bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of riluzole and sorafenib in patients with advanced solid tumors and melanoma.
Authors: Mehnert Janice M. , Semlani Neha , Wen Yvonne , Tan Antoinette R. , Moss Rebecca Anne , Adams Shari , Stein Mark N. , Ross Mikel , Kane Michael P. , Gibbon Darlene , Wright John Joseph , Aisner Joseph , Chen Suzie , Goydos James S
Published: March 2020

TPS3112

Background: Metabotropic glutamate receptor 1 (GRM1) has been identified as a potential therapeutic target in melanoma. Over 60% of human melanomas express this cell surface glutamate receptor and excitation of GRM1 results in the activation of MAPK and PI3K/AKT pathways. Riluzole, an oral GRM1 blocking agent, results in growth arrest of melanoma cells in vitro and in vivo. We previously reported that administration of riluzole to melanoma patients suppressed activity of the PI3K/AKT and MAPK pathways in paired tumor samples (Yip Clin Cancer Res 2009). In preclinical studies, the efficacy of riluzole was attenuated in melanoma cells harboring BRAFV600E mutations, but sorafenib, a RAF kinase inhibitor, enhanced the effect of riluzole on these cells. The combination of riluzole and sorafenib was additive or synergistic in both BRAF mutant and BRAF wildtype melanoma cells in vitro and in BRAF wildtype cells in a xenograft model (Lee HJ Clin Cancer Res 2011). We thus designed a phase I trial to test the combination of riluzole with sorafenib in patients with solid tumors and advanced melanoma. Methods: The primary objective of this trial is identification of the maximum tolerated dose (MTD). An expansion cohort at the MTD is planned for patients with advanced melanoma to examine the correlation of clinical or radiographic response with signaling through the MAPK and PI3K/AKT pathways and with GRM1 receptor status of individual tumors. Eligible patients must have advanced solid tumors (phase I) or stage III unresectable/stage IV melanoma with biopsiable tumor (expansion cohort) and ECOG PS ≤ 2. Riluzole will be administered at 100 mg twice daily combined with sorafenib beginning at 200 mg daily and escalating in subsequent cohorts at 200 mg increments. Correlative studies: Tumors will be assessed for BRAF and NRAS mutational status. Pretreatment tumor blocks will be examined for GRM1 receptor status by immunohistochemistry. Pre and post treatment levels of pERK and pAKT will be measured in paired tumor samples to assess effects of treatment on MAPK and PI3K signaling. Limited sampling pharmacokinetic studies will be performed. Progress: Accrual to three cohorts is complete without DLT. Accrual to the final planned cohort is in progress.
A randomized, phase II, multicenter, double-blind, placebo-controlled study evaluating onartuzumab (MetMAb) in combination with mFOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer.
Authors: Bendell Johanna C. , Ervin Thomas J. , Gallinson David H. , Singh Jaswinder , Wallace James Alfred , Saleh Mansoor N. , Vallone Marcy , Hack Stephen Paul
Published: March 2020

TPS3640

Background: Dysregulation of the HGF/Met (Met) pathway has been linked with poor prognosis in colorectal cancer. Crosstalk between the Met and vascular endothelial growth factor (VEGF) pathways may be important during tumorigenesis. Aberrant activation of the HGF/Met pathway may promote angiogenesis via tumor cell secretion of angiogenic factors or directly activating endothelial cells. Onartuzumab (MetMAb) is a monovalent, monoclonal antibody that specifically binds to the Met receptor. The combination of onartuzumab and VEGF inhibition in preclinical models resulted in enhanced antitumor activity over either treatment alone. Preclinical efficacy data support the combination of onartuzumab with platinum agents. In phase I studies, onartuzumab has been generally well tolerated alone and in combination with bevacizumab. Adverse events most commonly associated with onartuzumab are peripheral edema and fatigue. Methods: This is a randomized, two-arm, phase II study in patients with previously untreated metastatic colorectal cancer. Patients (n=188) will be randomized (1:1) to either mFOLFOX6/bevacizumab/placebo or mFOLFOX6/bevacizumab/onartuzumab. Oxaliplatin will be discontinued after 8 cycles with remaining drugs continued until progression. The primary endpoint of this study is PFS in all patients. PFS by Met IHC diagnostic status (Met positive vs Met negative) will also be analyzed. Secondary endpoints include OS, ORR, safety, and biomarker analyses. Primary and secondary analyses will include all randomized patients and will be conducted according to assigned treatment arm. Kaplan–Meier methodology will be used to estimate median PFS for each treatment arm. An estimate of HR with 95% CI will be determined using a Cox regression model. Safety will be assessed in all patients receiving at least one dose of any treatment. This study is open for accrual; further details can be found on ClinicalTrials.gov (NCT01418222).
ATTACHE: A phase III, multicenter, randomized comparison of chemotherapy given prior to and post surgical resection versus chemotherapy given post surgical resection for hepatic metastases from colorectal cancer.
Authors: Fawcett Jonathan , Sjoquist Katrin Marie , Padbury Rob , Christophi Christopher , Tebbutt Niall Christopher , Pilgrim Charles Henry Caldow , Gebski Val , Wong Nicole , Aiken Christine , Goldstein David ,   Australasian Gastro-Intestinal Trials Group (AGITG)
Published: March 2020

TPS3643

Background: No randomized studies have directly compared the role of peri-operative to adjuvant chemotherapy for resectable liver metastases. Benefit from post operative compared to peri-operative treatment has been suggested in a recent retrospective study of 499 patients with resected colorectal liver metastases which showed improved survival with entirely post-operative chemotherapy. Given this data and that of the small randomised trials demonstrating improved surgical outcomes with adjuvant chemotherapy, the role of entirely post-operative chemotherapy as a means of improving outcomes while reducing the negative effects of pre-operative treatment needs to be examined. Methods: 200 patients randomized 1:1 to 6 months of treatment post-operatively or 3 months of treatment pre-operatively and 3 months post-operatively. Site investigators will nominate chemotherapy schedule (mFOLFOX6, XELOX or FOLFIRI when adjuvant oxaliplatin received previously) prior to randomisation. Primary endpoint: proportion of patients in each arm with surgical complications within 30 days. Secondary endpoints: proportion of patients completing planned chemotherapy, post operative mortality rate (in each group), tolerability and safety of treatment, response rate by RECIST V1.1 and CEA, time to progression, time to treatment failure, overall survival, QoL (EORTC QLQ-C30 and QLQ-LMC21). A planned prospective meta-analysis with MRC (UK) and NSABP C-11 trials will have sufficient power to examine the effect of schedule (peri- or post-operative) on progression free survival (PFS). Eligibility: Patients with histologically proven colorectal cancer with radiologically confirmed, resectable liver metastases without evidence of extra-hepatic disease are eligible. Patients with synchronous metastases who have undergone resection of the primary tumour are eligible but patients requiring combined resection of primary cancer and liver metastatic disease are excluded. Patients with involved hilar nodes or wound implant metastases will not be eligible. Trial Status: Study opened to accrual August 2011.
PaFLO: Pazopanib with 5-fluorouracil, leucovorin, and oxaliplatin (FLO) as first-line treatment in advanced gastric cancer: A randomized phase II study of the Arbeitsgemeinschaft internistische Onkologie (AIO).
Authors: Breithaupt Kirstin , Bichev Dmitry , Lorenz Mario , Bohnen Daniela , Dogan Yasemin , Schlattmann Peter , Al-Batran Salah-Eddin , Moehler Markus Hermann , Thuss-Patience Peter C.
Published: March 2020

TPS4138

Background: VEGF inhibition in gastric cancer shows promising improvement of remission rate and progression-free survival (Ohtsu et al., JCO 2011). Pazopanib is an orally available tyrosine kinase inhibitor (TKI) selectively inhibiting VEGFR-1, -2, -3, c-kit and PDGFR. It is approved for treating renal cell cancer. A phase-I trial showed good tolerability of pazopanib with full-dose FOLFOX in solid tumors (Brady et al., ASCO, 2009). FLO is a widely used combination for advanced gastric cancer recommended in national guidelines. Methods: 75 Patients with HER-2-negative locally advanced or metastatic adenocarcinoma of the stomach or the gastro-esophageal junction will be randomized in a 2:1 ratio to A: FLO (F 2600mg/m2 as 24h infusion, L 200mg/m2, O 85 mg/m2) d1 + pazopanib (800mg) d1-14 and B: FLO; repeated for 12 2-week cycles, followed by a maintenance therapy with pazopanib alone in A and an observation period in B until disease progression. Primary endpoint is progression-free survival rate (PFSR) at 6 months, secondary endpoints are PFSR at 9 and 12 months, median PFS, response rate, duration of response, toxicity, tolerability and overall survival. Additionally, we evaluate the predictive and prognostic relevance of PIGF, VEGF, and the respective soluble receptors sVEGFR1 and sVEGFR2 as biomarkers for clinicopathological parameters, clinical response to treatment and tumor volume change. Based on a phase-III trial demonstrating a 6-month PFSR of 44% with FLO (Al-Batran et al., 2008), we estimate a 6-month PFSR of 55% in the experimental group. Given an alpha error of 0.1 and a beta error of 0.2 in a Simon 2-stage minimax design, in the first stage ≥12 of 30 patients need to be progression free at 6 months to continue and after the second stage ≥25 of 50 patients should be progression free at 6 months to justify further evaluation. Randomization is performed to estimate selection bias according to pazopanib-specific exclusion criteria for comparison with historical data. Study protocol received ethics committee approval in November 2011 and is currently recruiting patients in 15 AIO centers.
Postoperation chemotherapy with S1 and docetaxel in curatively resected gastric cancer of stage III (POST trial).
Authors: Jung Minkyu , Kang Seok Yun , Kim Bong-Seog , Kim Ki Hyang , Lee Kyung Hee , Lee Moon Hee , Shin Dong Bok , Zang Dae Young , Noh Sung Hoon , Chung Hyun Cheol , Rha Sun Young
Published: March 2020

TPS4142

Background: Complete surgical resections remains the only chance for cure in patients with gastric cancer, but approximately from 40% to 80% of patients still have recurrences and most patients ultimately die from their disease. The recent adjuvant trials in gastric cancer showed significantly improved survival in patients with adjuvant chemotherapy than those with surgery alone. However, further studies need for the effect of adjuvant chemotherapy following D2 dissected gastric cancer patients, especially in advanced gastric cancer. S-1 is an oral anticancer drug, a prodrug of fluorouracil, very effective in gastric cancer. Docetaxel is the first drug that showed survival benefits when added to the two drugs in advanced gastric cancer patients. And docetaxel is also synergistic anti-cancer effect with S-1 in advanced gastric cancer. Base on this background, the aim of this study is to detect a significant increase in 3 –year disease free survival (DFS) of adjuvant chemotherapy with docetaxel and S-1(DS) relative to those with S-1 and cisplatin (SP) in patients with stage III gastric cancer Methods: This study is an open-label, phase 3, randomized controlled trial, multicenter in South Korea. Patients with stage III (AJCC 7th edition) gastric cancer who had had curative D2 gastrectomy is randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of intravenous docetaxel (35 mg/m2 on day 1 and 8 of each cycle) plus oral S-1 (35 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months (DS) or chemotherapy of eight 3-week cycles of oral S1 plus intravenous cisplatin (60 mg/m2). After satisfying the screening criteria, patients have been randomized to the SD or SP arm in a 1:1 ratio. The randomization is stratified by institution and stage of disease (IIIA vs. IIIB vs. IIIC). The each stratum has been randomized by using the method of randomly permuted block. The primary endpoint is 3 year DFS, will analyze by intention to treat. A total of 290 patients will be enrolled, 67 patients have been treated to day, with continuing accrual. The trial is registered at ClinicalTrials.gov (NCT01283217).
Phase II trial of gemcitabine and cisplatin plus ipilimumab as first-line treatment for metastatic urothelial carcinoma.
Authors: Gartrell Benjamin Adam , Hahn Noah M. , Hutson Thomas E. , Sonpavde Guru , Hauke Ralph J. , Starodub Alexander , Small Alexander C. , Tsao Che-Kai , Galsky Matt D.
Published: March 2020

TPS4676

Background: While metastatic urothelial carcinoma is a chemosensitive neoplasm, current therapeutic approaches are inadequate. Preclinical and clinical data suggests that bladder cancer is immunogenic. For example, CD8+ tumor infiltrating lymphocytes correlate with survival in patients with muscle-invasive disease (Sharma, PNAS, 2007). However, immunotherapeutic approaches have been rarely investigated for advanced urothelial cancer. CTLA4 blockade with ipilimumab is a novel approach to immunotherapy that interrupts T-cell pathways responsible for immune down-regulation or tolerance. In a proof of concept study, ipilimumab was administered to 12 patients with muscle-invasive disease preoperatively (Carthon, Clin Can Res, 2010). Treatment resulted in perivascular infiltration of cells positive for CD3, CD8, CD4, and granzyme and intriguing evidence of antitumor activity. In the current trial, we will explore a “phased” schedule of chemotherapy and ipilimumab with the goal of “autovaccinating” patients to tumor antigen with chemotherapy prior to introduction of immune checkpoint blockade. Methods: We have initiated a phase II clinical trial of gemcitabine (G), cisplatin (C), plus ipilimumab in chemonaive patients with unresectable and/or metastatic urothelial cancer within the Hoosier Oncology Group network. During cycles 1 and 2, G (1000 mg/m2 D day 1 + 8) and C (70 mg/m2 D 1) will be administered every 21 days without ipilimumab. During cycles 3-6, GC plus ipilimumab (10 mg/kg day 1) will be administered every 21 days. Patients without evidence of disease progression after completion cycle 6 will continue single-agent ipilimumab “maintenance” every 3 months. The primary objective is to determine the 1-year overall survival. The trial will enroll 36 patients and is powered to detect an improvement in 1-year survival from 60% to 80%. Secondary objectives include progression-free survival, disease control rate, safety, and immunologic outcomes. Correlative studies will include serial measurements of the global composition of immune cells in the blood by polychromatic flow cytometry, whole blood transcriptional profiling, and tumor-antigen specific CD8+ T cells assays.
Phase I/II study of high-dose interleukin 2, aldesleukin, in combination with the histone deacetylase inhibitor entinostat in patients with metastatic renal cell carcinoma.
Authors: Pili Roberto , Shen Li , George Saby , Hammers Hans , Sandecki Anita , Collins Connie , Espinoza-Delgado Igor , Carducci Michael Anthony
Published: March 2020

TPS4687

Background: Immunosuppressive factors such as regulatory T cells (Tregs) limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have anti-tumor activity in different malignancies and to induce immuno-modulatory effects. We have previously reported that a class I specific HDAC inhibitor, entinostat, has synergistic anti-tumor effect in combination with high dose interleukin-2 (IL-2) in a renal cell carcinoma model (Kato Y et al Clinical Cancer Res 2007). Our group has also recently showed that low dose entinostat induces STAT3 acetylation, down-regulates Foxp3 expression in Tregs, and blocks Tregs suppressive function without affecting T effector cells (Shen Li et al PLoSONE 2012). Methods: Based on these preclinical evidences we have initiated a Phase I/II clinical study with entinostat and high dose IL-2 in patients with metastatic renal cell carcinoma. The primary objective of the study is to evaluate the safety, tolerability and efficacy of this combination strategy. The main eligibility criteria are clear cell histology, no prior treatments and being fit to receive high dose IL-2. The Phase I portion consists of two dose levels of entinostat (3 and 5 mg) and a fixed standard dose of IL-2 (600,000 units/Kg every 8 hrs.) according to a 3+3 design. The sample size of 36 patients in the Phase II portion is powered to detect an increase in objective response rate from 20% to 40% as compared to historical data with high dose IL-2 alone. Correlative studies include assessment of CD4+, CD8+, CD4+/Foxp3, NK cells in tumor and blood samples by immunohistochemistry and FACS analysis, and tumor metabolism by FDG PET. We are also exploring the relationship between entinostat exposure with pharmacodynamic endpoints. To date dose level one has been completed without DLT. Enrollment to dose level two has begun in the Fall 2011. The results from this study may confirm the role of entinostat in enhancing the effect of IL-2 and may be translated into other combination strategies involving immunotherapies. The clinical trial and correlative studies are supported by the National Cancer Institute- R21CA137649.
Phase II study of dovitinib in first-line metastatic or nonresectable primary adrenocortical carcinoma (ACC): SOGUG study 2011-03.
Authors: Jimenez Paula , Guix Marta , Lainez Milagro Nuria , Leon Mateos Luis , Mendez Vidal Maria Jose , Climent Duran Miguel Angel , Garcia-Donas Jesus ,   Spanish Oncology Genitourinary Oncology Group (SOGUG)
Published: March 2020

TPS4688

Background: Dovitinib is a novel targeted therapy, that has proven to inhibit, among other tyrosin kinases, the fibroblast growth factor receptor (FGFR). Since this pathway has been proposed to play a major role in ACC, we aim to test the clinical efficacy of dovitinib in this tumor. Methods: An open label phase II trial has been designed in patients with advanced non-resectable ACC. The objective will be to obtain at least a 15% response rate according to RECIST criteria. Taking as a basis the two-stage Gehan model, 15 patients would need to be included in the first stage to demonstrate a treatment efficacy of at least 15%. Sample size calculation was done based on the following parameters, probability of Type I error α = 0.05, power of the test (1 - β) = 0.8. Main inclusion criteria are advanced non-resectable disease and no prior therapy (other than mitotane). Dovitinib scheduled dose matches currently employed standard in the drug development (500mg daily for 5 days then 2 days off) for 6 months. If clinical benefit is obtained longer treatment will be allowed for particular patients. Since this is an extremely unfrequent disease 7 institutions, members of the SOGUG (Spanish Oncology Genitourinary Group), will participate. The active support of a big collaborative group will guarantee candidate patients to be refereed to such institutions. Starting January 26th 2012 recruitment is scheduled to last around 12 months. A translational research, including whole exome analysis, will be performed in order to improve our scarce knowledge of ACC.
CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients (pts) with metastatic chemotherapy-naive castration-resistant prostate cancer (CRPC).
Authors: Beer Tomasz M. , Logothetis Christopher , Sharma Padmanee , Bossi Alberto , McHenry Brent , Fairchild Justin P. , Gagnier Paul , Chin Kevin M. , Cuillerot Jean-Marie , Fizazi Karim , Gerritsen Winald R.
Published: March 2020

TPS4691

Background: Ipilimumab (Ipi), a fully human monoclonal antibody which blocks CTLA-4, augments antitumor immune responses. Ipi has demonstrated overall survival (OS) benefit in two Phase 3 trials for advanced melanoma, with side effects that were managed using product-specific treatment guidelines. In addition, in Phase 1/2 trials in metastatic CRPC, Ipi has shown clinical activity (as measured by prostate-specific antigen [PSA] declines and RECIST response) with no unexpected toxicities. While docetaxel is standard therapy for metastatic CRPC, its use may be delayed until pts develop symptoms. As such, this global (~150 sites in 25 countries) Phase 3 study (ClinicalTrials.gov identifier: NCT01057810) is evaluating Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or minimally symptomatic CRPC without visceral metastases. Methods: The primary endpoint is OS; secondary endpoints include progression-free survival, time to pain progression, and time to non-hormonal systemic therapy. The study is designed to detect a 9.3 month difference (HR=0.7) in OS with 90% power and 0.05 two-sided significance. Pts are randomized at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or placebo, respectively, as induction therapy. Eligible pts will continue to receive maintenance therapy of blinded study drug every 12 weeks until treatment stopping criteria are met, withdrawal of consent, or study closure. The accrual goal is 600 pts randomized. [Table: see text] [Table: see text]
First-line use of cabazitaxel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC): A three-arm study in comparison with docetaxel.
Authors: Oudard Stephane , Sengelov Lisa , Mainwaring Paul N. , Thiery- Vuillemin Antoine , Theodore Christine , Kulikov Evgeny , Yachnin Jeffrey , Kocak Ivo , Kataja Vesa V , Luukkaa Marjaana , Nosov Aleander , Hjelm-Eriksson Marie , Bubis Jeffrey , Shen Liji , Risse Marie-Laure , Sartor A. Oliver
Published: March 2020

TPS4696^

Background: Docetaxel (D) in combination with prednisone (P) as first-line (1L) chemotherapy in patients (pts) with mCRPC is the current standard of care. However, treatment is not curative and D-resistant disease typically develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and -resistant tumor models. Clinical activity of Cbz plus P (CbzP) was demonstrated in the Phase III TROPIC study in mCRPC pts previously treated with a D-containing regimen; CbzP showed a significant overall survival (OS) benefit vs mitoxantrone plus prednisone (median OS 15.1 vs 12.7 months; HR 0.70; P < 0.0001). Therefore, it is of interest to determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts. Methods: The phase III FIRSTANA study (NCT01308567) is a randomized, open-label, multinational trial in 1L mCRPC pts, designed to compare the efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm B) vs D 75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given concomitantly. Pts are stratified by ECOG PS (0–1 vs 2), measurable disease (yes/no) and region (depending on availability of Cbz as 2L). Pts with ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma, with no prior chemotherapy and with disease progression following medical or surgical castration are eligible. The primary endpoint is OS. Secondary endpoints include progression-free survival (PFS) (PCWG2 criteria), radiologic PFS, tumor response in measurable disease (RECIST 1.1), PSA response and PSA PFS, pain response and pain PFS, time to occurrence of any skeletal-related events, safety profile and health-related quality of life. Cbz pharmacokinetics and pharmacogenomics will be assessed in pt subgroups. Pts will be treated until progression, unacceptable toxicity or pt request. Planned enrollment is 1,170 pts; study size was calculated to achieve 90% power for OS. Study start was in May 2011; at January 2012, 219 pts were enrolled. The first DMC meeting recommended continuing the study without change.
A phase II study of the androgen signaling inhibitor ARN-509 in patients with castration-resistant prostate cancer (CRPC).
Authors: Rathkopf Dana E. , Shore Neal , Antonarakis Emmanuel S. , Berry William R. , Alumkal Joshi J. , Tutrone Ronald , Saleh Mansoor N. , Redfern Charles H. , Hauke Ralph J. , Liu Glenn , Steinbrecher Jill Elise , Danila Daniel Costin , Curley Tracy , Arauz Gabrielle , Rix Peter J. , Maneval Edna Chow , Chen Isan , Scher Howard I.
Published: March 2020

TPS4697

Background: ARN-509 is a novel small molecule androgen signaling inhibitor that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data suggests that the maximal therapeutic index of ARN-509 can be achieved at low steady state plasma levels with minimal toxicity (Clegg et al, 2012). Enrollment in the Phase 1 dose escalation study of ARN-509 in patients with progressive CRPC with and without prior chemotherapy was completed in January 2012. The recommended Phase 2 dose of 240 mg was determined based on safety, PSA kinetics, and pharmacokinetic and pharmacodynamic analysis (Rathkopf et al, GU ASCO, 2012). Methods: The primary objective of this Phase 2 study is to determine the PSA response at 12 weeks according to Prostate Cancer Working Group 2 (PCWG2) Criteria (Scher et al, 2008). Three expansion cohorts will enroll a total of 80-90 patients for treatment with 240 mg continuous oral ARN-509 daily. These cohorts include: 1) non-metastatic treatment-naïve CRPC (50 patients); 2) chemotherapy-naïve metastatic (m) CRPC (20 patients); and 3) chemotherapy-naïve, post abiraterone mCRPC (10-20 patients). The effect of food on the PK of ARN-509 and the effect of ARN-509 on ventricular repolarization will also be evaluated. Phase 2 enrollment is ongoing. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals. NCT01171898.
ACRIN 6695 perfusion CT as prognostic imaging biomarker in ovarian cancer.
Authors: Ng Chaan S. , Lee Ting Yim , Coleman Robert L. , Zhang Zheng , Dunning Bernadine , L'Heureux Darryl , Mannel Robert S. , Lee Susanna
Published: March 2020

TPS5114

Background: Tumor size and the cell surface glycoprotein CA125 levels have been traditional biomarkers for ovarian carcinoma, but remain suboptimal for assessing patients receiving chemotherapy. Current morphological criteria do not adequately evaluate lesion necrosis from anti-angiogenic therapy when no tumor volume change is measured. The evaluation of functional biomarkers rather than tumor volume may better distinguish responders from non-responders early in treatment with anti-angiogenic therapy. Perfusion CT can evaluate changes in tumor vascularity including blood flow (BF), blood volume (BV), mean transit time (MTT) and capillary permeability surface product (PS) before and after anti-angiogenic therapy with/out decrease in tumor volume. Objectives: The aims of the study are to evaluate the relationship between changes in tumor perfusion parameters and clinical outcomes of progression free survival, overall survival, and standard RECIST anatomic response criteria. A test-retest perfusion CT scan will also be performed to evaluate reproducibility of perfusion parameters in a subset of participants. Methods: In this collaborative trial, participants will be co-enrolled in the GOG-262 treatment trial. Participants will receive doublet chemotherapy of paclitaxel and carboplatin, followed by anti-angiogenic monoclonal therapy at cycle two. Perfusion CT will be performed at three time points: at baseline prior to therapy (T0), between days 18 and 21 of cycle one chemotherapy (T1), and at 8-10 days (T2) in anti-angiogenic monoclonal therapy. Participants with primary epithelial ovarian, peritoneal or fallopian tube cancer with optimally or suboptimally debulked FIGO Stage II, III or IV disease are eligible for the trial. Lesion eligibility will be evaluated by size and attenuation criteria. Accrual: ACRIN 6695 is activated at 12 GOG sites; 4/78 participants have accrued Discussion: Perfusion CT has been readily incorporated into the pre-existing clinical CT protocols and during scheduled RECIST scans. These perfusion CT functional maps of BF, BV, MTT and PS have been generated using vendor provided software without issue. Contact: Please contact Chaan Ng, MD cng@mdanderson.org for additional information.
LUX-breast 2: Phase II, open-label study of oral afatinib in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) who progressed on prior trastuzumab (T) and/or lapatanib (L).
Authors: Hickish Tamas , Tseng Ling-Ming , Mehta Ajay O. , Tsang Janice , Kovalenko Nadezhda , Udovitsa Dmitry , Pelling Katy , Uttenreuther-Fischer Martina Maria , Huang Chiun-Sheng ,   LUX-Breast 2 Study Group
Published: March 2020

TPS651

Background: Management of HER2-overexpressing MBC has improved over the past decade. However, pts still develop resistance to currently available HER2-targeted therapies and novel effective treatments are increasingly required as dual targeted combinations are given in early treatment lines already. Current therapies focus on targeting HER2 and do not inhibit all relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family Blocker that inhibits signaling through activated EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical studies have demonstrated efficacy in T-sensitive and T-resistant human BC xenograft models dependent on ErbB signaling. Efficacy of afatinib in a T-resistant SUM 190 xenograft model has been shown to be increased by addition of IV vinorelbine (V). Afatinib monotherapy has shown promising clinical benefit in 46% of HER2-overexpressing MBC pts who progressed on prior T, with 10% of pts achieving PR. Methods: This open-label Phase II trial (NCT01271725) investigates efficacy and safety of afatinib alone (40 mg/d) followed by afatinib ‘beyond progression’ plus chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed on prior neoadjuvant and/or adjuvant T and/or L. Pts who progress on afatinib monotherapy receive afatinib plus either weekly paclitaxel (P) 80 mg/m2 or V 25 mg/m2. Eligible pts have confirmed HER2-overexpressing BC, stage IV disease measurable by RECIST 1.1, progressed on T and/or L therapy in either neoadjuvant and/or adjuvant setting, are eligible for retreatment with P or V and should not have been pretreated with P (≤12 months) or V, respectively. Exclusion criteria: inadequate cardiac, renal, hepatic and hematological function, pre-existing gastrointestinal dysfunction, rapidly progressing visceral disease, ILD and active brain metastases. The primary endpoint is objective response (OR) and secondary endpoints include best overall response, duration of OR and PFS; safety will be assessed separately for afatinib mono- and combination therapy. Patient enrollment began in May 2011 in ~35 sites and 5 countries.
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.