bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I trial of the triplet veliparib + VX-970 + cisplatin in patients with advanced solid tumors.
Authors: O'Sullivan Coyne Geraldine Helen , Kummar Shivaani , Meehan Robert S. , Juwara Lamin , Piekarz Richard , Sharon Elad , Streicher Howard , Conley Barbara A. , Takebe Naoko , Harris Lyndsay , Doyle Austin , Quinn Mary Flanagan , Rubinstein Larry , Wilsker Deborah , Kinders Robert J. , Parchment Ralph E. , Levy Elliot B , Doroshow James H. , Chen Alice P. 
Published: September 2018

TPS2609 Background: The DNA damage response (DDR) pathway is a key element of cellular integrity. Platinum compounds form covalent bonds with purine bases causing DNA cross-links that stall replication forks halting transcription. Poly (ADP-ribose)polymerase-1 (PARP-1) plays a pivotal role in DDR and base-excision repair. Ataxia-telangiectasia-related (ATR) protein kinase is also central to DDR and homologous recombination, activating a series of phosphorylation cascades culminating in cell cycle arrest to allow time for DNA repair. Veliparib (ABT-888) is a PARP 1/2 inhibitor (PARPi) with clinical evidence of antitumor activity in combination with cisplatin in BRCA mutation carriers (Rodler et al, Cancer Res. 2011). VX-970 is a potent ATR inhibitor, with antitumor activity across a range of cell lines in combination with DNA damaging agents, including cisplatin (Huntoon et al, Cancer Res. 2013). In this trial, we will evaluate whether the combination of veliparib + VX-970 impairs DNA repair, inducing a “BRCA null”-like phenotype leading to potentiation of the antitumor activity of cisplatin. Methods: Open label phase I trial of the veliparib+VX-970+cisplatin combination, following a 3+3 design, with dose limiting toxicities defined during cycle 1. Estimated enrollment: 24 patients (pts); Dana Farber and MD Anderson planned as additional sites. Drug administration over a 21-day cycle: VX- intravenously (IV) on Days 2 and 9; Veliparib orally twice daily (q12 hours ± 1 hour) Days 1-3 and 8-10; cisplatin 40 mg/m2 IV Day 1 (with Day 8 added from DL3 onwards). Pts must be ≥ 18 years of age; have histologically confirmed solid tumors that have progressed on standard of care therapy known to prolong survival or without known standard, ECOG PS ≤2, and life expectancy ≥3 months. Pts with treated brain metastasis with stable disease ≥4 weeks without requiring steroids or anti-seizure medication are eligible. Exclusion criteria include a prolonged QTc interval, and sensory/motor neuropathy ≥grade 2 by CTCAE v.4. At this time, cohort 3 has enrolled 1 of 3 planned pts. Assessment of DDR and apoptosis biomarkers at the maximally tolerated dose using a validated and quantitative immunofluorescence assay is planned. Clinical trial information: NCT02723864.
Combination immunotherapy with IDO vaccine and PD-1 inhibitors in advanced NSCLC.
Authors: Mellemgaard Anders , engel-Norregaard Lotte , Andersen Mads Hald , Zocca Mai-Britt , Svane inge Marie 
Published: September 2018

TPS2610 Background: Multible checkpoints regulate host immune response, and development has focused on three of these: IDO, CTLA-4 and PD-1. Presently, several checkpoint inhibitors have been approved for advanced NSCLC including nivolumab, pembrolizumab, and atezolizumab all targeting PD-1 and PD-L1. Depending on level of PD-L1 tumor expression, response rates vary, and a substantial proportion of patients do not respond to treatment with immune checkpoint inhibitors. The combination of checkpoint inhibitors have been shown in malignant melanoma and other tumor types to clearly increase the effect. IO102 is a synthetic peptide under development as an immune-modulatory agent targeting cells expressing indoleamine 2,3-dioxygenase (IDO). IDO potently inhibits T-cell immunity in patients with cancer. Treatment with IO102 in NSCLC patients after first line palliative chemotherapy lead to long PFS in a number of patients in a small single arm study. Methods: IO102-001 is a randomized, double-blinded Phase 2 trial to evaluate the safety and efficacy of IO102 in combination with anti-PD-1 mAb in locally advanced and/or metastatic NSCLC stage III-IV patients eligible for anti-PD-1 mAb 2nd line treatment after first line of chemotherapy. Patients are randomized (2:1) to either a PD-1 inhibitor + IO201 vaccine or a PD-1 inhibitor (SOC). The PD-1 inhibitor will be administered according to label while IO102 will be given as s.c. injection every 2 weeks for the first 12 weeks, and subsequently every 4 weeks for 12 months or until progression, death or withdrawal from trial, whichever comes first. Treatment is continued to progression, unacceptable toxicity or withdrawal of consent. Main inclusion criteria is patients diagnosed with locally advanced and/or metastatic NSCLC Stage III-IV, measurable disease according to RECIST (1.1), patients eligible for anti PD-1 mAb treatment after 1st line of chemotherapy , ECOG performance status 0 or 1 and available tumor tissue for further analysis. A total of 90 patients will be included in the trial, and the trial will be active in countries in Europe and the US from Q2 2017.
Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer (MBC).
Authors: Anampa Mesias Jesus Del Santo , Oktay Maja H. , Xue Xiaonan , Condeelis John , Sparano Joseph A. 
Published: September 2018

TPS2611 Background: TMEM (Tumor Microenvironment of Metastasis) are microanatomic structures formed by a Mena-expressing tumor cell, Tie2-expressing macrophage, and endothelial cell in direct content, which serve as the primary portal for tumor cell intravasation into the circulation and subsequent metastasis. Paclitaxel (P) induces the formation of TMEM in the primary tumors of patients treated with neoadjuvant chemotherapy (NAC), and in the primary tumor and distant metastases in the PyMT/PDX models. Tumor cell intravasation is mediated by release of VEGF at TMEM sites from TMEM-associated Tie2HI/VEGFHI macrophages upon binding of the Tie2 receptor to angiopoietin. The Tie2 inhibitor rebastinib (R) inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either P or eribulin (E). We hypothesize that the addition of R to antitubulin therapy in patients with HER2-negative MBC will prevent hematogenous dissemination and distant metastasis by inhibiting TMEM function, reduce CTC burden; and improve clinical outcomes. Methods: Primary objective of this phase Ib study (NCT02824575) is to evaluate safety and tolerability of R in two dose levels (DL) (50mg or 100mg PO BID) combined with IV P 80mg/m2 (day 1, 8 and 15) or E 1.4mg/m2 (day1 and 8) for four 21-day cycles. Key eligibility includes histologically confirmed HER2 negative MBC, ≤ 2 non-taxane chemotherapy regimens for R plus P arm or ≥ 2 chemotherapy regimens (including a taxane) for E plus R arm, ≥2 endocrine therapies ( including CDK4/6 inhibitor) for ER positive patients, ECOG PS 0 or 1; and normal organ and marrow function. Exclusion criteria include significant ocular or cardiac disease. Pharmacodynamic biomarkers to be measured during cycle 1-3 include CTCs, angiopoietin 1/2 levels and Tie-2 expressing monocytes. Tissue biopsy after two treatment cycles in 6 patients will be performed to evaluate TMEM score and function. With two DL of rebastinib, and 3-6 patients at each DL, it is anticipated that 6-12 patients will be required. This trial has enrolled two patients assigned to P arm combined with R 50mg BID. Clinical trial information: NCT02824575.
A phase Ib/II, open-label, dose escalation study to evaluate the safety, pharmacokinetics, and efficacy of SM88 in patients with prostate cancer.
Authors: Del Priore Giuseppe , Hoffman Steve , Nixon Daniel W. 
Published: September 2018

TPS2615 Background: Non-hormonal treatments for biochemically recurrent non-metastatic prostate cancer (nmPC) are limited. SM88 is a novel combination of proprietary tyrosine isomer (TI) and other repurposed agents (CYP3a4 inducer, mTOR inhibitor and catalyst) designed to selectively increase metabolic oxidative stress in cancer cells. Early data reported SM88 activity in solid tumors without significant toxicity (Hoffman et al J Clin Oncol 2013; e22095, Hoffman et al Ann Onc 2016: vi551). Methods: This is an open-label multi-center, dose escalating, dose expansion study in nmPC who have failed or refused androgen deprivation. The study includes a dose escalation phase Ib and dose expansion phase 2. The primary objectives are to determine the effect of SM88 on circulating tumor cells (CTC), and progression-free survival. Secondary objectives are: LDH, bone-specific alkaline phosphatase, urinary N-telopeptide, neutrophyll/llymphocyte ratio, cutaneous hyper-pigmentation correlation, PSA doubling times, safety, and patient reported outcomes. As of Jan ‘17, Phase 1b cohorts 1 and 2, with TI and component PK evaluations, have completed enrollment with adequate numbers to establish the Phase 2 dose without DLT. Phase 2 has begun, with 33 patients planned for at least 6 cycles (@28d) to reach the desired power. This would be followed by a pivotal Phase 3 study in the same group of patients. We propose to conduct a pivotal randomized phase 3 of SM88 in rising PSA, nmPC versus patient’s and clinician’s choice, limited to 2 options i.e. observation or ADT therapy. Inclusion would include doubling time < 9 months, elevated CTCs and recurrent disease after localized curative intent therapy (the same population as our completed Phase I and ongoing phase II). Outcomes will include delay of radiographic PFS, and delay of time to subsequent toxic therapy i.e. cytotoxic systemic chemo and/or radiation therapy. We proposed this pivotal trial will lead to a successful NDA for an indication in this population of patients. Rapid accrual is expected at several institutions because of the urgent need for less toxic alternatives to androgen deprivation therapy.
Phase 1 study of intraperitoneal infusion of autologous monocytes with peginterferon alfa-2b and interferon gamma-1b in women with recurrent or refractory ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
Authors: Nunes Ana Tablante , Green Daniel , Ekwede Irene , Zoon Kathryn , Annunziata Christina M. 
Published: September 2018

TPS3092 Background: Monocytes can differentiate into classic M1 macrophages inhibiting tumor proliferation and promoting natural killer (NK) cell differentiation. We previously demonstrated that the combination of human monocytes, human interferon alfa-2b (IFNα-2b), and interferon gamma-1b (IFNγ 1b) act synergistically against tumor cells in vitro and in mouse models, providing a long and durable response. Additionally, monocytes, IFNα and IFNγ have been individually shown in early phase clinical trials to be safely administered intraperitoneally. As ovarian cancer is largely confined to the peritoneal cavity, it is likely that the administration of IFNs and monocytes intraperitoneally will create a strong anti-tumor environment and can overcome the immunosuppressive environment of epithelial ovarian cancer. We hypothesize that the monocyte and interferon administration will be tolerable to women with relapsed ovarian cancer. Methods: A Phase 1 single arm study to determine the maximum tolerated dose of intraperitoneal monocytes and pegylated IFNα-2b and IFNγ-1b is currently enrolling patients with recurrent or refractory ovarian cancer, fallopian tube cancer or primary peritoneal cancer without standard therapy options. Autologous monocytes obtained through apheresis 24 hours prior will be mixed with pegylated IFNα-2b and IFNγ-1b in a 3 + 3 dose escalation and administered intraperitoneally once every 28 days. Results: As of February 2017 we are enrolling our first cohort of patients and are evaluating for dose limiting toxicities. Conclusions: This is a novel therapy that if successful, may be efficacious alone or used to create a backbone on which to add novel agents such as SMAC mimetics or PD-L1 blockade, in order to increase immune-mediated killing of ovarian cancer. Clinical trial information: NCT 02948426.
A phase I single arm, open label clinical trial evaluating safety of MAGE-A10c796T in subjects with advanced or metastatic head and neck, melanoma, or urothelial tumors (NCT02989064).
Authors: Hong David S. , Butler Marcus O. , Sullivan Ryan J. , Erickson-Miller Connie L. , Trivedi Trupti , Chagin Karen , Bartlett-Pandite Arundathy N. , Amado Rafael G. 
Published: September 2018

TPS3098 Background: MAGE-A10 is a cancer/testis antigen that has been identified in 42, 26 and 17% of urothelial, melanoma and head and neck tumors, respectively. This study will evaluate the safety and antitumor activity of genetically engineered affinity enhanced autologous MAGE-A10c796T cells directed towards a MAGE-A10 peptide expressed on tumors in the context of HLA *02:01 and/or *02:06. Methods: This first-in-human T cell dose escalation study utilizes a modified 3+3 design to evaluate safety, including dose limiting toxicities (DLT). Secondary objectives include anti-tumor activity (overall response, duration of response, time to response, PFS, OS) and translational research assessments. Patients are screened under a separate protocol (NCT02636855). Those who are HLA*02:01 and/or *02:06 positive and have inoperable or metastatic (advanced) urothelial cancer, melanoma, or squamous cell head and neck tumors with MAGE-A10 expression and meet all other entry criteria are eligible for treatment. Patients must have received standard of care therapies and have progressive disease. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the MAGE-A10c796 TCR, and infused into the subject (Day 1) after receiving lymphodepleting chemotherapy (fludarabine 30 mg/m2/day and cyclophosphamide 600 mg/m2/day, on days -7, -6 and -5). The DLT observation period will be during the first 30 days following the infusion of MAGE-A10c796T for each patient in all groups. Up to 10 patients will be enrolled at the target dose. Disease assessments will be conducted at week 6, 12, 18 and 24, and then every 3 months until confirmation of disease progression. On study tumor biopsies and blood samples will be evaluated to compare the pre- and post-T cell infusion immune profile for association with treatment outcome. Clinical trial information: NCT02989064. [Table: see text]
Phase II study for the evaluation of efficacy of pembrolizumab (MK-3475) in patients with cancer of unknown primary.
Authors: Varadhachary Gauri R. , Raghav Kanwal Pratap Singh , Pant Shubham , Janku Filip , Fu Siqing , Hong David S. , Piha-Paul Sarina Anne , Colen Rivka R. , Subbiah Vivek , Painter Jeane , Tsimberidou Apostolia Maria , Stephen Bettzy , Karp Daniel D. , McQuinn Lacey , Mendoza Tito R. , Hess Kenneth R. , Meric-Bernstam Funda , Naing Aung 
Published: September 2018

TPS3103 Background: Cancer of unknown primary is a biopsy proven malignancy for which an anatomic primary remains unidentified after a focused search. It accounts for 3-4 % of all solid cancers and most investigators limit it to epithelial and undifferentiated cancers. Patients with metastatic melanoma and sarcoma are excluded. Sophisticated imaging, robust pathologic evaluation including immunostains, and genomic and proteomic characterization of these cancers have challenged the management of CUP. The paradigm has shifted from empiric platinum based combination doublets to a personalized approach. Nevertheless, without an anatomic primary, clinical trial opportunities are limited. There remains an unmet research need to evaluate the role of immunotherapy, specifically checkpoint blockade drugs in specific subsets of CUP patients. Methods: Adult Patients ≥ 18 years of age with ECOG PS 0-1, must meet the definition of a CUP cancer. Patients must be intolerant and/or refractory to at least one line of established therapy known to provide clinical benefit for their condition within the last 6 months (often, a platinum based therapy for carcinomas). Patients must have either measurable (RECIST 1.1) or evaluable disease. Although not limited to subtypes, there is a signficant interest in enrolling patients with isolated disseminated lymphadenopathy, HPV (+) CUP and those who have an IHC profile of those known cancers for which anti-PD therapy has been approved (lung, renal, others) The primary objective of this trial is to evaluate efficacy by evaluation of non-progression rate (NPR) at 27 weeks (9 cycles) as defined as the percentage of CUP patients who are alive and progression-free at 27 weeks (9 cycles) as assessed by RECIST 1.1. Secondary objectives include evaluating safety and tolerability of pembrolizumab (MK-3475); correlating efficacy, non-progression rate (NPR) at 27 weeks (9 cycles), objective response (CR or PR), progression-free survival (PFS), overall survival (OS) and duration of response (DOR) to PD-L1 status; and identifying imaging characteristics associated with immunological changes in tumor following treatment with pembrolizumab. Enrollment is ongoing. Clinical trial information: NCT02721732.
BEACON CRC (binimetinib [BINI], encorafenib [ENCO], and cetuximab [CTX] combined to treat BRAF-mutant metastatic colorectal cancer [mCRC]): A multicenter, randomized, open-label, three-arm phase III study of ENCO plus CTX plus or minus BINI vs irinotecan (IRI)/CTX or infusional 5-fluorouracil/folinic acid/IRI (FOLFIRI)/CTX with a safety lead-in of ENCO + BINI + CTX in patients (Pts) with BRAFV600E mCRC.
Authors: Huijberts Sanne , Schellens Jan H. M. , Fakih Marwan , Peeters Marc , Kopetz Scott , Grothey Axel , Van Cutsem Eric , Wasan Harpreet Singh , Desai Jayesh , Ciardiello Fortunato , Yoshino Takayuki , Maharry Kati , Gollerkeri Ashwin , Tabernero Josep 
Published: September 2018

TPS3622 Background: BRAF mutations are found in ≈10% of mCRC cases. Pts with BRAFV600E mCRC have a poor prognosis, with shorter progression-free survival (PFS) and overall survival (OS) than pts with BRAFwt mCRC (Van Cutsem et al 2011; Modest et al 2012; Sorbye et al 2015). The benefits of combined BRAF + EGFR inhibition in mCRC have been demonstrated in vitro (Corcoran et al 2012; Prahallad et al 2012; Yang et al 2012), and preclinical evidence suggests that adding MEK signaling inhibition improves antitumor activity. Early clinical data indicate that BRAF + EGFR + MEK inhibition has greater activity than BRAF + EGFR inhibition in pts with BRAFV600E mCRC (Van Cutsem et al 2016). Our study will examine the combination of BINI (a MEK inhibitor) + ENCO (a selective BRAF kinase inhibitor) + CTX (an anti-EGFR antibody) and of ENCO + CTX in pts with BRAFV600E mCRC. Methods: BEACON CRC (NCT02928224) is enrolling pts with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. A safety lead-in phase (≈30 pts) will determine the safety and tolerability of oral ENCO 300 mg QD + oral BINI 45 mg BID + intravenous CTX 400 mg/m2 followed by 250 mg/m2 QW. In the phase 3 portion, ≈615 pts will be randomized 1:1:1 to triplet (ENCO + BINI + CTX), doublet (ENCO + CTX), or control (investigator’s choice of IRI/CTX or FOLFIRI/CTX) arms. Pts will be treated in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anticancer therapy, or death. The primary endpoint is OS (triplet vs control). Secondary endpoints include OS (doublet vs control), confirmed investigator-assessed objective response rate according to RECIST version 1.1 (triplet or doublet vs control; triplet vs doublet), PFS (triplet or doublet vs control), duration of response, time to response, pharmacokinetics, and pt-reported outcomes. Safety will be summarized using standard adverse event reporting. Clinical trial information: NCT02928224.
Impact of early FDG-PET directed intervention on preoperative therapy for locally advanced gastric cancer: A Cooperative Group random assignment phase II study (Alliance A021302) Impac.
Authors: Shah Manish A. , Shi Qian , Strong Vivian E. , Strasser Jon , Ilson David H. , Kleinberg Lawrence , Iqbal Syma , Wuthrick Evan John , Levasseur Alexandra , Hall Nathan , Meyerhardt Jeffrey A. , O'Reilly Eileen Mary 
Published: September 2018

TPS4135 Background: Gastric cancer is a prevalent and morbid illness for which new treatment strategies are needed. Peri-operative therapy is a standard approach that is associated with only a 15% improvement in overall survival. Early FDG-PET scanning, performed prior to cycle 2, can distinguish patients (pts) responding to chemotherapy from those who are not. FDG-PET non-responding pts have poorer survival. This study addresses the question of salvage therapy in pts who are PET non-responders. Specifically, does salvage chemotherapy with docetaxel /irinotecan improve pt survival in FDG-PET-nonresponding pts with locally advanced gastric cancer. Methods: This is a multicenter, cooperative group, NCI supported, randomized phase II study of salvage chemotherapy + surgery versus surgery and post-operative chemoradiotherapy in pts who are FDG-PET non-responders (defined as a decrease in SUVmaxof the primary tumor of less than 35%). A total of 176 pts with locally advanced, resectable gastric cancer who were FDG-PET non-responders to cycle 1 of platinum/capecitabine based chemotherapy will be randomized in a 1:1 manner to receive either (Arm A) surgery followed by fluoropyrimidine-sensitized radiotherapy (4500 cGy), or (Arm B) salvage chemotherapy with docetaxel / irinotecan (DI) for 2 cycles followed by standard resection and 3 cycles DI post-operatively. DI is administered as D 30 mg/m2, I 50 mg/m2 given on D1, D8 of a 21 day cycle. 416 pts will be screened to yield 162 non-responders (81 FDG-PET non-responders per treatment group). With expected 120 events, the study will have 80% power to detect a hazard ratio of 0.625 for improved survival at the one-sided significant level of 0.15. Pts will be required to provide tissue at the time of resection, as well as whole blood prior to resection for correlative studies associated with platinum sensitivity, FDG avidity, and prognostic markers. This study is available through all cooperative groups (SWOG, ACRIN/ECOG, Alliance, and NRG) and the National Clinical Trials Network. Enrollment began in November 2015. Support: U10CA180821, U10CA180882; Clinical Trial Information: NCT02485834 .