bluuebunny/crossref_metadata_2025_split huggingface dataset:
A clinical trial simulation study of a new pediatric phase I trial methodology: The rolling six design
Authors: Skolnik J. , Jayaraman B. , Patel D. , O'Connor E. , Barrett J. S. , Adamson P. C. 
Published: March 2020

9564 Background: Phase I cancer trials have traditionally used the 3+3 study design in which cohorts of three patients at a time are enrolled. The study is suspended to accrual with every 3rd patient, and again suspended to replace inevaluable patients. As the pediatric phase I starting dose is based on adult phase I safety data, we hypothesized that pediatric study timelines could be shortened without increasing risk using a novel rolling six design, in which up to 6 patients are concurrently enrolled per dose level. Methods: A trial simulation approach comparing the standard 3+3 design to the rolling six design was performed. Discrete time events (accrual/enrollment, evaluation and/or time to dose limiting toxicity (DLT) or inevaluability) with outcome probabilities (DLT/inevaluability) assigned to each subject based on historical data from phase I pediatric oncology trials. The probability of DLT was a function of dose level and varied distributions were used to assign discrete time elements. Metrics for study efficiency (time to complete study, total number of patients required) were determined for each design. Simulated trials and decision rule logic were coded using PC/Windows SAS v9.1. Results: The rolling six design outperformed the 3+3 design for the most relevant metrics. Average (±SD) time to study completion was 373±90 days vs. 431±98 days and the total number of patients required was 20±5 vs. 17±4 for the rolling six vs. 3+3 designs, respectively. There was no difference in the number of DLTs per study (3±1) between designs. Conclusions: The rolling six design is predicted to shorten pediatric phase 1 study timelines and will be tested prospectively in upcoming COG phase I trials. No significant financial relationships to disclose.
Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study
Authors: Philip P. A. , Benedetti J. , Fenoglio-Preiser C. , Zalupski M. , Lenz H. , O'Reilly E. , Wong R. , Atkins J. , Abruzzese J. , Blanke C. 
Published: March 2020

LBA4509 Background: Epidermal growth factor receptor [EGFR] pathway is a rational target for therapeutic intervention. This study tested the efficacy of an anti-EGFR monoclonal antibody and gemcitabine [G] combination in the Phase III setting in patients with advanced PC. Methods: Eligibility included locally advanced unresectable or metastatic PC; adequacy of organ function; performance status (PS) 0- 2; no prior EGFR therapy; no prior systemic chemotherapy except for adjuvant chemotherapy; and submission of tumor for EGFR immunostaining. The primary endpoint was overall survival. Secondary endpoints included objective response, time to progression, pain control, and quality of life. Assuming 6 months median survival, the study was designed to detect a median improvement to 8 months (1.33 hazard ratio) with 90% power, based on a one-sided 0.0125 test, and 704 eligible patients. Primary analyses used a Cox regression model, stratified for factors used in the randomization. Patients were stratified by PS, stageand prior pancreatectomy, and randomized to either G alone or G plus C. G was given at a dose of 1,000 mg/m2/wk for seven weeks out of 8, then 3 weeks on and one week off. C was given as a loading dose of 400 mg/m2 on week 1 and then 250 mg/m2 weekly. Results: 766 pts (735 eligible) with a median age of 64 (30–91) were enrolled by SWOG and CTSU between January 2004 and April 2006. Of those, 51% were males, 21.5% had locally advanced disease, and 13% had PS of 2. The study closed with full accrual. The median survival was 6 months in the G arm and 6.5 months in the G plus C arm for an overall HR of 1.09 (95% CI 0.93–1.27, p= 0.14) . The corresponding PFS was 3 months and 3.5 months, for G and G+C arms, respectively (HR =1.13, 95%CI .97–1.3, p=.058). The confirmed response probabilities were 7 % in each arm, and inclusion of unconfirmed responses yielded 14% in the G arm and 12% in the G + C arm.702 pts were evaluable for toxicity. 90 pts experienced at least one grade 4 toxicity; 14% on the G plus C, 11% on G alone. Conclusions: This study failed to demonstrate a clinically significant advantage of the addition of cetuximab to gemcitabine for overall survival, PFS and response in advanced PC. No significant financial relationships to disclose.
Single agent, canfosfamide (C, TLK286) vs pegylated liposomal doxorubicin (D) or topotecan (T) in 3rd-line treatment of platinum (P) refractory or resistant ovarian cancer (OC): Phase 3 study results
Authors: Vergote I. , Finkler N. , del Campo J. , Lohr A. , Hunter J. , Matei D. , Spriggs D. , Kavanagh J. , Vermorken J. , Brown G. L. , Kaye S. 
Published: March 2020

LBA5528 Background: Canfosfamide (C) is a novel glutathione analog prodrug activated by glutathione S-transferase P1–1. P resistant OC has a poor prognosis and non-P agents are used for palliation. C reported objective responses in multicenter Phase 2 OC trials. Methods: Pts with P resistant OC who progressed after D or T, measurable disease (RECIST), adequate liver/renal/bone marrow function were eligible. Randomization was stratified by prior D or T treatment, ECOG PS (0 or 1 vs 2) and presence or absence of bulky disease (= 5cm). Patients received C at 1000 mg/m2 IV q3wks, or to D at 50 mg/m2 IV q4wks or T at 1.5 mg/m2 IV daily × 5 q3wks until progression. The trial had a 90% power to detect a 29% reduction in the relative risk of death. Results: 461 pts (C=232 and D or T=229) received 1052 cycles [median 3; range (r) 1–33], 699 (median 4; r 1–32), and 469 (median 5; r 1–21) for C, D and T respectively. Most common Grade 3–4 AEs for C were: nausea (31.6%), vomiting (8.7%), fatigue (6.1%), and anemia (5.6%), for D/T were: nausea (55.3%), anemia (15.2%), fatigue (6.9%), neutropenia (23.5%), thrombocytopenia (12.4%), febrile neutropenia (6%), stomatitis (6%), and PPE syndrome (6%). ORR for C was 4.3% including a CR, vs 10.9% ORR for D/T. Median survival (MS) was 8.5 mos for C, 13.6 mos for D/T (p=0.0001). Median progression-free survival was 2.3 mos for C and 4.4 mos for D/T, (p=0.0001). D/T MS was 14.2/10.8 mos, respectively. Conclusions: Canfosfamide did not meet the primary endpoint. C demonstrated single agent activity in P refractory or resistant OC and was well tolerated. C in combination with standard agents in less heavily treated OC trials are in progress. No significant financial relationships to disclose.
Results of a randomized phase III study to compare the overall survival of gefitinib (IRESSA) versus docetaxel in Japanese patients with non-small cell lung cancer who failed one or two chemotherapy regimens
Authors: Niho S. , Ichinose Y. , Tamura T. , Yamamoto N. , Tsuboi M. , Nakagawa K. , Shinkai T. , Jiang H. , Nishiwaki Y. , Fukuoka M. 
Published: March 2020

LBA7509 Background: This phase III study (V-15–32) compared gefitinib vs docetaxel on overall survival (OS) in Japanese patients (pts) with pretreated advanced NSCLC. Methods: Pts with advanced or metastatic (Stage IIIb or IV) NSCLC who failed 1 or 2 chemotherapy regimens were randomized to gefitinib (250 mg/day) or docetaxel (60 mg/m2 every 3 weeks). Non-inferiority of the primary endpoint, OS, was assessed by the confidence interval (CI) of the hazard ratio (HR; gefitinib/docetaxel) derived from an unadjusted Cox proportional hazard model. Results: 489 eligible pts were recruited. Non-inferiority in OS was not achieved (HR 1.12; 95.24% CI 0.89, 1.40) according to predefined criterion (upper CI limit for HR <1.25); however, no significant difference in OS (p=0.330) or PFS (p=0.335) was apparent between treatments. Post study, 36% of gefitinib-treated pts received subsequent docetaxel and 40% received no other therapy apart from gefitinib; 53% of docetaxel-treated pts received subsequent gefitinib and 26% received no other therapy apart from docetaxel. Gefitinib significantly improved ORR (22.5% vs 12.8%; p=0.009), TTF (HR 0.63; 95% CI 0.51, 0.77; p<0.001), and QoL (FACT-L trial outcome index 20.5% vs 8.7%; p=0.002; FACT-L 23.4% vs 13.9%; p=0.023), vs docetaxel. Additional subgroup analyses will be presented. Grade 3/4 AEs occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of pts. Incidence of interstitial lung disease (ILD) was 5.7% (n=14) and 2.9% (n=7), respectively. There were 4 deaths due to AEs in the gefitinib arm (3 possibly treatment-related due to ILD; 1 due to pneumonia that was not considered treatment-related) and none in the docetaxel arm. Conclusions: Whilst non-inferiority in OS between gefitinib and docetaxel was not demonstrated according to predefined criteria, there was no statistically significant difference in survival between the two arms. Secondary endpoints largely unaffected by subsequent therapy provide further evidence of clinical efficacy of gefitinib in these pts. AEs were consistent with those previously observed for both treatments. [Table: see text]
Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704
Authors: Manegold C. , von Pawel J. , Zatloukal P. , Ramlau R. , Gorbounova V. , Hirsch V. , Leighl N. , Mezger J. , Archer V. , Reck M. 
Published: March 2020

LBA7514 Background: The ECOG 4599 phase III trial demonstrated that the addition of bevacizumab (B) to carboplatin/paclitaxel improved overall and progression-free survival (PFS) in patients (pts) with advanced NSCLC [Sandler et al. NEJM 2006]. Cisplatin/gemcitabine (CG) is a common combination in regions outside of the US. Methods: This randomised, placebo-controlled phase III study compared two doses of B plus CG versus CG plus placebo. The primary endpoint was PFS; secondary endpoints include overall survival, response rate (RR) and safety. Eligibility criteria: histologically or cytologically documented previously untreated advanced or recurrent non- squamous NSCLC; ECOG PS 0–1; no brain metastases. Between 2/05 and 8/06 1,043 pts were randomised to: C 80mg/m2 on d1 and G 1,250mg/m2 on d1 and d8 every 3 wks for up to 6 cycles plus B continued to progression at 7.5mg/kg every 3 wks, or 15mg/kg every 3 wks or placebo. The study was designed to include the number of patients required to observe a 30% reduction in the risk of a PFS event in the B arms compared with control using a two-sided logrank test (a=2.5%) with 80% power. Results: PFS was significantly prolonged as analysed both in a primary analysis (without censoring for non-protocol anti-neoplastic therapy [NPT] prior to progression) and in a prespecified analysis with censoring for NPT. The RR and response duration were also increased. Overall survival is immature due to short duration of follow up. Conclusions: Both doses of B significantly improved PFS and RR, consistent with the results of the earlier phase III trial E4599. No unexpected safety signals were detected. [Table: see text] [Table: see text]
Ten-year results of a German Hodgkin Study Group randomized trial of standard and increased dose BEACOPP chemotherapy for advanced Hodgkin lymphoma (HD9)
Authors: Diehl V. , Franklin J. , Pfistner B. , Engert A. 
Published: March 2020

LBA8015 Background: The HD9 trial was designed to compare standard and dose escalated versions of a novel chemotherapy BEACOPP in advanced Hodgkin lymphoma. The previous analysis in 2004 showed improved tumor control and overall survival due to dose escalation. The present 10 year analysis in March 2007 aimed to update and confirm these results and to monitor late effects. Methods: Patients aged 16–65 years with untreated Hodgkin lymphoma stage IIB/IIIA and risk factors or stage IIIB/IV were randomized to (A) 4 double cycles COPP/ABVD, (B) 8 cycles standard-dose BEACOPP or (C) 8 cycles increased-dose BEACOPP (doxorubicin, cyclophosphamide and etoposide at 140%, 192% and 200% of standard doses, respectively), each followed by irradiation of initial bulky and residual disease. Accrual of at least 900 patients was planned so as to detect a 9–10% improvement in the primary endpoint, freedom from treatment failure (FFTF), with a power of 80% (alpha=5%). Results: 1196 of 1201 eligible, randomized patients were evaluable (261, 469 and 466 in arms A, B and C, respectively). Median follow-up times were 122, 111 and 107 months in arms A, B and C respectively (29–32 months longer than in 2004). Corresponding 10-year FFTF rates were 64%, 70% and 82% respectively (p<0.0001). FFTF was significantly better in the increased-dose arm than in the standard-dose arm (p<0.0001). 10-year overall survival rates were 75%, 80% and 86% respectively (p=0.0005). Overall survival was also significantly better in the increased-dose arm than in the standard-dose arm (p=0.0053). Death due to HL was 11.5%, 8.1% and 2.8% in arms A, B and C respectively. 74 second malignancies were documented: 1, 7 and 14 acute myeloid leukemias (AML); 7, 8 and 5 non-Hodgkin lymphomas; 7, 16 and 9 solid tumors/others in arms A, B and C respectively. The corresponding overall secondary malignancy rates were 6.7% , 8.9% and 6.8%. Conclusions: Even after 10 years, dose escalation of BEACOPP chemotherapy results in a stabilized significant improvement in long-term FFTF and OS rates. The risk of secondary AML, although increased in this study after increased-dose BEACOPP, amounts to 0.9% in the succeeding study with increased BEACOPP with 1502 patients and 4 years median follow-up. No significant financial relationships to disclose.
Pexidartinib for advanced tenosynovial giant cell tumor (TGCT): Long-term efficacy and safety from the phase 3 ENLIVEN and phase 1 PLX108-01 (TGCT cohort) studies.
Authors: Gelderblom Hans , Tap William D. , Palmerini Emanuela , Stacchiotti Silvia , Wainberg Zev A. , Desai Jayesh , Healey John H. , van de Sande Michiel , Bernthal Nicholas M. , Peterfy Charles , Shuster Dale Edward , Wang Qiang , Hsu Henry , Wagner Andrew J. 
Published: March 2020

11042 Background: TGCT is a rare, locally aggressive neoplasm of the joint/tendon sheath linked to colony-stimulating factor 1 (CSF1) overexpression. Pexidartinib (pex), a selective inhibitor of CSF1 receptor, KIT, and FLT3-ITD, had a compelling tumor response rate in the TGCT cohort of a phase 1 study (NCT01004861) and significant tumor response vs placebo by RECIST v1.1 (39% vs 0%, P< 0.0001) and tumor volume score (TVS) (56% vs 0%, P< 0.0001) in the randomized, 2-part, crossover phase 3 ENLIVEN study (NCT02371369). Updated efficacy and safety with longer treatment are reported. Methods: Patients (pts) were ≥18 y with TGCT that was inoperable or for which surgery would likely be associated with worsening functional limitation or severe morbidity. Best overall response (complete or partial [CR/PR]) and duration of response (DOR) by RECIST and TVS were assessed by independent central review. Data cutoff was Jan 31, 2018, 16-67 mo after pts’ first dose. Results: In both studies 130 pts received pex, 61 ongoing at data cutoff. Median treatment duration was 17 mo (1, 60+). CR/PR rates were high and consistent and, together with DOR, improved with prolongation of treatment (Table). Most frequent adverse events were hair color change (75%), fatigue (60%), nausea (45%), arthralgia (38%), AST increase (30%), and diarrhea (30%). In ENLIVEN part 1, 3 of 61 (5%) pts had reversible ALT and AST ≥3 × ULN with TBil and ALP ≥2 × ULN; all started in the first 8 weeks of treatment, and no new cases emerged with continuation of treatment. Conclusions: Tumor response rate increased with continuation of pex treatment. The safety profile remained similar, with no new mixed or cholestatic hepatotoxicity. Clinical trial information: NCT01004861 and NCT02371369. [Table: see text]
A phase II study of epacadostat and pembrolizumab in patients with advanced sarcoma.
Authors: Kelly Ciara Marie , Chi Ping , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Qin Li-Xuan , Adamson Travis , Condy Mercedes M. , Biniakewitz Matthew , Phelan Haley , Singer Samuel , Crago Aimee Marie , Yoon Sam S. , Ariyan Charlotte Eielson , Hwang Sinchun , Erinjeri Joseph Patrick , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P. 
Published: March 2020

11049 Background: Tumors express IDO1, an intracellular enzyme involved in the degradation of tryptophan to kynurenine, in order to evade immunosurveillance. Epacadostat inhibits IDO1 and shifts the tumor microenvironment from an immunosuppressive state to an immune-stimulated state. Pembrolizumab previously demonstrated activity in select sarcoma subtypes. We performed an open-label, single-center, phase II study of epacadostat and pembrolizumab in patients with advanced sarcoma. Methods: Patients received the recommended phase II dose of oral epacadostat (100mg) twice per day and intravenous pembrolizumab (200mg/dose) every 3 weeks. The primary endpoint was best objective response rate (ORR) (complete response and partial response [PR]) at 24 weeks by RECIST 1.1. Secondary endpoints included adverse events (AEs), ORR by irRECIST, progression free survival (PFS) and overall survival (OS). Correlative studies performed on pre/on-treatment biopsy specimens included PD-L1, IDO1, and kynurenine expression and characterization of tumor infiltrating lymphocytes by IHC, whole exome and RNA sequencing. Results: Twenty-nine patients were enrolled [median age 53 years (range, 24-78), 57% male, ECOG PS 0 83%]. Histological subtypes included leiomyosarcoma (17%), UPS (17%), myxofibrosarcoma (7%), liposarcoma (10.5%), EHE (10.5%), angiosarcoma (3%), “other” sarcoma subtype (35%). Patients were refractory to 0 (21%), 1 (38%), 2 (24%) and ≥ 3 (17%) prior lines of therapy. The most common ( > 20% of pts) grade (G)1 or 2 treatment related AEs (TRAEs) observed included fatigue (31%), rash (31%) and ALT elevation (24%). G3 TRAEs included AST elevation (10%), ALT elevation, anemia, hypophosphatemia and increased lipase each occurred in 3% of pts. Three patients discontinued therapy due to G3 immune mediated hepatitis. Among the 29 evaluable patients 1 (3%) confirmed PR (leiomyosarcoma), 13 stable diseases (45%) and 15 progressions (52%) were observed by RECIST 1.1. The median PFS was 8.0 weeks (two-sided 95% CI: 6.9 ~ 26.7) and the PFS rate at 24 weeks was 27.9% (two-sided 95% CI: 15.0% ~ 52.2%). The median OS was not estimable (two-sided 95% CI: 40.9 weeks ~ NE). The OS at 24 weeks was 85.2% (95% CI: 72.8%, 99.7%). Conclusions: Epacadostat in combination with pembrolizumab was generally well tolerated. Limited anti-tumor activity was observed among advanced sarcoma patients. Correlative analyses including determination of adequacy of IDO1 inhibition will be reported. Clinical trial information: NCT03414229.
Impact of cancer on physical and mental activities of daily living in young adult (YA) survivors.
Authors: Ketterl Tyler Garrett , McCabe Mary S. , Rosenstein Donald L. , Jacobs Linda A. , Palmer Steven C , Ganz Patricia A. , Casillas Jacqueline N. , Risendal Betsy C , Overholser Linda , Partridge Ann H. , Syrjala Karen L , Baker Kevin Scott 
Published: March 2020

11517 Background: Young Adult (YA) survivors face challenges unique from those survivors of childhood cancer or of middle and older age adults. The potential impact of cancer, its treatment or the lasting effects on daily mental and physical tasks are not fully understood. Methods: Eligibility included diagnosis of malignancy between ages 18-39, 1-5 years from diagnosis and ≥1 year from therapy completion. Participants were randomly selected from tumor registries of 7 academic institutions. Enrolled participants were asked to complete an online patient reported outcomes (PRO) survey related to the effects of cancer and its treatment on daily functionality, finances, and cancer-related distress. All enrolled subjects had diagnostic and treatment information abstracted by a standardized protocol and entered into a database. Results: Enrollment and the online PRO survey was completed by 872 survivors (43.5% of eligible survivors). Survivors were 72.3% female, 90% non-Hispanic or Latino and the most common cancer for males and females were testicular and breast cancer respectively. Cancer, its treatment or the lasting effects limited the kind or amount of instrumental activities of daily living (IADLs) in 649 (76.3%) of survivors. Exposure to chemotherapy was associated with a 3.2-fold increased odds of interference with IADLs (CI 2.08-4.83, p < 0.01) after controlling for diagnosis, age, gender, radiation and surgery exposure. This impairment lasted longer than 1 year in 268 (41.3%) of survivors. Cancer, its treatment or the lasting effects interfered with their ability to perform any mental tasks as part of their IADLs in 454 (53.3%) of survivors. Exposure to chemotherapy was associated with a 2.8-fold increased odds of interference with mental impairment of IADLs (CI 1.94-3.96, p < 0.01) after controlling for diagnosis, age, gender, radiation and surgery exposure. Exposure to radiation was also associated with an increased odds of interference with mental impairment of daily activities (CI 1.05-1.91, p < 0.01) after controlling for diagnosis, age, gender, chemotherapy and surgery exposure. Conclusions: In YA cancer survivors, cancer, its treatment or the lasting effects of treatment commonly impact the daily physical and mental IADLs and many survivors report ongoing limitations > 1 year from therapy completion.