bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx): NSABP B-43.
Authors: Cobleigh Melody A. , Anderson Stewart J. , Julian Thomas B. , Siziopikou Kalliopi P. , Arthur Douglas W. , Rabinovitch Rachel , Zheng Ping , Mamounas Eleftherios P , Luknic Alice Marie , Behrens Robert J. , Chu Luis , Leasure Nick C. , Atkins James Norman , Polikoff Jonathan , Seay Thomas E. , Noyes R Dirk , Stella Philip J. , McCaskill-Stevens Worta J. , Wolmark Norman 
Published: March 2020

TPS657 Background: Asignificant amount of DCIS is ER negative and/or overexpresses HER2. This provides an opportunity to test molecular therapy in DCIS. In xenograft models and cell lines, T boosts RT effectiveness. In T-treated HER2+ patients, apoptosis occurs within 1 wk of single agent T use, with T found in ductal aspirates. Ample safety evidence for T exists. T given during whole breast irradiation (WBI) may improve results for Lx-resected HER2+ DCIS. A trial to examine this question will enhance the understanding of breast tumor biology and the prevention of such tumors and could possibly extend breast-conserving surgery benefits for women with DCIS. Methods: After Lx for pure DCIS, each patient’s DCIS lesion is centrally tested for HER2 by IHC analysis. HER2 2+ tumors undergo FISH analysis. HER2 3+ or FISH+ patients can be randomly assigned to 2 doses of T, 3 weeks apart during WBI or to WBI alone. Women ≥18 yrs. with a margin-clear Lx for pure DCIS, with ECOG status 0/1 who are and clinically or pathologically node negative are eligible. Centrally tested DCIS must be HER2 +. ER and/or PR status must be known before randomization. Primary aims are to determine if T decreases ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary aims are to determine the benefit of T in preventing regional or distant recurrence and contralateral invasive breast cancer or DCIS. B-43 will determine if DFS, recurrence-free interval, and OS can be improved with the use of T. 2000 patients will be accrued over 7.9 yrs, with a definitive analysis of primary endpoints performed at163 ipsilateral breast cancer events (7.5 - 8 yrs. after protocol initiation) with an 80% power to detect a hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per 100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate. As of 12-31-11, 763 patients have been randomized. NCT00769379 Grant support: PHS NCI-U10-CA-69651, -12027, and NCI P30-CA-14599 from the US NCI and Genentech, Inc.
HALT MBC: HER2 suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (LPT112515).
Authors: Lin Nancy U. , Danso Michael A. , David Alice K. , Muscato Joseph J. , Rayson Daniel , Houck William A. , Ellis Catherine Elizabeth , DeSilvio Michelle , Garofalo Amanda , Nagarwala Yasir M. , Winer Eric 
Published: March 2020

TPS658 Background: Dual blockade of HER2 with the combination of trastuzumab (T) and lapatinib (L) enhances antitumor activity in HER2-positive breast cancer (BC) preclinical models due to the complementary mechanisms of action of the 2 agents. In patients (pts) with T-treated HER2-positive metastatic BC (MBC), treatment with the combination was associated with longer progression-free (PFS) and overall survival (OS) compared with L alone. In pts with stage II/III BC, preoperative treatment with the combination plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2-positive MBC. The present study is designed to evaluate whether the addition of L improves PFS among women with HER2-positive MBC receiving T as maintenance therapy. Methods: In this open-label, Phase III study, 280 pts will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]) or T (6 mg/kg q3w) alone. Pts will receive study treatment until disease progression, death, discontinuation due to adverse events, or other reasons. The primary endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and safety. Key eligibility criteria include pts with HER2-positive MBC who have completed 12 to 24 weeks of first- or second-line treatment with T plus chemotherapy with an objective response or stable disease at time of chemotherapy discontinuation. Pts with stable brain metastases are eligible if entering the study on second-line treatment. Efficacy endpoints will be analyzed in the ITT population. A total of 193 PFS events is required to detect a 50% increase in median PFS (hazard ratio=0.67) for L plus T compared with T alone (median PFS 27 vs 18 weeks, respectively). The hypothesis will be tested using a 1-sided test with 80% power and a type I error of 0.025. The trial is currently open for accrual in the United States and Canada.
The PERSEPHONE trial: Duration of trastuzumab with chemotherapy in women with HER2-positive early breast cancer.
Authors: Earl Helena Margaret , Cameron David A. , Miles David , Wardley Andrew M. , Ogburn Emma , Vallier A-L , Loi Shrushma , Higgins Helen B , Hiller Louise , Dunn Janet A 
Published: March 2020

TPS660 Background: Persephone is a phase III randomised controlled trial comparing six months of trastuzumab to the standard 12 month duration in patients with HER2 positive early breast cancer in respect of disease free survival, safety and cost-effectiveness. A Persephone sister study, the PHARE trial run by the National Institute for Cancer, successfully closed to recruitment in 2010. A prospective meta-analysis is planned once each trial has reported individually. Methods: A total of 4000 patients will be randomised into each of the two treatment groups. The power calculations assume that the disease-free survival (DFS) of the standard treatment of 12 months trastuzumab will be 80% at 4 years. On this basis, with 5% 1-sided significance and 85% power, a trial randomising 2000 in each arm will have the ability to prove non-inferiority of the experimental arm defining non-inferiority as ‘no worse than 3%’ below the control arm 4 year DFS. Primary outcome is disease-free survival non-inferiority (equivalence) of 6 months trastuzumab compared with 12 months in women with early breast cancer. Secondary outcomes are overall survival non-inferiority (equivalence); expected incremental cost effectiveness; cardiology function and analysis of predictive factors for development of cardiac damage. Two mandatory sub-studies are: Tumour block collection to discover molecular predictors of survival with respect to duration of trastuzumab treatment and blood sample collection, used to discover single nucleotide polymorphisms (SNPs) as genetic/pharmaco-genetic determinants of prognosis, toxicity and treatment outcome. A third optional sub-study is the quality of life questionnaires. Results: Persephone opened to recruitment in October 2007. To date, 1847 patients (46%) of its total have been randomised from 147 UK sites. Recruitment is due to complete by December 2013 and the first planned interim analysis of the primary outcome will be mid-2016. The IDSMC last reviewed the trial in June 2011 and congratulated the Trial Management Group on the conduct of the trial and the quality of the data. No safety concerns were identified, and the IDSMC proposed that the trial continue to planned recruitment.
ALTERNATIVE (EGF114299): A study of lapatinib, trastuzumab, and endocrine therapy in patients who received neo-/adjuvant trastuzumab (IV) and endocrine therapy.
Authors: Gradishar William John , Kahan Zsuzsanna , Tsang Janice , Timcheva Constanta , Tjulandin Sergei , Cardoso Fatima , Grigiene Ruta , Iwata Hiroji , Keane Maccon , Luebbe Kristina , Neskovic-Konstantinovic Zora , Simon Sergio D. , Stemmer Salomon , Vrbanec Damir , Arbani Tammy , Florance Allison M. , Huang Yingjie , Leigh Meggan , Wroblewski Susan , Johnston Stephen R. D. 
Published: March 2020

TPS661 Background: Approximately 50% of human epidermal growth factor receptor 2 positive (HER2+) breast cancers are also hormone receptor-positive (HR+). For patients with HER2+/HR+ disease, combining the aromatase inhibitor (AI) letrozole with the dual tyrosine kinase inhibitor lapatinib (L) has been shown to improve outcomes vs letrozole alone. Similar results were found for the combination of trastuzumab (T; a humanized monoclonal antibody targeting HER2) and anastrozole vs anastrozole alone. Finally, the combination of L and T has been shown to improve outcomes vs L alone. Methods: This phase III, randomized, open-label, multicenter trial (ALTERNATIVE) will enroll postmenopausal female patients with HER2+/HR+ metastatic breast cancer (MBC) who have not received prior treatment for MBC, have received neo/adjuvant T and endocrine therapy, and are not candidates for chemotherapy. Patients will be randomized 1:1:1 to 1 of 3 treatment arms: L plus T plus an AI; T plus an AI; or L plus an AI. The AI can be letrozole, anastrozole, or exemestane, to be selected by the investigator. The primary objective of ALTERNATIVE is to examine the efficacy of L/T/AI compared with T/AI alone. The primary efficacy endpoint is overall survival (OS; time from randomization until death due to any cause) for L/T/AI vs T/AI. Secondary efficacy objectives include: comparisons of OS between T/AI and L/AI as well as between T/L/AI and L/AI, comparisons of progression-free survival, overall response rate, time to response, duration of response, safety, and tolerability for all 3 treatment groups. The study is powered to detect a 42% reduction in risk of death (hazard ratio=0.70) in patients who receive L/T/AI (median 28.5 months) vs T/AI (median 20 months) using a 1-sided test for superiority with α=0.025. The required number of total events to achieve a power of 80% is 249. Secondary comparisons are not powered and will be based on the ITT population. This study is currently recruiting, with a target of 525 patients. If its objectives are reached, it will provide a valuable, chemotherapy-free treatment option for HER2+/HR+ MBC patients. Clinical trial registry number: NCT01160211.
Targeting microenvironment-mediated resistance in leukemias: Phase I trial of mobilization and elimination of FLT3-ITD+ acute myelogenous leukemia (AML) stem/progenitor cells by plerixafor/g-CSF/sorafenib.
Authors: Andreeff Michael , Zeng Zhihong , Kelly Mary A , Wang Rui-Yu , McQueen Teresa J , Duvvuri Seshagiri , Nowshad Gul , Borthakur Gautam , Burger Jan Andreas , Kadia Tapan M. , Jabbour Elias , Cortes Jorge E. , Kantarjian Hagop , Konopleva Marina 
Published: March 2020

TPS6635 Background: FLT3-ITD AML are associated with poor prognosis. We identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 2008; Borthakur G., Haematologica, 2010). FLT3-ITD is associated with overexpression of chemokine receptor CXCR4 and we found increased in vivo activity of S combined with CXCR4 inhibitor Plerixafor (P) and G-CSF (G) (Zeng Z et.al. Blood 2009). Here we report first data testing this concept in patients with R/R FLT3-ITD AML. Methods: G (10 ug/kg) and P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400-600mg), S on d 1 - 28(one cycle). G/P was held when blasts > 5x104/uL. CD34, 38, 123, CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were measured by flow cytometry. Results: 10 patients have been treated so far : 2 achieved CRp, 4 PR and 4 failed (NR), for an overall response rate of 6/10; 3/6 responders and 4/4 NR were previously treated with FLT3 inhibitors. 4/10 pts. developed hyperleukocytosis (and missed 1 to 5 doses of G/P), 6 skin rash and 3 hypertension. Analysis of cells mobilized in 22 cycles revealed a 29-fold increase in WBC, 41-fold in absolute blasts, 77-fold in granulocytes. Increase in circulating stem/progenitor cells was as follows: CD34+: 231-fold, CD34+/38- : 90-, CD34+/38-/123+(LSC) : 148-, CXCR4+: 139-, VLA-4+ : 68- and CD44+: 82-fold. Increase in LSC was correlated with baseline blasts and VLA4, not with CXCR4. FISH confirmed mobilization of leukemic cells. Increased levels of pERK and pAKT were observed in mobilized cells. Conclusion: The combination of G-CSF+Plerixafor appears superior in increasing circulating leukemic blasts and stem/progenitor cells in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast increase 2.1-fold; Uy et al. Blood, in press). Treatment resulted in 2/10 CRp and 4/10 PRs. Mobilized stem/progenitor cells displayed increased MAPK/AKT signaling and increased CXCR4 expression. This is the first clinical report of G-CSF/Plerixafor for the “mobilization” of AML cells, aimed at removing them from their protective bone marrow microenvironment. The initial results are providing proof-of–principle of this concept.
A single-arm, open-label, multicenter study of complete molecular response (CMR) in patients with newly diagnosed Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) treated with nilotinib.
Authors: Savona Michael R. , Flinn Ian W. , Goldberg Stuart , Robles Robert Leon , Rizzieri David , Radich Jerald P. , Mauro Michael J. , Ericson Solveig , Yi Sandy , Cortes Jorge E. 
Published: March 2020

TPS6636 Background: With more-potent tyrosine kinase inhibitors, increasingly sensitive methods are required to monitor treatment response and quantify minimal residual disease (MRD). Molecular monitoring is recommended by National Comprehensive Cancer Network and European LeukemiaNet guidelines; major molecular response (MMR) correlates with optimal long-term outcomes. CMR, while implying absence of BCR-ABL transcripts, is defined by levels undetectable by current technology (generally ≥4.5 logs reduced below a standardized baseline using quantitative real-time polymerase chain reaction [RT-PCR]). Newer technologies that can detect larger reductions will be important in analyzing correlations between decreased disease burden and long-term outcomes and may assist in selecting patients for “stopping” therapy. Methods: This US study plans to enroll 100 adults with newly diagnosed Ph+ CML-CP within 6 months of diagnosis to receive nilotinib 300 mg twice daily (BID) for up to 2 years. BCR-ABL transcripts are quantified using RT-PCR at a central laboratory. An exploratory molecular assay (digital detection [DiD]) with an additional >1-log sensitivity and mutation detection and quantification will be evaluated. Primary endpoint: the rate of confirmed CMR at 24 months (CMR confirmed by second PCR sample within 3 months; ≥4.5-log reduction of BCR-ABL from standardized baseline on the international scale [IS], equivalent to BCR-ABL ≤0.0032% IS). Dose escalation to 400 mg BID is allowed per protocol. Secondary endpoints: rate of, time to, and duration of complete cytogenetic response (CCyR), MMR, and CMR; rate of and time to loss of CCyR, MMR, and CMR and to progression to accelerated phase/blast crisis; rate of CMR in dose-escalated patients; and event-free, progression-free, and overall survival. Exploratory endpoints: BCR-ABL trends and correlation of mutations with response. The DiD assay data will provide information on BCR-ABL trends below the current CMR threshold and assist in evaluating lower levels of MRD.
VALOR, an adaptive design, pivotal phase III trial of vosaroxin or placebo in combination with cytarabine in first relapsed or refractory acute myeloid leukemia.
Authors: Ravandi Farhad , Ritchie Ellen K. , Sayar Hamid , Strickland Stephen Anthony , Craig Michael , Selleslag Dominik L. D. , Maertens Johan , Havelange Violaine , Lancet Jeffrey E. , Ketchum Steven B , Acton Gary , Mehta Cyrus R. , Silva Eric , Craig Adam , Fox Judith Ann , Stuart Robert K. , Erba Harry Paul , Vey Norbert , Schiller Gary J. , Feldman Eric Jay 
Published: March 2020

TPS6637 Background: The promising phase 2 activity/tolerability profile of vosaroxin with cytarabine in first relapsed or refractory AML (N=69) with median overall survival (OS) 7.1 mo, combined CR 28% (CR 25%), median LFS 25 mo and 30-day all‑cause mortality 3%, supported phase 3 trial. VALOR (NCT01191801), a phase 3, randomized, controlled, double-blind trial, evaluates vosaroxin and cytarabine versus placebo and cytarabine in patients with first relapsed or refractory AML and incorporates an adaptive design. Primary objective is OS; secondary/tertiary objectives include CR rates, safety, EFS, LFS, and transplantation rate. Key eligibility criteria: persistent AML or first relapsed AML after 1 or 2 induction cycles that include at least 1 regimen of cytarabine with an anthracycline/anthracenedione; adequate cardiac, hepatic, renal function; and adults with no upper age restriction. Methods: VALOR is recruiting patients at over 100 sites in 14 countries in North America, Europe, and Australia/NZ. Enrollment opened Dec 2010; 183 patients enrolled through Dec 2011. Adaptive design: Base case assumed 40% improvement in median OS (hazard ratio, HR=0.71), 90% power, 2-sided alpha of 0.05. At the interim analysis (50% events), DSMB may recommend a 50% sample size increase from 450 to 675 evaluable patients if results indicate a larger sample size is required to reduce the risk of failing to confirm a clinically meaningful OS benefit (Mehta, Pocock, Stat Med 2010). In consideration of FDA and EMA guidance on Data Monitoring Committees and adaptive design with respect to trial integrity, operational bias, firewalls, and data confidentiality and archival, VALOR uses the Access Control Execution System (ACES ) to store, share, and archive confidential DSMB reports in a secure environment with an audit trail, and to facilitate communication between the DSMB and trial sponsor. The DSMB periodically reviews a combination of blinded and unblinded analyses while the study team remains blinded as specified in the DSMB charter. The DSMB recommended VALOR continue as planned after reviewing safety data in Dec 2011.
International tailored chemotherapy adjuvant trial: Itaca trial.
Authors: Novello Silvia , Manegold Christian , Grohe Christian , Colantonio Ida , Serke Monika Heidi , Geissler Michael , Valmadre Giuseppe , Schuette Wolfgang , Stoelben Erich , Bria Emilio , Monica Valentina , Torri Valter , Scagliotti Giorgio 
Published: March 2020

TPS7109 Background: This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing -1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36). Methods: In all registered patients, before randomization, expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein. It is assumed that the 5-year survival in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of patients is 700. The final statistical analysis will group together all control arms and all tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, patients in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS) 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis. Currently, 312 patients have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 13 patients/month).
ARCHER: Dacomitinib (D; PF-00299804) versus erlotinib (E) for advanced (adv) non-small cell lung cancer (NSCLC)—A randomized double-blind phase III study.
Authors: Boyer Michael J. , Janne Pasi A. , Mok Tony , O'Byrne Kenneth John , Paz-Ares Luis G. , Ramalingam Suresh S. , Liang Jane Q , Taylor Ian , Campbell Alicyn , O'Connell Joseph P. , Letrent Stephen P. , Antic Vladan 
Published: March 2020

TPS7615 Background: D is a highly selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family of tyrosine kinases. In a randomized phase II trial in patients (pts) who had received 1–2 prior systemic therapy regimens for adv NSCLC, D demonstrated significantly longer progression-free survival (PFS) vs. E in the overall population (12.4 vs. 8.3 weeks; HR=0.66, P=0.012), with benefit consistent across several clinical and molecular subgroups. Median PFS in the KRAS wild-type (WT) subgroup was 16.1 vs. 8.3 weeks for D and E, respectively (HR=0.55, P=0.006). Methods: Based on phase II data, a randomized, double-blinded phase III clinical trial (ARCHER; NCT01360554) was designed to compare the efficacy of D with E in two co-primary populations of pts with adv NSCLC: (a) all enrolled pts with adv NSCLC, and (b) pts with KRAS WT NSCLC. Pts with locally adv/metastatic pathologically confirmed NSCLC, radiologically measurable disease, 1 or 2 prior chemotherapy regimens, ECOG PS 0–2, and tissue available for molecular analysis will be randomized to receive D 45 mg or E 150 mg orally once daily. As of Jan 31, 2012, 117 of a planned 800 pts have been enrolled. The primary endpoint is PFS. Secondary endpoints include overall survival, objective response rate, duration of response, safety and tolerability, and pt-reported outcomes of health-related quality of life and disease-/treatment-related symptoms. Study design provides 90% and 80% power to detect ≥33% and ≥45% improvement in PFS in all pts receiving D vs. E, and in pts with KRAS W T NSCLC, respectively, and HR ≤0.75 and ≤0.69 using a 1-sided stratified log-rank test at a significance level of 0.015 and 0.01, respectively. The final primary analysis stratified log-rank test will include ECOG PS, KRAS mutation status and EGFR mutation status as stratification factors. The sample sizes above will also allow the assessment of OS in the co‑primary populations with adequate power. Post-hoc analyses will be performed to explore EGFR, HER family, and KRAS mutation status, as well as other tumor-derived biomarkers collected from all pts in this trial.