bluuebunny/crossref_metadata_2025 huggingface dataset:
WJOG6110B (ELTOP): Randomized phase II trial comparing trastuzumab plus capecitabine (HX) and lapatinib plus capecitabine (LX) in HER2-positive metastatic breast cancer patients previously treated with trastuzumab and taxanes.
Authors: Takano Toshimi , Kimura Hideharu , Nishio Kazuto , Yamanaka Takeharu , Ito Yoshinori , Fukuoka Junya , Tsurutani Junji , Shigeoka Yasushi , Uehara Masahiro , Sato Kazuhiko , Nakamura Shinichiro , Nakanishi Yoichi , Saeki Toshiaki ,   West Japan Oncology Group
Published: March 2020

TPS659

Background: In patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab and taxanes, there are now two standard strategies: trastuzumab beyond progression or switch to lapatinib. A randomized trial comparing trastuzumab plus capecitabine (HX) and capecitabine alone (X) after first-line trastuzumab-based chemotherapy (GBG-26) showed that HX was superior to X in terms of time to progression (TTP). Another randomized trial comparing lapatinib plus capecitabine (LX) and X in patients previously treated with anthracyclines, taxanes, and trastuzumab (EGF100151) showed that LX was superior to X in terms of TTP. To evaluate which strategy is better, we are conducting an open-label, randomized phase II trial comparing HX and LX. Methods: Primary endpoint is progression-free survival, and secondary endpoints are overall response rate, overall survival, proportion of patients progressing brain metastases as site of first progression, and safety. Major eligibility criteria include: (1) HER2-positive MBC, (2) previously treated with taxanes, (3) disease progression or distant relapse while receiving trastuzumab, (4) previously untreated with capecitabine, S-1, and anti-HER2 drugs other than trastuzumab, (5) previously treated with no more than two chemotherapy regimens for MBC, (6) no symptomatic brain metastases (asymptomatic brain metastases are allowed), and (7) baseline left ventricular ejection fraction ≥50%. Patients in the HX arm receive capecitabine 2,500 mg/m2/day on days 1 to 14 plus trastuzumab (8 mg/kg loading dose and 6mg/kg thereafter) on day 1 every 3 weeks. Patients in the LX arm receive capecitabine 2,000 mg/m2/day on days 1 to 14 plus lapatinib 1250 mg/day on days 1 to 21 every 3weeks. Large-scale biomarker analyses are also performed to explore predictive factors of trastuzumab or lapatinib efficacy. We are investigating biomarkers related to HER family and other receptors, PI3K/Akt pathways, ligands, FcγR, circulating tumor cells, and so on. This study has just begun and 7 of planned 170 patients have been enrolled.
MDV3100-08: A phase I open-label, dose-escalation study evaluating the safety, tolerability, and pharmacokinetics of MDV3100 in women with incurable breast cancer.
Authors: Elias Anthony D. , Richer Jennifer K. , LoRusso Patricia , Peterson Amy C. , Steinberg Joyce Leta , Mordenti Joyce , Lopez Christian , Hudis Clifford , Traina Tiffany A.
Published: March 2020

TPS668

Background: MDV3100 is a novel, orally administered small molecule that directly binds the androgen receptor (AR) to potently inhibit AR-mediated signaling via three mechanisms: inhibition of androgen binding to AR; inhibition of AR nuclear translocation; and inhibition of nuclear AR association with DNA. MDV3100 is not known to agonize AR signaling, can be taken without prednisone, and demonstrated an overall survival benefit in post-docetaxel prostate cancer at 160 mg/day. AR expression is observed in ~70% of all breast cancer (BCa) regardless of histologic subtypes (estrogen receptor [ER] positive, HER2+, and triple negative [TN] disease). MDV3100 has demonstrated preclinical activity in AR+/TN and AR+/ ER+ BCa and could be a potential therapeutic strategy in patients with AR+ BCa. Methods: This Phase 1 study has 2 stages: a standard 3+3 dose-escalation stage (S1), evaluating safety, tolerability, and pharmacokinetics (PK) of MDV3100, starting at 80 mg MDV3100; and a dose-expansion stage (S2), evaluating the recommended Phase 2 dose in ~15 women with AR+ BCa. All patients must have received ≥2 chemotherapy-containing regimens for their incurable BCa, or ≥3 anti-HER2 containing regimens for their incurable HER2+ BCa to be eligible; ER+ patients must be post-menopausal. In S1, patients will receive their assigned dose of MDV3100 on Day 1, and PK samples will be collected through Day 8. Daily dosing will begin on Day 8 and will continue until predefined discontinuation criterion is met. Dose-limiting toxicities will be recorded through Day 35 and used to determine the Phase 2 dose. Extensive PK sampling is performed on Days 1 and 50 with predose PK samples collected throughout. In S2, patients with AR+ BCa (defined as 10% or more tumor cells with nuclear AR expression) will take daily MDV3100 at the recommended Phase 2 dose; there is no single dose PK period. Tumor tissue submission is mandatory in S2. Safety and tolerability will be documented by frequent assessments of adverse events, vital signs, and laboratory assessments. Tumor assessments occur at 2 months then approximately every 3 months thereafter. Enrollment of 27 subjects is anticipated.
Aromatase inhibitors, arthralgias, and exercise in breast cancer survivors.
Authors: Irwin Melinda , Cartmel Brenda , Ercolano Elizabeth , Fiellin Martha , Rothbard Marianna , Capozza Scott , Zhou Yang , Schmitz Kathryn , Ligibel Jennifer A. , Hershman Dawn L. , Neogi Tuhina , Gross Cary P.
Published: March 2020

TPS669

Background: A substantial number of breast cancer survivors who are taking aromatase inhibitors (AIs) complain of side effects including arthralgias. Given the efficacy of AIs, it is essential that we identify approaches to mitigate arthralgias. We are conducting an NCI-funded trial is to examine the impact of a year-long exercise intervention in 180 breast cancer survivors taking an AI and experiencing at least mild arthralgias. Outcomes include severity of arthralgias, endocrine-related quality of life, % body fat, bone mass, and serum markers of inflammation. The purpose of this abstract is to present preliminary recruitment and adherence results. Methods: Women are being recruited via the Connecticut Tumor Registry and Rapid Case Ascertainment Shared Resource of Yale Cancer Center into the Hormones and Physical Exercise (HOPE) Study. Participants are randomly assigned to exercise (n = 90) or usual care (n = 90). The exercise intervention includes supervised resistance and unsupervised aerobic exercise sessions over 12 months. Data are collected at baseline, 3-, 6-, 9 and 12-months. Results: Study recruitment began in April 2010 and will continue through December 2012. As of January 1, 2012, we have received 1605 names of potentially eligible women. Of these 1605, 777 women are waiting to be screened (e.g., letter mailed to patient or on hold because recently diagnosed), 244 women could not be screened (e.g., unable to contact by phone), and 584 women have completed a telephone screening. Of the 584 women screened, 24% were ineligible because of discontinuing AIs because of arthralgias or chose not to take AIs primarily because of this potential side effect; another 36% were ineligible for various reasons; 24% were not interested; 11% were randomized (n = 65 women); and 5% are undergoing baseline visits (n = 29). On average, women are 62 yrs old and have been taking an AI for 1.8 yrs. Twenty-three women have completed the trial, with high exercise adherence rates (attendance to supervised sessions = 82% ). Conclusions: A growing number of women are choosing to not take AIs or are discontinuing AIs because of side effects. Our study may prove beneficial for the growing number of women diagnosed with hormone receptor-positive breast cancer each year.
Postoperative follow-up of lung cancer: Randomized trial comparing two follow-up programs in completely resected non-small cell lung cancer (IFCT-0302).
Authors: Westeel Virginie , Barlesi Fabrice , Domas Jean , Girard Philippe , Foucher Pascal , Lafitte Jean-Jacques , Dumont Patrick , Wislez Marie , Quoix Elisabeth A. , Braun Denis , Lebitasy Marie Paule , Hermann Jacques , Derollez Marc , Ozenne Gervais , Raffy Olivier , Devin Etienne , Barbieux Hubert , Tredaniel Jean , Morin Franck , Debieuvre Didier ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

TPS7111

Background: There are no robust data published on the follow-up after surgery for non-small cell lung cancer (NSCLC). Current international guidelines are informed by expert opinion. Most of them recommend regular follow-up with clinic visit and thoracic imaging, either chest X-ray of Chest CT-scan. The IFCT-0302 trial addresses the question whether a surveillance program with chest CT-scan and fiberoptic bronchoscopy can improve survival compared to a follow-up only based on physical examination and chest x-ray. There is no such trial ongoing over the world. Methods: The IFCT-0302 trial is a multicenter open-label controlled randomized phase III trial. The objective of the trial is to compare two follow-up programs after surgery for stage I-IIIa NSCLC. The primary endpoint is overall survival. Patients are randomly assigned to arm 1, minimal follow-up, including physical examination and chest x-ray; or arm 2, a follow-up consisting of physical examination and chest x-ray plus chest CT scan and fiberoptic bronchoscopy (optional for adenocarcinomas). In both arms, follow-up procedures are performed every 6 months during the first two postoperative years, and every year between the third and the fifth years. The main eligibility criteria include: completely resected stage I-IIIA (6th UICC TNM classification) or T4 (in case of nodules in the same lobe as the tumor) N0 M0 NSCLC, surgery within the previous 8 weeks. Patients who have received and/or who will receive pre/post-operative chemotherapy and/or radiotherapy are eligible. Statistical considerations: 1,744 patients is required. Accrual status: 1,568 patients from 119 French centers had been included. The end of accrual can be expected for September 2012. Ancillary study: Blood samples are collected in 1000 patients for genomic high density SNP micro-array analysis. This collection will contribute to the French genome wide association study (gwas) of lung cancer gene susceptibility, and the genetic factors predictive of survival and lung cancer recurrence will be analyzed.
AvaALL: Open-label randomized phase IIIb trial evaluating the efficacy and safety of standard of care with or without continuous bevacizumab (BV) treatment beyond disease progression in patients (pts) with advanced nonsquamous non-small cell lung cancer (NSCLC) after first-line (1L) treatment with BV plus platinum-doublet chemotherapy (CT).
Authors: Gridelli Cesare , Bennouna Jaafar , De Castro Javier , Dingemans Anne-Marie C. , Griesinger Frank , Grossi Francesco , Thatcher Nick , Ohe Yuichiro , Perez-Moreno Pablo Diego , Langer Corey J.
Published: March 2020

TPS7612

Background: Pts with NSCLC have a poor prognosis upon progression following 1L CT. Although the disease may have progressed on 1L CT, it is likely still dependent on VEGF-mediated pathways. Thus, persistent VEGF suppression along with second- and third-line cytotoxic regimens may yield clinical benefit. Analyses have associated this strategy with improved survival in NSCLC (Nadler et al, Oncologist 2011) and mCRC (Grothey et al JCO 2008). Methods: AvaALL (MO22097; NCT01351415), a multicenter (144 centers, 20 countries) open-label randomized (1:1) 2-arm phase IIIb study, recruits pts with advanced non-squamous NSCLC that has progressed after 1L treatment with BV plus a platinum-doublet and at least 2 cycles of BV maintenance monotherapy. Pts in the experimental arm receive BV at the same dose from induction (7.5 or 15 mg/kg IV on D1 of every 21-day cycle) continuously along subsequent lines, plus investigator’s choice of second-line agent (limited to pemetrexed, docetaxel, or erlotinib) and subsequent lines of treatment. Pts in the control arm receive investigator’s choice of agent alone in second and subsequent lines of treatment, but no further BV treatment. Stratifications include nature of second-line standard treatment, number of cycles of BV maintenance (≤6 vs. >6) and smoking status. The primary endpoint is overall survival (OS). Secondary endpoints include 6-, 12-, and 18-month OS rates, progression-free survival, time to progression at second and third progressive disease (PD), response rate, disease control rate, duration of response at second and third PD, and safety of BV across multiple lines of treatment. Exploratory objectives include quality of life assessment through multiple treatment lines, and biomarker analysis. Assuming a median OS beyond PD of 7.9 months in the control group and 10.1 months in the treatment arm (HR 0.78), 528 events are required to achieve 80% power for the log-rank test at a 2-sided significance level of 5%. Enrollment began in June 2011.
The MetLUNG study: A randomized, double-blind, phase III study of onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in patients with advanced, MET-positive non-small cell lung cancer (NSCLC).
Authors: Spigel David R. , Edelman Martin J. , Mok Tony , O'Byrne Kenneth John , Paz-Ares Luis , Yu Wei , Rittweger Karen , Thurm Holger C. ,   on behalf of the MetLUNG Phase III Study Group
Published: March 2020

TPS7616

Background: Increased Met signaling is associated with poor prognosis in NSCLC and can result in acquired resistance to epidermal growth factor receptor (EGFR)-targeted drugs in EGFR-mutant lung tumors. Onartuzumab (MetMAb) is a humanized monovalent monoclonal antibody that binds to Met with high specificity, preventing HGF ligand binding and blocking downstream signaling. Onartuzumab has shown anticancer activity in preclinical studies (Merchant et al. AACR 2008:Abstr. 1336) and in a phase I study of patients with advanced solid tumors (Moss et al. Ann Oncol 2010;21(Suppl. 8):Abstr. 504P). In a phase II study, patients with Met-positive tumors (≥50% of tumor cells stain 2+ or 3+ intensity by IHC) (Met Dx+) who received onartuzumab + erlotinib had nearly twofold reduction in the risk of disease progression and threefold reduction in the risk of death compared with erlotinib alone (Spigel et al. J Clin Oncol 2011;29(Suppl.):Abstr. 7505). An increased incidence of peripheral edema was observed in patients treated with onartuzumab. Methods: This is a randomized, phase III, multicenter, double-blind, placebo-controlled study. Adults with Met Dx+ tumors who failed at least 1 but no more than 2 prior lines of platinum-based chemotherapy for advanced NSCLC are eligible. Around 480 patients will receive (1:1) erlotinib (150 mg PO daily) + placebo or onartuzumab (15 mg/kg IV Q3W) until disease progression, unacceptable toxicity, patient/physician decision to discontinue, or death. Patients are stratified for Met expression (2+ vs 3+), prior lines of therapy (1 vs 2), histology (squamous vs nonsquamous) and EGFR-activating mutation status (yes vs no). The primary endpoint is OS. Secondary endpoints include PFS, response rates, safety, patient-reported outcomes, and PK. An IDMC will monitor safety every 6 months after the 1st patient is enrolled and evaluate 1 interim analysis when ~67% of the total OS events have occurred. This study is open for accrual; further details can be found on ClinicalTrials.gov (NCT01456325).
Pilot study of MAGE-A3 protein vaccination and autologous stem cell transplantation (autoSCT) as consolidation therapy for multiple myeloma (MM).
Authors: Cohen Adam D. , Lendvai Nikoletta , Gnjatic Sacha , Jungbluth Achim A , Pan Linda S. , Bertolini Stephane V. , Venhaus Ralph Rudolph , Fellague-Chebra Rafik , Gruselle Olivier , Cho Hearn J.
Published: March 2020

TPS8111

Background: MAGE-A3 is a cancer-testis antigen (CT Ag) commonly expressed in MM but not in normal non-gonadal tissues. MAGE-A3 inhibited p53-dependent and independent apoptosis in MM cells (Clin Cancer Res 2011;17:4309), and spontaneous immunity against CT Ags in MM patients was associated with favorable clinical outcomes (Blood 2007;109:1103; Blood 2008;112:3362), making it a rational target for immunotherapy. In this study (NCT01380145), we are examining if a recombinant (rec) MAGE-A3 protein vaccine + adjuvant combined with vaccine-primed peripheral blood lymphocytes (PBL) can safely stimulate antigen-specific immunity in MM patients undergoing autoSCT for consolidation therapy. Methods: Patients meeting the following criteria are eligible: within 12 months of diagnosis; MAGE-A+ MM cells by immunohistochemistry; achieving at least a very good partial response with induction therapy; and meeting institutional criteria for autoSCT. One patient of a planned cohort of sixteen has been enrolled. Six weeks before SCT, subjects will receive their first vaccination (300 μg IM) and three weeks later undergo leukopheresis to collect vaccine-primed PBL. They then undergo stem cell mobilization followed by a standard melphalan-conditioned autoSCT. On day 3 after stem cell infusion, the unmanipulated, primed PBL will be re-infused followed by the second recMAGE-A3 vaccination on day 10. An additional six vaccinations will be administered on days 31, 52, 73, 94, 180, and 270 after autoSCT. The primary objectives are safety and tolerability. The secondary objectives of cellular and humoral immune responses and lymphocyte reconstitution will be assessed by a validated series of quantitative assays using established response criteria (PNAS 2008;105:1650). Success criteria based on immune response have not been specified for this pilot study, though induction of MAGE-A3 immunity in at least 50% of patients would merit consideration for further evaluation of clinical efficacy.
Phase I/II open-label, multiple-dose, dose-escalation study to evaluate the safety and tolerability of SNS01T administered by intravenous infusion in patients with relapsed or refractory multiple myeloma.
Authors: Lust John Anthony , Barranco Charles , Lacy Martha , Dispenzieri Angela , Gertz Morie A. , Dingli David , Russell Stephen J. , Buadi Francis , Zeldenrust Steven R. , Hayman Suzanne R. , Rajkumar S. Vincent , Kumar Shaji , Usmani Saad Zafar , Thompson John , Taylor Catherine , Dondero Richard
Published: March 2020

TPS8116

Background: Eukaryotic translation initiation Factor 5A (eIF5A) has been implicated in the regulation of apoptosis and is the only known protein to be modified by hypusination. Hypusinated eIF5A is the predominant form of eIF5A in cancer cells. However, in its unhypusinated form, eIF5A is pro-apoptotic. SNS01-T, designed to treat myeloma, consists of two components: a plasmid DNA expressing eIF5AK50R (human eIF5A containing a lysine to arginine substitution at position 50) which remains pro-apoptotic because it cannot be hypusinated, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced delivery to tissues. The eIF5AK50R transgene is under the control of the B29 promoter and enhancer, which restricts expression to B cells. The mode of action of SNS01-T is to use an eIF5A-specific siRNA to deplete the pool of hypusinated eIF5A in myeloma cells while simultaneously adding pro-apoptotic eIF5AK50R. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. Methods: Eligible patients are enrolled sequentially into four cohorts of increasingly higher doses. Each cohort will receive SNS01-T by intravenous infusion twice weekly for 6 consecutive weeks and then be observed every 4 weeks during a 24-week follow-up period. Eligible patients must have been diagnosed with multiple myeloma according to IMWG criteria, have measurable disease, have relapsed disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple escalating doses of SNS01-T. Secondary objectives include pharmacokinetics, immunogenicity studies, proinflammatory cytokine quantitation, and therapeutic efficacy. Two of the planned 15 patients have been enrolled. (Clinical Trials.gov Identifier: NCT01435720.)
Prospective and working memory decline as a result of impaired sleep and/or impared blood glucose in breast cancer patients during chemotherapy treatment.
Authors: Moyers-Ruiz Liliana , Hickish Tamas , Thompson Simon
Published: March 2020

TPS9148

Background: Breast cancer patients might develop impaired sleep patterns during chemotherapy, and impaired cognitive function has been associated with sleep patterns disruption. It has been suggested that sleepiness (sleep tendency) in cancer patients is prevalent and causes distress in the patient’s quality of life, that and their cognitive abilities are also affected. Furthermore, increased blood glucose levels among women undergoing chemotherapy may contrubute to memory deficits in breast cancer patients. It is proposed that Prospective and Working Memory are being affected by the disturbance of these biological factors over the course of chemotherapy. Methods: Ninety participants will be invited to take part in the study. Thirty will be breast cancer patients receiving chemotherapy treatment, thirty breast cancer patients receiving treatment other than chemotheray, and thirty healthy controls. Measures of sleep and sleepiness, will be administered at 4 testing sessions during a 9-month period, along with a neuropsychological battery. Additionally, blood samples will be analysed. Eight of planned 60 cancer patients have been enrolled, and four of them have completed the second testing session. For the assessment of sleep/wake activity, participants will be required to wear a sleeping monitor (sensewear armband) for 7 days. Pupil dilatation to observe sleepiness will be meassured by using a Pupillometry developed at Poole hospital in the UK. Prospective Memory will be assessed using CAMPROMT test to analyse if this is a more sensitive measure for mild cognitive impairment. Discussion: Impairment on variables such as sleep, sleepiness and glucose have not been studied within the context of Chemo-Brain on breast cancer patients.Therefore we want to observe whether impaired sleep and sleepiness, and impaired glucose levels are at the core of Prospective and Working Memory decline in Chemo-Brain patients in order to find a cause-and-effect relationship as a consequence of chemotherapy.
The BERNIE study: A phase II study evaluating addition of bevacizumab (Bv) to chemotherapy in children and adolescents with metastatic rhabdomyosarcoma (mRMS) and non-rhabdomyosarcoma soft tissue sarcoma (mNRSTS).
Authors: Chisholm Julia C. , Casanova Michela , Merks Johannes H. , Geoerger Birgit , Rousseau Raphael F. , Moore Nicola , Dhalluin Christophe , Oberlin Odile ,   on behalf of the European Innovative Therapies for Children with Cancer (ITCC) Consortium and the European Paediatric Soft Tissue Sarcoma Group (EpSSG)
Published: March 2020

TPS9597^

Background: Despite therapeutic advances, patient outcomes in mRMS and mNRSTS remain poor. The phase I study (Glade-Bender et al., J Clin Oncol. 2008) indicated that Bv is well tolerated in children with refractory solid tumors and yielded pharmacokinetic (PK) data that support further studies of Bv in childhood cancer. Reports of Bv used in children with solid tumors showed safety profiles consistent with data from adults. Methods: In this phase II trial, 150 patients aged 6 months to 18 years who present with mRMS or mNRSTS are randomized to receive 18 months of standard combined modality therapy as per EpSSG guidelines, either alone or with Bv. Treatment consists of 2 phases: induction therapy [9 three-weekly cycles including 4 cycles of IVADo (ifosfamide, vincristine, actinomycin D, and doxorubicin), followed by 5 cycles of IVA (i.e., without doxorubicin)] and maintenance therapy (12 four-weekly cycles of vinorelbine and cyclophosphamide). Local therapy is considered after the 6th induction cycle. Primary endpoint is event-free survival (EFS). PK sampling is performed on all patients randomized to the experimental arm during the first 4 cycles of induction. After the primary efficacy and safety analysis, all patients who have not met the primary endpoint are followed for at least 47 months for survival and long-term effects of treatment. The study enrolled 75 patients between July 2008 and January 2012; 37 patients discontinued study treatment (including 17 patients who died, all due to disease progression) and 9 patients have completed study treatment.
Effect of dexamethasone (DEX) dose modification on osteonecrosis (ON) risk associated with intensified therapies for standard risk acute lymphoblastic leukemia (SR-ALL): A report from the Children’s Oncology Group (COG) study AALL0331.
Authors: Mattano Leonard A. , Devidas Meenakshi , Friedmann Alison M. , Raetz Elizabeth A. , Hunger Stephen , Winick Naomi Joan , Carroll William L. , Maloney Kelly W. ,   Children's Oncology Group
Published: March 2020

10002

Background: ON is a known toxicity of childhood ALL therapy, particularly in patients (pts) >9 years (y). Intensified use of DEX, methotrexate (MTX), and asparaginase (ASNase) may increase the risk of developing ON among B-precursor NCI SR-ALL pts despite their younger age. Methods: Newly diagnosed SR-ALL pts 1-9y enrolled on AALL0331 between 4/05 and 5/10 were prospectively monitored for symptomatic ON within three treatment cohorts risk-stratified by clinical, cytogenetic, and early response criteria. ON sites were confirmed by imaging. SR-Low (SRL) pts were randomized to standard therapy +/- 4 additional doses of PEG-ASNase. SR-Average (SRA) pts were randomized (2x2) to standard therapy +/- an intensive consolidation (IC) +/- an augmented interim maintenance/delayed intensification (AIM/ADI). SR-High (SRH) pts all received IC and two AIM/ADI phases. After 6/08, alternate week DEX (AWD, days 1-7/15-21) replaced continuous DEX (days 1-21) during DI, and escalating-dose MTX replaced oral MTX during IM. All pts received DEX days 1-28 during induction and 5-day pulses every 4 weeks during maintenance. Results: Overall ON cumulative incidence (CI) at 5y was 2.7% (133/5261), correlating with sex (F 3.7%, M 1.9%, p<0.0001), age (1-2y 0.8%, 3-4y 2.0%, 5-6y 3.3%, 7-9y 7.8%, p<0.0001), and risk group (SRL 2.6%, SRA 2.9%, SRH 5.7%, p=0.0009). Before 6/08, ON CI was higher for SRA pts given intensive vs standard consolidation (5.8% vs 1.9%, p=0.002), and trended higher for SRL pts given additional PEG-ASNase (4.0 vs 2.3%, p=0.09). Use of AWD significantly reduced ON CI at 3y among SRH pts (7.4% vs 1.5%, p=0.003) and further reduced ON events in SRL/SRA pts. Conclusions: Young children receiving intensified therapy for SR-ALL therapy are at risk for ON. Extended exposure to PEG-ASNase is a likely contributing factor, possibly by potentiating DEX exposure during DI. ON risk can be significantly reduced by using AWD during DI, which is now COG standard of care. Clinical trial information: NCT00103285.
Bortezomib reinduction therapy to improve response rates in pediatric ALL in first relapse: A Children’s Oncology Group (COG) study (AALL07P1).
Authors: Horton Terzah M. , Lu Xiaomin , O'Brien Maureen Megan , Borowitz Michael J. , Devidas Meenakshi , Raetz Elizabeth A. , Brown Patrick Andrew , Zeng Hui , Zheng Hao W. , Hunger Stephen , Whitlock James ,   Children's Oncology Group
Published: March 2020

10003

Background: Bortezomib (bortez) is a reversible inhibitor of the 26S proteasome. Promising results have been reported adding bortezomib to reinduction chemotherapy in patients (pts) with ALL in 2nd or later relapse (Messinger, Blood 2012). Methods: This was a phase 2 study of bortez with reinduction chemotherapy in 1st relapse pediatric ALL that enrolled pts with pre-B ALL (relapse <36 months (m) from diagnosis). This report summarizes results from 61 evaluable pre-B ALL pts ≤21 yrs old, either <18m (stratum 1) or 18-36m (stratum 2) from diagnosis. Therapy consisted of bortez (1.3 mg/m2, days 1, 4, 8, and 11) with reinduction chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin). Complete response (CR2) rates and minimal residual disease (MRD) were determined at the end of the first 5-week therapy block. AALL07P1 utilized a stratified 2-stage design (London 2005) with the primary objective of comparing CR2 rates at the end of block 1 of therapy to historical control CR2 rates (AALL01P2). Block 2 included cyclophosphamide, etoposide, and bortez followed by 5g/m2 methotrexate. Biology studies included assessment of NF-κB activity. Results: 61 evaluable pre-B ALL pts were assessed. Toxicities were similar to AALL01P2, including 10 Grade 3- 4 hypotension, 4 Grade 4 hypertriglyceridemia, 3 Grade 3-4 typhlitis, and 2 Grade 3-4 enterocolitis. There were 2 deaths due to infection. Although Grade 3-4 infections were not infrequent (13 in block 1 and 7 in block 2) there were no reports of respiratory distress syndrome or Grade 4 peripheral neuropathy. 42 of the 61 patients enrolled (18/28 (64%) in Stratum 1 and 24/33 (73%) in stratum 2) attained CR2 at the end of Induction I. Based on CR2 response rate compared to historical controls, the study met its primary response objective. The number of pts in CR2 with MRD <0.1% also improved from AALL01P2; among pts achieving CR2, MRD was <0.1% in 41% (16/39) in AALL01P2 vs. 71% (25/35) (p= 0.073, Fisher’s exact test). Conclusions: Based on response rates in the very early and early first relapse pre-B ALL, AALL07P1 met its predefined efficacy benchmark. We conclude that bortezomib is worthy of further study in pediatric ALL. Clinical trial information: NCT00873093.
Long-term survival after alternative donor transplantation in children with acute leukemia.
Authors: Collins Chelsea Lee , Ahn Kwang Woo , Wang Zhiwei , Eapen Mary
Published: March 2020

10006

Background: Most reports describing long-term survival after allogeneic transplantation are in adults after transplantation of bone marrow (BM) from HLA-matched siblings. This report compares long-term survival after transplantation of unrelated donor BM to that after umbilical cord blood (UCB) in children with acute leukemia. Methods: Included were patients aged less than 18 years with acute myeloid or lymphoblastic leukemia, alive and leukemia-free for at least 1 year after transplantation. Transplants occurred 2000-2009. Patients received BM grafts that were HLA-matched (N = 205) or mismatched at 1-HLA locus (N = 112) and UCB grafts that were matched (N = 55) or mismatched at 1 (N = 160) or 2 HLA-loci (N = 134). Multivariate Cox regression models were constructed to explore differences in survival between groups. UCB transplants were treated as a single group as there were no significant differences between HLA-matched and mismatched UCB grafts. Multivariate models held 3 treatment groups: HLA-matched BM, HLA-mismatched BM and UCB grafts. Results: The disease characteristics of the three groups were similar. There were differences in patient and transplant characteristics. Recipients of UCB transplants were younger, more likely non-Caucasian, and more likely to have received a non-irradiation-containing conditioning regimen, in-vivo T-cell depletion and GVHD prophylaxis with cyclosporine and either prednisone or mycophenolate. In multivariate analysis, the risks of long-term mortality were not significantly different after UCB and HLA-matched BM transplants (HR 0.83, p=0.41). Mortality risks were significantly higher after HLA-mismatched BM transplants compared to UCB (HR 1.66, p=0.03) and HLA-matched BM transplants (HR 2.00, p=0.008). In this cohort, surviving disease-free at least 1-year after transplantation, the 8-year probabilities of overall survival after UCB, HLA-matched and HLA-mismatched BM transplants were 78%, 81% and 68%. Conclusions: This is the first report to document long-term durability of UCB grafts. The data continue to support the use of UCB grafts either in the absence of an HLA-matched donor or when transplantation is needed urgently for children with acute leukemia.
Cytological and molecular remissions with blinatumomab treatment in second or later bone marrow relapse in pediatric acute lymphoblastic leukemia (ALL).
Authors: Gore Lia , Zugmaier Gerhard , Handgretinger Rupert , Locatelli Franco , Trippett Tanya M. , Rheingold Susan R. , Bader Peter , Borkhardt Arndt , Cooper Todd Michael , O'Brien Maureen Megan , Zwaan Christian M. , Fischer Anja , Whitlock James , von Stackelberg Arend
Published: March 2020

10007

Background: Pediatric B-precursor acute lymphoblastic leukemia (ALL) in second or later relapse is an aggressive malignancy that needs therapeutic approaches with new mechanisms of action. Blinatumomab, a bispecific T-cell engaging (BiTE) antibody, has shown a hematological remission rate of 69% in adult patients with relapsed/refractory ALL. In order to establish a recommended dose in pediatric patients, a phase I multicenter trial was initiated. Methods: The primary endpoint is to determine the maximum tolerable dose defined by ≤1 of 6 patients experiencing dose limiting toxicity (DLT) within the 1st course of treatment. Up to 6 different dose levels of blinatumomab are being evaluated. Eligible patients must be <18 years old and have B-precursor ALL that is refractory or in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoetic stem cell transplantation (HSCT). Blinatumomab is administered by continuous IV infusion over 28 days followed by a 14-day treatment-free interval (up to 5 cycles). To date, 3 dose levels have been explored (Table). Results: Seventeen patients have been treated thus far with a total of 32 cycles. One DLT (gastrointestinal hemorrhage) at dose level 2 (15 µg/m²/d) and two DLTs at dose level 3 (30 µg/m²/d; both cytokine release syndrome) with 1 death have been observed. One patient had generalized seizures on the 3rd day of the 2nd treatment cycle at the first dose level of 5 µg/m2/d, which was completely reversible. The patient successfully underwent an allogeneic HSCT after blinatumomab. Eight (47%) of the 17 patients reached a cytological complete remission in bone marrow and a molecular remission defined as MRD by PCR <10-4. Conclusions: A phase I trial of blinatumomab in patients with relapsed/refractory pediatric ALL has shown hematological and molecular remissions. Dose-limiting cytokine release syndrome has been noted. Alternative dosing regimens are being explored in current cohorts to refine the recommended dose of blinatumomab in this patient population. Clinical trial information: NCT01471782. [Table: see text]
Evaluation of early response by anatomic imaging to predict survival among patients with group III rhabdomyosarcoma: A report from the Children’s Oncology Group.
Authors: Hawkins Douglas S. , Rosenberg Abby R. , Lyden Elizabeth , Anderson James Robert , Rodeberg David A. , Wolden Suzanne L. , Kao Simon C , Parham David , Arndt Carola A. S. ,   Children's Oncology Group
Published: March 2020

10012

Background: The prognostic significance of response to induction therapy for rhabdomyosarcoma (RMS) by anatomic imaging (computerized tomographic [CT] or magnetic resonance imaging [MRI] scan) is controversial. We previously reported no relationship between early response and failure-free survival (FFS) for patients on IRS-IV. We repeated the same analysis using an independent cohort of patients with non-metastatic, initially unresected RMS treated on a more recent clinical trial. Methods: A total of 338 patients enrolled in Children’s Oncology Group study D9803 met the following inclusion criteria for this analysis: 1) non-metastatic, initially unresected (Group III); 2) embryonal (ERMS) or alveolar (ARMS) histology; 3) documented response to induction chemotherapy (excluding progressive disease) based on anatomic imaging; and 4) documented therapy beyond week 12. Response at week 12 was determined by the treating institution as complete response (CR, complete resolution), partial response (PR, decrease of >= 50% of the sum of the products of maximum perpendicular diameters), or no response (NR, between 50% reduction and 25% increase in the sum of the products of maximum perpendicular diameters). FFS was estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. Results: Overall objective response rate (CR+PR) at week 12 of therapy was 85%, with similar responses for ERMS and ARMS. FFS was similar among all patients with CR, PR, or NR (p=0.49). Restricting the analysis to either ERMS or ARMS, there was no difference in FFS by histology (p=0.20 and p=0.45, respectively). Conclusions: These findings provide additional evidence that anatomic imaging assessment of early response to therapy among RMS patients does not predict outcome and should not be used to tailor subsequent therapy. Clinical trial information: NCT00003958. [Table: see text]
Survival in metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS) following consolidation immunotherapy with autologous lymphocyte infusion, dendritic cell vaccines ± CYT107 (rhIL-7).
Authors: Mackall Crystal , Baird Kristin , Bernstein Donna B , Wood Bradford J , Steinberg Seth M. , Beq Stephanie , Croughs Therese , Sabatino Marianna , Stroncek Dave , Merchant Melinda S.
Published: March 2020

10013

Background: Higher lymphocyte levels correlate with better survival in a variety of cancers, but it remains unclear whether there is a causal relationship between immune function and survival in cancer patients. A pilot study in high-risk pediatric sarcomas was undertaken to determine if a regimen designed to enhance immune reconstitution following standard cytotoxic therapy could improve survival. Methods: Forty-four patients (median 16 yrs, range 5-33) enrolled following a diagnosis of metastatic or late recurrent pediatric sarcoma, and underwent apheresis to collect mononuclear cells and tumor biopsy to generate tumor lysate, then received standard therapy at their home institution. After standard therapy, 29 patients received immunotherapy, comprising a single infusion of autologous lymphocytes depleted of CD4+CD25+regulatory T cells, plus dendritic cell vaccines pulsed with autologous tumor lysate and keyhole limpet hemocyanin (KLH, Q14d x 6). After the first 5 patients, CYT107 (rhIL-7, 20 mcg/kg SQ Q14d x 4) was added to the regimen. Intensive biologic analyses measured global and regulatory T cell immune reconstitution and vaccine responses. Results: This outpatient regimen was well tolerated with toxicities limited to rash, low-grade fever and mild constitutional symptoms. CYT107 dramatically enhanced global immune reconstitution and diminished regulatory T cell frequency. All patients developed immune responses to KLH and 31% developed immune responses to tumor lysate. Intent-to-treat analysis of all patients enrolled shows 56% 5-yr OS, with immunotherapy recipients having a 64% 5-yr OS (median f/u 30 mos, range 23-65). Intent-to-treat analysis of the subset of patients enrolled at the time of a new diagnosis of metastatic EWS or RMS shows 83% 5-yr OS and 54% 5-yr EFS (n=13, median f/u 35 mos, range 24-63), which is superior to previous outcomes reported for this population. Conclusions: A low intensity immunotherapy regimen focused on enhancing immune reconstitution following standard therapy may diminish recurrence in newly diagnosed metastatic EWS and RMS. Clinical trial information: NCT00923351.
The RIST design: A molecularly targeted multimodal approach for the treatment of patients with relapsed and refractory neuroblastoma.
Authors: Corbacioglu Selim , Steinbach Daniel , Lode Holger N. , Gruhn Bernd , Fruehwald Michael , Broeckelmann Mechthild , Suttorp Meinolf , Escherich Gabriele , Cario Gunnar , Ehlert Karoline , Meister Bernhard , Simon Thorsten , Debatin Klaus-Michael , Kuhlen Michaela , Feddersen Isa
Published: March 2020

10017

Background: The prognosis for children with recurrent or refractory neuroblastoma (rNB) remains dismal. Novel therapeutic approaches are urgently needed. Methods: Based on promising in vitro data unselected patients with rNB were treated as compassionate use according to a multimodal approach (RIST design). The treatment consisted of metronomic courses of Rapamycin/Dasatinib (R/S) for 4 days followed by 5 days of Irinotecan and Temozolomide (I/T). Twenty-one patients (median age: 38 months) with stage IV (n=19) and stage III (n=2) disease, 5 with refractory disease, 8 with 1st and 8 with 2nd and 3rd relapses were included. Seven patients presented within 18 months after diagnosis (median age: 28 months). 18 patients were MIBG positive, 4 MYCN amplified. Dissemination was present in the bone in 15, bone marrow in 11 and lymph nodes in 6 patients, respectively. Results: The patients received a median of 16 courses of R/S (4 to 72) and 7 courses of I/T (4 to 65). 19 patients (90%) showed an initial response according to imaging criteria after a median of 7 R/S and 4 I/T courses (median treatment duration 12 weeks): CR in 12 (57%), a PR in 3 (14%) and a SD in 4 (19%). The median PFS was 90 weeks. The OS after a median of 148 weeks was 43% with 7 patients in CR, 1 VGPR and 1 in PR. There were no toxic deaths in this highly pretreated population. Grade III and IV toxicities (CTC 3.0) were thrombocytopenia in 81%, leukopenia in 76%, anemia in 71%, and diarrhea in 71% respectively. Conclusions: This RIST treatment design applied as a multimodal approach in a compassionate use setting exhibited very promising results considering the adequately long follow-up period of 3 years. This molecular targeted therapy design for rNB warrants confirmation in a prospective clinical trial.
Implementation and evaluation of clinical exome sequencing in childhood cancer care: The BASIC3 study.
Authors: Parsons Donald W. , Chintagumpala Murali M. , Berg Stacey L. , López-Terrada Dolores H. , Roy Angshumoy , Kerstein Robin A. , Scollon Sarah , Hilsenbeck Susan G. , Ramamurthy Uma , Eng Christine M. , Yang Yaping , Gibbs Richard A. , Wheeler David A. , Street Richard L. , McCullough Laurence B. , McGuire Amy L. , Monzon Federico A. , Plon Sharon E. ,   Baylor College of Medicine
Published: March 2020

10023

Background: Advances in sequencing technologies allow for provision of genome-scale data to oncologists and geneticists caring for pediatric cancer patients. The goal of the BASIC3 (Baylor Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating CLIA-certified tumor and constitutional exome sequencing into the care of children with newly diagnosed solid tumors. Methods: Blood and frozen tumor samples obtained at initial surgery are submitted for clinical exome sequencing (target enrollment 280 patients). Results are deposited into the electronic medical record and disclosed to families by their oncologist and a genetic counselor. Identification of germline cancer susceptibility mutations is compared with standard testing practices. Oncologists are surveyed on prioritization of treatment options in the hypothetical event of tumor recurrence before and after receiving tumor exome results. Patients will be followed for two years to assess the clinical utility of exome data. Preferences for reporting this complex information are obtained by interviews and audiorecording of disclosure visits. Results: Initial results reveal that41 of 49 (84%) ethnically diverse families have consented to enroll on study. Adequate tumor samples were available from 35 of 41 patients (85%), including 11 of 15 (73%) patients with CNS tumors and 24 of 26 (92%) with non-CNS tumors. Pathogenic germline cancer susceptibility mutations (TP53, MSH2) were reported in 2 of the first 11 patients, with a medically-actionable mutation in a gene (SCN5A) unrelated to cancer in 1 patient and 0-4 (median of 2) recessive carrier mutations per patient. Between 9 and 33 protein altering mutations (median of 11) have been identified in tumors, including known cancer genes such as TP53 and others with no known link to pediatric cancer. Conclusions: A robust clinical pipeline for exome sequencing of blood and tumor samples has been successfully developed with significant parental interest. Data assessing the clinical utility of both the tumor and constitutional exomes and the preferences of oncologists and parents for reporting of these results are under study. Supported by NHGRI 1U01HG006485.
Phase I/II study of brentuximab vedotin in pediatric patients (pts) with relapsed or refractory (RR) Hodgkin lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL): Interim phase (ph) I safety data.
Authors: Neville Kathleen , Gore Lia , Mauz-Körholz Christine , Rosolen Angelo , Landman-Parker Judith , Sanchez de Toledo Jose , Beishuizen Auke , Keating Franklin Anna Rachel , Fasanmade Adedigbo , Wang Jingyuan , Huebner Dirk , Locatelli Franco
Published: March 2020

10028

Background: Brentuximab vedotin (ADCETRIS) is a novel antibody-drug conjugate that targets CD30, a cell surface antigen expressed by HL and sALCL. The ph 1 portion of this study evaluated safety, pharmacokinetics (PK), and recommended ph 2 dose (RP2D) of brentuximab vedotin in pediatric pts with RR CD30-expressing tumors. Methods: Ph 1/2, open-label, multicenter study in pts aged 2 to <18 years with RR HL or sALCL (5 to <18 years for HL). Pts received brentuximab vedotin by IV infusion once every 21 days (Q3wk). Ph 1 start dose was 1.4 mg/kg escalated to 1.8 mg/kg in a traditional 3+3 design. Results: 12 pts (median age 14.5 y; 10 HL; 2 sALCL) received brentuximab vedotin in the ph 1 portion (mg/kg/dose [n]: 1.4, [3]; 1.8 [9]). 1.8 mg/kg cohort was expanded from 6 to 9 pts to raise the ph 1 pediatric experience to 12 pts before the ph 2 portion. At data cut, pts had received a median of 3 cycles (range, 1–8). 11 pts (92%) had ≥1 treatment-emergent adverse event (TEAE): 2 at 1.4 mg/kg, 9 at 1.8 mg/kg. 6 pts (50%) had Gr ≥3 TEAE: 1 at 1.4 mg/kg, 5 at 1.8 mg/kg. The most frequent (≥15%) TEAE were nausea (50%), abdominal pain, diarrhea (25% each), upper abdominal pain, cough, fatigue, hypokalemia, leukopenia, decreased lymphocyte count, pain, paresthesia, vomiting, weight loss (17% each). 1 pt (8%) discontinued due to TEAE (Gr 3 hepatotoxicity). 7 serious AE (SAE) were reported in 4 pts at 1.8 mg/kg: Gr 2 supraventricular tachycardia unrelated to treatment in 1 pt; Gr 3 febrile neutropenia, Gr 3 hepatotoxicity and Gr 3 cardiac failure (not a cardiac event per later analysis) in 1 pt; Gr 3 bronchospasm and Gr 2 laryngeal edema in 1 pt; 1 cardiac arrest resulting in death, unrelated to treatment. 2 dose limiting toxicities were reported in 1 pt in the 1.8 mg/kg cohort (SAE: prolonged Gr 3 liver event, Gr 3 febrile neutropenia). PK data will be presented. Conclusions: Brentuximab vedotin is generally well tolerated in pediatric pts with RR CD30-positive HL or sALCL up to 1.8 mg/kg Q3wk. For the majority of pts, toxicities were generally mild to moderate and did not lead to discontinuation. 1.8 mg/kg is the RP2D for pediatric and adult pts. The ph 2 portion is ongoing. Clinical trial information: NCT01492088.