bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.