bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of afatinib (BIBW 2992) in patients with advanced HER2-positive trastuzumab-refractory esophagogastric cancer.
Authors: Janjigian Yelena Yuriy , Ilson David , Kelsen David Paul , Schattner Mark , Heguy Adriana , Vakiani Efsevia 
Published: March 2020

TPS4144 Background: Trastuzumab, approved by the FDA, has been the standard of care for patients (pts) with HER2-positive esophagogastric cancer. Acquired and de novo resistance to trastuzumab is an important clinical issue. Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination with cetuximab, demonstrated a 40% partial response (PR) rate, with clinical benefit in >90% in lung cancer patients with acquired resistance to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive NCI-N87 gastric cancer xenograft showed that while trastuzumab alone was minimally effective, single-agent afatinib resulted in near complete tumor regression by inducing apoptosis and downregulation of HER2, p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In light of these data and the efficacy of afatinib in patients with trastuzumab-refractory breast cancer, we designed a phase II study to determine if afatinib will benefit patients with trastuzumab-refractory HER2-positive esophagogastric cancer. We hypothesize that simultaneous inhibition of ErbBB receptor family components with afatinib will overcome trastuzumab resistance. Molecular bases of trastuzumab resistance will be examined. Methods: Pts with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression on a trastuzumab-containing regimen will receive afatinib 40 mg once daily. Primary endpoint RECIST 1.1 response (SD+CR+PR) at 4 months, with imaging every 8 wks. 13 pts will be enrolled in the 1st stage and if ≥1 responses are observed, additional 14 ps (total of 27) will be treated. An initial biopsy prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis of archival pre-trastuzumab tissue and blood sample for matched normal DNA control are mandated. Changes in signaling following afatinib therapy will provide insight into response heterogeneity. Degree of target inhibition will be correlated with responses. Archival baseline (pre-trastuzumab) and pre-afatinib tissue will be assessed for abnormalities in pathways implicated in trastuzumab resistance.
A multicenter, randomized, double-blind, phase III study of ramucirumab (IMC-1121B; RAM) and best supportive care (BSC) versus placebo (PBO) and BSC as second-line treatment in patients (pts) with hepatocellular carcinoma (HCC) following first-line therapy with sorafenib (SOR).
Authors: Zhu Andrew X. , Chau Ian , Blanc Jean-Frédéric , Okusaka Takuji , Rojas Maria , Yang Ling , Von Broen Ingo 
Published: March 2020

TPS4146 Background: Blockade of vascular endothelial growth factor (VEGF) signaling in HCC has been shown in preclinical models with monoclonal antibodies and small molecule multikinase inhibitors, and in clinical trials with SOR, to have anti-tumor activity and improve survival. RAM, a fully human monoclonal antibody, binds to the VEGF receptor-2 (VEGFR-2), potently blocks the binding of the VEGF ligand to VEGFR-2, inhibits VEGF-stimulated activation of VEGFR-2, and neutralizes VEGF-induced mitogenesis of human endothelial cells. In a single-arm, Phase 2 study of RAM as 1st-line monotherapy in 42 pts with advanced HCC (Zhu, ILCA 2010, abstr. O-033), preliminary results included median progression-free survival (PFS) of 4 months (m), time to progression (TTP) of 4.2 m, overall survival (OS) of 12 m and disease control rate of 70% (best overall response: 10% partial response, 60% stable disease). Methods: Pts with HCC with disease progression during or following 1st-line therapy with SOR (or who were intolerant to SOR) are randomized 1:1 to receive RAM (8 mg/kg) or PBO once every 2 weeks, with BSC, until disease progression or intolerable toxicity. Eligibility includes prior SOR as 1st-line systemic treatment for HCC, Child-Pugh A, B7 or 8 cirrhosis, ECOG PS 0-1, bilirubin < 3 mg/dL, transaminases ≤ 5 × upper limit of normal (ULN), creatinine ≤ 1.2 × ULN, and platelets ≥ 75×103/µL. The primary endpoint is OS. Secondary endpoints include PFS, best objective response rate, TTP, patient-reported outcome measures of disease-specific symptoms and health-related quality of life, safety, and RAM pharmacokinetics, pharmacodynamics, and immunogenicity. With 544 patients, this study is designed to detect an increase in OS (median 6 m with PBO to 8 m with RAM; 1-sided α= 2.5%, 85% power). As of 18 January 2012, approximately 52% of planned pts have been randomized. The IDMC reviewed this study on 21 June and 3 November 2011 and recommended the study to continue unmodified.
Treatment of refractory metastatic renal cell carcinoma (RCC) with lenvatinib (E7080) and everolimus.
Authors: Molina Ana M. , Motzer Robert John , Hutson Thomas E. , Larkin James M. G. , Gold Anne , Andresen Corina , Wood Karen , Michaelson M. Dror 
Published: March 2020

TPS4682 Background: Lenvatinib (E7080) is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor 1-4, RET, KIT and platelet-derived growth factor receptor beta. Lenvatinib has demonstrated acceptable toxicity and antitumor activity in Phase I and II studies (Glen H et al. JCO 2008, 26;15S: 3526;Yamada K et. al. Clin Cancer Res 2011, 17:2528-2537; Sherman S I et al. JCO 2011, 29; 15S: 5503). Improved understanding of the molecular basis of renal cell carcinoma (RCC) has led to the development of targeted therapies (inhibitors of mTOR and of the VEGF pathway) that have shown clinical benefit in patients with metastatic RCC. However patients develop resistance and ultimately progress during treatment with available single agents. Combination therapy targeting different pathways have the potential to improve efficacy. Methods: This multicenter, randomized, open-label, phase Ib/II study is investigating everolimus (an oral mTOR inhibitor) in combination with lenvatinib in RCC patients with unresectable or metastatic disease (NCT01136733). The study is being conducted in two phases. The phase Ib dose-escalation component will determine the maximum tolerated dose (MTD) of the combination; starting doses are 12 mg/day lenvatinib and 5 mg/day everolimus. A cohort expansion will follow to confirm the MTD and establish a recommended phase II dose (RP2 dose). Approximately 150 patients will be enrolled in phase II and randomized 1:1:1 to receive: lenvatinib and everolimus at the RP2 dose (Arm A); lenvatinib 24 mg/day (Arm B); or everolimus 10 mg/day (Arm C). Patients with clear cell RCC, ECOG performance score <2 and progression during or after one prior VEGF-targeted treatment are eligible for phase II. The primary endpoint for Phase II is to compare progression-free survival of the investigational arms (A and B) with single agent everolimus (Arm C). Three phase Ib dose escalation cohorts have completed enrollment, and enrollment of the expansion cohort commenced in November 2011. Participating phase II centers will be located in the US, UK, Spain, Poland and Czech Republic and are expected to enroll patients throughout 2012.
Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC).
Authors: Swanton Charles , Cromer Jamie ,   1200.89 study group
Published: March 2020

TPS650 Background: IBC is an aggressive and rare form of BC (1–6% cases). Despite recent treatment advances, prognosis remains poor, with 3-yr survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbour HER2 gene ampliﬁcation (~40%), and EGFR overexpression (~30%) associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in T-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM 149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, HER2-positive metastatic BC pts who progressed after T, with PR in 10% and clinical benefit in 46% of pts. The purpose of this biomarker-driven study is to investigate efficacy and safety of afatinib alone and in combination with V upon progression on afatinib monotherapy and the genomic changes that occur through treatment in pts with T pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. Key eligibility criteria: histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and oedema (peau d’orange) while dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon disease progression, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m2/week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or SD) for ≥6 months. Secondary endpoints: objective response rate, PFS, OS and safety. Endpoints are assessed separately for Part A and Part B. Fresh biopsy and blood samples are taken prior to treatment and upon progression in Part A, to explore predictive markers of response/resistance to afatinib, to describe the IBC population which may benefit most, and for next generation sequencing and proteomic analysis. Enrollment ongoing since Aug 2011.
Pertuzumab in combination with trastuzumab plus an aromatase inhibitor in patients with hormone receptor-positive, HER2-positive metastatic breast cancer: A randomized phase II study (PERTAIN).
Authors: Rimawi Mothaffar F. , Poole Christopher John , Ferrero Jean-Marc , De la Haba Rodriguez Juan R. , Mitchell Lada , Pelizon Christina H. , Arpino Grazia 
Published: March 2020

TPS654^ Background: Resistance to endocrine therapy in patients (pts) with breast cancer remains a major clinical concern. Preclinical studies suggest that complete blockade of the hormone receptor (HR) combined with the inhibition of HER family members may be necessary to overcome resistance and improve clinical outcome in HR-positive and HER2-positive breast cancer (BC). The combination of pertuzumab (P) and trastuzumab (H) with docetaxel significantly improves patient outcome by blocking, more efficiently and completely, the HER signalling pathway. This benefit, however, may be smaller in HR-positive patients. PERTAIN is the first clinical trial to study whether a more potent blockade of the HER pathway with P and H in combination with endocrine therapy may restore or enhance endocrine sensitivity of HER2-positive BC and provide an effective treatment option in pts with HER2-positive and HR-positive MBC. Methods: PERTAIN is a multicenter, open-label, Phase II trial for post-menopausal women with HER2- and HR-positive BC, studying the efficacy of the combination of P plus H with an aromatase inhibitor (AI) as first-line therapy for MBC. Pts will be randomized 1:1 to Arm 1 (P: 840 mg loading dose, 420 mg q3w IV; H: 8 mg/kg loading dose, 6 mg/kg q3w IV; AI [anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H + AI at same dose as Arm 1). Pts in either arm may also receive induction chemotherapy (docetaxel or paclitaxel) for up to 18 weeks at the investigator’s discretion. Study medication will be administered until disease progression or unacceptable toxicity. Pts must not have previously been treated with anti-HER2 agents except H and/or lapatinib in the (neo)adjuvant setting, and must have no CNS involvement or clinically significant cardiovascular disease. The primary endpoint is PFS, and secondary endpoints include overall survival, overall response rate, clinical benefit rate, duration of response, time to response, safety and tolerability, and quality of life. The study opened in January 2012 and will recruit 250 pts. Analysis of the primary endpoint will be performed after 165 PFS events using the Kaplan-Meier approach.
A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2-positive (HER2+) breast cancer.
Authors: Munster Pamela N. , Miller Kathy , Krop Ian E. , Dhindsa Navreet , Reynolds Joe , Geretti Elena , Niyikiza Clet , Nielsen Ulrik , Hendriks Bart , Wickham Thomas J. , Moyo Victor M. , LoRusso Patricia 
Published: March 2020

TPS663 Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use in the clinic and led to the exploration of anthracycline-free regimens, particularly with HER2-positive cancers that require treatment with another cardiotoxic agent, trastuzumab. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clear-cut efficacy advantages and can involve other toxicities. To address the safety and efficacy limitations of currently available anthracyclines, we have designed a new liposomal formulation, MM-302, that targets doxorubicin to HER2-overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin. MM-302 specifically binds and enters tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. This first-in-human phase I study evaluates the safety of MM-302 in patients and provides preliminary efficacy data in HER-2+ advanced breast cancer (ABC). Methods: Patients aged > 18 years with histologically confirmed HER-2+ advanced breast cancer that have progressed or recurred on standard therapy or for which no standard therapy exists who have adequate performance status, bone marrow reserve, and organ function, are eligible for the study. Following a standard 3 + 3 dose escalation design, the maximum tolerated dose (MTD) or maximum feasible dose (MFD) is determined and up to 25 additional patients with HER-2+ ABC will be enrolled for a planned total of 40-49 patients. The primary endpoint is determination of the MTD/MFD. Secondary endpoints include determination of dose-limiting toxicity, adverse event(s), and pharmacokinetic and immunogenicity profiles of MM-302, as well as overall response and clinical benefit rates of MM-302. MM-302 is administered intravenously weekly in 4-week cycles. At the time of this submission, 8 patients have been enrolled in the dose escalation portion.
JAKARTA: A phase III, multicenter, randomized, double-blind, placebo-controlled, three-arm study of SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF with splenomegaly.
Authors: Pardanani Animesh Dev , Cortes Jorge E. , Cervantes Francisco , Harrison Claire N , Passamonti Francesco , Lebedinsky Claudia , Neumann Frank , Cohen Pamela , Tefferi Ayalew 
Published: March 2020

TPS6639 Background: SAR302503 is an orally administered selective JAK-2 inhibitor being evaluated for the treatment of MF. In a phase 1 study, SAR302503 reduced spleen size and disease-related symptoms and provided clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in patients with primary MF, post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789). An ongoing open-label extension of this trial confirmed the durability of those results and found that doses between 400–500 mg/day of SAR302503 represented the optimal balance between safety and efficacy (Pardanani, ASH 2011;Abs 3838). These results led us to initiate a Phase 3 trial in December 2011 to evaluate SAR302503 at doses of 400 mg/day and 500 mg/day, compared with placebo, for the treatment of patients with MF (NCT01437787; EFC12153). Methods: Eligibility criteria include age of at least 18 years, platelets >50,000/µl, ECOG PS 0–2, and a diagnosis of high- or intermediate-risk 2 primary MF, post-PV MF, or post-ET MF according to IPSS criteria (Blood 2009;113:2895). Patients are being randomized (1:1:1) to receive 400 mg or 500 mg of SAR302503 or placebo orally once a day for at least 6 consecutive 28-day cycles. Assigned treatment will continue as long as patients are deriving benefit or until progression or unacceptable toxicity. Cross-over is allowed after 6 cycles or in case of progression before completion of 6 cycles according to predefined criteria. The primary endpoint is spleen response (≥35% reduction in spleen volume by MRI/CT at the end of cycle 6). Key secondary objectives are symptom response rate and durability of spleen response. Additional secondary endpoints include assessment of allele burden and bone marrow fibrosis reduction. It is planned to randomize 75 patients per treatment group at approximately 130 sites worldwide.
A phase I study of BKM120, a novel oral selective phosphatidylinositol-3-kinase (PI3K) inhibitor, in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer.
Authors: Nagaraj Gayathri , Ma Cynthia X. , Luo Jingqin , Ellis Matthew J. 
Published: March 2020

TPS664 Background: PI3K pathway activation plays a crucial role in mediating endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. We have shown previously that BKM120 in combination with fulvestrant induced synergistic apoptotic cell death in long-term estrogen deprived ER+ breast cancer (LTED) cell line models, supporting the clinical investigation of this combination in ER+ breast cancer. Methods: The study is composed of the dose escalation cohort (phase IA) and the expansion cohort (phase IB). In phase IA, a standard 3+3 phase I design is employed to determine the maximum tolerated dose (MTD) of the combination of BKM120 and fulvestrant in patients (pts) with ER+ metastatic breast cancer (MBC). In phase IB, an additional 10 pts will be enrolled at the MTD to further examine the toxicity profile and preliminary efficacy of this combination. Steady state concentrations of BKM120 will be analyzed. Postmenopausal women with ER+ MBC and measurable disease per RECIST are eligible. Pts who are currently taking fulvestrant without disease progression are eligible. There is no restriction on the number of prior lines of systemic therapy for metastatic disease in phase IA but < 3 lines is required in phase IB. Treatment consists of fulvestrant 500 mg IM administered monthly on day (d) 1 of each 28-d cycle, following the loading dose of 500 mg on d1 and d15, and BKM120 orally daily on d1-28 of each cycle. The starting dose level (DL) is DL1 (Table). Correlative studies include assessing PI3K pathway abnormalities (loss of PTEN and PIK3CA mutation) on archival tumor specimen, and treatment induced inhibition of PI3K pathway activity (pAKT, pS6, Cyclin D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation (Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining) on tumor biopsies collected at baseline and cycle 2 day 1 in consented patients. Enrollment to DL1 is complete and the study is currently enrolling pts to DL2. [Table: see text]
ASTER 70s: Benefit of adjuvant chemotherapy for estrogen receptor-positive HER2-negative breast cancer in women over 70 according to genomic grade—A French GERICO/UCBG UNICANCER multicenter phase III trial.
Authors: Brain Etienne , Girre Veronique , Rollot Florence , Bonnetain Franck , Debled Marc , Lacroix Magali , Baffert Sandrine , Latouche Aurelien , Falandry Claire , Peyro Saint Paul Helene P. , Orsini Christine , Andre Fabrice , Bonnefoi Herve R. ,   UNICANCER GERICO and UCBG groups
Published: March 2020

TPS667 Background: The benefit of adjuvant chemotherapy (CT) is highly controversial for elderly breast cancer (BC) women presenting with an oestrogen receptor-positive (ER+) HER2-negative (HER2-) phenotype. Conversely to hormonal treatment (HT) that remains the cornerstone of adjuvant treatment for such luminal tumours, CT may severely decompensate comorbidities and alter quality of life in elderly patients. As disappointing as it is in drug development, elderly have been constantly excluded from trials evaluating new modern prognosis classifiers. This prospective multicentre trial funded by a French national grant (PHRC 2011) is the first phase III trial to investigate the impact on overall survival (OS) of adjuvant CT in elderly ER+ HER2- BC patients selected with a modern prognosis classifier and taking into account competing risks for mortality (EudraCT 2011-004744-22). Methods: Following surgery, 2,000 women 70+ with ER+ HER2- BC (any pT/pN), will have a genomic grade (GG, derived from frozen MapQuantDx™, Ipsogen) centrally assessed on formalin-fixed paraffin-embedded samples. Only those with a high GG (estimation~700) will be randomized between HT alone vs CT followed by HT. CT regimen is left to the choice of investigators amongst 3 regimen of same duration [4 q3w cycles, docetaxel+cyclophosphamide, doxorubicin or non pegylated liposomal doxorubicin (Myocet)+cyclophosphamide, all with G-CSF], as well as HT (aromatase inhibitor±tamoxifen). Those with low GG or not included for other reasons (estimation~1,300) will be followed as an observational parallel cohort with HT alone. Sample size is based on 4-year OS as primary endpoint (87.5 vs 80%), bilateral α=0.05, β=0.20 and HR= 0.60. Secondary endpoints include assessment of competing risks for mortality, cost-effectiveness and Q-TWiST analysis, geriatric items (e.g. Lee’s 4-year mortality score and G8 screening tool), acceptability, quality of life (QLQ-C30 and specific elderly scale ELD15), and translational research on ageing/prognostic biomarkers and pharmacogenetic. The trial has been just opened to inclusion in February 2012.