bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of pembrolizumab in combination with nab-paclitaxel in patients with metastatic HER2-negative breast cancer.
Authors: Kwa Maryann J. , Iwano Alyssa , Esteva Francisco J. , Novik Yelena , Speyer James L. , Oratz Ruth , Meyers Marleen Iva , Axelrod Deborah M. , Hogan Rebecca , Mendoza Sandra , Goldberg Judith D. , Muggia Franco , Adams Sylvia 
Published: September 2018

TPS1124 Background: Immunotherapy has shown therapeutic promise in several cancers, including breast cancer. Monotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated durable responses in patients with metastatic triple-negative breast cancer (mTNBC) (Nanda et al, JCO 2016) and metastatic estrogen receptor-positive (mER+)/HER2-negative breast cancer (Rugo et al, SABCS 2015). Furthermore, response rates have been increased with combination approaches with chemotherapy (Adams et al, ASCO 2016). Based on these results, we seek to study the anti-tumor efficacy and safety of pembrolizumab (anti-PD-1 antibody) and nab-paclitaxel, the impact of therapy on the tumor microenvironment, and predictive markers of response. Methods: This is an ongoing single-arm open-label multi-cohort phase II study of pembrolizumab and nab-paclitaxel in patients treated with ≤2 prior lines of therapy for metastatic HER2-negative breast cancer (n = 50) (ClinicalTrials.gov: NCT02752685). Thirty patients with mTNBC and 20 patients with mER+/HER2-negative breast cancer will be enrolled. Enrollment of patients with metaplastic breast cancer is encouraged. Patients will receive pembrolizumab 200 mg IV on day 1 plus nab-paclitaxel 100 mg/m2 IV on day 1 and 8 (21-day cycle). Prior taxane therapy given > 3 months before cycle 1 is allowed. Primary objective is treatment efficacy, as determined by overall response rate (RECIST 1.1). Secondary objectives include safety, progression-free survival, overall survival, and duration of response. Serial tumor biopsies will be performed to assess changes in the tumor microenvironment from baseline with chemotherapy alone (cycle 1) and then with chemoimmunotherapy (cycle 2 and subsequent cycles). Mutational and neoantigen load, TILs by histopathological assessment, TCR by immunosequencing, and immune gene profiles in tumors will be evaluated. PD-L1 expression in tumor tissue is not required for enrollment but will be assessed as a predictive marker. The potential role of the gut microbiome in modulating the immune response will also be evaluated by 16S rRNA. An initial safety run-in with 12 subjects has been completed with no unexpected toxicity. Clinical trial information: NCT02752685.
A phase 0/II study for ribicoclib in patients with recurrent glioblastoma.
Authors: Sanai Nader , Tien An-Chi , Honea Norissa , Mehta Shwetal , Li Jing 
Published: September 2018

TPS2083 Background: Disruption of CDK4/6-dependent G1-S cell cycle regulation is a hallmark of glioblastoma (GBM) progression in 78% of cases. Newly-developed CDK4/6 inhibitors have shown promise in non-CNS cancer trials and glioma animal models. To explore the utility of Ribociclib, a specific CDK4/6 inhibitor, in treating recurrent GBM patient, we designed a phase 0/II clinical trial to examine the pharmacokinetic (PK) and pharmacodynamics (PD) of Ribociclib. Methods: 24 adult patients are allocated to 3 time-escalation arms and receive 5 days of daily Ribociclib prior to planned GBM resection. Eligible patients are selected based on intact Rb expression and loss of Ink4a/Arf locus. Intensive PK sampling of blood, CSF, and tumor is performed intraoperatively and Ribociclib concentrations are determined by a validated LC-MS/MS method. PD endpoints, including RB phosphorylation and FoxM1 expression, are compared to matched archival tissue. Patients exhibiting positive PK and PD outcomes will graduate to a therapeutic regime of Ribociclib as part of the Phase II component of the study with a primary endpoint of progression-free survival, as determined by Response Assessment in Neuro-Oncology (RANO) criteria. Clinical trial information: NCT02933736.
REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib (REG) activity in relapsed glioblastoma (GBM) patients (PTS).
Authors: Lombardi Giuseppe , De Salvo Gian Luca , Eoli Marica , Brandes Alba Ariela , Ruda Roberta , Faedi Marina , Pace Andrea , Lolli Ivan , Pasqualetti Francesco , Rizzato Simona , Germano Domenico , Maiello Evaristo , Indraccolo Stefano , Cabrini Giulio , Gardiman Marina Paola , Zagonel Vittorina 
Published: September 2018

TPS2085 Background: GBM is the most common and malignant form of primary brain tumor with a high recurrence rate after surgery, radiation therapy and temozolomide. Currently, there is no established regimen for the treatment of recurrent GBM. GBMs are highly vascularized tumors with high expression of pro-angiogenic factors and activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR, and PDGFR, which control the tumor vasculature. REG, an oral multikinase inhibitor, inhibits these angiogenic kinases and the mutant oncogenic kinases KIT, RET and B-RAF. REG was demonstrated to be safe and effective in metastatic colon-rectal cancer, hepatocellular carcinoma and GIST PTS. It was shown that REG inhibits tumor angiogenesis and tumor cell proliferation in rat GBM tumor xenografts (Wilhelm S.M, et al. Regorafenib: a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int. J. Cancer:129,245-255.2011). Methods: Primary aim of the study is to assess the role of REG activity in prolonging the overall survival in relapsed GBM PTS after surgery and Stupp regimen; secondary aims are to analyze progression free survival, objective response rate, disease control rate and quality of life. Eligible PTS with ECOG PS 0-1, documented progression of disease (after Stupp treatment) as defined by RANO criteria, adequate bone marrow, liver and renal function are randomized in a 1:1 ratio to REG 160 mg/die (3 weeks on, 1 week off) or lomustine 110 mg/m2 (every 6 weeks). A total of 112 PTS will be randomized (α = 0.20, β = 0.20) and stratified based on surgery at recurrence. Disease evaluation is performed with gadolinium brain MRI every 8 weeks according to RANO criteria. Additional exploratory objectives include analysis of specific angiogenic and metabolic biomarkers in tissue as possible predictors of response to REG. The trial started in Nov 2015; as of Jan 2017, 105 PTS have been enrolled. Final analysis is planned in Dec 2017. Clinical trial information: NCT02926222.
A phase 1, open-label, dose escalation study of enoblituzumab (MGA271) in pediatric patients with B7-H3-expressing relapsed or refractory solid tumors.
Authors: Desantes Kenneth , Maris John M. , McDowell Kimberly , Mackall Crystal , Shankar Sadhna , Vasselli Jim , Chen Francine , Loo Deryk , Moore Paul A. , Wigginton Jon M. , Sondel Paul M. 
Published: September 2018

TPS2596 Background: Enoblituzumab, is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family. It is Fc-engineered to enhance effector function including antibody dependent cellular cytotoxicity (ADCC). IHC analyses with the parental anti-B7H3 mAb specificity incorporated in enoblituzmab revealed limited B7-H3 expression in normal tissues but high expression in many cancers (Loo et al., 2012). Among pediatric solid tumors, high expression of B7-H3 has been reported in neuroblastoma, rhabdomyosarcoma, osteosarcoma, Wilms tumor, Ewing’s sarcoma and desmoplastic small round cell tumor. B7-H3 overexpression correlates with poor prognosis in a broad range of cancers in adults suggesting a potential role in enabling tumor immune escape. ADCC and potential modulation of T cell function resulting in enhanced antitumor immune response are presumed mechanisms of action of enoblituzumab. Methods: This is an open-label, dose escalation / cohort expansion phase 1 study (NCT02982941) designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of enoblituzumab in children and young adults with B7-H3-expressing relapsed or refractory malignant solid tumors. A 3+3 design is used in escalating dose cohorts of weekly intravenous (IV) enoblituzumab starting at 10 mg/kg. Response is first determined at 8 weeks. irRECIST is used for response assessment for patient management. Enoblituzumab may continue up to 2 years based on response. Cohort expansion phase, to further define the safety and initial antitumor activity of enoblituzumab, will start after maximum tolerated dose is determined. The patients are assigned to 1 of 5 cohorts based on disease type as follows: 1) neuroblastoma - measurable disease, 2) neuroblastoma - non-measurable disease, 3) rhabdomyosarcoma, 4) osteosarcoma, and 5) Ewing’s sarcoma, Wilms’ tumor and desmoplastic small round cell tumors. Enrollment is ongoing. Ref : Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Loo D, Alderson RF, Chen FZ, Huang L et al. Clin Cancer Res. 2012; 18:3834-45. Clinical trial information: NCT02982941.
A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of daily oral BAL101553, a novel tumor checkpoint controller (TCC) in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.
Authors: Ingles Garces Alvaro Henrique , Plummer Elizabeth R. , Lopez Juanita Suzanne , Kristeleit Rebecca Sophie , MacDonald Julie , Sweeting Lorna , Devlin Michael-John , Drew Yvette , Hannah Alison L. , Aceto Nicola , Anderson Stephanie , Lane Heidi A , Larger Patrice , Maurer Martina , McKernan Phil , Engelhardt Marc Frederick , Greystoke Alastair , Coleman Niamh , Evans T.R. Jeffry , Mulholland Paul James 
Published: September 2018

TPS2601 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule (MW 387) shown in rats to penetrate the brain (1:1 plasma ratio) and has shown promising antitumor activity in orthotopic preclinical models of GBM as monotherapy or in combination with radiotherapy (RT) with/without chemotherapy. In a completed Phase 1 study with 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. J Clin Oncol 34, 2016 suppl; 2525), dose-limiting vascular effects were observed and appeared Cmax related. Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients; no vascular toxicities were observed at doses up to the MAD of 30 mg QD. Given this absence, the study was amended to enroll separate cohorts of patients with progressive or recurrent GBM or high-grade glioma. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of daily oral administration of BAL101553 in consecutive 28-day cycles at a starting dose of 8 mg QD. Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, are eligible for enrollment. This includes patients with histologically-confirmed low-grade glioma with unequivocal evidence by imaging of transformation to high-grade glioma. Adverse events are assessed using CTCAEv4; tumor response by RANO (every 2 cycles). The dose escalation allows for doubling of dose levels depending on observed toxicities. PD assessments include circulating tumor cells. PK profiles are assessed throughout the first two treatment cycles. Clinical trial information: NCT02490800.
A phase Ib, first-in-human, dose escalation and expansion study of XMT-1522, a novel antibody-drug conjugate (ADC) directed against HER2, in patients with advanced breast cancer and other advanced tumors expressing HER2.
Authors: Burris Howard A. , Barve Minal A. , Hamilton Erika Paige , Bardia Aditya , Soliman Hatem Hussein , Jarlenski Donna , Mosher Rebecca , Bergstrom Donald Alan 
Published: September 2018

TPS2606 Background: XMT-1522 is an ADC consisting of a novel human IgG1 anti-HER2 monoclonal antibody conjugated to an auristatin-based cytotoxic payload (AF-HPA). An average of 12 AF-HPA molecules is conjugated to each antibody via a biodegradable polymer. In pre-clinical xenograft experiments XMT-1522 achieved complete, durable tumor regressions in models of HER2-positive and HER2 1+/2+ breast cancer, HER2 2+/3+ NSCLC, and HER2-positive and HER2 1+ gastric cancer. Methods: This study (NCT02952729) is comprised of two parts: a dose escalation segment (DES) and an expansion segment (EXP). The primary objectives of the DES are determination of the maximum tolerated dose and recommended Phase 2 dose (RP2D) and assessment of safety and tolerability. The DES will enroll patients with advanced or metastatic breast cancer who have progressed following standard therapies and have HER2 protein at least 1+ by IHC. XMT-1522 will be administered intravenously every 3 weeks. DES uses a 3+3 design. Post-dose assessments include LVEF measurement at the end of cycles 1, 3, then every 3 cycles, ophthalmologic exams at the end of cycles 1, 2, then every 2 cycles, and re-staging CT scans every 2 cycles. Pharmacokinetics of antibody, AF-HPA payload and an AF-HPA metabolite will be measured. Two patients have completed dose level 1 without DLT. The EXP segment will open at the RP2D and will further assess safety and tolerability of XMT-1522 and assess efficacy in selected patient populations. EXP will enroll 4 cohorts (N = 20 each). Cohort 1: HER2 1+/2+ advanced breast cancer with 2-3 prior chemotherapy regimens Cohort 2: HER2-positive advanced breast cancer with prior pertuzumab and ado-trastuzumab emtansine (T-DM1) Cohort 3: HER2-positive advanced gastric cancer with prior trastuzumab Cohort 4: HER2 2+/3+ NSCLC with at least 1 prior platinum regimen The protocol requires archival tumor tissue for central confirmation of HER2 status, alternative HER2 measurements, and targeted gene expression and sequencing studies. Tumor biopsies will be requested at the time of progression from patients who responded to XMT-1522. Clinical trial information: NCT02952729.
A phase I, open-label, first-time-in-patient dose escalation and expansion study to assess the safety, tolerability, and pharmacokinetics of nanoparticle encapsulated Aurora B kinase inhibitor AZD2811 in patients with advanced solid tumours.
Authors: Burris Howard A. , Wang Judy Sing-Zan , Johnson Melissa Lynne , Falchook Gerald Steven , Jones Suzanne Fields , Strickland Donald K , Greenlees Carol , Brugger Wolfram , Charlton Julie , Pease Elizabeth , MacDonald Alexander 
Published: September 2018

TPS2608 Background: Aurora kinase B performs key roles in the regulation of the cell cycle and represents a potential target for anticancer therapy. AZD2811, formerly designated AZD1152 hydroxy-quinazoline pyrazole anilide (AZD1152 hQPA), is a potent and selective inhibitor of Aurora B kinase activity and has been incorporated into a polymer nanoparticle carrier for intravenous (IV) administration. The phosphate pro-drug of AZD2811, known as AZD1152 (barasertib), reached Phase II of clinical development as a continuous IV infusion. While promising efficacy was seen with barasertib in elderly acute myeloid leukaemia (AML) patients ( Kantarjian HG et al., Cancer 2013;119:2611-19), continuous intravenous drug delivery precluded subsequent development in this disease setting and there were limited clinical responses in solid tumour patients due to dose-limiting myelotoxicity. AZD2811 nanoparticle has been designed to overcome these issues. Methods: Patients with relapsed advanced solid malignancies with no standard treatments are eligible for the part A dose escalation. Primary endpoint is to determine the maximum tolerated dose of AZD2811 nanoparticle using a 3+3 design. Patients with refractory/relapsed small cell lung cancer (SCLC) will be eligible for the part B expansion, where the safety, PK and anti-tumour activity of AZD2811 nanoparticle will be assessed as monotherapy and in combination with chemotherapy. Study enrolment is ongoing. Clinical trial information: NCT02579226.
Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: A phase I exposure escalation study.
Authors: Mammatas Lemonitsa Hillegonda , Zandvliet Anthe S. , Rovithi Maria , Honeywell Richard , Swart Eleonora , Peters Godefridus J. , Menke Catharina Wilhelmina , Verheul Henk M.W. 
Published: September 2018

TPS2620 Background: Sorafenib is currently prescribed at a standard fixed dose of 400 mg twice daily in a continuous schedule. Increased exposure to sorafenib is associated with improved outcome. However, further increase in the dose of this continuous schedule is precluded due to toxicity. A high-dose, pulsatile schedule may result in increased sorafenib exposure while maintaining acceptable toxicity and has demonstrated promising preclinical antitumor activity.1 Sorafenib plasma concentrations present with large interpatient variability. As drug effectivity is largely dependent on AUC exposure, personalized dose titration based on the sorafenib plasma AUC0-12h of an individual patient seems more suitable than a standard fixed dose. In this phase I trial, a high-dose, weekly schedule of sorafenib is being studied, using exposure escalation cohorts based on a target AUC0-12h, instead of conventional dose escalation cohorts. Methods: Adult patients are included with locally advanced or metastatic solid tumors for whom no standard therapy exists. High-dose sorafenib is administered once a week. Pharmacokinetic monitoring is performed during the first 3 weeks of treatment in each patient to evaluate if the target plasma sorafenib AUC0-12h of the cohort is reached and sorafenib dose is adjusted accordingly. Cohorts consist of 3-6 patients per exposure level, starting with target AUC0-12h 25-50 mg x h/L, analogous to the continuous schedule. The target AUC0-12h is increased in subsequent cohorts until exposure limiting toxicity occurs. Main objectives are to assess safety and establish the maximum tolerated plasma AUC0-12h of high-dose, pulsatile sorafenib. At this dose level 10 extra patients will be included. Tumor biopsies are required in all patients of this expansion cohort to study antitumor effects and for direct comparison of plasma and intratumor sorafenib concentrations. Furthermore, a simplified method will be developed for measurement of plasma sorafenib exposure using dried blood spot sampling at 1-2 time points. Nine patients have already been included. Reference: 1Wang X. et al. J Transl Med 2011;9:220. Clinical trial information: NCT02636426.
The Molecular Screening and Therapeutics (MoST) Program: A precision medicine framework for biomarker-driven signal-seeking clinical studies for rare cancers.
Authors: Hess Dominique , Sebastian Lucille T , Sjoquist Katrin Marie , Lee Chee Khoon , Hague Wendy , Miller Danielle , Cowley Mark , Qiu Min Ru , Fox Stephen B. , Joshua Anthony M. , Simes John , Thomas David Morgan 
Published: September 2018

TPS2621 Background: Precision medicine aims to link molecular targets in tumors to cognate therapies and has the potential to yield new treatments for cancer patients with unmet clinical need. With the accelerating pace of discovery and genomic capacity, innovative approaches are needed to translate molecular opportunities into clinical care. The MoST program tests a novel paradigm for evaluation of biomarker-driven treatment of patients with advanced cancer. The key elements of the design are a molecular screening platform to identify ‘actionable’ variants and an overarching protocol for multiple, parallel, signal-seeking clinical substudies. Methods: 1000 patients with advanced solid cancer of any histologic type, having failed all standard therapies will undergo tumor molecular profiling on archival tissue with a 393-gene panel and other molecular assays. Eligibility for biomarker-driven substudies of targeted treatments is based on tumor variants assessed by a Molecular Tumor Board. A novel framework design allows expedited addition of substudies, with ≥12 open-label, single-arm, signal-seeking substudies planned. The primary objective is to identify signals of clinical activity, as measured by objective tumor response or the ratio of time-to-progression on study treatment over the preceding period. Cohorts of 16 patients will be recruited to each substudy. Substudies with ≥3/16 responding patients will be considered sufficiently interesting to investigate further.As of Feb 2017, 65 patients have been screened, and 8 recruited to 2 open sub-studies: CDK4/6 inhibitor (palbociclib) for Rb pathway defects; CTLA-4 plus PD-L1 checkpoint inhibitors (durvalumab + tremelimumab) for patients with no actionable mutations. Additional substudies under development include: PARP plus PD-L1 inhibitors (olaparib + durvalumab) for HR DNA repair defects; SMO inhibitor (vismodegib) for Hh pathway defects. The modular signal-seeking trial design will be evaluated and is intended to expedite testing of biomarker-based therapies for rare cancers. Clinical trial information: ACTRN12616000908437; ACTRN12616000931471; ACTRN12616001019493.
A NKG2D-based CAR-T therapy in a multinational phase I dose escalation and expansion study targeting multiple solid and hematologic tumor types.
Authors: Verma Bikash , Aftimos Philippe Georges , Awada Ahmad , Machiels Jean-Pascal H. , Brayer Jason B. , Sallman David A , Kerre Tessa , Odunsi Kunle , Lonez Caroline , Gilham David Edward , Lehmann Frederic 
Published: September 2018

TPS3093 Background: Chimeric Antigen Receptor (CAR)-T therapy has potentially serious limitations related to target antigen loss, toxicity due to pre-conditioning regimen, and lack of activity in many tumor types. To overcome these limitations, we have developed a novel CAR-T, called NKR-2, incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain. When expressed in T-cells, the naturally-expressed DAP10 provides co-stimulatory signals to NKR-2 to produce cytokines and selectively target tumor cells upon recognition of up to 8 different stress-induced NKG2D ligands expressed in many solid and hematologic malignancies. In preclinical studies, NKR-2 demonstrated long-term anti-tumor activity towards a breadth of tumor indications, in the absence of pre-conditioning, whilst simultaneously targeting tumor cells and cells from the local tumor neo-vasculature and suppressive immune environment. In our recently completed First-in-Human Phase 1 study (NCT02203825) in hematologic cancers, a single administration of autologous NKR-2 was safe with initial signs of clinical benefit. Methods: Exploiting the multiple ligand targeting capability and unique mode of action of NKR-2, the THINK trial (THerapeutic Immunotherapy with NKR-2) is an open-label Phase I study that will assess the safety and clinical activity of multiple infusion NKR-2 treatment (every 2 weeks x 3 infusions) in relapse/refractory patients with metastatic or locally advanced CRC, urothelial carcinoma, TNBC, pancreatic cancer, recurrent epithelial ovarian and fallopian tube carcinoma, AML/MDS and MM, post standard treatment. The study contains two consecutive segments. The dose escalation segment will enroll 18 patients in two separate hematologic and solid malignancy arms, and will evaluate 3 dose levels of NKR-2 (3x108, 1x109 and 3x109 per injection) following a 3+3 design. The expansion segment will then enroll 96 additional patients in 7 separate cohorts for each indication with 3 steps of statistical analysis (overall futility, cohort futility and final evaluation). The study is open for recruitment in both EU and US. Clinical trial information: NCT03018405.