bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer.
Authors: Ahmed Shabina Roohi , Azad Nilofer Saba , Ball Douglas Wilmot , Rudek Michelle A. , Nelkin Barry , Cosgrove David , Gong Jing , Finkelstein Daniel , Zahurak Marianna , Janku Filip , Downs Melinda , O'Connor Ashley , Markus Susan , Carducci Michael Anthony , Sherman Steven I. , Kurzrock Razelle
Published: March 2020

TPS3117

Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway, especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the development of many different types of cancers, including breast, colorectal, melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, but there is currently no approved therapy for advanced radioiodine-resistant disease. In DTC xenograft models, vertical inhibition of this pathway, achieved by targeting the vascular endothelial growth factor receptor (VEGFR) and MEK, has shown greater clinical efficacy than with either agent alone. Pazopanib (P) is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infante et al. reported an ORR of 81% in BRAF mutant melanoma patients when G was combined with a RAF inhibitor. Methods: A phase I, open label, dose escalation trial with P+G is currently accruing pts with advanced malignancies. The study is a standard 3+3 design with an expansion cohort of 25 pts with advanced DTC for correlative endpoints and PK studies. Pts will be treated with P at 400 mg QD, 600 mg QD and 800 mg QD, with G held constant at 1 mg QD; G will then be escalated to 1.5 mg QD and 2 mg QD. Eligibility includes advanced solid tumor, good end organ function and performance status, and PD within 6 months in the expansion cohort. The primary objective is to determine the safety and tolerability of the combination and determine the MTD. Secondary objectives include assessing preliminary efficacy as defined by RECIST criteria and PFS, and exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for changes in signaling through p-ERK. RAS and RAF mutation sites will be sequenced in order to correlate with PD endpoints and disease response. Currently, DL1 has accrued with no DLTs.
MAVERICC: A randomized phase II study of mFOLFOX6-bevacizumab (BV) versus FOLFIRI-BV with prospective biomarker stratification in previously untreated metastatic colorectal cancer (mCRC).
Authors: Thomas Sachdev P. , Badarinath Suprith , Greenberg Richard H. , Huh Sang Y. , Sivarajan Kulumani M , Feng Shibao , Scherer Stefan , Litz Curry Christine , Langer Christiane , Lenz Heinz-Josef
Published: March 2020

TPS3635^

Background: The identification of prognostic and predictive biomarkers could significantly improve the risk-benefit ratio and cost-effectiveness of 1st-line mCRC regimens. This is the first prospective study of tumoral ERCC1 (chemo-resistance marker to platinum compounds) and plasma VEGF-A as potential biomarkers for oxaliplatin- and BV-containing regimens, respectively, in an effort to further define the optimal chemotherapy backbone with biologic therapies, including BV, for mCRC. Methods: In this randomized, open-label, global, phase II study, patients (N=360) with histologically or cytologically confirmed CRC and ≥1 measurable metastatic lesion are stratified at screening by tumoral ERCC1 mRNA expression (high vs low, cutoff of 1.7 [ERCC1/β-actin mRNA]). Eligibility criteria include completion of adjuvant therapy >12 months before screening and an ECOG performance status ≤1. Blood samples are collected to quantify plasma VEGF-A levels. Patients within each ERCC1 stratification group are randomized 1:1 to mFOLFOX6-BV or FOLFIRI-BV administered in 2-week cycles. BV will be given at a dose of 5 mg/kg IV q2w. Patients will remain on study treatment until disease progression (PD) or unacceptable toxicity. If oxaliplatin or irinotecan need to be discontinued, BV and 5-fluorouracil or capecitabine are to be continued until PD. The primary objectives are: 1) to assess ERCC1 and VEGF-A as biomarkers of progression-free survival (PFS) for oxaliplatin- and BV-containing regimens in 1st-line mCRC, and 2) within ERCC1 high patients, to test whether FOLFIRI-BV is associated with a prolonged 1st-line PFS compared to mFOLFOX6-BV. Secondary objectives include assessing the impact of these markers on overall survival, objective response, hepatic metastases resection, and safety. Exploratory endpoints include correlative analyses with additional tumor tissue, blood, and SNP markers. The first patient was enrolled in August 2011. An interim biomarker distribution assessment of the first 100 patients is planned, and the evaluation of the primary endpoints is estimated for early 2015. Clinicaltrials.gov: NCT01374425.
PAN1: A randomized phase II study evaluating potential predictive biomarkers in the treatment of metastatic pancreatic cancer.
Authors: Chua Yu Jo , Karapetis Christos Stelios , Underhill Craig , Nott Louise M. , Goldstein David , Cronk Michelle F. , Gebski Val , Wong Nicole , Sjoquist Katrin Marie , Biankin Andrew Victor ,   Australasian Gastrointestinal Trials Group (AGITG)
Published: March 2020

TPS4137

Background: Biomarker-based selection of cancer treatments has already entered routine clinical practice in some cancer types. Recent retrospective data suggests the human equilibrative nucleoside transporter 1 (hENT1) to be promising predictive marker for benefit from gemcitabine in pancreatic cancer, at least in resected disease. Methods: 80 patients will be randomised to receive either gemcitabine or FOLFOX chemotherapy (folinic acid (FOL) fluorouracil (F) and oxalipatin (OX)) with stratification based on hENT1 status. All patients will be required to have tumour samples tested for hENT1 prior to randomisation, with both hENT1 positive and negative patients eligible for inclusion. Patients will continue their assigned treatment until progression, or unacceptable toxicity. Primary endpoint: Progression free survival in each chemotherapy arm (FOLFOX/gemcitabine). Secondary endpoints: efficacy/activity of gemcitabine and FOLFOX as assessed by OS (overall survival), TTP (time to progression), RR (response rate according to RECIST v1.1), CA19.9 response; Percentage of eligible patients able to be randomised within 14 days of screening; PFS in each biomarker-selected cohort (hENT1 positive/negative); Treatment related toxicity in each chemotherapy group (CTCAE v4.0) and in biomarker cohorts (hENT1 positive/negative); establishment of a tissue bank from patients treated with and without gemcitabine for further biomarker studies. Eligibility: Adult patients with radiologically and histologically confirmed metastatic pancreatic adenocarcinoma who have not previously received treatment for metastatic disease, and who have tumour tissue available for hENT1 testing are eligible for the study. Patients who do not have tumour tissue available will be required to undergo core biopsy to obtain tissue for hENT1 testing. Status: Opened to accrual July 2011.
An open-label, randomized phase II study comparing first-line treatment with dovitinib (TKI258) versus sorafenib in patients with advanced hepatocellular carcinoma.
Authors: Cheng Ann-Lii , Lim Ho Yeong , Poon Ronnie Tung Ping , Throngprasert Sumitra , Reddick Cathy , Zhang Yong , Shi Michael , Tan Eugene , Wang Yongyu
Published: March 2020

TPS4147

Background: Hepatocellular carcinoma (HCC) is a highly vascularized tumor that may rely on tumor angiogenesis for growth, invasion, and metastasis. Inhibition of the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) pathways temporarily prevents HCC tumor progression. However, because the fibroblast growth factor receptor (FGFR) pathway can serve as an escape pathway for these tumors, simultaneous inhibition of FGFR may be required to provide a sustainable antitumor response. Dovitinib (TKI258) has been shown to be a potent oral tyrosine kinase inhibitor that inhibits multiple angiogenic factors, including FGFR, VEGFR, and PDGFR, with IC50 values of < 20 nM. Preclinical studies in HCC xenograft models have demonstrated that the antitumor effects of dovitinib are superior to those of the kinase inhibitor sorafenib, which is approved for use in advanced HCC. These data support additional testing of dovitinib in advanced HCC patients. Methods: This study (NCT01232296) is an open-label, randomized phase II trial being conducted at multiple centers in the Asia-Pacific region. Adult patients are eligible if they have advanced HCC (Barcelona Clinic Liver Cancer stage C) with Child-Pugh class A cirrhotic status. Patients must also have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and cannot be eligible for (or have had disease progression after) surgical or locoregional therapies. Patients are randomized 1:1 to receive dovitinib (500 mg/day on a 5-days-on/2-days-off dosing schedule) or sorafenib (400 mg twice daily). Patients will be treated until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover will be permitted. The primary end point of this trial is overall survival. Secondary end points include time to tumor progression, disease control rate, time to definitive deterioration in ECOG status, safety, and pharmacokinetics. The pharmacodynamic effects of dovitinib and sorafenib on plasma/serum biomarkers will also be explored. As of 30 January 2012, 93 of the planned 150 patients have been enrolled.
Sorafenib in combination with local microtherapy guided by gadolinium-EOB-DTPA enhanced MRI in patients with inoperable hepatocellular carcinoma (HCC) (SORAMIC).
Authors: Ricke Jens , Schuette Kerstin , Rosmorduc Olivier , Jakob Augustinus , Verslype Chris , Sangro Bruno , Walecki Jerzy , Klumpen Heinz-Josef , Peynircioglu Bora , Yalcin Bulent , Bartolozzi Carlo , Amthauer Holger , Malfertheiner Peter
Published: March 2020

TPS4148

Background: HCC is a leading cause of cancer-related mortality in both men and women. It represents the fifth most common cancer worldwide with an increasing incidence. For the individual patient tumor stage at diagnosis (number and size of nodules, presence or absence of vascular invasion, presence or absence of extrahepatic spread), liver function and general health status are the principal prognostic factors. The clinical management of HCC requires a comprehensive, multidisciplinary approach. In early HCC curative treatment can be achieved by local ablation, resection or liver transplantation. In intermediate stages patients (pts) are offered locoregional treatment with palliative intent (transarterial chemoembolisation (TACE), Yttrium-90-radioembolisation (SIRT)). In advanced disease systemic therapy with sorafenib (sor) has the potential to prolong survival of pts and is standard of care in pts with preserved liver function. Studies on the combined use of locoregional and systemic therapy with their potential of a beneficial synergism are few and conducted in a small number of pts. Methods: This phase II-study is composed of three substudies with the following primary objectives: 1. In pts in whom local ablation is appropriate to determine if sor in combination with RFA prolongs the time-to-recurrence in comparison with RFA plus placebo. Primary endpoint (PEP): time to recurrence, n = 290 pts 2. In pts in whom RFA is not appropriate (palliative treatment group) to determine if the combination of SIRT and sor improves the overall survival in comparison to sor alone. PEP: overall survival, n = 375 pts 3. To confirm in a 2-step procedure that Gd-EOB-DTPA enhanced MRI is non-inferior or superior compared with contrast-enhanced multislice CT for stratification of pts to a palliative or a local ablation treatment strategy. PEP: correct stratification of pts to a palliative versus local ablation treatment strategy; n = 830 pts The trial has started in December 2010 as a multinational and multicentric study. 90 pts have been enrolled until January 31st 2012 with 51 pts randomized in the palliative arm and 14 pts treated in the curative arm.
Randomized phase II trial of TACE plus everolimus as first-line therapy in localized unresectable hepatocellular carcinoma (HCC): The TRACER trial.
Authors: Poon Ronnie Tung Ping , Chen Li-Tzong , Xue Hong-Ling , Tannir Bayane , Wang Jia Hua , Tanwandee Tawesak , Paik Seung-Woon
Published: March 2020

TPS4149

Background: Transcatheter Arterial Chemoembolization (TACE) has shown benefit in improving survival and is a widely used treatment for unresectable HCC. However, TACE induces hypoxia leading to up-regulation of HIF-1α and VEGF signaling, and tumor progression. Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR) and its downstream signaling including HIF-1α. Everolimus has also been shown to increase chemosensitivity of HCC in preclinical study (Cancer Lett; 273(2):201-9). Combining everolimus with TACE may delay tumor progression. TRACER (Tace with Rad001 in Asian Centers for Evaluation and Research) aims to evaluate the efficacy and safety of everolimus plus TACE in patients with localised unresectable HCC. Methods: TRACER is a multinational, randomized, double-blind, placebo-controlled phase II trial. Patients aged ≥18 years newly diagnosed with localized unresectable Child A HCC; ECOG PS of <2; ≥1 unidimensional lesion measurable according to RECIST; and adequate bone marrow, liver, and renal function. Exclusion criteria include main portal vein invasion and/or extrahepatic spread; prior local or systemic treatment for HCC, or contraindications to TACE. Eligible patients who have successfully undergone the first TACE are randomized 1:1 to oral everolimus 7.5mg or matching placebo daily. TACE is repeated every 10 weeks or so. A short everolimus dose interruption of 48 hours before and after each TACE has been designed to allow recovery from complications of TACE. For standardization, doxorubicin-eluting beads are being used in every TACE. Patients shall exit the trial upon tumor progression, unacceptable toxicity, death, or trial discontinuation. All endpoints will be assessed on an ITT basis. The primary endpoint is time to progression base on Modified RECIST Criteria. Secondary endpoints include objective response rate, overall survival, and incidence of extrahepatic spread, safety and exploratory biomarkers. An independent data monitoring committee has been established to safeguard the trial subjects. Estimated total enrollment is 80, of which 12 subjects have been enrolled. (Clinical Trial Registry Number: NCT01379521.)
The CLARINET study: Assessing the effect of lanreotide autogel on tumor progression-free survival in patients with nonfunctioning gastroenteropancreatic neuroendocrine tumors.
Authors: Delavault Patrick , Caplin Martyn E , Liyange Nilani , Blumberg Joelle ,   UK and Ireland Neuroendocrine Tumour Society/European Neuroendocrine Tumor Society
Published: March 2020

TPS4153

Background: Somatostatin analogs (SSAs) provide good symptom control in patients with neuroendrocine tumors (NETs). Clinical studies suggest SSAs also stabilize tumor growth. In a previous double-blind study (PROMID) in a mixed functioning and non-functioning gastroenteroNET population (n=85), octreotide LAR significantly increased time to tumor progression compared with placebo. The CLARINET study is being undertaken to explore the antiproliferative effects of SSAs in a more homogeneous population. Specifically, the CLARINET study is a double-blind, placebo-controlled trial assessing the effect of 120 mg of lanreotide Autogel (lanreotide Depot in the USA) on progression-free survival in patients with non-functioning gastroenteropancreatic NETs (GEP-NETs). Methods: CLARINET is a 96-week, multinational study being conducted in collaboration with UKI NETS and ENETS in patients with well or moderately differentiated non-functioning GEP-NETs and a proliferation index (Ki67) of <10%. Patients are stratified by prior tumor progression status and presence/absence of previous therapies, and treated with lanreotide Autogel 120 mg or placebo. The primary endpoint is time to either disease progression (using Response Evaluation Criteria In Solid Tumors) or death. Two baseline computed tomography scans (≥12 weeks apart) are being performed, followed by additional scans at intervals up to 96 weeks. Secondary endpoints include proportion of patients alive and without tumor progression at 48 and 96 weeks, time to progression, overall survival, safety, quality of life, plasma chromogranin A levels, tumor markers, and pharmacokinetic parameters. The primary study population for the analysis will be the intention-to-treat population. Recruitment is now complete (n=204) and, thus far, the drug safety monitoring committee has identified no safety concerns. The trial is registered with ClinicalTrials.gov (NCT NCT00353496).
Randomized phase II study of docetaxel with or without ramucirumab (IMC-1121B) or icrucumab (IMC-18F1) in patients with urothelial transitional cell carcinoma (TCC) following progression on first-line platinum-based therapy.
Authors: Petrylak Daniel Peter , Chi Kim N. , Vogelzang Nicholas J. , Sonpavde Guru , Rutstein Mark D. , Schwartz Jonathan D. , Fox Floyd E. , Wang Weigang , Abad Leslie W , Cosaert Jan , Grebennik Dmitri O.
Published: March 2020

TPS4675^

Background: The vascular endothelial growth factor (VEGF) pathway may play an important role in the pathogenesis of bladder cancer. Two antibodies (ramucirumab or icrucumab) in combination with docetaxel are being tested in this clinical study. Ramucirumab is a fully human IgG1 monoclonal antibody (MAb) that specifically binds with high affinity to VEGF receptor-2 (VEGFR-2), thereby blocking the interaction of VEGF ligands. Ramucirumab inhibits VEGF-mediated proliferation of human endothelial cells and migration of human leukemia cells. Icrucumab is a fully human IgG1 MAb that specifically binds with high affinity to VEGFR-1 and blocks the binding of VEGF-A, VEGF-B, and placental growth factor (PlGF) to the receptor, thereby inhibiting subsequent signaling. Blockage of VEGFR-1 and VEGFR-2 by antibodies demonstrates antiangiogenic and antitumor activity and prevents dissemination and growth of lung metastases in several tumor xenograft models. Methods: This study includes patients (pts) with TCC with progressive disease after prior platinum-based therapy. Pts are randomized equally to 1 of 3 open-label treatments given on a 21-day cycle: docetaxel (75 mg/m2) on Day 1 (Arm A); docetaxel on Day 1 and ramucirumab (10 mg/kg) on Day 1 (Arm B); or docetaxel on Day 1 and icrucumab (12 mg/kg) on Days 1 and 8 (Arm C). Randomization is stratified by the absence/presence of visceral metastases and receipt of prior antiangiogenic therapy. The primary endpoint is progression-free survival (PFS). Secondary outcome measures include response rate and duration of response, overall survival, and pharmacodynamic markers, including circulating levels of PlGF, VEGF-A, VEGF-B, soluble VEGFR-1, and soluble VEGFR-2. Exploratory analyses of VEGF, VEGFR-1, and VEGFR-2 genetic polymorphisms will be performed. As of 12 January 2012, approximately 20% of 138 planned pts were randomized in the US and Canada. The sample size will allow differentiation of an expected increase in median PFS from 3.0 months to 4.5 months with a one-sided alpha of 0.1 and a power of 71%. ClinicalTrials.gov identifier: NCT01282463.
A phase II study of bevacizumab and erlotinib in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) or sporadic papillary renal cell cancer (RCC).
Authors: Singer Eric A. , Friend Julia C. , Hawks Geri , Vocke Cathy , Metwalli Adam R. , Pinto Peter A. , Bratslavsky Gennady , Linehan W. Marston , Srinivasan Ramaprasad
Published: March 2020

TPS4680

Background: There are currently no treatment options of proven efficacy for patients with advanced papillary RCC. The evaluation of families with inherited forms of RCC has allowed for the identification of genetic alterations associated with papillary RCC. HLRCC is one such familial condition with a propensity for the development of a clinically aggressive variant of papillary RCC characterized by unique histopathologic features. Germline mutations in the gene for the Krebs cycle enzyme fumarate hydratase (FH) are the genetic hallmark of HLRCC. Mutational inactivation of FH leads to von Hippel-Lindau-independent upregulation of hypoxia inducible factors (HIF) and their downstream transcriptional targets such as vascular endothelial growth factor (VEGF) and transforming growth factor-alpha (TGF-α) / epidermal growth factor receptor (EGFR). Upregulation of the HIF pathway may also be important in sporadic papillary RCC, although the prevalence of FH inactivation in these patients is unknown. We propose to evaluate the activity of dual VEGF/EGFR blockade with bevacizumab/erlotinib in patients with HLRCC-associated RCC and sporadic papillary RCC. Methods: This is a single arm phase II study based on an open label Simon two-stage minmax design with a maximum accrual of 20 patients in each of two cohorts: Cohort 1- patients with HLRCC; Cohort 2- patients with sporadic papillary RCC. The primary endpoint is RECIST overall response rate, assessed independently in each cohort. Patients will receive bevacizumab (10mg/Kg IV every 2 weeks) and erlotinib (150mg PO daily). Dose reductions and drug interruptions for toxicity are allowed. Patients will be evaluated for response every 8 weeks. Major eligibility criteria include: advanced RCC associated with HLRCC or sporadic papillary RCC; age >18 years; ECOG 0-2; measurable disease by RECIST; no brain metastases; no more than 2 prior regimens containing a VEGF inhibitor; and no prior therapy with bevacizumab. The prespecified activity goal for the first stage of accrual has been met for both cohorts. NCT01130519.
A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.
Authors: Dreicer Robert , Agus David B. , Bellmunt Joaquim , De Bono Johann Sebastian , Petrylak Daniel Peter , Tejura Bindu , Shi Yuanjun , Fizazi Karim
Published: March 2020

TPS4693

Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after receiving a total of ≥360 mg/m2 docetaxel within a 6-mo period. Patients who are clearly intolerant to docetaxel or have progressive disease before receiving ≥360 mg/m2 are also eligible if they have received at least 225 mg/m2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility criteria include radiographically documented metastatic disease and baseline testosterone <50 ng/dL following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell and endocrine marker changes, and patient-reported outcomes. After disease progression, men may continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).
A phase I/IIa study of the safety and efficacy of radium-223 chloride (Ra-223) with docetaxel (D) for castration-resistant prostate cancer (CRPC) patients with bone metastases.
Authors: Morris Michael J. , Hammers Hans J. , Sweeney Christopher , Bloma Marianne , Aksnes Anne-Kirsti , O'Bryan-Tear C. Gillies , Carrasquillo Jorge A.
Published: March 2020

TPS4694

Background: Ra-223is a first-in-class alpha-pharmaceutical that targets bone metastases (mets) with high energy alpha-particles of short range (< 100 μm). In the ALSYMPCA trial, Ra-223 plus best standard of care (BSC) significantly improved OS vs placebo plus BSC in CRPC patients (pts) with bone mets (Parker et al. ECCO/ESMO 2011), and was shown to have an excellent safety profile. Since D is an approved chemotherapy with demonstrated survival benefit for pts progressing after castrating hormone therapy, it is logical to explore combining Ra-223 plus D in pts with CRPC and bone mets. This study is being conducted in the Prostate Cancer Clinical Trials Consortium with an aim to establish the safe dose of Ra-223 and D when used in combination in pts with bone mets with CRPC. Methods: This ongoing phase I/IIa trial (NCT01106352) is enrolling pts with bone mets from CRPC intended for treatment with D. D naïve pts are preferred, although up to 10 previous infusions of D are acceptable if D was well tolerated and the patient is in good condition and fulfills all eligibility criteria at study entry. Phase I dose-escalation study: minimum of 9 pts (max. 18 pts) will be included if no dose limiting toxicity (DLT) is observed. Dose escalation will follow a ‘3+3’ design, with no intra-patient dose escalation or overlapping of cohorts permitted. Ra-223 doses are 25 or 50 kBq/kg, with number of Ra-223 injections (inj) (2, 4, 5, or 10) and interval between inj (3 or 6 wks) varying by escalation schema; D doses are 60 or 75 mg/m2 q3wk. DLT will be assessed when 6 wks post-inj safety data are available after 1st Ra-223 +D inj. Phase IIa open-label expanded safety study: pts will be randomized 2:1 to the recommended dose of Ra‑223 to be used with D or to treatment with D alone (approx. 42 pts will be included). Primary endpoint is to assess safety of combining Ra-223 with D. Exploratory efficacy endpoints for the open-label expanded safety portion of the study include change in disease-related biomarkers, time to 1st radiological or clinical progression, CTC and pain assessment. Enrollment in dose-escalation portion of the study is complete; expanded safety cohort to begin enrolling in March 2012.
Targeting castration resistant prostate cancer (CRPC) with autologous PSMA-directed CAR+ T cells.
Authors: Slovin Susan F. , Wang Xiuyan , Borquez-Ojeda Oriana , Stefanski Jolanta , Olszewska Malgorzata , Taylor Clare , Bartido Shirley , Scher Howard I. , Sadelain Michel , Riviere Isabelle
Published: March 2020

TPS4700

Background: Based on our preclinical animal models, we initiated a phase I dose-escalating study to assess safety, dose requirement and targeting efficiency of genetically directed autologous human T cells targeted to Prostate Specific Membrane Antigen (PSMA). Our approach is based on the infusion of autologous PSMA-targeted T cells utilizing the P28z second generation chimeric antigen receptor (CAR) in patients (pts) with metastatic CRPC, following iv cyclophosphamide (Cy) (trial NCT01140373). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, and renders T cells sensitive to ganciclovir for immediate T cell elimination if needed. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize adoptively transferred T cells. The aims of the trial are to assess: (1) safety of PSMA-targeted T cells; (2) biologic and anti-tumor effects; (3) T cell persistence at tumor site; and (4) immune response. Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts will be treated at 3 dose levels from 107 to 108 CAR+ T cells/kg. Four patients have been enrolled; 3 have been treated with 300mg/m2 of Cy one day before infusion of 107 CAR+ T cells/kg. Pts underwent baseline and post treatment CT, bone and PET scans. Pts are followed weekly, then monthly with blood work including immune and vector sequence monitoring. Results: The first 3 pts within the first cohort were successfully treated without toxicity. Two had stable disease for greater than 6 months with the third patient having disease progression. There were no acute adverse events. Conclusion: We have established an ex vivo transduction, expansion and therapeutic protocol for the generation and testing of safe, clinical-grade, PSMA targeted T cells. Pts enrolled at the next dose level of 3 x 107 CAR+ T cells/kg will be assessed as described and by imaging the transduced T cell population using 18F-FIAU as a radiotracer. The data pertaining to the planned T cell imaging will be presented as well.
Randomized phase II clinical trial to assess MUC1 specific immune response to L-BLP25 vaccine in addition to standard therapy in newly diagnosed high-risk prostate cancer.
Authors: Singh Nishith K. , Bilusic Marijo , Kim Joseph W. , Heery Christopher Ryan , Falk Martin H. , Wood Bradford J , Pinto Peter A. , Dahut William L. , Kaushal Aradhana , Couvillon Anna , Rauckhorst Myrna , Choyke Peter L. , Turkbey Ismail B. , Trepel Jane B. , Tsang Kwong Yok , Schlom Jeffrey , Gulley James L. , Madan Ravi A.
Published: March 2020

TPS4701

Background: In high-risk prostate cancer, radiation therapy (RT) + androgen deprivation therapy (ADT) improve survival. Nonetheless, 10-year disease specific mortality is about 25%. L-BLP25 is a cancer vaccine containing the BLP25 lipopeptide that targets MUC1 tumor antigen. It may enhance immune targeting of cells that express MUC1 (e.g. prostate cancer). In murine models, RT synergizes with vaccine-induced anti-cancer immunity (augments T-cell mediated cancer cytolysis, up-regulates cellular Fas and co-stimulatory/adhesion molecules). ADT augments T-cell trafficking to prostate. Immune response to combining the three (L-BLP25 + RT + ADT) is not known. The current trial intends to study this immune response to L-BLP25 + RT + ADT and compare it to RT+ADT alone. Using ELISPOT, endo-rectal MRI and serial prostate biopsies, this trial was designed to correlate systemic immune response with changes in tumor imaging and/or tumor microenvironment after treatment with L-BLP25. This trial may provide insight into immune response biomarkers that are most appropriate in this setting. Methods: A randomized (1:1), open-label, phase II trial of 42 pts is planned. Eligibility: Adult males with newly diagnosed high-risk prostate cancer (T3 or Gleason ≥ 8 or seminal vesicle involvement or N1 or PSA>20) and HLA-A2/A3 positivity (to allow for ELISPOT analysis). The vaccine arm will receive RT + 2-year ADT + L-BLP25. Standard arm will receive RT + 2-year ADT. L-BLP25 vaccine schedule: biweekly X 5 starting with neo-adjuvant ADT, then 6 weekly X 4 starting with RT. A single 300mg/m2 cyclophosphamide infusion (decreases suppressor T-cells) will be given 3 days before L-BLP25 to enhance immune response in the vaccine arm. The impact of L-BLP25 + RT+ADT on MUC-1-specific systemic immune response will be determined using interval peripheral blood ELISPOT assays. Endo-rectal coil MRI will be done before and after treatment to study prostate signal changes for correlative and predictive analysis. MRI-UltraSound guided lesion-targeted serial prostate biopsies will be obtained to assess immune response in tumor microenvironment. Two pts have been enrolled.
A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The OUTBACK TRIAL.
Authors: Mileshkin Linda R. , Narayan Kailash , Moore Kathleen N. , Rischin Danny , Trimble Edward Lloyd , Stockler Martin R. , King Madeleine , Kolodziej Ilka , Martyn Julie , Friedlander Michael , Quinn Michael , Shrivastava Shyam K , Small William , Thomas Gillian , Craighead Peter S , Gebski Val ,   Gynecologic Cancer Intergroup
Published: March 2020

TPS5116

Background: Cervical cancer is a global health problem and the most common cause of cancer-related death among women in developing nations. Despite the recently developed cervical cancer vaccine, many women will continue to die from cervical cancer for many decades unless existing treatments can be improved. Unscreened women often present with locally-advanced disease that has a 5 year overall survival (OS) rate of 60% or less following standard chemo-radiation. Although some evidence suggests that adjuvant chemotherapy following chemo-radiation may be of value, its role remains controversial. Methods: OUTBACK is a randomized phase III Gynecologic Cancer InterGroup (GCIG) trial designed and led by the Australia New Zealand Gynaecological Oncology Group (ANZGOG) in collaboration with the NHMRC Clinical Trials Centre. Participating countries (groups) include Australia and New Zealand (ANZGOG), India, the USA and Canada (GOG, RTOG). OUTBACK is suitable for women with locally advanced cervical cancer (FIGO stage IB1 and node positive, IB2, II, IIIB or IVA). The primary objective is to determine if the addition of adjuvant chemotherapy to standard cisplatin-based chemo-radiation improves OS. Women are randomized to either A) standard cisplatin-based chemo-radiation or B) standard cisplatin-based chemo-radiation followed by 4 cycles of carboplatin and paclitaxel chemotherapy. Secondary objectives are to compare progression-free survival, treatment-related toxicity, patterns of disease recurrence, quality of life and psycho-sexual health, and the association between radiation protocol compliance and outcomes. Blood and tumour samples are collected from consenting patients for future translational studies. 780 women will be enrolled to determine if the addition of adjuvant chemotherapy can improve the 5-year OS rate by ≥ 10%. OUTBACK opened in Australia and New Zealand in 2011. In early 2012 the trial opened in the USA and activation of GOG sites is ongoing. 15 patients have been randomized. It is expected that RTOG and India will open the trial later this year with recruitment increasing substantially once all sites are activated.
BOLERO-1: A randomized, phase III, double-blind, placebo-controlled multicenter trial of everolimus in combination with trastuzumab and paclitaxel as first-line therapy in women with HER2-positive (HER2+), locally advanced or metastatic breast cancer (BC).
Authors: Hurvitz Sara A. , Andre Fabrice , Burris Howard A. , Toi Masakazu , Buyse Marc E. , Sahmoud Tarek , Mukhopadhyay Pabak , Massacesi Cristian , Taran Tanya , Ko Jennifer , Rupin Matthieu
Published: March 2020

TPS648

Background: Up to 25% of BCs overexpress human epidermal growth factor receptor 2 (HER2). Patients with HER2+ disease have a higher rate of relapse and shorter overall survival (OS). Trastuzumab, a monoclonal antibody targeting HER2, is the standard of care and improves OS for HER2+ BC, but acquired resistance is common. The combination of trastuzumab and paclitaxel has shown good tolerability and excellent objective response rates (ORR) in up to 84% of patients with HER2+ metastatic BC (MBC) (Gasparini G, et al. BCRT. 2007;101:355-65). Everolimus is an orally bioavailable inhibitor of mammalian target of rapamycin (mTOR), a protein kinase central to multiple protein synthesis pathways and implicated in trastuzumab resistance. Everolimus-containing regimens have shown promising results in patients with ER+, HER2– advanced BC in phase II/III trials; everolimus plus trastuzumab/paclitaxel or vinorelbine has shown encouraging ORR with an acceptable safety profile in phase I/II trials in patients with HER2+ MBC. The present phase III study was undertaken to assess the effectiveness of adding everolimus to first-line standard therapy in HER2+ advanced BC. Methods: Women with HER2+, locally advanced or metastatic BC who have received no prior systemic therapy (except endocrine) are eligible. Local disease must not be amenable to resection with curative intent. Women with a history of central nervous system metastasis are excluded. Patients are randomized 2:1 (everolimus vs control) to receive standard therapy (paclitaxel and trastuzumab) plus everolimus (10 mg daily) or placebo. The primary endpoint is progression-free survival. Secondary endpoints include OS, ORR, and clinical benefit rate. Additional endpoints are safety, performance status, and biomarkers. This trial is sponsored by Novartis Pharmaceuticals and is registered (ClinicalTrials.gov: NCT00876395). Enrollment began September 2009, with a planned accrual of 717. The current accrual is 719, and the estimated primary completion date is October 2012.
LUX-breast 1: Randomized, phase III trial of afatinib and vinorelbine versus trastuzumab and vinorelbine in patients with HER2-overexpressing metastatic breast cancer (MBC) failing one prior trastuzumab treatment.
Authors: Harbeck Nadia , Im Seock-Ah , Huang Chiun-Sheng , Im Young-Hyuck , Xu Binghe , Hurvitz Sara A. , Lee Keun-Seok , Ahn Jin-Hee , Mehta Ajay O. , Arora Rajender Singh , Sun Qiang , Qin Shukui , Jacob Linu Abraham , Jassem Jacek , Staroslawka Elzbieta , Sufliarsky Jozef , Wojtukiewicz Marek , Lahogue Annick , Uttenreuther-Fischer Martina Maria , Piccart-Gebhart Martine J. ,   on behalf of the LUX-Breast 1 Study Group
Published: March 2020

TPS649

Background: Afatinib is an ErbB Family Blocker that irreversibly blocks signaling from all relevant ErbB Family dimers. Afatinib is being developed in EGFR (ErbB1)-driven (NSCLC/HNSCC) and HER2 (ErbB2)-driven (breast) malignancies. In trastuzumab-resistant, HER2-positive (SUM190) xenografts, afatinib showed antitumor activity which was superior to lapatinib and increased by addition of IV vinorelbine. Afatinib monotherapy also demonstrated clinical activity (progression-free survival [PFS] = 15.1 wk; objective response [OR] = 10%) in an open-label, single-arm, Phase II trial in patients with HER2-positive MBC after progression on trastuzumab. Methods: LUX-Breast 1 (NCT01125566) is a Phase III, open-label, multicenter trial evaluating the efficacy and safety of afatinib + vinorelbine vs. trastuzumab + vinorelbine in patients with HER2-overexpressing MBC who progressed on, or after one prior trastuzumab-based treatment regimen. Patients are randomized 2:1 to afatinib (40 mg/d oral) + vinorelbine (IV 25 mg/m2/wk) or trastuzumab (IV 2 mg/kg/wk after 4 mg/kg loading dose) + vinorelbine (IV 25 mg/m2/wk). Patients receive continuous treatment in the absence of disease progression or adverse events. Key eligibility criteria include histologically-confirmed HER2-positive BC, stage IV disease; no prior treatment with vinorelbine or HER2-targeted treatment other than trastuzumab; progression on one prior trastuzumab based regimen in either the adjuvant (or <12 months after trastuzumab completion) or first-line (or <6 months after trastuzumab completion) setting; prior anthracycline and/or taxane chemotherapy; ECOG score 0 or 1. The primary endpoint is PFS and secondary endpoints include OR, overall survival and safety. Serum and tissue biomarkers will be assessed on archival tissue. HER-receptor and HER-ligand reprogramming, putative resistance markers and EGFR response signature will be explored in fresh tissue biopsies. Enrollment began in June 2010 and is ongoing, targeting >240 sites with a recruitment target of 780 patients.
A phase II trial of trabectedin (T) in patients with hormone receptor-positive, HER2-negative advanced breast cancer, according to xeroderma pigmentosum gene (XPG) expression.
Authors: Awada Ahmad , Cortes Javier , Martin Miguel , Aftimos Philippe , Oliveira Mafalda , Espie Marc , Lardelli Pilar , Extremera Sonia , Kahatt Carmen Maria , Fernandez-Garcia Eva , Delaloge Suzette
Published: March 2020

TPS652

Background: Hormone receptor-positive, HER2-negative breast cancer (BC) is currently associated with 3-4 years overall survival in the metastatic setting and, after ≥2 relapses, therapeutic approaches are reduced. XPG expression is frequently modified in BC. T is a cytotoxic agent that forms a complex with the XPG, inducing cell apoptosis. As a single agent, T has shown anti-tumor activity in patients with poor prognosis BC, and a better response to T in BC patients with XPG RNA overexpression has been observed. Methods: This is an open-label, phase II study of T (1.3 mg/m2 in 3-hour intravenous infusion every 3 weeks) in patients with hormone receptor-positive, HER2-negative advanced BC, according to their primary tumor’s XPG expression. Primary endpoint: to evaluate the efficacy of T in terms of progression free survival rate at 4 months (PFS4) according to the patient’s XPG expression. Secondary endpoints: Comparison of PFS, overall response rate, duration of response, overall survival and safety profile in XPG-high and XPG-low patients. Assignment: BC patients who have previously received anthracyclins and/or taxanes and who progressed after 2-5 chemotherapy lines will be assigned according to their XPG expression from paraffin embedded tumor samples to stratum A (XPG-high [>3]) or to stratum B (XPG-low [≤3]) (threshold was selected from median XPG expression values observed in a previous trial). Statistical methods: A two-stage design was chosen: at a first stage 20 patients will be enrolled in each stratum. A futility analysis (O’Brien Fleming boundary) based on the primary endpoint (PFS4) will be conducted once 40 evaluable patients have been recruited. If ≥ 7 out of 20 patients achieve PFS4, recruitment will continue to a maximum sample size of 50 evaluable patients per stratum. If ≥ 22 out of 50 patients achieve PFS4, T will be considered active in this group (alpha error: 0.025, power: 80%). To date, 35 patients (16 XPG-high and 15 XPG-low) have been enrolled from three countries and five centers. Recruitment is ongoing.
A combination of pertuzumab, trastuzumab, and vinorelbine for first-line treatment of patients with HER2-positive metastatic breast cancer: An open-label, two-cohort, phase II study (VELVET).
Authors: Perez Edith A. , Lopez-Vega Jose Manuel , Del Mastro Lucia , Petit Thierry , Mitchell Lada , Pelizon Christina H. , Andersson Michael
Published: March 2020

TPS653

Background: Pertuzumab (P) is a humanized monoclonal antibody directed against the dimerization domain of HER2: it prevents HER2 heterodimerization and thus activation of downstream signaling. Since P targets a different epitope than trastuzumab (H), a more comprehensive HER2 blockade is achieved by combining the two agents. Data from CLEOPATRA showed improved efficacy for P and H plus docetaxel. The combination of P and H has not yet been assessed with other chemotherapy partners in the metastatic setting. H plus vinorelbine (V) has shown comparable efficacy to H plus docetaxel but with a superior safety profile. VELVET will assess the overall response rate (ORR) of P with H+V in first-line patients (pts) with HER2-positive MBC. Co-administration of P and H within the same infusion bag will also be investigated as this could increase pt convenience by reducing administration and observation time. Methods: VELVET is a multicenter, open-label, two-cohort, Phase II trial. Pts with HER2-positive LABC or MBC not previously treated in the metastatic setting with non-hormonal anticancer therapy are eligible. Pts must have an LVEF >55% at baseline and an ECOG PS of 0 or 1. Study enrollment started in January 2012. A total of 210 pts will be included. Based on statistical assumptions, 95 pts must be evaluable per cohort, which assumes a withdrawal rate around 10%. Pts in Cohort 1 (the first 105 pts enrolled) will receive P and H sequentially and pts in Cohort 2 (the next 105 pts) will receive P and H in the same infusion bag at Cycle 2 onwards if drug administration in Cycle 1 was well tolerated. V will be given in both cohorts. Treatment duration is until disease progression or unacceptable toxicity. Study dose: P: 840 mg loading dose, 420 mg q3w (iv); H: 8 mg/kg loading dose, 6 mg/kg q3w (iv), and V: 25 mg/m2 Day 1 and 8 (first cycle) then 30−35 mg/m2 Day 1 and 8 q3w (iv) (dose escalation at investigator’s discretion). The primary endpoint is ORR by independent assessment. Secondary endpoints include investigator assessment of ORR, time to response, duration of response, PFS, time to progression, overall survival, safety and tolerability, and QoL.
LCCC 1025: A phase II study evaluating the mTOR inhibitor everolimus with trastuzumab and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.
Authors: Anders Carey K. , Deal Allison Mary , Dees Elizabeth Claire , Irvin William Johnson , Muss Hyman Bernard , Noe Jeanne , Karginova Olga , Adamo Barbara , Prat Aleix , Carey Lisa A.
Published: March 2020

TPS656

Background: HER2+ breast cancer (BC) is an aggressive subset of BC with high rates of brain metastases (BM) and poor survival. A recent study illustrates activation of the PI3K/mTOR pathway in approximately two-thirds of BCBM across all subtypes. Everolimus, a novel oral derivative of rapamycin that selectively inhibits mTOR, is clinically-active in combination with trastuzumab (with or without chemotherapy) in advanced HER2+ BC. Everolimus penetrates the blood brain barrier. We are evaluating the efficacy and safety of everolimus plus trastuzumab and vinorelbine in patients (pts) with HER2+ BCBM. Methods: Pts with HER2+ BCBM progressing following cranial radiation and measuring > 0.5cm are eligible for enrollment. Treatment with prior vinorelbine or mTOR inhibition is prohibited. Steroid treatment is allowed if stable or decreasing doses ≥7 days prior to study entry. Pts with leptomeningeal disease are excluded. Pts receive everolimus (5mg orally daily), trastuzumab 2mg/kg and vinorelbine 25mg/m2 (both IV days 1, 8, 15) of a 21 day cycle. Intra- and extracranial disease is assessed every 9 weeks by gadolinium-enhanced brain MRI and CT chest/abdomen/pelvis, respectively. The primary endpoint is intracranial response rate (RR) assessed by modified RECIST. Secondary objectives include extracranial RR (assessed by RECIST 1.1), intra- and extracranial time to progression, progression free survival, overall survival, quality of life, and correlative science endpoints. Statistical considerations: In this two stage design, a sample size of 28 evaluable pts (n=11 in Stage 1) has 80% power to detect a difference between the null (≤5% intracranial RR) and alternative hypothesis (>5%) at a 0.05 significance level. If 1 pt has a CR, PR or SD for ≥ 3 months in the 1st stage, 17 additional pts will be enrolled. Assuming a 20% drop-out rate, 35 total pts will be enrolled. Correlative studies: Archival primary and/or metastatic tissues are required from all pts to evaluate intrinsic BC subtype, protein (p-AKT, pS6, PTEN) and gene expression to identify biomarkers that may be predictive of response or resistance to this novel combination (NCT01305941).