bluuebunny/crossref_metadata_2025 huggingface dataset:
HIT antibody positivity as a predictor for early cancer diagnosis.
Authors: Alirhayim Zaid , Dyal Herman , Heidemann Danielle , Perez Cesar Ochoa , Alarhayem Abdulqader , Hassan Syed , Qureshi Sophia , Khalid Fatima , Alqalyoobi Shehabaldin , Qureshi Waqas
Published: March 2020

e22184

Background: Heparin induced thrombocytopenia (HIT) is known to be caused by the presence of PF 4 antibody. Tumors exert immunomodulatory effects on the host immune response, including development of antibodies. Our aim was to analyze the presence of HIT in cancer patients and determine if HIT Ab is an adverse risk factor in patients with cancer. Methods: Patients with suspected HIT were selected. A case – control study was designed with 1:1 age and gender matched controls. We used chi – square analysis to compare proportions and Cox proportional hazard model to detect various predictors. Time to survival analysis was performed using Kaplan – Meier method. Results: Of 600 patients, 300 (63±15 years, women 48.8%) had a mean 4T pre – probability score of 4 ± 1.6. There were 132 cancers in both groups. 65 of these (49.2%) were in patients with probable HIT. The numbers of carcinomas and sarcomas were not significantly different between the two groups. There were no significant differences between the two groups when comparing the number of cancer diagnoses or the particular types of cancer diagnosed. The mean time to detection of cancer was within 9 ± 23 months for patients with HIT Ab versus 31 ± 54 months in cancer patients without HIT Ab (p <0.0001). In addition, there was a greater number of patients with at least 2 primary cancers among the HIT Ab positive group (p = 0.003). No predictive relationship between the type of cancer and the presence of HIT Ab was found (p >0.05). Patients with advanced cancer (stage 3 or 4) were also more likely to be HIT Ab positive (HR 3.61; 95% CI 1.31 – 10.11, p = 0.013). Cancer patients with HIT Ab were more likely to have venous thromboembolism as compared to cancer patients without HIT Ab (7.7% vs. 4.7, p = 0.0001). Kaplan – Meier’s showed worse mortality for cancer patients with HIT Ab than patients without the HIT Ab (Breslow statistic = 0.04). Conclusions: Among our cohort with suspected HIT, cancer was a common finding. Patients with HIT antibody positivity were more likely to have a new cancer diagnosis within 1 year of a positive result. These patients were also more likely to have thromboembolic complications and worsened mortality. These findings require further study, but perhaps suggest that the presence of HIT Ab should trigger earlier surveillance for cancer.
Association between c-Met and lymphangiogenic factors in patients with colorectal cancer.
Authors: Kim Kyoungha , Kim Hanjo , Lee Min Young , Ahn Tae Sung , Yun Jina , Kim Se Hyung , Kim Hyun Jung , Lee Sang Cheol , Bae Sang-Byung , Kim Chan Kyu , Lee Namsu , PARK Seong Kyu , Lee Kyu Taek , Won Jong-Ho , Hong Dae Sik , Park Hee Sook , Park Suk-Young , Lee Moon Soo , Baek Moo Jun
Published: March 2020

e22199

Background: Lymphangiogenesis plays an important role in cancer metastasis. Although animal models show a strong relationship between lymphangiogenesis and lymph node metastasis and survival, the clinical significance of lymphangiogenesis in colorectal cancer (CRC) remains uncertain. The goal of this study was to evaluate the association between c-Met and lymphangiogenic factors and to elucidate their prognostic significance for patients with CRC. Methods: A total of 379 tissue samples were obtained from surgically resected specimens from patients with CRC in Soonchunhyang University Cheonan Hospital between January 2002 and December 2010. The expressions of c-Met, vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, and podoplanin were examined by immunohistochemistry. The expression of each marker and clinical factors were analyzed. Results: Three hundred and one of 379 (79.4%) tissues had c-Met expression. High expression of c-Met in tumor cells was significantly associated with high expression of VEGF-C (P < .001) and VEGFR-3 (P = .001). But, there was no statistically significant association with podoplanin (P = .587) and VEGF-D (P = .096). Of the 103 evaluable patients, expression of c-Met in tumor cells was significantly associated with advanced clinical stage (P = .020), positive lymph node status (P = .038), and high expression of VEGF-C (P = .020). But, there was no statistically significant association with podoplanin (P = .518), VEGFR-3 (P = .085), VEGF-D (P = .203), and overall survival (P = .360). Conclusions: Our results provide indirect evidence for an association and possible regulatory link of c-Met with the lymphangiogenic factors. But, c-Met expression in patients with CRC are not prognostic indicator for overall survival in this retrospective study.
Cyclophosphamide-induced renal damage in nude mice prevented by traditional Chinese medicine (TCM) herbal mixture LQ.
Authors: Wu Chengyu , Zhang Lei , Hoffman Robert M.
Published: March 2020

e22210

Background: Renal damage is a dose-limiting side effects of cyclophosphamide (CYC). In the current study, we determined if a TCM herbal mixture LQ could be protective against CYC renal toxicity. Methods: Mice were treated with CYC or CYC+LQ. The histology of each organ was observed under microscopy after H&E staining. Results: The histology of the heart, liver, spleen, lung and intestine showed normal histopathological structure in all groups. The kidney of the CYC-treated mice showed toxicity including the glomeruli, the tubules, and the interstitium. The structures of the cortex in CYC pretreated group showed a disconnection between glomeruli and tubules. The ducts in the medulla were destroyed. In contrast, the kidneys in the control mice, LQ-treated mice, and CYC+LQ-treated mice showed normal architecture of the kidney cortex and medulla. In the untreated controls and the CYC+LQ-treated mice, the cortex showed normal renal corpuscles, proximal convoluted tubules, and distal convoluted tubules. The inner medulla and outer medulla all contained a thick ascending limb of the loop of Henle, and interstitial connective tissue. LQ also protected against weight loss and cachexia induced by CYC. Conclusions: TCM is a promising for combination with CYC to reduce toxicity.
Randomized phase III trial of imatinib (IM) rechallenge versus placebo in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) after failure of at least both IM and sunitinib (SU): Right study.
Authors: Kang Yoon-Koo , Ryu Min-Hee , Ryoo Baek-Yeol , Kim Hyun Jin , Lee Jong Jin , Yoo Changhoon , Nam Byung-Ho , Ramaiya Nikhil , Jagannathan Jyothi Priya , Demetri George D.
Published: March 2020

LBA10502

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
MAP plus maintenance pegylated interferon α-2b (MAP-IFN) versus MAP alone in patients (pts) with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomization.
Authors: Bielack Stefan S. , Smeland Sigbjorn , Whelan Jeremy , Marina Neyssa , Hook Jane , Jovic Gordana , Krailo Mark D. , Butterfass-Bahloul Trude , Kühne Thomas , Eriksson Mikael , Teot Lisa A. , Gelderblom Hans , Kager Leo , Sundby Hall Kirsten , Gorlick Richard Greg , Randall R. Lor , Hogendoorn Pancras C. W. , Calaminus Gabriele , Sydes Matthew Robert , Bernstein Mark L.
Published: March 2020

LBA10504

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation: Final results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study.
Authors: Stupp Roger , Hegi Monika E. , Gorlia Thierry , Erridge Sara , Grujicic Danica , Steinbach Joachim Peter , Wick Wolfgang , Tarnawski Rafal , Nam Do-Hyun , Weyerbrock Astrid , Hau Peter , Taphoorn Martin JB , Nabors Louis B. , Reardon David A. , Van Den Bent Martin J. , Perry James R. , Hong Yong Kil , Hicking Christine , Picard Martin , Weller Michael ,   on behalf of the European Organisation for Research and Treatment of Cancer (EORTC), the Canadian Brain Tumor Consortium, and the CENTRIC Study Team
Published: March 2020

LBA2009

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III trial comparing chemoradiation (CRT) with and without BEV in patients with newly diagnosed glioblastoma (GBM).
Authors: Sulman Erik P. , Won Minhee , Blumenthal Deborah T. , Vogelbaum Michael A. , Colman Howard , Jenkins Robert B. , Chakravarti Arnab , Jeraj Robert , Brown Paul D. , Jaeckle Kurt A. , Schiff David , Dignam James , Atkins James Norman , Brachman David , Werner-Wasik Maria , Komaki Ritsuko , Gilbert Mark R. , Mehta Minesh P. , Aldape Kenneth D.
Published: March 2020

LBA2010

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
SAMIT: A phase III randomized clinical trial of adjuvant paclitaxel followed by oral fluorinated pyrimidines for locally advanced gastric cancer.
Authors: Yoshida Kazuhiro , Tsuburaya Akira , Kobayashi Michiya , Yoshino Shigefumi , Takahashi Masazumi , Takiguchi Nobuhiro , Tanabe Kazuaki , Takahashi Naoto , Imamura Hiroshi , Tatsumoto Naokuni , Hara Akinori , Nishikawa Kazuhiro , Fukushima Ryoji , Kurita Akira , Kojima Hiroshi , Miyashita Yumi , Oba Koji , Buyse Marc E. , Morita Satoshi , Sakamoto Junichi
Published: March 2020

LBA4002

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Clinical outcomes in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone randomized in the factorial trapeze trial to docetaxel (D) with strontium-89 (Sr89), zoledronic acid (ZA), neither, or both (ISRCTN 12808747).
Authors: James Nicholas David , Pirrie Sarah , Barton Darren , Brown Janet Elizabeth , Billingham Lucinda , Collins Stuart I. , Daunton Adam , Birtle Alison J. , Chakraborti Prabir Ranjan , Ford Daniel , Hussain Syed A. , Jones Helen , Pope Ann , Porfiri Emilio , Russell John Martin , Stanley Andrew , Staffurth John , McLaren Duncan , Parker Chris , Wylie James
Published: March 2020

LBA5000

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
A randomized multicenter phase III study comparing weekly versus every 3 week carboplatin (C) plus paclitaxel (P) in patients with advanced ovarian cancer (AOC): Multicentre Italian Trials in Ovarian Cancer (MITO-7)– European Network of Gynaecological Oncological Trial Groups (ENGOT-ov-10)–Gynecologic Cancer Intergroup (GCIG ) trial.
Authors: Pignata Sandro , Scambia Giovanni , Lauria Rossella , Raspagliesi Francesco , Benedetti Panici Pierluigi , Cormio Gennaro , Katsaros Dionyssios , Sorio Roberto , Cavazzini Giovanna , Ferrandina Gabriella , Breda Enrico , Murgia Viviana , Sacco Cosimo , Asensio Sierra Nuria Maria , Pisano Carmela , Salutari Vanda , Weber Beatrice E. , Pujade-Lauraine Eric , Gallo Ciro , Perrone Francesco
Published: March 2020

LBA5501

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
An adaptive randomized phase II trial to determine pathologic complete response with the addition of carboplatin with and without ABT-888 to standard chemotherapy in the neoadjuvant treatment of triple-negative breast cancer.
Authors: Avery Tiffany P. , Berger Adam C. , Kovatich Albert J. , Rui Hallgeir , Hyslop Terry , Mitchell Edith P.
Published: March 2020

TPS1135

Background: Inhibition of poly (ADP-ribose) polymerase (Parp) is a potential targeted therapy for triple-negative breast cancer (TNBC). Clinical trials of Parp inhibitors in metastatic TNBC have shown conflicting results. Issues regarding the use of Parp inhibitors in TNBC include choosing a selective Parp inhibitor and selecting an appropriate chemotherapy backbone. The current trial addresses these questions by combining a validated Parp inhbitor, ABT-888, with carboplatin and paclitaxel. Platinum agents have shown synergy with Parp inhibitors in preclinical models and efficacy in clinical trials. The combination of paclitaxel and carboplatin with Parp inhibitors has shown efficacy in phase I trials. Methods: This is a phase II, two-arm neoadjuvant trial of women with TNBC. Eighty patients will be enrolled. Randomization will follow a 1:1 allocation initially, then will follow a Bayesian adaptive allocation in which each prior response will be evaluated and patients assigned preferentially to the better responding arm. The primary endpoint is pathologic complete response (pCR). Secondary endpoints include correlation of pCR with biomarkers, imaging, and circulating tumor cells (CTCs). Treatment: Arm 1: Paclitaxel 80 mg/m2 + carboplatin AUC=2 (12 weekly cycles) + filgrastim followed by doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 (4 cycles every 3 weeks) + pegfilgrastim. Arm 2: ABT-888 (150mg PO bid) + paclitaxel 80 mg/ m2 + carboplatin AUC=2 (12 weekly cycles) + (filgrastim) followed by doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 (4 cycles every 3 weeks) + (pegfilgrastim). Eligibility: Women ≥ 18 years old with clinical stage IIB or stage IIIA, IIIB, or IIIC untreated TNBC (ER <1% , PR <1% , Her-2/neu 0, 1+ on IHC or 2+ and FISH ratio < 1.8) are eligible. Correlative Studies: Correlation of pCR with tissue expression of CK5, EGFR, ERCC1, Ki-67, Parp1, and longitudinal enumeration of CTCs will be done. Exploratory tissue biomarkers with prognostic and predictive value will be correlated with pCR. Enrollment: The trial will begin accrual in February 2013.
Phase II study of eribulin mesylate as first- or second-line therapy for metastatic HER2-negative breast cancer.
Authors: Iwamoto Mitsuhiko , Sato Nayuko , Terasawa Risa , Fujioka Hiroya , Takahashi Yuko , Kimura Kosei , Tanaka Satoru , Uchiyama Kazuhisa
Published: March 2020

TPS1140

Background: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor that is approved in patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens (including an anthracycline and a taxane) for metastatic breast cancer. In a previous phase III study, eribulin mesylate demonstrated to significant improvement in overall survival in patients with heavily pretreated, locally recurrent or metastatic breast cancer when compared to treatment of physician’s choice. The majority of patients were HER2-negative and all had previously failed 2 or more regimens. Overall, the tolerability and positive phase III findings in this patient population suggest eribulin mesylate may provide a treatment advantage when given earlier in the course of therapy for HER2-negative, metastatic breast cancer. Methods: This study is phase II, multicenter, open-label, single-arm in patients with HER2-negative metastatic breast cancer who have been treated with chemotherapeutic regimens including an antheracycline and a taxane. Eribulin mesylate (1.4mg/m2) will be given on days 1 and 8 of each 21-day cycle. The primary endpoint is objective response rate, and secondary endpoints include duration of response, progression-free survival, overall survival, the safety of the treatment, and quality of life. Eligibility Criteria: Patients must have confirmed HER2-negative metastatic breast cancer with at least 4 weeks since prior neoadjuvant or adjuvant chemotherapy, and have not received over 2 chemotherapeutic regimens for metastatic disease. Additional eligibility criteria include adequate performance status (ECOG PS:0-2) and end organ/marrow function, and ejection fraction > 50%. Accrual: This study began in December 2012. The expected end of accrual of 35 patients will be the last quarter 2015.
Randomized controlled phase II trial of simvastatin as prophylaxis against radiation-induced skin toxicity in breast cancer patients.
Authors: Joseph Shibu , Round Glenys , Jameson Michael B. , Boyd Jenny May , Ragupathy Rajan
Published: March 2020

TPS1143

Background: Most women receiving adjuvant radiation (RT) for breast cancer (BC) have significant acute skin toxicities ranging from erythema to moist desquamation. Late skin toxicities include fibrosis and telangiectasia. The inflammatory response to RT is mediated by RT-induced endothelial cell expression of the cell adhesion molecule E-selectin, to which neutrophils and monocytes adhere and then infiltrate into tissues. Blockade of this mechanism could interrupt the inflammatory cascade at an early stage. Preclinical studies have shown that statins can inhibit RT-induced E-selectin expression and skin and intestinal inflammation in vivo without impairing DNA damage or tumour response to RT. Retrospective clinical studies have shown reduced relapse rates with statins in breast cancer patients. Thus statins have the potential to reduce the acute RT-induced inflammatory component without compromising the DNA-damaging effects essential to cancer cell death. This is the only registered trial evaluating the effects of statins on acute RT toxicity. Methods: Randomised open controlled phase II trial of simvastatin 40mg daily during and for 3 weeks after RT. Eligibility: women with invasive or in-situ BC receiving whole-breast +/- lymphatic RT; dose fractionation schedules include 50Gy/25 #, 45Gy/20#, 42.5Gy/16 # or 40Gy/15#, with or without a boost; may have had prior chemotherapy, and be on hormonal or Trastuzumab therapy during RT; no prior statins within 6 weeks of starting RT. Stratification by breast conserving surgery vs mastectomy, use of boost and fraction size (<2 Gy vs >2 Gy). Primary endpoint: incidence of > grade 2 acute RT-related skin toxicity. Secondary endpoints: time to onset of skin toxicity, proportion requiring additional topical treatment, compliance with trial medication, statin-related toxicities and subjective RT-related toxicities (breast discomfort and fatigue). Statistical design: 130 randomised patients gives 90% power (one-sided a 0.20) to detect a reduction in > grade 2 acute skin toxicity from 55% to 35%. Enrolment opened January 2013, planned to complete by April 2014. Clinical trial information: ACTRN12612000662864.
SHAVE: A randomized controlled trial of routine shave margins versus standard partial mastectomy.
Authors: Chagpar Anees B. , Stavris Karen , Killelea Brigid K. , Tsangaris Theodore , Horowitz Nina Ruth
Published: March 2020

TPS1145

Background: It is well known that partial mastectomy for breast cancer is associated with a positive margin rate of 20-40% in most series. This has led some surgeons to advocate for routine cavity shave margins as a means of reducing re-excision rates. Others, however, feel that such a practice may be unwarranted and question the volume of tissue removed, cosmetic outcome and increase in operative time. It is unclear which of these two approaches is optimal; therefore, a prospective randomized controlled trial was proposed. Methods: Given the primary endpoint of positive margin rates (defined as a margin of < 1mm), the study was powered to find a difference between 30% in the standard partial mastectomy group and 15% in the routine shave margin group. To reach a power of 80% with alpha of 5%, 122 patients were required in each arm; we therefore set N=250 with a 1:1 randomization scheme. Patients are evaluated preoperatively and all patients undergoing a partial mastectomy for stage 0-III breast cancer are eligible; including those who have completed neoadjuvant chemotherapy. Patients are stratified according to stage and randomized within strata. After informed consent, patients undergo a standard partial mastectomy (including specimen radiography as needed). Surgeons may resect additional tissue at that time according to their standard practice. At the completion of this procedure, the randomization envelope is opened in the operating room and surgeons are instructed to either shave (ie., take additional circumferential margins) or close (no shave). Patients will be followed for five years. Outcome measures include: positive margin/re-excision rate, local recurrence, volume of tissue resected, cosmetic outcome, and intraoperative time. To date, over 130 patients have accrued to this trial. Initial results are expected to be reported in 2014. Clinicaltrials.gov identifier: NCT01452399
Investigating hereditary risk from T790M (inherit): A prospective multicentered study of risk associated with germ-line EGFR T790M.
Authors: Oxnard Geoffrey R. , Heng Jennifer C. , Rainville Irene R. , Dahlberg Suzanne Eleanor , Sable-Hunt Alicia L. , Wiesner Georgia L. , Taylor Kelly A. , Jackman David Michael , Janne Pasi A. , Garber Judy Ellen
Published: March 2020

TPS1606

Background: The EGFR T790M mutation, commonly associated with acquired resistance to EGFR kinase inhibitors, has also been seen as a germline mutation in association with familial lung cancer. In collaboration with the Addario Lung Cancer Medical Institute (www.ALCMI.net), we initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize their cancer risk. Preliminary data: In a prior study (Oxnard et al, JTO, 2012), it was found that patients with lung cancers found to harbor EGFRT790M at diagnosis have a 50% chance of carrying an underlying germline T790M mutation. This suggests that study of patients known to carry T790M in their cancer will enrich for a germline event that otherwise is too rare to study prospectively. Subject eligibility: Three cohorts are eligible: (1) Patients with a cancer (lung or other) harboring EGFR T790M on tumor genotyping; lung cancers that acquire EGFR T790M only after treatment are ineligible. (2) First-degree relatives of patients carrying a germline EGFR mutation. (3) Patients already known to carry a germline EGFRmutation on prior testing. Subjects are referred to cohort 1 based upon routine genotyping results from commercial laboratories (e.g. Response Genetics Inc., Los Angeles, CA). Methods: Subjects may present at a participating cancer center or may participate remotely through a study website (www.Dana-Farber.org/T790Mstudy). Eligible patients submit a saliva and/or blood specimen for central testing in a CLIA lab. After counseling, patients carrying germline EGFR mutations have the option of inviting first-degree relatives to participate. Genetic counseling is coordinated at the participating center or offered over the phone. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule characteristics. Patients are clinically followed for 2 years. At time of submission, 6 subjects have enrolled from 3 different families and 4 different US states. (NCT01754025) Funding: Supported by grants from the Conquer Cancer Foundation of ASCO and the Bonnie J. Addario Lung Cancer Foundation. Clinical trial information: NCT01754025.
Evaluation of whole body MRI for early detection of cancers in subjects with germ-line TP53 mutation (Li-Fraumeni syndrome).
Authors: Caron Olivier , Frébourg Thierry , Bourbouloux Emmanuelle , Bonadona Valérie , Mari Véronique , Maugard Christine , Eisinger François , Barouk-Simonet Emmanuelle , Gauthier-Villars Marion , Tinat Julie , Nogues Catherine , Dugast Catherine , Canale Sandra , Guillemeau Claire , Benusiglio Patrick R. , Brugieres Laurence ,   French LFS Working Group
Published: March 2020

TPS1607

Background: The TP53 germline mutation carriers have a huge increase of cancer risk. The cancer spectrum is particularly broad (breast, sarcoma, brain tumour, leukaemia, …). The clinical management of these people is challenging, mainly concerning sarcoma screening. Moreover, some data let speculate that normal cells of these carriers are particular hypersensitive to X-rays. Among major breakthroughs in radiology, whole-body MRI (WBMRI) may contribute to TP53 carriers surveillance. In order to update the french guidelines on Li-Fraumeni families management, the LIFSCREEN study ( NCT01464086 ) was designed to assess its usefulness in France. Methods: This open, randomized, multicentric trial will evaluate the efficacy and tolerability of two screening schemes, avoiding irradiating exams. In the standard arm, people undergo clinical exam, abdominal sonography, brain MRI, Complete Blood Count, breast MRI, breast sonography, depending on the age) at inclusion, Month 12, Month 24, and a study visit at Month 36. In the experimental arm, people included undergo the same scheme, completed by a diffusion WBMRI at M0, M12, M24. At each round, quality of life and psychological impact will be assessed by self-questionnaires and semi-structured qualitative interviews. In an ancillary study, serums will be collected at each step. Subjects meeting these criteria are eligible: any TP53 germline mutation carrier, with or without personal cancer history, aged >5 and <71. A hundred people will be enrolled and randomized. The primary objective is to assess the efficiency of each scheme, evaluated by the cancer incidence at 3 years. Notably, sensitivity and specificity of each exam will be studied. As a secondary objective, the acceptability of each scheme will be assessed by quality of life / psychological questionnaires interpretation (SF-36, HADS, TAS 20, CBCL, CDI, R-CMAS, depending on subject’s age). Recruitment began in December, 2011. To date, 32 patients have been enrolled on 8 french study sites. The study will soon be implemented in another 12 sites. This academic study is, to our knowledge, the first randomized trial on this topic, and supported by the french “Ligue contre le cancer.” Clinical trial information: NCT01464086.
Change in mammographic density with metformin use: A companion study to NCIC study MA.32.
Authors: Wood Marie E. , Qin Rui , Le-Petross Huong T. , Hwang E Shelley , Ligibel Jennifer A. , Mayer Ingrid A. , Marshall James Roger , Goodwin Pamela Jean
Published: March 2020

TPS1608

Background: Metformin may have growth inhibitory effects on many cancer types including breast cancer. NCIC MA.32 is a randomized placebo-controlled trial examining the effects of 5 years of metformin in women with breast cancer ( http://clinicaltrials.gov/show/NCT01101438 ). This trial offers us the opportunity to explore the effects of metformin on breast cancer biomarkers to gain an understanding of the potential chemo preventive effects of this drug. The primary aim of this companion to MA.32 (Alliance trial # A211201) is to examine the effects of 1 year of metformin vs placebo on breast density for women with Estrogen Receptor negative (ER-) breast cancer. Secondary aims of this study include: evaluation of breast density following 2 years of metformin use, and correlation of density with fasting insulin, glucose and Homeostasis Model Assessment (HOMA). Exploratory aims include examination of the effects of metformin on second cancer rates. Methods: Eligible women must have been enrolled on MA.32 (North America accrual completed January 23, 2013), have hormone receptor-negative breast cancer, and breast composition on mammography >25% glandular density, have a digital mammogram within 12 months of registration on MA.32 and have an intact, unaffected contralateral breast. Women enrolled on this study must provide menstrual cycle data (if premenopausal) and digital mammograms. All other study related information is gathered through participation in MA.32. Mammographic density will be calculated using Cumulus software (the Boyd method). Our accrual goal is 458 patients (229 per arm) and with an assumption of 20% drop out due to drug intolerance and another 20% due to ineligibility. Therefore, with a sample size of 274 (137 per arm) we will have at least 85% power to detect a 4% difference between study arms, i.e., 5% change from baseline to one year of treatment for metformin vs. 1% for placebo, using the two-sided two-sample t-test at a significance level of 5%. This study was activated in the United States on 8/22/2012 and 15 patients have been accrued to date. This study is sponsored by the NCI and the Alliance for clinical trials. Clinical trial information: NCT01666171.
Sequential therapy with the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas: An Adult Brain Tumor Consortium phase I study (ABTC1101).
Authors: Holdhoff Matthias , Grossman Stuart A. , Supko Jeffrey G. , Ye Xiaobu , Fisher Joy D. , Desideri Serena , Wahl Richard L. , Schiff David
Published: March 2020

TPS2105

Background: Despite recent advances in their treatment, high-grade gliomas (HGG) carry a dismal prognosis. Treatment options at recurrence are particularly limited and a re-challenge with temozolomide (TMZ) frequently appears as the most appropriate systemic treatment option in patients whose progression occurred off TMZ. This study investigates the sequential treatment of mibefradil (MIB), a selective Cav3 calcium channel blocker, and standard dose TMZ. Preclinical data showed that Cav3 inhibitors such as MIB can slow tumor growth without significant effect on normal tissues and can induce cell cycle arrest in cancer cells at the G1/S-phase checkpoint. We hypothesize that withdrawal of MIB could synchronize and release cells into S-phase, thereby potentiating the cytotoxic effect of TMZ. Methods: This trial is an open-label, multicenter phase I study, structured into a dose escalation phase to determine the maximum tolerated dose of MIB (MTD; Primary Objective) and an expansion cohort of 10 patients at the MTD level. Adults with recurrent HGG (WHO grade 3 or 4) who have previously received standard adjuvant therapy with radiation (RT) and TMZ (last dose ≥ 3 months prior to enrollment) and who have not received other cytotoxic therapy (except for carmustine wafers) are eligible. Patients receive oral MIB for 7 days on a 4 x/day (QID) schedule, followed by standard dose TMZ at 150-200 mg/m2 for 5 days each 28-day cycle. Dose finding uses a modified 3+3 design, starting at MIB 25 mg po QID (100 mg/day) with dose increases of 25 mg/dose per dose level. The target dose-limiting toxicity (DLT) rate is ≤ 33%. Secondary Objectives: (1) safety and adverse event analysis (incl. cardiac monitoring during cycle 1), (2) pharmacokinetic profile of MIB, (3) response assessment (RANO criteria), and (4) assessment of the potential effect of MIB on tumor DNA synthesis as determined by fluorothymidine positron emission tomography (FLT PET; extension cohort). Enrollment status as of January 2013: cohort 1 completed without DLT; cohort 2 enrolling at MIB 200 mg/day. Clinical trial information: NCT01480050.
Phase I lead-in to a 2x2x2 factorial trial of dose-dense temozolomide, memantine, mefloquine, and metformin as postradiation adjuvant therapy of glioblastoma (GBM).
Authors: Penas-Prado Marta , Groves Morris D. , Mammoser Aaron G. , Melguizo Isaac , De Groot John Frederick , Conrad Charles A. , Tremont-Lukats Ivo , Loghin Monica Elena , Puduvalli Vinay K. , Sulman Erik P. , Hess Kenneth R. , Aldape Kenneth D. , Gilbert Mark R. , Yung W. K. Alfred
Published: March 2020

TPS2106

Background: Treatment for GBM is an area of unmet need. Despite optimal therapy, survival is poor and 2nd line therapies are scarce. There is an urgent need to find better treatments for recurrence, but also more effective 1st line therapies. Dose-dense temozolomide (ddTMZ) using the 7/14-day regimen has shown promising preliminary results in combination with cytostatic agents. Memantine (MEM) is a glutamate receptor (NMDA) blocker with antiproliferation properties and possibly neuroprotective effect. Mefloquine (MFQ) induces autophagy and apoptosis. Metformin (MFM) has mTOR inhibitor properties. Methods: Trial Design: Phase I/II trial to evaluate adjuvant ddTMZ with MEM MFQ and MFM. Primary objective Phase I: MTDs of ddTMZ with MEM/MFQ/MFM, 3+3 design. MTDs will be the recommended Phase II doses for a subsequent randomized factorial Phase II trial (ddTMZ alone and single, double and triple combinations). Accrual of about 55 eligible patients was calculated for Phase I (48-144). Clinical trial registry number is NCT01430351. Treatment planned: Patients accrued sequentially to ddTMZ with 1, 2, or 3 drugs. Arm 1 (ddTMZ alone) will be enrolled in Phase II only. Patients were first accrued to 1-drug Arms 2-4. Once MTDs were determined, accrual started to 2-drug Arms 5-7. Once completed, accrual to Arm 8 will start. Arms 2-4 were started at a predetermined target dose, and deescalated if excessive toxicity. Treatment in Arms 5-8 will be escalated for each drug to reach MTDs of Arms 2-4. Major eligibility criteria: Adults (≥ 18) with supratentorial GBM, KPS ≥60, adequate bone marrow and organ function. Post chemoradiation MRI ≤14 days before enrollment on stable/decreasing steroids and no progression; registration ≤5 weeks of chemoradiation. Patients on MFQ: no EIAED, EKG without prolonged QTc or arrhythmia. Pregnancy not allowed; adequate contraception required. Informed consent in keeping with IRB policies. Current enrollment: To date, 49 patients started treatment and 18 are still active. Enrollment to Arms 2-4 and 6 is completed and MTDs determined. Accrual is ongoing in Arms 5 and 7, and pending in Arm 8. Clinical trial information: NCT01430351.
A phase I, dose-escalation, safety, pharmacokinetic, pharmacodynamic study of thioureidobutyronitrile, a novel p53 targeted therapy, in patients with advanced solid tumors.
Authors: Shapiro Geoffrey , Supko Jeffrey G , Cho Daniel C. , Hilton John Frederick , Hadfield Matthew , Pruitt-Thompson Solida , Bordoli-Trachsela Eveline , Zvereva Nela , Wolanski Andrew , Sato-DiLorenzo Aya , Gotthardt Susan , Fox Edward A. , Verselis Sigitas Jonas , Kumar Ashok , Holden Sylvia A. , Ram Siya , Chafai-Fadela Karima , Harding Kimberly , Menon Krishna E.
Published: March 2020

TPS2627

Background: Thioureidobutyronitrile, kevetrin, has demonstrated anti-tumor activity in several wild type and mutant p53 human tumor xenografts without evidence of genotoxicity. In wild type p53 models, kevetrin induces cell cycle arrest and apoptosis through activation and stabilization of wild type p53, resulting in increased expression of p53 target genes p21 and PUMA. Kevetrin also alters processivity of MDM2, and induces monoubiquitination of wild type p53, enhancing its stability (AACR 2011 abstract 4470). Mutant p53 is a complex target since it is an array of mutant proteins with oncogenic properties. Kevetrin induces degradation of oncogenic mutant p53 and induces apoptosis (AACR 2012 abstract 2874). Kevetrin therefore has the unique ability to target both wild type and mutant p53 tumors thereby controlling tumor growth in a wide range of preclinical tumor models. Methods: Adults with refractory locally advanced or metastatic solid tumors, acceptable liver and kidney function, and hematological status were eligible. Objectives include determination of DLT, MTD, recommended phase 2 dose, pharmacokinetics (PK), pharmacodynamics (PD), and evaluating preliminary evidence of antitumor activity. Kevetrin is given as a 1-hour intravenous infusion once weekly for 3 weeks in 28-day cycles. The starting dose was 10 mg/m2. In a 3+3 design, groups of 3-6 patients are evaluated for toxicity at each dose level. Dose escalation is based upon the number and intensity of adverse events in cycle 1. Kevetrin PK is characterized for the first and last doses given in cycle 1. Kevetrin induced expression of p21 in lymphocytes in preclinical studies; therefore p21 expression in peripheral blood mononuclear cells will be measured as a PD biomarker. Antitumor activity by RECIST 1.1 criteria and serum tumor markers will be assessed. The p53 status of tumors of selected patients will be determined. The second cohort is currently under evaluation. Conclusion: In preclinical models, Kevetrin has activity against tumors harboring both wild type and mutant p53 by diverse mechanisms. A first-in-human dose escalation trial is underway. Clinical trial information: NCT01664000.
Phase I dose escalation study of recombinant interleukin-21 (rIL-21, BMS-982470) in combination with ipilimumab (Ipi) in patients (pts) with advanced or metastatic melanoma (MM).
Authors: Bhatia Shailender , Curti Brendan D. , Gordon Michael S. , Chesney Jason , Logan Theodore , Thompson John A. , Royer Nels , Bittner Rachel , Fontana David , Grosso Joseph , Clemens Pamela L. , Cohen Lewis J. , Ahlers Christoph Matthias , Wigginton Jon M. , Hwu Patrick
Published: March 2020

TPS3109

Background: Ipilimumab is a monoclonal anti-CTLA-4 antibody that promotes T-cell activation and has been approved for the treatment of pts with advanced melanoma. The cytokine rIL-21 is a T-cell and NK-cell growth factor that has also demonstrated antitumor activity in selected solid tumors including MM. We hypothesize that coordinated stimulation of T and/or NK cell function with rIL-21 in conjunction with T-cell checkpoint inhibitor blockade with Ipi will achieve enhanced biologic and clinical activity compared to either agent alone. Here we describe an ongoing phase Ib study to investigate the clinical and biologic effects of combined treatment with rIL-21 and Ipi in pts with MM. Methods: The phase I study includes dose escalation (Part 1) using a 6 + 6 design and cohort expansion (Part 2). In Part 1 (n=48), successive cohorts of pts with melanoma will be treated with rIL-21 in combination with Ipi as follows: Arm A, rIL-21 (10, 30, or 50 μg/kg daily x 5) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle; or Arm B, rIL-21 (30, 100, or 150 μg/kg weekly) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle. In Part 1, all subjects will receive an initial cycle with rIL-21 monotherapy (lead-in) for biomarker and PK assessment that will be the same as the dose of rIL-21 specified for the cohort. Four cycles of combination treatment will follow the lead-in with restaging evaluation after 4 combination cycles. Subjects with initial benefit are eligible for retreatment at progression. In Part 2, pts (n=25/arm) will be randomly assigned to one of 3 cohorts: Ipi monotherapy at 3 mg/kg Q3W or Ipi + weekly rIL-21 or Ipi + daily rIL-21 at the MTD determined for each schedule in Part 1. The primary objectives of this study are to evaluate the safety of rIL-21 + Ipi and to define the MTD of the respective rIL-21 + Ipi regimens. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunologic effects of this combination in peripheral blood and paired tumor biopsy specimens, and the association of these effects with clinical outcome. Clinical trial information: NCT01489059.
Evaluation of the safety and immunogenicity of intratumoral injection of interferon gamma (IFNg) during vaccination in patients with subcutaneous or cutaneous metastases of melanoma (Mel51; NCT00977145).
Authors: Slingluff Craig L. , Petroni Gina R. , Dengel Lynn , Mullins David W. , Grosh William W. , Weiss Geoffrey R. , Strieter Robert M , Neese Patrice , Nail Carmel , Patterson James W , Olson Walter C. , Chianese-Bullock Kimberly A.
Published: March 2020

TPS3118^

Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are induced by interferon gamma (IFNg). This protocol tests whether administering peptide vaccine activates circulating tumor antigen-specific CD8+ CXCR3+ T cells, followed by intratumoral IFNg to increase CXCR3 ligands (CXCL9-11) at the tumor site and thus to recruit the CXCR3+T cells. Methods: This pilot clinical trial is enrolling patients (n=14) with subcutaneous or cutaneous metastases of melanoma (stage IIIB-IV), who have adequate accessible tumor in 1-4 lesions to provide 100-300 mm3 tumor on each of the three biopsy days, and with at least one lesion amenable to intratumoral IFNg injection. Patients must also express HLA-A1, A2, A3, or A11. Patients undergo tumor biopsy d1, then are vaccinated days 1, 8, and 15 with a multipeptide vaccine. A biopsy day 22 provides information on the effect of vaccination alone on T cell infiltration into tumor. IFNg (up to 2 million units) is injected into at least 1 metastasis, which is biopsied day 24. Additional vaccines are given days 24, 43, and 64. Primary goals are to determine the safety of intratumoral interferon gamma (IFNg) plus a multipeptide melanoma vaccine, and to evaluate the biological effects of vaccine plus IFN-g at the tumor site, to include expression of CXCR3 ligands (CXCL9, CXCL10 & CXCL11) and the magnitude of infiltration of CD8+ CXCR3+ T cells and vaccine-specific T cells. Secondary goals include evaluating effects of vaccine on CXCR3 expression by circulating antigen-experienced CD4 and CD8 T cells, estimating the effects of vaccine plus IFNg on changes in the percentage of FoxP3+ CD25hi CD4+(putative regulatory T cells, Tregs) among tumor infiltrating T cells and to obtain preliminary data on the clinical response of cutaneous or subcutaneous metastases of melanoma to the proposed combination regimen. Clinical trial information: NCT00977145.
Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases.
Authors: Janosky Maxwell Dale , Demaria Sandra , Novik Yelena , Oratz Ruth , Tiersten Amy , Goldberg Judith D , Wang Ena , Marincola Francesco , Formenti Silvia , Adams Sylvia
Published: March 2020

TPS3122

Background: To assess the local and systemic effects of the novel combination of local radiotherapy (RT) with imiquimod (IMQ) applied topically to breast cancer metastatic to skin, and measure immunologic correlates (clinicaltrials.gov NCT01421017). Breast cancer is the 2nd most common tumor to metastasize to the skin. Current therapies for unresectable skin lesions are rarely curative. Patients ultimately die of visceral metastases, necessitating more effective therapies. IMQ, a synthetic TLR-7 agonist has profound effects on the tumor immune microenvironment and can lead to regression of cutaneous breast cancer metastases (Adams, Clin Ca Res, 2012). The trial was designed based on accumulated data supporting the synergy of combined RT/immunotherapy (Formenti, JNCI, 2013), and pre-clinical data demonstrating the synergy of topical IMQ and local RT in a mouse model of mammary adenocarcinoma which ulcerates through the skin, and mimics a chest wall recurrence. In the mouse model, the combination was superior with complete regressions of the treated tumors, responses at untreated sites and improved survival (Dewan, Clin Ca Res, 2012). Methods: Eligibility: patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. RT is delivered to 1 area of skin metastases in 5 fractions of 6 Gy (days 1, 3, 5, 8, 10). IMQ cream is applied topically 5 nights/week for 8 weeks, beginning on day 1. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with 25 additional patients planned. Primary endpoint is the response rate in untreated distant metastases, assessed by immune-related response criteria. The local tumor responses and safety of the combination will also be determined; tumor biopsies will be studied for immune-mediated rejection signatures and peripheral lymphocytes for antigen-specific T and B cell responses. To date, 10 patients have been enrolled. The phase I portion has been successfully completed with 6 patients without DLT. Phase II enrollment has begun. Clinical trial information: NCT01421017.
A randomized, double-blind, placebo-controlled, multicenter, multinational, phase II trial immunotherapy with L-BLP25 (tecemotide) in patients with colorectal carcinoma following R0/R1 hepatic metastasectomy.
Authors: Kasper Stefan , Overkamp Friedrich , Moehler Markus Hermann , Kullmann Frank , Lang Hauke , Schoen Michael , Smith-Machnow Victoria , Hegewisch-Becker Susanna , Seehofer Daniel , Bechstein Wolf , Heike Michael , Voehringer Matthias , Heinemann Volker , Greil Richard , Geissler Michael , Lordick Florian , Peeters Marc , Van Cutsem Eric , Galle Peter Robert , Schimanski Carl Christoph
Published: March 2020

TPS3124^

Background: 15-20% of all patients (pts) diagnosed with colorectal cancer (crc) develop metastases (mets) surgical resection remains the only potentially curative treatment available. Current 5-year survival rate following R0 resection of liver mets lies between 28-39%, recurrence occurs in up to 70% of pts. To date, adjuvant chemotherapy has not significantly improved clinical outcomes. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active MUC1-specific cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in crc pts following R0/R1 resection of liver mets known to highly express MUC1 glycoprotein. Phase III data from L-BLP25 in NSCLC will be reported at this meeting. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 pts from 20 centers in 3 countries. Pts must have stage IV cr adenocarcinoma limited to liver mets. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous mets, eligible pts are randomized 2:1 to receive either L-BLP25 or placebo. L-BLP25 arm receives a single dose of 300 mg/m2 cyclophosphamide (CPA) 3 d before 1st L-BLP25 dose, then primary treatment with sc L-BLP25 930 μg weekly for 8 weeks, followed by sc L-BLP25 930 μg maintenance doses at 6-week (year 1 and 2) and 12-week (year 3) intervals until recurrence. Control arm: CPA is replaced by saline solution and L-BLP25 by placebo. Primary endpoint (PE) is RFS time. Secondary endpoints: Overall survival (OS), safety, tolerance, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. Study start was in Q3 2011. 19 centers were initialized and 36 patients recruited, no SUSARs occurred. Study recruitment will end Q3 2013: follow-up until Q3 2017. PE assessment is in Q3 2016. Interim analyses are not planned.No major practical issues were identified during setup and early conduct of the study. Clinical trial information: 2011-000218-20.