bluuebunny/crossref_metadata_2025 huggingface dataset:
Dasatinib plus SMO antagonist versus dasatinib alone for treating patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): Design of CA180-363, a phase II, open-label randomized trial.
Authors: Trudel Geralyn C. , Paliwal Prashni , Lainas Ioannis
Published: March 2020

TPS6634

Background: Dasatinib 100 mg once daily (QD) is approved as first-line therapy for pts with newly diagnosed Ph+ CML-CP and those who are resistant or intolerant to prior therapy, including imatinib, based on demonstrated efficacy and tolerability. BMS-833923 (SMO antagonist), selectively blocks hedgehog (Hh) pathway signaling by binding to and antagonizing Smoothened (SMO), preventing downstream signaling and activation of target genes. In preclinical studies, SMO loss or inhibition reduces hematopoietic stem cell renewal, induces CML stem cell depletion, and inhibits imatinib-resistant CML cell growth (Dierks, Cancer Cell 2008; Zhao, Nature 2009). In pts with CML, Hh signaling genes (Sonic hedgehog, SMO, and Gli1) are significantly upregulated compared with control pts (Long, J Exp Clin Cancer Res 2011), suggesting that drug resistance and disease recurrence may be overcome by targeting the Hh signaling pathway. Methods: CA180-363 is a phase 2 trial to assess dasatinib activity with or without SMO antagonist in pts with newly diagnosed Ph+ CML-CP. Pts receive dasatinib 100 mg QD for 12 months and are then randomized 1:1 to continuing dasatinib 100 mg QD with or without SMO antagonist up to 24 months, followed by dasatinib 100 mg QD alone until end of study (60 months). Randomization is stratified by Sokal score at diagnosis and major molecular response (MMR) at 12 months (yes/no). Eligible pts are aged ≥18 years, have an Eastern Cooperative Group (ECOG) performance status of 0-2, and previously untreated Ph+ CML-CP diagnosed within 6 months of enrollment. Primary endpoint (evaluated in pts who do not achieve MMR prior to randomization) is comparison of MMR rates for dasatinib alone vs dasatinib plus SMO antagonist. Other endpoints (evaluated in all pts) are complete molecular response, progression-free survival, event-free survival, transformation-free survival, and safety of the combination regimen. Recruitment started in September 2011 (14 pts enrolled to date); estimated primary completion date is November 2014. ClinicalTrials.gov ID: NCT01357655.
Prospective, observational registry of branded imatinib (IM) and nilotinib (NIL) exposure in pregnant women: Voluntary post-authorization safety study.
Authors: Juma Matthews , Ericson Solveig , Eng Dawn Fun , Acharya Sandip , Wariabharaj Darshan , Owugah Tina , Avenia Bettine , Zernovak Oleg
Published: March 2020

TPS6638

Background: Family planning decisions for cancer patients of childbearing age are impacted by their diagnosis. IM and NIL are category D drugs (demonstrated risk to the fetus based on mechanism of action and findings in animals; however, the benefits of therapy may outweigh the potential risk to the fetus); women should be advised not to become pregnant when taking these drugs. Limited data exist concerning safety of these drugs during pregnancy and consequences of interrupting treatment. The registry does not recommend patients receiving IM or NIL become pregnant, but serves only to document exposures that occur, and collect information on pregnancy outcome, maternal course of disease, and infant follow-up. Methods: The registry intends to enroll 150 women (≥18 years) treated with branded IM and NIL within 6 mo before or during pregnancy (generic IM and NIL reports are excluded). Schedule of visits and treatment is according to local standard of care. Women are divided into 2 exposure cohorts: 1) pregnancy/fetal: received tyrosine kinase inhibitors (TKIs) within 14 d of conception or at any time during pregnancy; 2) interrupted TKI: received TKIs within 6 mo before conception but interrupted TKIs in preparation for/due to pregnancy. To identify signals of teratogenicity, the registry uses a general population baseline rate of birth defects, and the prevalence of defects in cohorts 1 and 2 may be compared. Cases are quantitatively analyzed for the emergence of unique defects or patterns of defects. Primary objective: monitor TKI-exposed pregnancies to estimate the prevalence of birth defects (calculated by dividing number of birth defects by total number of exposed live births from cohort 1). Secondary objectives are to: 1) determine the impact of treatment interruption on maternal disease status; 2) assess and estimate the prevalence of serious adverse pregnancy outcomes; and 3) assess and estimate the prevalence of developmental delays and functional deficits among infants during the first year of life. Maternal disease status is analyzed, comparing disease status at registration, pregnancy outcome, and 1 y after birth, stratified by length of TKI interruption.
RESPONSE: A randomized, open-label, phase III study of ruxolitinib in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU).
Authors: Verstovsek Srdan , Kiladjian Jean-Jacques , Sandor Victor , Lukawy Jacek , Li Jingjin , He Shui , Garrett William M. , Malek Kamel , Pirron Ulrich , Mookerjee Bijoyesh , Vannucchi Alessandro M.
Published: March 2020

TPS6643^

Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation, significant morbidity, shortened life span and possible evolution to myelofibrosis and acute myeloid leukemia. Splenomegaly, debilitating constitutional symptoms, and frequent phlebotomy requirements are common in advanced disease. HU, an established first-line agent for cytoreduction, can be associated with cytopenias, aphthous and leg ulcers, and other side effects. Control of hematocrit is not always achieved with HU, and many patients are either intolerant of or become resistant to HU. JAK2 plays a key role in the pathophysiology of PV; nearly 100% of patients harbor either the JAK2V617F or JAK2 exon 12 mutations. In a phase 2 study in HU-resistant or -intolerant PV patients, ruxolitinib, a potent and selective inhibitor of JAK1/JAK2, was well tolerated and achieved rapid and durable clinical responses, including phlebotomy independence, resolution of splenomegaly, and improvements in white blood cell (WBC) and platelet (PLT) counts and disease-related symptoms. Methods: RESPONSE is a randomized (1:1), open-label, global phase 3 study (NCT01243944) designed to compare the safety and efficacy of ruxolitinib with best available therapy (BAT) in adult patients with PV who are resistant to or intolerant of HU (modified European Leukemia Net criteria) and require phlebotomy because of inadequate hematocrit control. Inclusion criteria have been amended to include patients who exhibit palpable splenomegaly with an MRI-confirmed volume of ≥ 450 cm3 (ie, approximately 2.5 x median normal volume; instead of ≥ 5 cm by palpation) and PLT > 100 x109/L; the requirement for either elevated WBC (> 15 x109/L) or PLT count (> 600 x109/L) was removed. The primary efficacy endpoint is the achievement of both phlebotomy independence and a ≥ 35% reduction in spleen volume after 32 weeks of treatment. Patients will be treated for 80 weeks to assess safety and durability of response. Patients randomized to BAT may be eligible to cross over to receive ruxolitinib after week 32. Enrollment is planned for 145 investigational sites (134 currently open), with a target of 200 patients.
CA184-156: A randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) plus etoposide/platinum (EP) versus EP in subjects with newly diagnosed extensive-stage disease small cell lung cancer (ED-SCLC).
Authors: Spigel David R. , Zielinski Christoph , Maier Sabine , de Pril Veerle , Fairchild Justin P. , Cuillerot Jean-Marie , Reck Martin
Published: March 2020

TPS7113

Background: EP (4-6 cycles) is standard of care 1st-line therapy for metastatic SCLC, and no multinational studies have reported any improvement beyond that reported for EP. Evidence of an ongoing immune response to SCLC tumors suggests that immunotherapy that enhances this immune response to SCLC may enhance the clinical benefit of EP. Ipi, a fully human monoclonal antibody which blocks CTLA-4, augments antitumor immune responses. Because some responses to Ipi may differ from those observed with cytotoxic therapies, immune-related response criteria (irRC) were derived from WHO criteria to better capture response patterns observed with Ipi. A randomized Phase 2 study of Ipi with paclitaxel/carboplatin (PC) in pts with ED-SCLC showed significant improvement in progression-free survival (PFS), as measured by irRC, over PC alone in pts receiving Ipi and PC in a phased regimen (Ipi started after 2 cycles of PC). Furthermore, addition of Ipi did not exacerbate PC toxicity, and immune-related adverse events were managed using protocol-specific guidelines. This multicenter phase III study in pts with ED-SCLC (ClinicalTrials.gov identifier NCT01450761) will determine whether adding Ipi to EP increases OS vs EP alone. Methods: EP consists of 4 cycles of etoposide (100 mg/m2, IV on Days 1-3 every 3 weeks [Q3W]) and cisplatin (75 mg/m2, IV) or carboplatin (AUC=5, IV) once Q3W. Pts will be randomized to receive 4 doses of Ipi (10 mg/kg, IV) in Arm A or placebo in Arm B, Q3W during induction, starting after 2 cycles of EP (phased schedule). Eligible pts will then receive blinded study drug (Ipi in Arm A; placebo in Arm B) Q12W until disease progression or unacceptable toxicity. The primary objective is to compare OS. Secondary objectives are to compare OS in those who receive blinded study drug, compare PFS between study arms, and to estimate best overall response rate and duration of response. First-line ED-SCLC pts with ECOG performance ≤1 will be included. Pts with symptomatic CNS metastases or a history of autoimmune disease will be excluded. The study will randomize 1100 pts at a 1:1 ratio.
TIME: A phase IIb/III randomized, double-blind, placebo-controlled study comparing first-line therapy with or without TG4010 immunotherapy product in patients with stage IV non-small cell lung cancer (NSCLC).
Authors: Quoix Elisabeth A. , Nemunaitis John J. , Burzykowski Tomasz , Bastien Berangere , Lacoste Gisele
Published: March 2020

TPS7610

Background: TG4010 is an immunotherapy product based on a poxvirus (MVA) coding for the MUC1 tumor-associated antigen and interleukin-2. A previous study, TG4010.09, which evaluated the combination of first-line chemotherapy with and without TG4010 in advanced NSCLC, achieved its primary endpoint based on 6-month progression-free survival (PFS) and showed that the pre-treatment level of activated Natural Killer (aNK) cells may be a potential predictive biomarker for TG4010 efficacy (E. Quoix et al., Lancet Oncol. 2011;12:1125-33). Methods: TIME is a double-blind phase IIb/III study comparing the combination of first-line therapy with TG4010 or placebo in stage IV NSCLC patients, Performance Status (PS) 0 or 1 with a MUC1 expressing tumor by immunohistochemistry. The Phase IIb part of the study aims at prospectively validating aNK level as a predictive biomarker with PFS as a primary endpoint, by comparing the two treatment arms in two subgroups defined according to the level of aNK cells at baseline (normal or high). Bayesian criteria, derived from the TG4010.09 study results, will be used to confirm that, with a large probability, the true hazard ratio is <1 in patients with normal level of aNK cells and >1 in patients with high level of aNK cells. The Phase III part of the study will then compare, by using a frequentist approach, the two treatment arms with overall survival as a primary endpoint in the patient population confirmed to be of interest in the Phase IIb part. The phase III part is powered to detect a 27% reduction in the hazard rate of death. Phase IIb and III parts of the study will enroll respectively 206 and 800 patients. A dynamic minimization procedure will be applied at randomization for histology, prescription of bevacizumab, type of chemotherapy, PS and center. If qualifying for, patients will receive maintenance therapy after chemotherapy according to labeling. The study TIME is open to recruitment and referenced in ClinicalTrials.gov with the identifier NCT01383148.
CA184-161: A phase I/II trial of vemurafenib and ipilimumab in patients with BRAF V600 mutation-positive metastatic melanoma.
Authors: Ribas Antoni , Hodi F. Stephen , Kurland John F. , Shahabi Vafa , Francis Stephen , Konto Cyril , Joe Andrew K. , Lainas Ioannis , Wolchok Jedd D.
Published: March 2020

TPS8603

Background: Ipilimumab (ipi) is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipi significantly improved overall survival (OS) in two separate phase III trials of metastatic melanoma (MM): (1) at 3 mg/kg as monotherapy in previously treated patients and (2) at 10 mg/kg combined with dacarbazine in previously untreated patients. The most common drug-related adverse events with ipi were immune-related, and were generally reversible using treatment guidelines. Vemurafenib (vem) is a potent inhibitor of BRAF V600E-mutated kinase, which occurs in ~50% of MM. In clinical studies, vem produced objective response rates of ~50% with a significant improvement in the rate of OS in patients with previously untreated BRAF V600-positive MM. The purpose of this phase I/II study is to determine the safety and feasibility of ipi plus vem in patients with BRAF V600-positive MM, and to evaluate the efficacy of the combination in comparison to historical results observed with each agent alone. Methods: In phase I, an escalating dose design is used to assess safety/tolerability and to determine the maximum tolerated dose (MTD) of each agent. Vem will initially be given alone for 28 days at 960 mg p.o. BID, followed by vem in combination with ipi i.v. at 3 mg/kg [induction (q3w x 4) and maintenance (q12w)]. The next cohort will receive vem at 960 mg plus ipi increased to a dose of 10 mg/kg. Phase I will enroll an estimated 20 patients who have not previously received a CTLA-4 antagonist or BRAF inhibitor. If new or heightened frequency or severity of toxicities is not observed, a phase II single-arm extension at the MTD of each agent will be conducted in patients with previously untreated MM. The primary objectives of phase II (estimated enrollment of 30 patients) are to obtain preliminary evidence of efficacy (OS, 1- and 2-year survival rates) and to evaluate safety of the combination. Major inclusion criteria are ≥ 18 years of age, BRAF V600-positive MM, measurable tumor, no active brain metastasis, and an ECOG PS of 0-1. The first patient was enrolled in November 2011 and enrollment is ongoing (ClinicalTrials.gov identifier: NCT01400451).
OPTiM: A randomized phase III trial to evaluate the efficacy and safety of talimogene laherparepvec (T-VEC) compared with subcutaneously (sc) administered GM-CSF for the treatment (tx) of unresectable stage IIIb, IIIc, and IV melanoma.
Authors: Kaufman Howard , Wagner Volker Jean , Goldsweig Howard , Yao Bin , Coffin Robert
Published: March 2020

TPS8604

Background: T-VEC (formerly OncoVEXGM-CSF) is an oncolytic HSV1 that selectively replicates in tumors. The proposed MOA includes lytic destruction of injected tumors and induction of a systemic anti-tumor immune response enhanced by local GM-CSF expression. Intratumoral T-VEC tx in a 50-patient (pt) ph II study in advanced melanoma (Stage IIIc-IVM1c) was well tolerated and achieved a high rate and duration of response, including 20% CR (Senzer et al., JCO 2009; 27: 5763-71). As immune effects may be delayed, progressive disease (PD) often occurred before response. Based on the ph II data, a randomized ph III trial of T-VEC in unresectable melanoma (the OPTiM study; clinical trials registry NCT00769704) was designed taking into account the response patterns seen with T-VEC and other immunotherapeutic agents. T-VEC is the first "armed" oncolytic agent to enter pivotal testing worldwide. Methods: OPTiM compares the efficacy and safety of intratumoral T-VEC to sc GM-CSF in 430 pts with treated or untreated unresectable Stage IIIb-IVM1c melanoma stratified by typical prognostic factors. Pts are randomized 2:1 to T-VEC (priming dose of up to 4 x 106 pfu intratumorally then 3 wks later by up to 4 x 108 pfu Q2W) or GM-CSF 125 µg/m2 qd sc x 14 days every 28 days. Key eligibility criteria are ≥ 18 yrs old, ECOG 0-1, and at least 1 injectable cutaneous, sc, or nodal tumor. The primary endpoint is durable response rate (DRR: CR or PR continuously maintained for ≥ 6 mo initiating within 12 mo of starting tx; secondary endpoints include OS. Responses are subject to independent review. Pts are treated until wk 24, even with PD. Thereafter pts are treated until clinically significant PD, CR, or for 1 yr. The study has 90% power to show a 10% difference in DRR with 2-sided Fisher Exact Test (α = 5%). Enrollment closed in July 2011 with 439 pts randomized in the US, UK, S Africa, and Canada. Interim analysis in Dec 2010 on 75 pts on study > 9 mo concluded that the study should continue. Results are expected during 2012. Conclusions: T-VEC provides a novel potential tx for melanoma. This pivotal ph III study is expected to report during 2012.
A randomized phase II study of sunitinib versus dacarbazine in the treatment of patients with metastatic uveal melanoma.
Authors: Marshall Ernest , Coupland Sarah , Corrie Philippa , Damato Bertil , Danson Sarah , Dobson Lisa , Evans T.R. Jeffry , Goodman Andrew , Kalirai Helen , Jones Sarah , Kumar Satish , Larkin James M. G. , Lorigan Paul , Nicholson Steve , Ottensmeier Christian , Silcocks Paul , Steven Neil , Tudur-Smith Catrin , Nathan Paul D.
Published: March 2020

TPS8605

Background: Metastatic uveal melanoma represents an orphan disease area with a median survival of less than 6 months. There is currently no effective systemic therapy for metastatic uveal melanoma and few clinical trials have been conducted. In the absence of phase III data, many patients in the UK continue to receive single agent dacarbazine or best supportive care outside of the context of clinical trials. Uveal melanoma is characterized by activation of the MAP kinase pathway via functionally activating mutations in Gnaq/11. Evidence also suggests that dysfunctional c-Kit signalling and angiogenesis may both play a role in disease progression and a small single-arm phase II trial recently reported preliminary activity using the multi-targeted receptor tyrosine kinase inhibitor, sunitinib (Tijani et al, ASCO 2010). Methods: The SUAVE trial aims to evaluate the Progression Free Survival (PFS) of good performance status patients treated with sunitinib or dacarbazine. Secondary objectives include: Overall Survival (OS), Overall Response Rate (ORR), safety, crossover PFS and response and biomarker analyses. SUAVE is a CR-UK-funded, open-label, randomised, phase II trial that will include 124 patients. Patients will be stratified according to their Helsinki Prognostic Index (ALP, largest diameter of largest metastasis, ECOG). Inclusion Criteria: good performance status patients with confirmed unresectable metastatic uveal melanoma, with at least one target lesion measurable by RECIST 1.1. Patients must not have received previous systemic therapy. At confirmed progression, good performance status patients may crossover to the other study treatment. The trial opened in Oct 2010 and as of 23 January 2012, had randomized 49 patients with at least 1 recruited from each of the 12 recruiting sites. There will be a total of 13 sites. Completion of the recruitment phase is expected within 36 months. Prospective tissue and blood sample collection for translational biomarker analyses is also ongoing. The SUAVE trial represents one of the largest randomised trials in this rare disease area (Clinical trial registry number: 2008-008794-55).
Do we need to perform pulmonary function tests in non-small cell lung cancer patients never diagnosed as COPD?
Authors: Nakwan Narongwit , Geater Sarayut Lucien
Published: March 2020

TPS9151

Background: Although chronic obstructive pulmonary disease (COPD) and lung cancer share a common risk factor, namely smoking, health care providers usually overlook the symptom of COPD in the management of lung cancer. Should, then, lung cancer patients undergo pulmonary function tests (PFT) to identify the presence of COPD? Our study was performed to describe the results of pulmonary function tests and define risk factors for COPD in non-small cell lung cancer (NSCLC) patients. Methods: A total of 31 eligible patients with NSCLC but no obvious symptoms of COPD participated. We collected baseline characteristics and conducted a detailed assessment of pulmonary function, particularly spirometry, lung volume measurement, and diffusing capacity of carbon monoxide (DLCO). Dyspnea was assessed using modified Borg (mBorg) and modified Medical Research Council (mMRC) scores. Results: Twelve patients had airflow limitation (FEV1/FVC<0.7). These patients had mean percent predicted FEV1, RV and DLCO of 52%, 143% and 66% respectively, and a mean RV/TLC of 0.55. Being male, and having a smoking history, low body mass index and squamous cell carcinoma were significantly associated with obstruction in univariate analysis. However, obstruction was not more common in advanced stage than in locally advanced NSCLC. Neither mBorg nor mMRC differed between obstructive and non-obstructive groups. Discussion: COPD was found in patients with NSCLC who had never been diagnosed as, or showed symptoms of, COPD. Male, smoking history, low BMI and squamous cell carcinoma were significantly associated with obstruction.
Radioprotection study of topical norepinephrine in postsurgical breast cancer patients.
Authors: Cleary James F. , Cannon George M. , Eickhoff Jens C. , Thunberg Allen L , Fahl William E
Published: March 2020

TPS9152

Background: This study derives from radiodermatitis studies in a rat model evaluating radioprotection from topical norepinephrine application. In the model, increasing radiation doses induce dermatitis of increasing severity, ranging from mild erythema to wet desquamation. The model was initially designed to identify topical radioprotectants that function as oxygen free radical scavengers. In an experiment designed to test the hypothesis that the co-application of a topical vasoconstrictor and an aminothiol scavenger would limit the systemic uptake of the scavenger, it was observed that the combination was synergistic and that the topical vasoconstrictor was active when administered alone as a control. Subsequent experiments demonstrated that topical a-adrenergic receptor agonists are active in preventing radiodermatitis. The data are consistent with a mechanism based on local and transient vasoconstriction within the skin, which reduces local tissue oxygenation. This subsequently limits the formation of radiation-induced reactive oxygen species and protects skin stem cells from radiation damage. Methods: Two Phase 1 safety studies have been conducted, one in normal volunteers and one in cancer patients receiving palliative radiation therapy for bone metastases. This study is a nonrandomized, open-label safety and exploratory study in post-surgical breast cancer patients treated with 45 to 50 Gy to the whole breast and axilla. A 10-16 Gy boost to the lumpectomy region is permitted. Eligible patients are age 18 years or older with a diagnosis of Stage Ia (T1, N0, M0), Stage Ib (T0 or 1, N1mic, M0) or Stage IIa (T<3cm, N0, M0) infiltrating ductal or lobular carcinoma of the breast or ductal carcinoma in situ (DCIS). The dose is a single daily topical application of 3.0 mL of norepinephrine HCl (82.3 mg/mL in 70% ethanol) applied to the same 50 cm2 treatment site in the axilla about 20 minutes prior to each radiotherapy fraction. The radiodermatitis severity at the treatment site will be compared to surrounding (untreated) control areas. 5 of planned 12 patients have been enrolled. Clinical trial registry number NCT01263366.
Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children’s Oncology Group study.
Authors: Borowitz Michael J. , Wood Brent L. , Devidas Meenakshi , Loh Mignon L. , Raetz Elizabeth A. , Larsen Eric , Maloney Kelly W. , Carroll Andrew J , Friedmann Alison M. , Gastier-Foster Julie M , Heerema Nyla A. , Mattano Leonard A. , Nachman James B. , Winick Naomi Joan , Carroll William L. , Hunger Stephen
Published: March 2020

10001

Background: Response to initial therapy is a powerful prognostic factor in pediatric ALL. Traditionally, slow early response (SER) has been defined by marrow morphology 8 or 15 days after start of induction therapy. More recently, MRD has been identified as the most important predictor of adverse outcome. The value of morphologic assessment of response in the setting of MRD has not been established. Methods: In COG studies AALL0331 (for NCI Standard Risk (SR) B ALL patients (pts)) and AALL0232 (High Risk (HR) B ALL pts), SER was defined by morphology as either ≥5% blasts in a day 15 marrow, or by flow cytometry as ≥0.1% MRD in a d29 marrow (SER MRD). Assignment to treatment arms also depended upon cytogenetic findings and extramedullary disease; each protocol had randomized treatment questions. SER pts were non-randomly assigned to receive augmented BFM therapy (ABFM) with 2 interim maintenance and delayed intensification phases (and CNS radiation for HR SER pts only). All pt treatment groups were combined for these analyses. Rapid early responders (RER) had a better outcome than SER pts (Table). However, pts who were SER only by morphology had a 5y DFS that was not significantly different from that of RER pts, and superior to that of pts who were SER MRD, or SER by both morphology and MRD. In multivariate analysis, SER by morphology was not an adverse prognostic factor after adjusting for risk group and MRD, or separately in SR or HR pts after adjusting for MRD. However, pts with .01-.1% MRD who were SER by morphology had a better 5y DFS than the.01-.1% MRD pts who were RER (90±6%, n=91 vs 77±3%, n=592). Only the former group received ABFM, suggesting intensification based on response rescues some poor risk pts. We conclude that a day 15 marrow is not needed to assess response if MRD is measured at end induction, provided that SER MRD is defined using a .01% cutoff, the threshold for intensifying therapy in current COG ALL trials. Clinical trial information: NCT00103285, NCT00075725. [Table: see text]
Prognostic implications of gain of 1q in favorable histology Wilms tumor: A report from the Children’s Oncology Group.
Authors: Gratias Eric J. , Jennings Lawrence J , Anderson James Robert , Dome Jeffrey , Grundy Paul Edward , Perlman Elizabeth
Published: March 2020

10014

Background: Wilms tumor is the most common childhood renal tumor. While the majority of patients with favorable histology Wilms Tumor (FHWT) have good outcomes, many patients still experience recurrence and death from disease. This study’s goal was to determine if chromosome 1q gain is associated with event-free (EFS) and overall survival (OS) in FHWT. Methods: Unilateral FHWT samples were obtained from patients enrolled on National Wilms Tumor Study-4 and Pediatric Oncology Group 9046, “A Molecular Genetic analysis of Wilms Tumor.” 1q gain, 1p loss, and 16q loss were determined using multiplex ligation-dependent probe amplification (MLPA). Results: The eight-year EFS was 87% (95% CI 82%, 91%) for the entire cohort of 212 patients. Tumors of 58/212 patients (27%) displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The eight-year EFS was 76% (95% CI 63%, 85%) for those with 1q gain and 93% (95% CI 87%, 96%) for those lacking 1q gain (p=0.0024). The eight-year OS was 89% (95% CI 78%, 95%) for those with 1q gain, and 98% (95% CI 94%, 99%) for those lacking 1q gain (p=0.0075). Gain of 1q did not correlate with disease stage (p=0.16). After stratification for stage, 1q gain was associated with a significant increase in the risk of failure (risk ratio estimate: 2.72, p=0.0089). Conclusions: Gain of 1q is associated with inferior EFS and OS in FHWT and may provide a new and valuable prognostic marker to stratify therapy for patients with FHWT. A confirmatory study is necessary before this biomarker is incorporated into risk stratification schema of future therapeutic studies.
PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer.
Authors: Telli Melinda L. , Jensen Kristin C. , Kurian Allison W. , Vinayak Shaveta , Lipson Jafi A. , Schackmann Elizabeth A. , Wapnir Irene , Carlson Robert W. , Sparano Joseph A. , Head Bobbie , Goldstein Lori J. , Haley Barbara B. , Dakhil Shaker R. , Manola Judith , Ford James M.
Published: March 2020

1003

Background: TN and BRCA1-deficient breast cancer (BC) cell lines exhibit enhanced sensitivity to DNA damaging agents. This study was designed to assess efficacy, safety and predictors of response to iniparib in combination with GC in early-stage TN and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled pts with clinical stage I-IIIA (T ≥ 1cm by MRI) ER-negative (≤ 5%), PR-negative (≤ 5%), and HER2-negative or BRCA1/2 mutation-associated BC. Neoadjuvant G (1000 mg/m2; IV; D1, 8), C (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles, with enrollment of 80 pts at multiple PrECOG institutions. The primary endpoint is pathologic complete response (pCR), defined as no invasive carcinoma in the breast and axilla. Pathologic response was centrally assessed by the residual cancer burden (RCB) index. Assuming 76/80 eligible and treated pts, the regimen would be deemed effective if the lower bound of a 90% exact binomial CI on the pCR rate exceeded 25%. Secondary endpoints are safety, MRI response, and breast conservation. Results: Among 80 eligible pts treated with 6 cycles, median age is 48 years, 19 pts have germline BRCA1/2 mutations (90% tested to date) and clinical stage is I (13%), IIA (36%), IIB (36%), IIIA (15%). Pathologic response data (ITT population) are detailed below. 69 pts completed treatment per protocol: 5 progressed, 5 discontinued due to an AE and 1 mutation carrier was lost to follow-up. Most common G3/4 adverse events are neutropenia (49%), elevated ALT/AST (14%), and anemia (10%). Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage TN and BRCA1/2 mutation-associated BC. Clinical trial information: NCT00813956. [Table: see text]
Comparison of Taqman low density array (TLDA) five-gene assay for tumor cells in bone marrow and blood with histologic bone marrow examination and imaging for disease assessment and outcome in patients with recurrent/refractory neuroblastoma (NBL): A new approaches to neuroblastoma therapy (NANT) study.
Authors: Marachelian Araz , Villablanca Judith , Asgharzadeh Shahab , Liu Wei Yao , Liu Betty , Young Sabrina , Weiss Brian D. , Katzenstein Howard M. , Cohn Susan Lerner , Baruchel Sylvain , Twist Clare , Granger Meaghan , Matthay Katherine K. , Malvar Jemily , Sposto Richard , Seeger Robert
Published: March 2020

10039

Background: Accurate quantification of tumor burden in NBL patients is needed to define homogenous populations for therapy and establish response criteria that predict outcome. The 5-gene TLDA assay was developed for quantification of NBL cells in bone marrow (BM) and blood (BLD). Methods: Expression of CHGA, DCX, DDC, PHOX2B, and TH (NBL genes) was quantified with TLDA and reported as the geometric mean cycle threshold for the 5 genes (DGS=detection gene score; inversely related to tumor content, 40=negative). Sixty-three patients with recurrent/refractory NBL had TLDA performed on 107 BM and 99 BLD samples (66 paired) at 140 time points. Based on central review of reports, tumor longest diameter (LD) on CT/MRI (n=118), and number of 123I-MIBG avid sites (n=120) were recorded. Percentage of tumor cells in BM was from institutional reports of bilateral BM aspirates/biopsies (n=109). Overall response was assessed per NANT Response Criteria. Spearman rank correlation was performed. Results:TLDA detected tumor cells in 62/99(63%) BLD (average DGS=37.45) and 91/107(85%) BM samples (average DGS=33.42). 39/91(42%) with positive BM TLDA were negative by morphology. BLD and BM TLDA were correlated r = 0.6540, p< 0.0001 with stronger correlation with lower BM DGS scores. The BM and BLD DGS correlated with % BM involvement (BM r= -0.63, p<0.0001; BLD r= -0.35, p=0.0023) and number of MIBG sites (BM r=-0.34, p=0.001, BLD r=-0.51 p<0.0001) but not LD. Number of MIBG sites was also correlated with % BM involvement (r= 0.45, p<0.001) and LD (r= 0.28, p=0.0039). Analysis of 43 BM pairs demonstrated decreasing DGS correlated with overall progressive disease (r= 0.39, p=0.01). Conclusions: This TLDA assay detects NBL cells in both BM and BLD at high rates, and frequently detects tumor cells when BM morphology is negative. Quantification of tumor with DGS correlates with % BM involvement and number MIBG sites. TLDA may provide an additional parameter to delineate response in NBL. Clinical trial information: NCT01587300.
Integrated analysis of RNAi screens in pediatric rhabdomyosarcoma.
Authors: Arnaldez Fernanda Irene , Chakka Sirisha , Smith Carly J , Yeung Choh L , Caplen Natasha , Helman Lee J.
Published: March 2020

10040

Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Embryonal RMS (ERMS) are characterized by 11p15 LOH, while alveolar RMS (ARMS) harbor a translocation between PAX3 or PAX7 and FOXO1. Relapsed or metastatic RMS has a poor prognosis with a 5-year survival rate of 25%. We hypothesized that a reduction in proliferation of ARMS cell lines as result of the loss of function (LOF) of a specific protein via RNAi likely point to novel targets that exhibit “synthetic lethality” with the PAX3/7-FOXO1 translocation, and can be used to reveal unique ARMS vulnerabilities. Methods: We are using two complementary screening strategies to identify genes critical for RMS cell growth and survival. One RNAi screening strategy used an inducible LOF shRNA screen of 15,000 shRNA -5,000 genes- introduced into RH30 (ARMS) or RD (ERMS) cells. Data analysis after subtraction of targets related to common survival pathways revealed 40 genes with close association with RMS cell growth. Follow up analysis included further comparison of the effects of gene specific LOF in ARMS and ERMS cell lines and assessment in orthotopic xenografts. To increase the strength of our findings, we have also conducted parallel siRNA screens of the human kinome targeting 704 kinase genes (3 siRNAs per gene) in RH30 or RD cells. Results: Of the 40 genes identified by shRNA screening, 15 genes were identified as selectively needed for ARMS cell growth. Follow up analysis of one of these genes, TNK-2 (tyrosine kinase, non-receptor 2) in orthotopic xenografts, confirmed that LOF of TNK2 markedly decreases ARMS cell growth. The siRNA screen has identified a further putative 26 genes that selectively reduce ARMS cell growth. These screens have led us to focus on members of the ERK, PI3K and IGF1R pathways as potential targets for the treatment of ARMS. Conclusions: RNAi screening affords an unbiased method for the discovery and elucidation of gene function. Ongoing efforts are focused on the integration of results obtained to gain further insight into the signaling networks influencing alveolar rhabdomyosarcoma biology and thus identify a small group of druggable genes that could represent alveolar rhabdomyosarcoma specific vulnerabilities.
Double akylating agents treatment with ifosfamide (IFOS) and cyclophosphamide (CYCLO) for relapsed pediatric solid tumors.
Authors: Epelman Sidnei , Gorender Ethel , Beaugrand Annick , Melaragno Renato , Meirelles Priscila , Oliveira Renato Guedes
Published: March 2020

10057

Background: CYCLO and IFOS are two of the most active agents in childhood cancer. There is non-cross resistance between CYCLO and IFOS and they have dissimilar toxic side effects. In vitro, tumor model systems document that alkylator resistance may be overcome by several fold increases in drug concentration. We developed a strategy in attempt to limit side effects and increase anticancer activity of high doses oxazaphosphorines therapy: an association of IFOS plus CYCLO, giving an equivalent to 20g/m2 of IFOS or 5g/m2 of CYCLO. The schedule is the association of these two drugs: CYCLO 2,5g/m2 (corresponding to 10g/m2 of IFOS) plus IFOS 10g/m2. Methods: Eligibility included recurrent/refractory measurable disease, life expectancy > 6 weeks, adequate renal, hepatic and bone marrow function. CYCLO (2,5g/m2) and IFOS (10g/m2) with Mesna, with interval of 21 days. Responses were evaluated after 2 cycles.So far, 13 patients were enrolled: median age 17 years (5-26), 9M:4F,6 osteosarcoma, 1 hemangioperycitoma, 2 medulloblastoma, 1 nasopharyngeal carcinoma, 1 Wilms tumor,1 synoviosarcoma, 1 retinoblastoma. Six patients received IFOS previously (Total= 38 - 63 g/m²) and 5 CYCLO. Results: Thirty four cycles were evaluated. Toxicity was tolerable with no death. Main adverse event was neutropenia grade (GR) 4 in all cycles, median duration of seven days (3-15), GCS-F was used in all cycles; anemia GR 3 and 4 and thrombocytopenia GR 4 in 14 cycles; infection GR 3 and 4 in 15 cycles; hemorrhage cystitis GR 1 in 2 cycles and neurologic toxicity GR 2 in 6 cycles. No acute renal toxicity was observed. Responses were 2 complete response (CR), 5 partial responses (PR), 3 stable disease, and 3 progress disease. Conclusions: This schedule is feasible with high response rate (CR+PR=54%). Due to lack of new agents, innovative approaches for high risk patients can have a potential benefit. More patients are warranted.
Treatment results of children with neuroblastoma in Hospital Infantil de Mexico Federico Gomez.
Authors: Juarez Villegas Luis , Zapata-Tarres Marta , Lezama del Valle Pablo
Published: March 2020

10059

Background: Neuroblastoma (NB) is the main extracraneal cancer in children. Progress in survival has not been the same as in other neoplasms despite molecular markers research and new drugs. Our aim was to describe low and high risk patients at Hospital Infantil de México Federico Gómez (HIMFG) and their results. Methods: We included children from 0 to 18 years con NB diagnosed at HIMFG between january, 2002 and december 2011. We perform a retrospective, retrolective and descriptive study analyzing demographic variables and survival with Kaplan Meier. Results: 64 consecutive patients were included. 73.4% had metastasis at diagnosis (bone marrow 23.4%, liver 18.8%, bone 17.2%, 4.7% central nervous system, 9.4% other). 87.5% of patients received neoadyuvant chemotherapy. Patients were treated with POG 8104 y 8441. Global survival of patients with E4 stage was 50% at 120 months, with E3 of 76.5% at 110 months; stage 1, 2 patient´s survival was 4S 100% at120 months. Conclusions: At HIMFG, in Mexico City, 75% of patients with NB arrive with metastatic disease. Clinical prognosis factors are still current in development countries. Our results are similar as in developed countries suggesting that with low resources, we can obtain satisfactory results only with clinical evaluation.
Predictors of declining levels of physical activity among adult survivors of childhood cancer.
Authors: Wilson Carmen L , Leisenring Wendy M. , Oeffinger Kevin C. , Nathan Paul C. , Wasilewski-Masker Karen , Hudson Melissa M. , Castellino Sharon M. , Stovall Marilyn , Armstrong Gregory T. , Brinkman Tara M. , Robison Leslie L. , Ness Kirsten K.
Published: March 2020

10062

Background: Childhood cancer survivors are at increased risk of developing obesity-related diseases, yet many survivors do not meet established guidelines for physical activity. We aimed to identify demographic and health-related predictors of declining physical activity among participants in the Childhood Cancer Survivor Study (CCSS). Methods: Analyses included 6617 >5 year childhood cancer survivors diagnosed between 1970-86 who completed the CCSS 2003 and 2007 follow-up questionnaires, and1992 siblings. Participants were classified as active if they reported engaging in any physical activity other than their regular job duties in the prior month. Generalized linear models using a log-link and Poisson distribution were used to compare participants whose physical activity levels fell from active to inactive over the study interval to those who remained active or whose activity levels improved. In addition to analyses comparing survivors to siblings, selected demographic factors and chronic conditions (CTCAE v4.0 Grade 3 and 4) were evaluated as risk factors in an analysis among survivors alone. Risk ratios (RR) with 95% confidence intervals (CI) are reported. Results: The median age at last follow-up among survivors and siblings was 36 (range: 21-58) and 38 (range: 21-62) years, respectively. Approximately 14% of survivors and 9% of siblings reported declines in physical activity across the study interval (p<0.01). Factors that predicted declining levels of physical activity included BMI≥30kg/m2 (RR=1.4, 95% CI=1.3-1.7, p<0.01), BMI<18.5kg/m2 (RR=1.4, 95% CI=1.0-1.8, p=0.03), not completing high school (RR=1.7, 95% CI=1.2-2.2, p<0.01), and black race (RR=1.6, 95% CI=1.2-2.1, p<0.01). In a model limited to survivors, declining levels of physical activity were more likely among survivors who reported the presence of Grade 3 or 4 neurological (RR=1.5, 95% CI=1.2-1.8, p<0.01) or cardiac conditions (RR=1.5, 95% CI=1.3-1.9, p<0.01). Conclusions: Childhood cancer survivors are at increased risk of becoming inactive over time compared to siblings. Interventions targeting survivors at highest risk of decline are required to reduce the risk of chronic diseases associated with an inactive lifestyle.
Turkish National Pediatric Cancer Registry 2002-2008 (Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Society).
Authors: Kutluk M. Tezer , Yesilipek Akif ,   Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Society
Published: March 2020

10067

Background: In childhood cancers cure rates increased up to 80% in the developed countries. On the other hand cure rates goes down 10-20% percent in countries with low resource settings. Reliable pediatric cancer data is essential for all countries. We established a nationwide pediatric cancer registry. Methods: Turkish Pediatric Oncology & Pediatric Hematology Society established a web-based database for the registry of all pediatric cancers. 11898 cases were registered between 2002-2008 from 65 centers. Various demographic data & survival endpoints were recorded & analyzed. Diseases were grouped according to the International Classification of Childhood Cancer. Results: In all 11898 cases, median age was 6 years (M/F= 6786/5112=1.32). Distribution in age groups were: 0-4 years, 42.5%; 5-9 years, 27.2%; 10-14 years, 23.4%; 15-19 years, 6.8%; >19 years, 0.1%. Only 3.8% of cases were diagnosed with clinical+radiological, the rest with histopathological data Distribution of cases in disease groups were [median age in yrs, M/F]: Leukemias (n=3777) 31.7% [5.5, 2137/1640=.31]; Lymphomas (n=2040) 17.1% [8.3, 1405/635=2.21]; CNS tumors (n=1588) 13.3% [6.9, 913/675=1.3 ]; Sympathetic tumors (n=889) 7.5% [2.1, 453/436=1.03]; Retinoblastoma (n=371) 3.1% [2, 181/190=0.95]; Renal tumors (n=655) 5.5% [3, 333/322=1.03]; Hepatic (n=166) 1.4% [1.8, 101/65=1.5]; Bone tumors (n=717) 6% [12.2, 407/310=1.3]; Soft tissue tumors (n=773) 6.5% [6.5, 442/331=1.3]; Germ cell tumors (n=531) 4.5% [5, 210/321=0.6 ]; Carcinomas and other malignant epithelial tumors (n=323) 2.7% [12, 164/159=1.03]; Others/unspecified malignant tumors (n=68) 0.6% [4.5, 40/28=1.4]. Five-year overall survival in all cases was 65%. Conclusions: This registry provides a critical information about the distribution of childhood cancer since this is the only nationwide pediatric cancer registry in Turkey. With the recent trends in non-communicable diseases at global level, registry data will be very helpful for national cancer control plans, which will also be used to compare at national and international level. This will also be a good example for many other countries with similar resources to do such projects.
Access to cancer chemotherapy and predictors of early mortality for childhood cancers in Uganda.
Authors: Mutyaba Innocent , Orem Jackson , Wabinga Henry , Phipps Warren , Casper Corey
Published: March 2020

10070

Background: Although many childhood cancers respond well to chemotherapy, survival among children with cancer in sub-Saharan Africa is poor. Little is known about children’s access to specialized cancer care in SSA or factors contributing to poor early outcomes. We aimed: 1) To estimate the proportion of childhood cancer patients without access to chemotherapy in Uganda; 2) To describe 30-day survival rates and predictors of mortality post diagnosis among children with lymphoma or Kaposi sarcoma (KS), the two most common pediatric cancers in Uganda. Methods: A retrospective study of incident childhood (age< 20 years) cancers diagnosed in Kyandondo County, Uganda from 2006-2009. We compared records of the population-based Kampala Cancer Registry (KCR) and patient records at the Uganda Cancer Institute (UCI), Uganda’s sole dedicated cancer treatment center. Patient characteristics were compared using Mann-Whitney and Pearson’s chi-square tests. Kaplan-Meier method and Cox regression models were used to describe mortality. Results: Of the 658 pediatric cases recorded in the KCR, only 238 (36%) presented to UCI. Patients identified in the KCR who did not present for care were more likely to be female, diagnosed in earlier years of the study, and to have a cancer other than KS or lymphoma. Of the 177 lymphoma and KS cases at UCI, 43.7% were Burkitt lymphoma (BL), 32.5% KS, and 23.8% other lymphomas. The post diagnosis 30-day overall survival rate was 77%. In multivariate analysis, age, gender, HIV status, platelets, and stage of cancer did not impact mortality. An increased risk of death at 30 days was predicted by presence of B-symptoms (HR=10.3, p=0.05), a diagnosis of BL compared to other lymphomas (HR=14.8, p=0.007), poor performance status (Karnofsky score <70, HR=14.7, p<0.001), and anemia (HR 1.5-fold per 1g/dL decrease in hemoglobin, p=0.002). Conclusions: Childhood cancer patients in Uganda have limited access to comprehensive care. Among those presenting to the UCI, a significant proportion die before they can benefit from chemotherapy. BL diagnosis, B-symptoms, performance status and hemoglobin level may be important predictors of early mortality among childhood cancer patients in sub-Saharan Africa.