation with age-related growth in body weight. T1/2 ranged from 21–37 hours across groups, slightly shorter than adult T1/2 of 40 hours. Complete Response (no emesis no rescue, 0–24 hours) rates showed overlapping Confidence Intervals in the two dose groups (37.1% [22.0%-55.1%] at 3 mcg/kg, n=35; and 54.1% [37.1%-70.2%] at 10 mcg/kg, n=37). Conclusions: PALO, dosed according to patient's weight at 3 and 10 mcg/kg, was effective and well tolerated in the pediatric population.

No significant financial relationships to disclose.
Anglo-Celtic IV: First results of a UK National Cancer Research Network randomized phase III pharmacogenetic trial of weekly compared to 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC)
Authors: Verrill M. W. , Lee J. , Cameron D. A. , Agrawal R. , Coleman R. E. , McAdam K. , Wardley A. , Bowman A. , Ferrigan L. , Yellowlees A.
Published: March 2020

LBA1005

Background: Phase II studies of weekly paclitaxel (P) confirm this to be a well tolerated regimen in ABC with potentially superior efficacy to standard q3w schedules. This was tested in the phase III CALGB 9840 trial, which used a “patient resource conserving” design, combining randomised patients with imported control data from a previous CALGB study of predominantly 2nd line treatment. This and the higher total dose of P in the weekly arm, left many unsure if there really was superior activity for the weekly schedule. Methods: The primary efficacy objective was to detect a 2 month improvement (6 to 8 months, HR = 1.33) in time to progression (TTP) by the giving the same total dose of P weekly (wP) vs. 3 weekly (3wP). 560 randomised patients were required to give 90% power to detect this difference at the 0.05 significance level. A single analysis was planned six months after study closure. Secondary endpoints include overall survival, toxicity and quality of life. The primary translational endpoint is a pharmacogenetic (PG) study of the effect of MDR and CYP single nucleotide polymorphisms. Between Sept. 2002 and July 2006, 569 patients were randomized to receive either wP 90 mg/m2 for 12 weeks or 3wP 175 mg/m2 for 6 cycles. Patients were stratified for measurable disease, prior treatment for ABC and Trastuzumab use. Results: The investigator reported response rates were 27% (3wP) and 42% (wP), p=0.002. Median TTP was 22.0 weeks for 3wP (95% CI 19.7–24.6) and 23.9 weeks for wP (95% CI 20.7–26.7), HR=0.92, p=0.06. Both schedules were well tolerated. PG samples from 325 patients are being matched to the unblinded efficacy data. Conclusions: This phase III trial shows that, for a matched total dose, wP produces a higher response rate than 3wP. This confirms the result from CALGB 9840. The mismatch in treatment duration in this trial may explain why TTP with wP was superior in CALGB 9840 while in the current study we have failed to detect superiority despite a higher response rate. Combining the trial results supports the hypothesis that total dose and schedule of P are important. Our results support the widespread adoption of wP as the standard schedule.

No significant financial relationships to disclose.
Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)
Authors: Boku N. , Yamamoto S. , Shirao K. , Doi T. , Sawaki A. , Koizumi W. , Saito H. , Yamaguchi K. , Kimura A. , Ohtsu A.
Published: March 2020

LBA4513

Backgrounds: We conducted a 3-arm phase III study to investigate superiority of CP and non-inferiority of S-1 to 5-FU for advanced gastric cancer in the primary endpoint of overall survival (OS) and secondary endpoints of response rate (RR), time to treatment failure (TTF), non-hospitalized survival (NHS) and toxicities. Methods: Treatments with 5-FU (800mg/m2/d, ci, d1–5, q4w), CP (irinotecan, 70mg/m2, div, d1&15 and cisplatin, 80mg/m2, div, d1, q4w) and S-1 (40mg/m2, b.i.d., d1- 28, q6w) were continued until disease progression or unacceptable toxicities. Tumors were evaluated every two months. With 230 patients (pts) per arm, this study had 80% power to demonstrate 10% superiority of CP and non-inferiority with 5% margin (hazard ratio, HR=1.16) of S-1 and 0.05 study-wise 1-sided alpha. Results: 704 pts having unresectable or recurrent gastric adenocarcinoma with/without target lesions (TL) were randomized between Nov 2000 and Jan 2006. Final analysis was performed in Feb 2007 when 601 pts (85%) were dead. The results of OS are shown in Table . Median TTF/NHS were 2.3M/7.2M for 5-FU, 3.7M/9.5M for CP, and 4.0M/9.2M for S-1. Incidences (%) of grade 4 neutropenia, grade ≥3 febrile neutropenia, infection with neutropenia, anorexia, diarrhea within 6M, and treatment related death (5- FU/CP/S-1) were 0/37/0, 0/9/0, 0/8/0, 13/33/12, 0/9/8, and 0/1.3/0.4. In the subset having TL, RRs of 5-FU/CP/S-1 (n=175/181/175) were 9%/38%/28%, and their median survival times (MST) were 9.0M/12.1M/10.5M and HRs to 5-FU were 0.78 (95%CI, 0.63–0.98) for CP and 0.85 (0.68–1.06) for S-1. In the subset not having TL, the MSTs of 5-FU/CP/S-1 (n=59/55/59) were 13.5M/14.4M/18.1M and HRs were 1.02 (0.68–1.55) for CP and 0.82 (0.55–1.24) for S-1. Conclusions: S-1 showed a significant non-inferiority to 5-FU. Although CP did not show statistically significant superiority to 5-FU in all pts, it may have a benefit for some subgroups such as pts with measurable metastatic diseases.

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Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab (H)
Authors: Rastogi P. , Jeong J. , Geyer C. E. , Costantino J. P. , Romond E. H. , Ewer M. S. , Keefe D. L. , Levine T. , Swain S. M. , Wolmark N.
Published: March 2020

LBA513

Background: Trastuzumab (H) has been shown to improve survival in HER2 positive, node-positive breast cancer patients when combined with paclitaxel following AC (Romond NEJM 2005:353;1673–1684). Cardiac dysfunction is the major toxicity associated with this regimen. Methods: NSABP B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node- positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on MUGA scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by a panel of cardiologists to determine whether criteria were met for a cardiac event (CE), defined as NYHA class III or IV CHF or possible/probable cardiac death. Among patients with normal post-AC LVEF who began post-AC treatment, 10 of 872 (1.3%) control patients subsequently had confirmed CEs (9 CHFs and 1 cardiac death) compared with 35 of 932 (3.9%) trastuzumab-treated patients (35 CHFs and no cardiac deaths). The difference in cumulative incidence at 5 years was 2.7%. Risk factors for CHF were age 50 (5.2–5.3%), requirement for hypertension medication (7.7%), and post AC-LVEF values of 50–54% (13.0%). Conclusion: Administering trastuzumab with paclitaxel after AC increases incidence of CHF. Risk factors for increased risk of cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.

No significant financial relationships to disclose.
A randomized phase III study of gemcitabine (GEM) versus pegylated liposomal doxorubicin (PLD) in progressive/recurrent ovarian cancer (OC)
Authors: Ferrandina G. , Lorusso D. , Pignata S. , Breda E. , Savarese A. , Nardi M. , Scaltriti L. , Ludovisi M. , Scambia G.
Published: March 2020

LBA5506

Background: This multi-center Phase III study was designed to compare the efficacy and safety of PLD vs GEM in ovarian cancer (OC) patients relapsing within 12 months from platinum/paclitaxel treatment. Methods: Recurrent OC patients failing only one line of platinum/paclitaxel regimen with a platinum-free interval (PFI) ≤12 months, and with measurable or evaluable disease were eligible. Patients were randomized to receive PLD 40 mg/m2 d1 over 1 hr q 4 wk versus GEM 1,000 mg/m2 d1,8,15 over 30 min q 4 wk. The primary endpoint was time to progression (TTP), with overall survival (OS), overall response rate (ORR), safety/toxicity, and quality of life (QoL) as secondary endpoints. A total of 147 patients was calculated to be required (alpha=0.05, beta=0.80) in order to detect an increase in median TTP from 12 to 19 weeks in control (PLD) versus experimental (GEM) arm. Results: As of December 2006, 147 patients were enrolled; 74 and 73 patients were randomized to PLD versus GEM, respectively: overall, median age was 65 yrs (range 28–80); 69 (46.9%) patients had a PFI < 6 months, while 78 (53.1%) had a PFI between 6–12 months. response evaluation was possible in 129 cases: in PLD arm, the ORR was 15.9%, compared to an ORR=28.3% in GEM arm, p value=0.13). With a median follow up of 9 months, there was no difference in TTP between PLD and GEM arms (median TTP=16 versus 20 weeks, respectively; p value=0.44). Median OS was 56 weeks in PLD patients versus 50 weeks in GEM arm (p value=0.17). Total number of cycles was 301 in PLD arm, and 275 in GEM arm. Grade 3–4 leukopenia was documented in 8.7% of patients allocated to PLD versus 22.0% of patients administered GEM (p value=0.03); no difference in the distribution of severe anemia and thrombocytopenia was observed. There was no difference in non hematological toxicity. A total of 121 patients were considered for QoL data analysis: a trend to a better global QoL score was documented in PLD arm. (p value=0.015) Conclusions: PLD and GEM show similar activity in OC recurring within 12 months from primary treatment.

No significant financial relationships to disclose.
Pemetrexed in advanced non-small cell lung cancer: A randomized trial of 500 mg/m2 vs 900 mg/m2 in 588 patients who progressed after platinum-containing chemotherapy
Authors: Cullen M. , Zatloukal P. , Sörenson S. , Novello S. , Fischer J. R. , Joy A. , Zereu M. , Peterson P. , Visseren-Grul C. , Iscoe N.
Published: March 2020

LBA7727

Introduction: The mild toxicity profile of pemetrexed (P), seen in a phase III trial of P 500 mg/m2 vs docetaxel 75 mg/m2 in vitamin-supplemented patients (pts), suggests higher doses of P can be given in pts with previously treated advanced non-small cell lung cancer (NSCLC) without significant toxicity. We conducted a phase III trial to determine if a higher dose of P (900 mg/m2) could improve survival vs the standard P dose in pts with NSCLC. Methods: Pts with stage III/IV NSCLC, previously treated with platinum-based chemotherapy, were randomized to P 500 or 900 mg/m2 iv q3week. After the second planned interim analysis, the Data Safety Monitoring Board recommended discontinuation of enrollment due to low probability of demonstrating a survival advantage and a greater incidence of some toxicities on the P 900 arm. Patients were allowed to continue treatment at the P 500 dose. Results: 588 randomized pts were evaluated for efficacy and 581 pts, who received =1 dose, for safety. Safety data for pts who transitioned from P 900 to P 500 were analyzed separately. The treatment arms were balanced regarding baseline characteristics and prior treatment. Both arms had: ∼67% males, median age 62 yrs, 87% pts with an ECOG PS of 0 or 1, and 77% pts with stage IV disease. Key results are shown in the table . There was no statistical difference between arms for any efficacy measure. In general, the incidence of adverse events (AEs) was comparable or numerically higher in the P 900 arm. Some AEs (all grades) reported a >5% difference between the P 900 (N=240) and P 500 arms: fatigue (41.7% vs 32.8%), anemia (32.9% vs 22.1%), vomiting (20.0% vs 13.1%), stomatitis (17.9% vs 10.0%), diarrhea (15.4% vs 10.0%), and thrombocytopenia (11.3% vs 5.5%). Conclusion: P 900 offers no advantage over P 500 mg/m2 as second-line therapy for pts with advanced NSCLC. Certain toxicities were somewhat more pronounced in the P 900 group.

No significant financial relationships to disclose.

[Table: see text]
Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): Final results of SARC028 expansion cohorts.
Authors: Burgess Melissa Amber , Bolejack Vanessa , Schuetze Scott , Van Tine Brian Andrew , Attia Steven , Riedel Richard F. , Hu James S , Davis Lara Emily , Okuno Scott H. , Priebat Dennis A. , Movva Sujana , Reed Damon R. , D'Angelo Sandra P. , Lazar Alexander J. , Keung Emily Zhi-Yun , Reinke Denise K. , Baker Laurence H. , Maki Robert G. , Patel Shreyaskumar , Tawbi Hussein Abdul-Hassan
Published: March 2020

11015

Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and < 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.
Sequenced circulating tumor (ct) DNA to detect the molecular landscape in advanced GIST.
Authors: Kelly Ciara Marie , D'Angelo Sandra P. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Wheeler Samantha , Hasan Maysun , Berger Michael F. , Antonescu Cristina R. , Tap William D. , Chi Ping
Published: March 2020

11036

Background: Molecular (mol) characteristics-guided precision therapy has well-established utility in GIST management. The GIST mol landscape is poorly represented by selective tumor biopsy (bx) material, especially in metastatic and treatment-refractory GIST. ctDNA can overcome some of the limitations of selective tissue bx specimens and provide comparable or greater mol information. ctDNA represents an emerging mol biomarker in advanced (adv) GIST. Methods: Next generation sequencing analyses (MSK-IMPACT or custom-capture GIST specific panel) were performed on ctDNA prospectively collected from patients (pts) with adv GIST. MSK-IMPACT was performed on tumor material (archival tissue or paired tissue bx specimens taken in parallel with ctDNA collection from clinical trial participants). The primary objective was to determine the concordance between the mol landscape of GIST identified by sequenced tumor tissue versus ctDNA. Secondary objective was to correlate characteristics of sequenced ctDNA with standard measurements of response assessment. Results: 47 ctDNA samples collected from 25 pts with adv GIST were sequenced using MSK-IMPACT ( > 400 genes). MSK-IMPACT was performed on archival tumor material. Sequenced ctDNA detected the mutational spectrum of tumor tissue in 48% of cases. In 50% of these cases, ctDNA identified novel treatment-resistance mutations not previously identified in the archival tissues. To optimize sensitivity of detection, a custom-designed GIST specific ctDNA sequencing panel was developed incorporating 19 of the most commonly altered genes observed from MSK-IMPACT analysis performed on > 75 imatinib-refractory adv GIST tumor samples. 52 ctDNA samples collected from 30 pts with paired tumor bx samples have been sequenced using the custom-capture GIST panel. The tumor bx samples have been sequenced using MSK-IMPACT. Results are pending and will be presented. A separate cohort of ctDNA samples serially collected in the setting of a prospective clinical trial are being sequenced. The mol results with correlated treatment response by RECIST will also be presented. Conclusions: ctDNA could detect a broad spectrum of mol heterogeneity and potentially be used as a biomarker to guide precision therapy in adv GIST. Further research is necessary to determine the optimal ctDNA sequencing assay and the appropriate clinical setting to utilize in GIST.