bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental differences in health-related quality of life (HRQL) in adolescent and young adult (AYA) survivors of childhood cancer.
Authors: Becktell Kerri , Phelan Rachel , Schmidt Debra , Anderson Lynnette , Nichols Julie , Simpson Pippa , Bingen Kristin
Published: March 2020

e21524

Background: AYAs experience many distinct periods of developmental transition within this life stage. AYA survivors of childhood cancer are at risk for chronic physical and psychosocial health conditions due to treatment-related exposures. Few studies have evaluated HRQL differences that may exist among developmental subgroups of AYA cancer survivors. This study examined HRQL differences across AYA developmental subgroups (early teens 12-14 years; late teens 15-17; emerging adults 18-24; young adults 25-39) of long term childhood cancer survivors. Methods: Cancer survivors ages 12-39 years who were seen in a long term follow up clinic at time of survey completion (as part of larger HRQL study) and completed therapy ≥2 years ago were included. HRQL was assessed using PedsQL (< 18) and FACT-G (> 18) measures. Demographic and treatment data were obtained from EMR. Analyses compared HRQL measure scores among AYA age subgroups and investigated predictors of HRQL outcomes. Results: A total of 155 patients were included in analysis. Mean age at survey completion was 17.9 [range 12-33] years. PedsQL school functioning was significantly lower for 15-17 year-old compared to 12-14 year-old survivors (M = 77.60, p = 0.01). There were no differences between 18-24 and 25-39 year-old survivors on the FACT-G. PedsQL school functioning was significantly lower for survivors (< 18) compared to normative data (p = 0.004). FACT-G scores for survivors were significantly higher compared to population norms in all domains (p≤0.001) except emotional well-being. Regression CART analysis indicated survivors who were ≤15 years-old and had not relapsed and survivors who were > 15 years old and had ≥2 late effects had lower PedsQL scores. Survivors who were ≥21 years-old had lower FACT-G scores compared to < 21 years. Survivors who were < 21 years-old, > 7 years-old at diagnosis, and > 6 years from end of treatment had lower FACT-G scores. Conclusions: Adolescent survivors may be at risk for school problems years after cancer treatment. Young adult survivors may be at greater risk of poor HRQL. This study highlights potential developmental differences in HRQL predictors and outcomes in long term AYA cancer survivors.
Tumor control with palliative external beam radiation therapy (EBRT) in advanced and unresectable osteosarcoma (OS) progressing after standard treatment.
Authors: Tolomeo Francesco , Gatti Marco , D'Ambrosio Lorenzo , Rampino Monica , Boglione Antonella , Merlini Alessandra , Manessi Giulia , Miano Sara , Salatino Antonia , Cattari Gabriella , Bertotto Ilaria , Robba Tiziana , Mussano Anna , Rossi Laura , Piana Raimondo , Comandone Alessandro , Aliberti Sandra , Aglietta Massimo , Grignani Giovanni
Published: March 2020

e22508

Background: Advanced OS still represents an unmet medical need. Chemotherapy and targeted therapies have only limited activity in this disease. Moreover, OS is considered a radioresistant tumor at doses conventionally achieved by EBRT. We retrospectively evaluated the impact of palliative EBRT in patients (pts) with advanced OS. Methods: Main inclusion criteria: confirmed histological diagnosis of OS; EBRT for advanced/metastatic disease deemed unresectable after multidisciplinary tumor board discussion; ECOG performance status ≤3, age ≥18 years at RT start; progressive disease at site of irradiation with symptoms (e.g., pain or neurological deficit) or involving critical structures (e.g., superior vena cava compression). Endpoints: progression-free survival (PFS), PFS for RT-treated lesions (RT-PFS), best response with RT, overall survival. All survival endpoints were computed from RT start. We calculated the equivalent total dose in 2 Gy fractions (EQD2). Results: 23 pts, 15 males, median age at diagnosis 33 (17-82), median age at RT start 36 (20-83) were included. All pts had grade 3-4 OS (12 osteoblastic; 6 chondroblastic; 5 other), 7 were metastatic at diagnosis. At time of RT, median metastatic sites were 2 (1-5), 15 pts were symptomatic (11 pain, 4 neurological deficit) and were mainly heavily pretreated [median previous chemotherapies 2 (1-5), median previous surgery 1 (0-2)]. Overall, 45 lesions underwent EBRT. Median EBRT dose per lesion was 33 Gy (IQR 25 - 46.5) with a median dose per fraction of 3 Gy (IQR 3-7.5). Calculated median EQD2 was 50 Gy (IQR 36 - 88). Median PFS, RT-PFS, and overall survival were 5 (95%CI 2-9), 11 (5-15), and 12 months (8-16), respectively. Compared to systemic progression, median progression delay of irradiated lesions was 6 months (95%CI 2 - 12). In 40 lesions evaluable for dimensional response, we observed tumor shrinkage > 30% in 7 lesions, stability in 24, and progression in 9. Conclusions: EBRT might have a role in the treatment of advanced OS. In consideration of the limited activity of medical treatments, EBRT might help in disease control in the advanced setting, delaying progression especially at critical sites.
Work productivity loss in patients with tenosynovial giant cell tumors in the United States.
Authors: Lin Feng , Kwong Jackie , Ionescu-Ittu Raluca , Pivneva Irina , Wynant Willy , Shi Sherry , Wu Eric Q. , Abraham John A.
Published: March 2020

e22527

Background: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive and debilitating tumor that generally affects young working-age adults. This study assessed work productivity loss in TGCT patients. Methods: Incident patients aged 18-64 years with diagnosis of TGCT, who had earning and disability data, were identified in the OptumHealth database (Q1 1999 – Q1 2017). Patients were classified into surgical and non-surgical groups depending on the presence of joint surgery claim in postindex period. Control patients without TGCT were matched 10:1 with TGCT patients on age, gender, year of TGCT diagnosis, and follow-up duration. The number of days missed from work due to disability and medical visits post diagnosis was compared using Poisson regressions. General linear models were used to compare indirect costs associated with productivity loss. Results: A total of 1,395 TGCT patients (724 surgical; 671 non-surgical) were matched to 13,950 controls (36% female; mean age = 47 years). Both surgical and non-surgical TGCT patients had more comorbidities (mean Charlson Comorbidity Index (CCI): 0.3 vs 0.2; 0.4 vs 0.2; p < 0.001), had greater use of analgesic drugs (44% vs 20%; 40% vs 21%; p < 0.001) and MRI tests (47% vs 4%; 26% vs 3%; p < 0.001) in the 12 months before TGCT diagnosis compared with controls. Both surgical and non-surgical TGCT patients missed more time from work due to disability and medical visits and had higher indirect cost associated with productivity loss than matched controls. Disability burden was greater in patients receiving surgery. Conclusions: Regardless of receiving surgery or not, TGCT is associated with significant work productivity loss. These findings highlight the unmet need for effective treatments to reduce disability and restore function in TGCT patients. [Table: see text]
Outcome of patients with refractory malignant peripheral nerve sheath tumors (MPNST) enrolled on phase 2 trials.
Authors: Akshintala Srivandana , Mallory Nicole C. , Lu Yao , Ballman Karla V. , Kim AeRang
Published: March 2020

e22534

Background: Multiple phase 2 trials using objective radiographic response rates (ORR) as end point have shown negative results in MPNST. Alternative endpoints such as progression free survival (PFS) may be more appropriate for identifying active agents. PFS from prior trials can provide a historical baseline for future single arm phase 2 trials in this rare disease. Methods: Outcomes of patients with recurrent or unresectable MPNST enrolled on one of five negative phase 2 trials (SARC001, 002, 009, 016, and 023) conducted by the Sarcoma Alliance for Research through Collaboration (SARC) from Nov 2001 – Mar 2016 were retrospectively analyzed to calculate PFS. PFS from SARC006, the phase 2 trial of upfront chemotherapy in newly diagnosed patients with unresectable or metastatic MPNST, was analyzed separately. The impact of neurofibromatosis type 1 (NF1) status, tumor location, metastatic involvement, and prior therapy on PFS was evaluated. Results: Sixty-four patients (29 male, median age 39 years (range 15-81)) with MPNST were enrolled on one of five trials of primarily single agent or combined targeted therapy that were determined to be inactive. Primary endpoint was ORR per RECIST, WHO, or Choi criteria. Patients had received a median of 1 (range 0-5) prior systemic therapies and majority had received prior surgery (77%) and radiation (61%), and had metastatic disease (73%) at enrollment. Median PFS was 1.77 months (95% CI 1.61-3.45), and PFS at 4 months was 16%. Greater number of prior systemic therapies was associated with worse PFS (univariate hazard ratio 1.31, 95% CI 1.03-1.68, p = 0.03). There was no significant difference in PFS based on treatment trial, response criteria, NF1 status, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. PFS at 4 months was 94% in 40 patients enrolled on SARC006 trial, none of whom had received prior systemic or radiation therapy. Conclusions: PFS in patients with recurrent/refractory MPNST enrolled on phase 2 trials is poor and the number of prior regimens may impact PFS. Our data provides a historical baseline PFS that can be used as a comparator in future single arm phase 2 trials in refractory and upfront MPNST patients.
Prognostic implications of tumor associated macrophages (TAMs) in soft tissue sarcoma.
Authors: Raj Shailaja KS , Kooshki Mitra , Winters Melissa , Russell Greg B. , Miller Lance D , Laurini Javier A , Pierre Triozzi , Savage Paul David
Published: March 2020

e22548

Background: Clinical responses in patients with soft tissue sarcoma administered immune checkpoint inhibitors have been infrequent. Little is known regarding the immune microenvironment in soft tissue sarcoma that leads to a lack of effective responses with immune therapies. Whilst several studies have shown T cell infiltration in sarcomas, these tumors do not respond to immunotherapies. Macrophages are important regulators of immune responses in the tumor microenvironment. Studies in mouse models indicate that macrophages regulate immune checkpoint inhibitor response. With the overall goal of developing more effective combination immunotherapies for sarcoma, we examined tumor associated macrophages in patients with soft tissue sarcoma administered neoadjuvant chemotherapy. Interactions between macrophage infiltration, tumor immunogenicity and overall survival were also assessed using publicly available RNAseq and exome mutation data. Methods: Immunohistochemistry was performed on formalin fixed soft tissue sarcoma tissue. Tissues from 20 patients with soft tissue sarcoma pre and post neo-adjuvant chemotherapy were included. TAMs were detected by CD68; M2 subtype were detected by CD163. CD4, CD8, and CD25 T cells were also examined. The density of CD68+ TAMs, CD163+ TAMs and the ratio of CD163+ TAMs / CD68+ TAMs were calculated and their correlation with survival was also made. Publicly available RNAseq and exome mutation data were assembled from The Cancer Genome Atlas (TCGA) sarcoma cohort (n = 259). For each tumor, a relative measure of abundance of tumor-infiltrating macrophages was estimated using gene expression. Tumor mutational burden (TMB), expressed as the rate of non- synonymous mutations per megabase of sequenced DNA, was used as a measure of tumor immunogenicity. Interactions between macrophage infiltration, tumor immunogenicity and overall survival were assessed by Cox regression and Kaplan-Meier analysis. Categorical relationships involving clinical, immunologic, and genomic features of the tumor immune subclasses were compared. Results: Specific alteration in the density of CD68+ TAMs, CD163+ TAMs, and the CD163 / CD68 ratio were observed in patients with soft tissue sarcoma responding to neoadjuvant chemotherapy. Categorical relationships involving macrophage infiltration, TMB, and survival were also observed. Conclusions: These study support the targeting of tumor associated macrophages in patients with soft tissue sarcoma and suggest that changes in TAMs may be achievable using neoadjuvant chemotherapy.
Alveolar soft PART sarcomas (ASPS): A tertiary care center experience from India.
Authors: Simha Vijai , Mullapally Sujith Kumar , Dandekar Sonal , Turkar Siddharth , Rekhi Bharat , Bajpai Jyoti
Published: March 2020

e22553

Background: Alveolar soft part sarcomas (ASPS) are rare, vascular, soft tissue sarcomas and response to conventional chemotherapy is disappointing. There is sparse data from India and other lower and middle-income countries (LMICs) and merits exploration. Methods: This is a retrospective analysis of patients of ASPS treated at Tata Memorial Center, patterns of care and outcomes were analyzed. Results: Fifty four patients of ASPS were treated between January 2002 to July 2018. The median age was 30 years and most common primary site 45 (80%) was extremities. Distant metastasis were seen in 36 (67%) patients; 20 upfront and 16 on recurrence. In the period from 2002-2014, 18/34 (54%) patients were declared “best supportive care” for want of effective systemic therapies. Only 16 (47%) patients with metastatic disease received systemic chemotherapy. 8 (11%) patients received conventional chemotherapy. Most commonly used regimen was combination of Ifosfamide and Adriamycin, however, 5/8 ( 62.5%) had progressive disease on chemotherapy and 37.5% had grade ≥3 toxicity mainly in form of neutropenias . Since the year 2015, the pattern of care evolved and 6 patients with metastatic disease were treated with antiangiogenic therapies (Sunitinib and Pazopanib). Responses were seen in 4/6 (66.6%) including 2 partial and 2 complete responses. The median progression free survival of these patients was 23 months (95% CI 14.3- 27.3 months) and was significantly better than that of conventional therapies - 7 months (95% CI 5.1-9.8 months) p = 0.03. Conclusions: ASPS is a systemic disease with high metastatic potential and poor chemosensitivity. Our institute practice has evolved from a policy of therapeutic nihilism to that of effective and feasible treatment in form of antiangiogenic therapy with meaningful responses.
Exploring ceramide metabolism as a potential target in dedifferentiated liposarcoma.
Authors: Demoret Bryce , Patt Andrew , Stets Colin W , Hoang Mindy , Hays John L. , Mathe Ewy , Chen James Lin
Published: March 2020

e22558

Background: Dedifferentiated liposarcomas (DDLPS) are highly aggressive mesenchymal tumors characterized by MDM2 amplification. Elevated MDM2 amplification levels are associated with tumor growth, chemoresistance, and changes in cellular metabolism. Previous work from our laboratory has demonstrated that lipid metabolism, particularly increased glycosylated ceramides (Gly-Cer), is profoundly altered as a function of MDM2 amplification. Importantly, ceramides have been identified to play a key role in proliferation arrest and apoptosis or autophagy by stabilizing p53 through the binding and disrupting the MDM2-p53 interaction. Gly-Cer clears out ceramides, thereby preventing the ceramides from performing their anti-proliferative activity. We hypothesized that restoring Gly-Cer levels would induce anti-proliferative effects in DDLPS. Methods: 6 DDLPS cell lines (MDM2-high: Lipo224, Lipo141, Lipo224B, Lipo246; MDM2-low: Lipo815, Lipo863) were selected for in vitro assessment. MDM2 levels were ascertained via Western blot and RNA-sequencing. Metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling were conducted on all cell lines. Inhibitory concentration 50% (IC50) of the C6-ceramide (C6C) and nanoliposomal C6-Ceramides (C6CNL) were tested in vitro by XTT . Adjusted t-tests were used to determine metabolite relevance. Results: Metabolomic/lipidomic analyses identified a correlation between MDM2 amplification status and elevated levels of glycosylated ceramides (nom: Pval < 0.001), including GlcCer_NS(d18:1/24:1), GlcCer_NS(d19:1/24:1), GlcCer_NS(d18:1/25:0), glycosyl-N-palmitoyl-sphingosine, and glycosyl-N-stearoyl-sphingosine. Further, the ratio of glycosylated to un-glycosylated ceramides in DDLPS cell was also associated with MDM2 status for Cer(d19:1/24:1) (Pval < 0.01) and borderline associated for Cer(d18:1/16:0) and Cer(d18:1/25:0) (Pval < 0.2). In vitro treatment of DDLPS cell lines with C6C resulted in a reduction of cellular viability most prominent in MDM2-high cell lines (IC50: 17 vs. 55 µM). When treated with C6CNL, all DDLPS cell lines exhibited equal sensitivity (IC50: ~9 µM). Western blots demonstrate C6CNL treatment resulted in a reduction in MDM2 expression and restoration of p53 function. Conclusions: Exogenous ceramide treatment reduces MDM2 expression, restores TP53 status, and manifests anti-proliferative activity in DDLPS. C6CNL exhibited lower effective concentrations relative to free C6 ceramide. Prospective in vivo studies are underway to confirm these findings.
The impact of blinding on patient-reported outcomes (PROs) in randomized controlled trials of immune checkpoint inhibitors versus traditional chemotherapies.
Authors: Dickerson James , Hall Evan Thomas , Singhal Surbhi , Gabster Brooke Peterson , Schapira Lidia
Published: March 2020

e23160

Background: Immune checkpoint inhibitors (ICIs) have been met with a wave of excitement due to their novel mechanism. We hypothesized that this may impact how patients (via PROs) report treatment tolerability in comparison to traditional therapies. We sought to examine if there was a notable difference in PROs in blinded vs unblinded trials of ICIs. Methods: We systematically searched PubMed, CINAHL, Embase, Web of Science, and Scopus in August 2018 for publications with quantitative PRO data comparing ICIs to cytotoxic chemotherapy. Case series, narrative reviews, and publications lacking original data were excluded. Eligible publications were reviewed to assess if patients were blinded to the agent received, and a comparison for common PRO metrics was performed. Results: Of the 1,450 unique references identified, eight met inclusion criteria: 1 double blinded placebo-controlled trial and 7 trials where patients were aware of the assigned arm. The blinded trial had quantitative PRO data in the form of the European Organisation for Research and Treatment of Cancer (EORTC) global health status (GHS) score and patient reported symptom burden at week 12. Most (6 of 7; 86%) unblinded trials reported the GHS at either week 12 or 15, and patient symptom burden at these time points as well (5 of 7; 71%). For the EORTC GHS, the blinded trial showed no inter-arm difference at week 12. 4 of 6 (67%) open label trials noted statistically significant differences in GHS favoring the ICI arm. For symptom burden at week 12 or 15, there was no difference found in the blinded study. In unblinded trials, there were domains where patients receiving ICIs reported a statistically significant lower symptom burden than those receiving chemotherapy: fatigue (4 of 5 trials favoring ICIs; 80%), dyspnea (2 of 5; 40%), insomnia (1 of 4; 25%), appetite loss (1 of 4; 25%), and diarrhea (1 of 5; 20%). There were no differences in pain (n = 5), nausea/vomit (n = 5), and constipation (n = 5). Conclusions: We found a trend towards more favorable reporting on common symptoms in unblinded studies of patients receiving ICIs. Our analysis is limited by the lack of available comparisons in the published literature.
One-minute time interval estimation as a novel potent indicator of need for help in cancer patients prior to starting chemotherapy.
Authors: Stoyanov Dragomir , Donev Ivan , Conev Nikolay Vladimirov , Panayotova Teodorika , Ivanova Martina
Published: March 2020

e23161

Background: Perception of time strongly correlates with people’s current emotional state. Our study explored the potential relationship between the time estimation and the need of help in cancer patients prior to starting chemotherapy. Methods: Time estimation was assessed in 375 chemonaïve patients with solid tumors by evaluating each subject’s prospective estimation of how fast one minute passed compared to the actual time. The median value (40 sec) of time estimation was used to stratify the patients into two categories of fast and slow time estimation. The National Comprehensive Cancer Network Distress Thermometer and Problem List were used at the beginning of treatment to evaluate levels of distress and patients’ concerns. Additional question was asked “Do you need help?”. Results: Patients who reported the need of help were 134 (35.7%). The need of help correlated with fast time estimation, high level of distress and younger age (< 65y). Patients who reported a need of help estimated time significantly faster than those who did not report it (37.2±15.5 vs 42.7±17.2; p = 0.004). ROC analysis revealed that at the optimal cutoff value of time estimation, patients who reported a need of help and those who did not can be discriminated with an AUC = 0.59 (95% CI: 0.53-0.65, p = 0.003) and with a sensitivity of 61.9% and a specificity of 50.6%. Moreover, in a multivariate logistic regression model, fast time estimation was an independent predictor of reporting the need of help (OR 1.59; 95% CI 1.02-2.45; p = 0.04). Conclusions: Time estimation is a novel potent indicator for the need of help in cancer patients. This test is an easily performed, time-saving and nonintrusive ultrashort screening tool for the need of help that is even suitable for patients who are not willing to reveal their need of help via direct questionnaires.
The development of an instrument to identify cancer caregivers at risk for metabolic syndrome.
Authors: Jones Reyna , Moore Debra , Geller David A. , Miceli Jessica , Hecht Carol Lynn , Spring Michael , Pathak Ritambhara , Chen Qi , Steel Jennifer Lynne
Published: March 2020

e23174

Background: Cancer caregivers are at increased risk for cardiovascular disease. The aims of the present study were to develop an instrument to identify cancer caregivers at risk for the development of cardiovascular disease. Methods: Cancer caregivers were enrolled in a prospective study examining predictors of metabolic syndrome. Predictors included perceived stress, caregiver stress, depression, hostility, physical activity, diet, alcohol and tobacco use, social support and relationship with the patient. Regression analyses and factor analyses was performed to reduce the number of items to develop an instrument that would identify cancer caregivers at risk for cardiovascular disease. Internal consistency and Area Under the Receiver Operator Curve was also performed to test the new instrument. Results: A total of 111 caregivers were included in the analyses. The mean age of caregivers was 59.6 ( SD= 12.7) and the majority of caregivers were female (74.8%), Caucasian (94.6%), and were the spouse of the cancer patient (65.8%).Using regression analyses, the items from the caregiver stress, hostility, and social support questionnaires were most likely to predict metabolic syndrome. Preliminary findings suggest that a 35-item instrument was predictive of metabolic syndrome [B = 0.067, HR = 1.07, p = 0.001]. The reliability of the instrument was good with a Cronbach Alpha = 0.83. The Area Under the Receiver Operator Curve was also fair (AUROC = 0.703; 95% CI = 0.597-0.808, p = 0.001). Based on the AUROC, the best cut point to detect metabolic syndrome would be a score of 24 (Sensitivity = 0.75 and Specificity = 0.55). Conclusions: Preliminary findings suggest that this 35-item questionnaire may be useful in identifying cancer caregivers at risk for metabolic syndrome, an intermediate endpoint for cardiovascular disease. The questionnaire may be used to screen cancer caregivers for interventions to reduce metabolic syndrome.
MDM2 inhibitor AMG-232 and radiation therapy in treating patients with soft tissue sarcoma with wild-type TP53: A phase IB study (NRG-DT001).
Authors: WELLIVER Meng XU , Van Tine Brian Andrew , Houghton Peter , Rudek Michelle A. , Pollock Raphael E. , Kane John Michael , Schwartz Gary K. , Zhang Peixin , Kirsch David G. , Wakely Paul , Jiang Steve B. , Jiwani Shahanawaz , Rogers Alan D. , Wang Dian
Published: March 2020

TPS11076

Background: Over-expression of mdm2 is a major block to p53 activation in soft tissue sarcoma (STS). AMG-232 specifically inhibits human MDM2-p53 interactions in vitro and in vivo, thereby activating p53. Resistance mechanisms to MDM2 inhibition by AMG-232 is through accumulation of MDM2 and MDMX. However, DNA damaging agents, such as radiotherapy (RT), promote MDMX degradation and lead to sustained p53 activation, which is critically important for radiation-induced tumor cell killing in STS. Indeed, preclinical studies reveal that AMG-232 synergizes with RT in vitro and in vivo when treating STS with wild type (WT) P53 gene . Since a majority of STS harbor WT TP53 gene and RT is part of the standard of care in treating STS; it is the next rational step to test the safety and efficacy of combination of AMG-232 and RT followed by surgery. In this clinical trial, we hypothesize that preoperative AMG-232 plus RT is safe and well tolerated in 2 separate cohorts: (A) extremity and body wall; (B) abdomen/pelvis/retroperitoneum. Methods: A key feature of this trial is to incorporate TP53 NGS sequencing result as one of the eligibility criteria. Adult patients with pathologically proven grade 2-3 STS with size ≥ 5 cm are eligible to enroll if there is a planned definitive surgical resection of the primary tumor. There must be sufficient tissue to submit to central laboratory for NGS sequencing of the TP53 gene, which is an integral biomarker. Only those with tumors harboring WT p53 gene will be allowed to continue protocol treatment. The primary objective is to evaluate the safety and tolerability of AMG-232 in combination with standard-dose RT in STS in two separate cohort; as well as to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of AMG-232 in combination with RT. We define DLT as grade 4-5 toxicities attributable to AMG-232 for up to 4 weeks after the completion of combination treatment (prior to surgery) as well as any AMG-232 related grade 3 toxicity that should lead to > 2 weeks treatment delay or ≥ two dose reductions. There are 3 dose levels for AMG-232: dose level 1 is 120 mg daily for 3 days per week; dose level 2 is 120 mg daily 4 days per week and dose level 5 is 120 mg daily 5 days a week. If patients did not tolerate dose level 1, AMG-232 will be de-escalated to a lower level, which is 120 mg daily 2 days a week. The trial was open since 11/2017; 3 patients have been enrolled to cohort A and 2 patients in cohort B at dose level 1. The first patient has a tumor with WT p53 gene and has completed protocol treatment safely. Clinical trial information: NCT03217266.
CBT-1 in combination with doxorubicin in patients with metastatic, unresectable sarcomas who previously progressed on doxorubicin.
Authors: Cote Gregory Michael , Chawla Sant P. , Burgess Melissa Amber , Thornton Katherine Anne , Oldham Robert K. , Okuno Scott H. , Ballman Karla V. , Matlow Susan , Barnett Daryl , Attia Steven
Published: March 2020

TPS11077

Background: The response rates of advanced soft tissue sarcomas (STS) to single-agent, first-line anthracycline are typically less than 25%. P-glycoprotein 1 (P-gp), a cell membrane drug efflux pump, is believed to be a resistance mechanism in STS. CBT-1 is a small molecule, orally administered, P-gp antagonist currently under clinical development. This is a multi-institutional open label phase I study of CBT-1 in combination with doxorubicin in patients with anthracycline-refractory sarcoma. The study is designed to determine a maximum tolerable dose (MTD), recommended phase II dose (RP2D), and the safety/tolerability of the combination of CBT-1 and doxorubicin. The study will evaluate anti-cancer activity as a secondary objective as measured by Disease Control Rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) at 12 weeks. Objective Response Rate (ORR; CR+PR) and Progression Free Survival (PFS) will be monitored. Correlative studies include assessment of pharmacokinetic and pharmacodynamicendpoints. Methods: Patients 18 years or older with locally advanced metastatic, unresectable STS, prior progression on ≤ 150 mg/m2 of doxorubicin (or another anthracycline equivalent), ECOG PS ≤ 1 and normal organ function, are eligible for this study. Dosing includes fixed doxorubicin (37.5 mg/m2 IV day 5 and day 6) and escalation of oral CBT-1 on days 1-7 of a 21 day cycle. This study follows a standard 3+3 phase I design where dose escalation will occur if < 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted at Week 6 and Week 12. For patients with response or stable disease, treatment is allowed to continue for 4-5 cycles to a maximum of 450 mg/m2 lifetime doxorubicin exposure. Once RP2D is defined, an additional 10 patients will be enrolled into the dose expansion phase. To date, Cohorts 1 (50 mg CBT-1) and 2 (100 mg CBT-1) have been completed with one DLT of grade 4 neutropenia lasting longer than 7 days in Cohort 1. Enrollment to Cohort 3 began December 2018. (References: Oldham, R. K., Reid, W. K., Preisler, H. D., and Barnett, D. (1998) Cancer Biother. Radiopharm. 13, 71-80; Kelly, R. J., Robey, R. W., Chen, C. C., Draper, D., Luchenko, V., Barnett, D., Oldham, R. K., Caluag, Z., Frye, R. A., Steinberg, S. M., Fojo, T., Bates, S. E. (2012) The Oncologist 17 (4) 512-e523; Robey, R. W., Shukla, S., Finely, E. M., Oldham, R. K., Barnett, D., Ambudkar, S. V., Fojo, T., Bates, S. E., (2008) Biochemical Pharmacology 75, 6, 1302-1312). Clinical trial information: NCT03002805.
Benefit of intensified perioperative chemotherapy within high-risk CINSARC patients with resectable soft tissue sarcomas (CIRSARC).
Authors: Italiano Antoine , Blay Jean-Yves , Le Cesne Axel , Bompas Emmanuelle , Piperno-Neumann Sophie , Duffaud Florence , Bertucci Francois , Bellera Carine A. , Honoré Charles , Stoeckle Eberhard , Bonvalot Sylvie , Chevreau Christine
Published: March 2020

TPS11078

Background: We have recently identified a gene expression signature so called “CINSARC” which is related with chromosomal instability and highly predictive of metastasis-free and overall survival in soft-tissue sarcoma (STS) patients. The prognostic relevance of this signature has been validated recently in an independent set of sarcomas from the Cancer Genome Atlas (TCGA) consortium. Despite optimal locoregional treatment, patients with high-risk CINSARC have a very poor outcome.However, the main issues with peri-operative chemotherapy in STS patients are the identification of patients who are more likely to benefit from this approach and the characterization of the best chemotherapy regimen. Indeed, in all clinical trials investigating peri-operative chemotherapy in STS, patients were included on the basis of classical histological criteria (grade, tumor size, deep location). The CINSARC is more discriminant than grade to evaluate the prognosis of STS patients (35% of grade 3 are low-risk CINSARC and 40% of grade are high-risk CINSARC). We hypothesize than: (1) 6 cycles of anthracyclines-ifosfamide is associated with improved outcome in comparison to 3 cycles of chemotherapy (ISG-STS 10-01) in patients with high-risk CINSARC STS; (2) Chemotherapy-free strategy is not associated with detrimental outcome in low-risk CINSARC STS. Methods: This is a multicenter phase III trial (sponsor: Institut Bergonié) which aims to evaluate the efficacy (intent-to-treat analysis) of 6 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy+ surgery +/-radiotherapy (Arm B) in comparison with 3 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy + surgery +/- radiotherapy (Arm A) in terms of 3-year progression-free survival (PFS) in high-risk CINSARC patients with resectable STS. Patients with low-risk CINSARC signature will be treated at investigator discretion. 334 patients will have to be recruited over 36 months in 10 centers of the French Sarcoma Group. This is the first study assessing the impact of peri-operative chemotherapy in STS based on a prognostic molecular signature. The study is open for accrual at time of submission. Clinical trial information: NCT03805022.
CLI24-001: First-in-human study of SEL24/MEN1703, an oral dual PIM/FLT3 kinase inhibitor, in patients with acute myeloid leukemia.
Authors: Ravandi Farhad , Strickland Stephen Anthony , Solomon Scott R. , Nazha Aziz , Walter Roland B. , Valimberti Ilaria , Tagliavini Alessia , Fiesoli Caterina , Binaschi Monica , Brzozka Krzysztof , Baldini Simone , Heeger Steffen , Pellacani Andrea Ugo
Published: March 2020

TPS7062

Background: FLT3-ITD is one of the most common genetic lesions in acute myeloid leukemia (AML). PIM kinases are oncogenic FLT3-ITD targets expressed in AML cells and increased PIM kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. In addition, inhibition of PIM kinases restores sensitivity to FLT3 inhibitors and dual FLT3/PIM inhibition eradicates FLT3-ITD+ cells including primary AML cells. SEL24/MEN1703, a potent PIM/FLT3 dual inhibitor, demonstrates a significantly broader spectrum of activity in AML cell lines and primary AML blasts, irrespective of FLT3 status, compared to monotherapy with either FLT3 or PIM inhibitors such as quizartinib or AZD1208. Methods: CLI24-001 is a First in Human, open label, non-randomized, multi-center, Phase I/II dose-escalation and cohort expansion study of SEL24/MEN1703 in AML patients (excluding APL) not suitable for chemotherapy. SEL24/MEN1703 is given orally, QD, for 14 days in a 21-day cycle with cycles repeated until disease progression or unacceptable toxicity. Dose escalation follows a 3+3 design to identify the recommended phase 2 dose (RP2D). In the phase 2 part/cohort expansion, subjects will receive SEL24/MEN1703 at the RP2D, to further investigate the safety profile and signs of antileukemic activity. In both study parts, patients are eligible regardless of mutational status and/or prior exposure to FLT3 inhibitors; prior treatment with PIM inhibitors is not allowed. Main inclusion criteria comprise a white blood count (WBC) of ≤30 x 109/L (hydroxyurea/leukoapheresis permitted to lower WBC). Key secondary objectives include pharmacokinetics (PK) and single agent efficacy. The study is enrolling at 5 US sites and will be extended, both in US and EU, in the cohort expansion part. This is the first trial testing a dual PIM/FLT3 inhibitor with the potential to be active in AML regardless of FLT3 status andwith a potential to overcome FLT3 inhibitor resistance. (Sci Adv. 2015;1:e1500221; Oncotarget. 2018 Mar 30;9(24):16917-16931) Clinical trial information: NCT03008187.
A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504.
Authors: Schwartz Marc Saul , Jeyakumar Deepa , Damon Lloyd Earl , Schiller Gary J. , Wieduwilt Matthew Joseph
Published: March 2020

TPS7064

Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with < 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2nd- or 3rd-generation TKI or be TKI intolerant, > 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.
A phase II study of myeloablative allogeneic hematopoietic stem cell transplantation (aHSCT) for acute lymphoblastic leukemia (ALL) in older patients using fludarabine and total body irradiation (Flu/TBI).
Authors: Jamy Omer Hassan , Salzman Donna E. , Di Stasi Antonio , Innis-Shelton Racquel , Luciano Costa , Lamb Lawrence S. , Mineishi Shin , Saad Ayman A.
Published: March 2020

TPS7069

Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI (12 Gy) is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing aHSCT, but with less NRM confering survival benefit over Cy/TBI 12 Gy. Methods: This study is a single center, single-arm phase II clinical trial of Flu 40 mg/m2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. Patients aged 40-65 years with ALL in CR, KPS ≥ 70, adequate organ function, and having HLA-matched sibling or unrelated donor will be eligible. The primary endpoint of the study is 1-year DFS post-transplant. Secondary endpoints include 1-year overall survival (OS), incidence and severity of acute and chronic GVHD, immune reconstitution and regimen related toxicity. The study has just finished accrual (January 2019) enrolling a total of 16 patients. This number of patients was pre-determined to give a probability ≤ 0.05 of concluding that the 1-year DFS rate exceeds 45%, and a probability of at least 0.80 of concluding that the 1-year DFS rate exceeds 45% (expecting 1-year DFS of 75%). Clinical trial information: NCT01991457.
FREEDOM: A phase 3b efficacy and safety study of fedratinib in intermediate- or high-risk myelofibrosis patients previously treated with ruxolitinib.
Authors: Verstovsek Srdan , Harrison Claire N. , Barosi Giovanni , Kiladjian Jean-Jacques , Buglio Daniela , Chia Vincent , Gerike Torsten , Jessent-Ciaravino Valerie , Mostillo Joseph , Zhang Jun , Mesa Ruben A.
Published: March 2020

TPS7072

Background: Myelofibrosis (MF) is a serious life-threatening condition characterized by splenomegaly, constitutional symptoms, and shortened survival. Ruxolitinib (RUX) is currently the only approved drug for treatment (Tx) of Intermediate- (Int) or High-risk MF. RUX discontinuation rates are high, mainly due to lack of response, loss of efficacy, intolerance, and drug-induced cytopenias, resulting in an important unmet medical need for a JAK2 inhibitor that is effective after RUX failure. Fedratinib (FEDR) is an oral, JAK2-selective inhibitor that produces substantial spleen volume reduction (SVR) and improves constitutional symptoms as initial therapy of MF (Pardanani, 2015) and in pts resistant to or intolerant of RUX (Harrison, 2017). Methods: This multicenter, open-label, single-arm study (NCT03755518) is enrolling adult pts with primary, post-polycythemia vera, or post-essential thrombocythemia MF; Dynamic International Prognostic Scoring System (DIPSS) Int- or High-risk disease; splenomegaly; ECOG PS ≤2; and platelet counts ≥50 × 109/L. Pts must have received prior RUX Tx for ≥3 mo or during ≥28 days of RUX therapy were RUX-intolerant (developed RBC transfusion dependence [≥2 units/mo for 2 mo] or grade ≥3 thrombocytopenia, anemia, hematoma/hemorrhage). Pts receive continuous FEDR 400 mg QD in 28-day cycles. Spleen volume is assessed by MRI/CT scan at screening, after cycles 3, 6, and 12, and at end of treatment. Primary endpoint is spleen response rate (RR; ≥35% SVR from BL by cycle 6 end). Secondary endpoints include duration of spleen RR, spleen size reduction, rate and duration of symptom response (≥50% reduction in total symptom score on the Myelofibrosis Symptom Assessment Form), and safety. Risk mitigation strategies for gastrointestinal adverse events and Wernicke encephalopathy are evaluated. Exploratory endpoints include survival, patient-reported outcomes, and biomarkers of FEDR efficacy and biochemical activity. The study will enroll ~110 pts. Assuming a spleen RR of 35%, the study will have ~90% power to detect the lower bound of the 95% CI that excludes 20%. Enrollment is ongoing. Clinical trial information: NCT03755518.
ALINA: A phase III study of alectinib versus chemotherapy as adjuvant therapy in patients with stage IB–IIIA anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC).
Authors: Solomon Benjamin J. , Ahn Jin Seok , Barlesi Fabrice , Dziadziuszko Rafal , Nishio Makoto , Shaw Alice Tsang , Bordogna Walter , Meyenberg Christoph , Wu Yi-Long
Published: March 2020

TPS8569

Background: Patients with early-stage NSCLC (stage IA–IIIA) account for ~40% of cases at diagnosis; despite surgery, 5-year survival rates are low. Platinum-based adjuvant chemotherapy is the standard of care (SoC) for stage II–IIIA disease. Although patients with stage IA NSCLC do not benefit from adjuvant chemotherapy, patients with stage IB disease and large tumors (≥4cm) do. Adjuvant chemotherapy produces a 4–5% increase in 5-year survival rates, leaving significant unmet need for improved treatments. Approximately 5% of patients with NSCLC harbor an oncogenic fusion of the ALK gene. Treatment of advanced ALK+ NSCLC with ALK inhibitors improves efficacy and safety compared with chemotherapy. Alectinib, a potent ALK inhibitor, is the SoC first-line treatment for advanced ALK+ NSCLC. The ongoing ALINA trial will compare alectinib versus chemotherapy as adjuvant treatment for patients with stage IB–IIIA ALK+ NSCLC. Methods: ALINA is a randomized, multicenter, open-label phase III study investigating the efficacy and safety of adjuvant alectinib versus chemotherapy in ALK+ NSCLC (confirmed by an FDA-approved and CE-marked test). Adult patients (≥18 years) with completely resected stage IB (tumors ≥4cm) to IIIA disease and ECOG PS 0–1 are eligible for inclusion. Patients (N=255) from ~170 centers across ~30 countries will be randomized 1:1 to receive twice-daily alectinib 600mg for 24 months or four 21-day cycles of platinum-based chemotherapy (cisplatin 75mg/m2 [day 1] plus vinorelbine 25mg/m2 [days 1 and 8] or gemcitabine 1250mg/m2 [days 1 and 8] or pemetrexed 500mg/m2 [day 1]) according to local prescribing information. Stratification factors are disease stage (stage IB [≥4cm] vs stage II vs stage IIIA) and race (Asian vs non-Asian). Treatment will continue until planned completion, disease recurrence, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first. The primary endpoint is disease-free survival per investigator; secondary endpoints are overall survival, safety, and pharmacokinetics. Clinical trial information: NCT03456076.
Tislelizumab (BGB-A317) + concurrent chemoradiotherapy (cCRT) followed by tislelizumab monotherapy for newly diagnosed locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) in a phase III study (RATIONALE 001).
Authors: Paz-Ares Luis G. , Senan Suresh , Planchard David , Wang Luhua , Cheong Alicia , Nguyen Marie Huong , Slepetis Ruta , Vokes Everett E.
Published: March 2020

TPS8574

Background: cCRT improves survival vs RT alone and is a global standard of care in patients (pts) with stage III NSCLC, but survival remains poor for these pts. Combining PD-1/PD-L1-targeting immunotherapies and cCRT may lead to synergistic activity and improved outcomes. Tislelizumab (anti–PD-1) demonstrated clinical activity and tolerability in solid tumors, including NSCLC. This phase III, randomized, double-blind, placebo-controlled study (RATIONALE 001) will evaluate efficacy and safety of tislelizumab + cCRT. Methods: Pts (N ≈ 840) will be randomized 1:1:1 in a 3-arm study design to evaluate whether the timing of giving tislelizumab earlier upfront with cCRT in addition to as consolidation (Arm 1) or giving tislelizumab as consolidation only (Arm 2) will improve outcomes vs cCRT alone (Arm 3; Table). RT will be given in 2 Gy fractions to a target dose of 60 Gy (30 fractions). Chemotherapy will be investigator’s choice of cisplatin + etoposide or carboplatin + paclitaxel. A safety analysis specific to the cisplatin + etoposide component of the cCRT + tislelizumab combination is planned. All sites must pass a radiation quality assurance review process. The primary endpoint is PFS. Secondary endpoints include ORR, OS, OS at 24 months, and safety. As an exploratory endpoint, blood and tumor biomarkers will be assessed for correlations with clinical benefit. With a one-sided α of 1.25%, a total of 580 PFS events are required to allow ≈ 90% power to detect a HR for progression or death of 0.7 for either pairwise comparison (Arm 1 vs Arm 3 or Arm 2 vs Arm 3). Key eligibility criteria are locally advanced, unresectable, stage III NSCLC; FDG-PET and brain imaging confirmation of stage III status; no prior treatment; and ECOG PS ≤ 1. PD-L1 expression assessment is not required prior to randomization. EudraCT number 2018-001132-22. Clinical trial information: NCT03745222. [Table: see text]