bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer.
Authors: Sparano Joseph A. , Cescon David W. , Oliveira Mafalda , Stover Daniel G. , Tan-Chiu Elizabeth , Kremer Brandon Edward , Barbash Olena , Wu Yuehui , Mathew Lijoy , Cunningham Elizabeth Ann , Carpenter Christopher L. , Ballas Marc S. , Dhar Arindam
Published: September 2018

TPS1114

Background: Advanced or metastatic ER+BC (estrogen receptor positive breast cancer) is an incurable illness that will prove fatal for most afflicted women. Current standards of care include endocrine, targeted, and chemotherapy. Preclinical data suggest that reducing expression of the estrogen receptor (ER) as well as other ER-responsive genes may provide therapeutic benefit for women for whom endocrine therapy alone has proven inadequate. The bromodomain (BRD) and extra-terminal (BET) family of proteins (BRD2, BRD3, BRD4 and BRDT) bind to acetyl-histone residues and epigenetically control transcription of genes driving cell survival and proliferation. In preclinical models, BET proteins reduce ER expression and down regulate ER-dependent gene expression and may be a novel therapeutic target in multiple tumors e.g. ER+BC. GSK525762 is a pan-BET inhibitor showing strong synergistic activity with fulvestrant in killing ER+BC cells in vitro and in xenograft models. The combination of BET agents with endocrine therapy may provide therapeutic benefit and restore sensitivity to ER targeting agents like fulvestrant. Methods: The study is a Phase I/II dose-escalation, expansion (Phase I) and randomized control (Phase II) study with oral administration of GSK525762 in combination with fulvestrant in advanced or metastatic ER+BC subjects, whose disease has progressed on prior treatment with ≥ 1 line of endocrine therapy. Phase I of the study is designed as parallel single arms to determine the recommended Phase 2 dose based on safety, tolerability, PK, and efficacy profiles in two distinct populations of ER+ BC: 1. Subjects with disease that progressed on anti-estrogen and/or ≥ 1 AIs, OR. 2. Subjects with disease that progressed on CDK4/6 inhibitor plus letrozole. Phase I will employ a Bayesian predictive adaptive design. Phase II of the study is a randomized, double-blind, placebo-controlled study, the composition of which will be selected at the end of Phase I. Patients must have received < 3 lines of anti-cancer therapy (≤1 line of chemo), measurable disease, and PS 0-1. Funding: GSK. Clinical trial information: NCT02964507.
Effect of bariatric surgery on breast tissue and biomarkers in obese women at increased risk for breast cancer.
Authors: Ballinger Tarah Jean , Miller Kathy , Ludwig Kandice , Badve Sunil S. , Selzer Don , Zhang Ying , Storniolo Anna Maria , Mina Lida A.
Published: September 2018

TPS1592

Background: Obesity represents a challenging epidemic associated with increased risk of several malignancies, including breast cancer in post-menopausal women. Proposed mechanisms for the association between obesity and breast cancer risk include increased insulin resistance, elevated levels of circulating estrogens, and chronic inflammation. Intentional weight loss from bariatric surgery has been associated with decreased risk of breast cancer. While rapid improvements in serologic markers of metabolism and inflammation are seen following bariatric surgery, short- and long- term changes in breast tissue remain less clear. This study investigates the effect of bariatric surgery on breast density and biomarkers of increased risk in breast tissue. Methods: This pilot, single institution, observational study (NCT02681120) is recruiting pre- and post-menopausal women with BMI ≥30 from a University bariatric surgery clinic using the Hughes risk application as a screening tool. Eligible patients must have a lifetime risk for breast cancer of ≥20%. Participants are evaluated by imaging, breast biopsy, and blood samples at baseline, 14 days post-operatively to determine the effects of rapid metabolic changes, and 1 year post-operatively to determine the effects of significant weight loss. The impact of bariatric surgery on known imaging parameters of breast cancer risk is assessed by background parenchymal enhancement on MRI and breast density on mammogram. Breast tissue is evaluated for changes in immune infiltrates, aromatase expression, and the presence of crown-like structures, a marker of inflammation seen in the breast tissue of obese women. Tissue samples at each time point are also compared to samples from lean women in the Susan G. Komen Tissue Bank at the IU Simon Cancer Center. Blood is collected for correlative studies evaluating markers of inflammation, insulin resistance, metabolism, and hormone synthesis. Enrollment is currently ongoing with a planned accrual of 40 patients, and data collection is estimated to complete by the end of 2018. Clinical trial information: NCT02681120.
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 .
Phase 2, open-label, multicenter study of the efficacy and safety of INCB054828 in patients (pts) with advanced, metastatic, or surgically unresectable cholangiocarcinoma (CCA) with inadequate response to prior therapy.
Authors: Borad Mitesh J. , Davis Sarah Lindsey , Lowery Maeve Aine , Lihou Christine F. , Abou-Alfa Ghassan K.
Published: September 2018

TPS4145

Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR translocations and activating mutations is implicated in many cancers, including CCA. FGFR2 translocation, the most common FGFRalteration, occurs in ~13% of pts with intrahepatic CCA. INCB054828 is a novel, orally available, selective inhibitor of FGFR1, FGFR2, and FGFR3 tyrosine kinase activity (AACR 2015; Abstract 771). Methods: This phase 2, open-label trial will evaluate INCB054828 monotherapy in pts with advanced/metastatic or unresectable CCA (NCT02924376). Pts will be prescreened locally or centrally for FGF/FGFR status prior to enrollment (Table): FGFR2 translocation (Cohort A); other FGF/FGFR alteration (Cohort B); no FGF/FGFR alteration (Cohort C; negative control for effects of FGF/FGFR alteration on objective response rate [ORR]). Eligibility criteria include: age ≥18 years; ECOG performance status ≤2; adequate liver and renal function; life expectancy ≥12 wks; disease progression after ≥1 prior systemic therapy; no prior use of selective FGFR inhibitors. Pts will self-administer INCB054828 orally at a starting dose of 13.5 mg QD on a 21-day cycle (2 wks on; 1 wk off); treatment will continue until disease progression or unacceptable toxicity. The primary endpoint will be ORR (complete or partial response, independent radiologic review committee, RECIST v1.1) in pts with FGFR2 translocation (Cohort A). Secondary endpoints include ORR in pts positive or negative for any FGF/FGFRalteration and duration of response, PFS, OS, and safety (all cohorts). The study has currently enrolled 2 pts (recruitment ongoing; estimated primary completion, April 2018). Clinical trial information: NCT02924376. [Table: see text]
P3BEP (ANZUP 1302): An international randomised phase 3 trial of accelerated versus standard BEP chemotherapy for adult and paediatric male and female patients with intermediate and poor-risk metastatic germ cell tumours (GCTs).
Authors: Grimison Peter S. , Lawrence Nicola Jane , Stockler Martin R. , Martin Andrew James , Yip Sonia , Wong Nicole , Yeung Annie , Friedlander Michael , Mazhar Danish , Pashankar Farzana , Quinn David I. , Walker Rick , Winstanley Mark , Hanning Fritha J. , Weickhardt Andrew James , Stevanovic Amanda Gwendolyn , Davis Ian D. , Toner Guy C. ,   Australian and New Zealand Urogenital and Prostate Cancer Trials Group
Published: September 2018

TPS4592

Background: Bleomycin, etoposide, cisplatin (BEP) administered 3-weekly x 4 remains standard 1st line chemotherapy for metastatic GCTs. Accelerating regimens by giving them 2-weekly rather than 3-weekly has improved cure rates in other cancers. This is the first international randomised clinical trial for intermediate and poor-risk metastatic extra-cranial GCTs involving both adult and paediatric age groups open to both males and females. We aim to determine if accelerated BEP is superior to standard BEP. Methods: DESIGN: Open-label, randomised, stratified multicentre, 2 stage, phase 3 trial. Primary endpoint for stage I (n = 150) is complete response rate (RR), and for entire trial (n = 500) is progression free survival (PFS). SAMPLE SIZE: 150 and 500 patients gives > 80% power to detect a 20% improvement in RRs and 7% absolute improvement in 2yr PFS, respectively. POPULATION: Males and females aged 11-45 yrs with intermediate or poor-risk metastatic GCTs of the testis, ovary, retroperitoneum or mediastinum for 1st line chemotherapy. TREATMENT:Randomisation 1:1 to 4 cycles of “standard BEP” or “accelerated BEP”: cisplatin 20mg/m2 IV days 1-5; etoposide 100mg/m2 IV days 1-5; bleomycin 30000 IU IV weekly; and pegylated G-CSF 6mg SC on Day 6; given every 3 weeks or every 2 weeks respectively. Accelerated BEP arm receives 4 additional weekly doses of bleomycin. ASSESSMENTS: Response assessments at 30-day safety assessment, and 6 months from randomisation or after all post-chemotherapy intervention is completed. Regular follow-up to 5 years, then annually. Archival tumour tissue and baseline blood collected for translational substudies. STATUS: 27 sites open in ANZ, 34 patients recruited by February 2017. International collaborations with UK (led by Cambridge Clinical Trials Unit) and US (led by Childrens Oncology Group) confirmed with sites expected to open by early 2017, and more sites sought for stage 2. Funded by Cancer Council Australia and Cancer Australia. ANZUP supported by Cancer Australia and previously CINSW. ANZCTR: ACTRN12613000496718. Clinical trial information: NCT02582697.
Trial of rucaparib in prostate indications 3 (TRITON3): An international, multicenter, randomized, open-label phase 3 study of rucaparib vs physician’s choice of therapy for patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).
Authors: Ryan Charles J. , Watkins Simon Paul , Despain Darrin , Karlovich Chris Alan , Simmons Andrew , Golsorkhi Anthony A. , Chowdhury Simon
Published: September 2018

TPS5087

Background: Pts with mCRPC often initially receive androgen receptor-targeted therapy (eg, abiraterone or enzalutamide), but they almost always progress. Poly(ADP-ribose) polymerase (PARP) inhibitors (eg, olaparib) have demonstrated clinical activity in pts with mCRPC with a deleterious mutation in a homologous recombination (HR) DNA repair gene; 14 of 16 evaluable pts with mCRPC and a tumor alteration in an HR gene, including BRCA1, BRCA2, and ATM, responded to olaparib (Mateo et al. N Engl J Med. 2015;373:1697-708). The PARP inhibitor rucaparib is approved in the US for treatment of pts with ovarian carcinoma that harbors a deleterious BRCA1 or BRCA2 mutation (germline and/or somatic) who have received ≥2 chemotherapies. These data support investigating rucaparib as a treatment option in pts with mCRPC with HRD. Methods: TRITON3 (NCT02975934)is a phase 3 study evaluating rucaparib (600 mg BID) vs physician’s choice (abiraterone, enzalutamide, or docetaxel) in pts with mCRPC who have a deleterious germline or somatic mutation in BRCA1, BRCA2, or ATM as determined by local and/or central testing. All pts must have progressed on abiraterone or enzalutamide in the mCRPC setting; pts who received prior chemotherapy for mCRPC or PARP inhibitor treatment are excluded. Pts will be randomized 2:1 to rucaparib or physician’s choice of comparator therapy; pts randomized to physician’s choice may cross over to rucaparib on radiographic progression confirmed by independent radiology review (IRR). The primary endpoint is IRR-confirmed radiographic progression-free survival (modified RECIST version 1.1/PCWG3 criteria). Secondary objectives include overall survival, objective response rate, duration of response, clinical benefit rate, pt-reported outcomes, and safety. Pretreatment blood samples will be collected from all pts to enable development of a plasma-based companion diagnostic to identify pts who may benefit from rucaparib treatment. Pts (≈400) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02975934.
A phase II randomized trial of observation versus stereotactic ablative radiation for oligometastatic prostate cancer (ORIOLE).
Authors: Phillips Ryan , Radwan Noura , Ross Ashley , Rowe Steven P. , Gorin Michael A. , Antonarakis Emmanuel S. , Deville Curtiland , Greco Stephen C , Denmeade Samuel R. , Paller Channing Judith , Song Daniel Y. , Diehn Maximilian , Wang Hao , Carducci Michael Anthony , Pienta Kenneth J. , Pomper Martin G. , DeWeese Theodore L. , Dicker Adam P. , Eisenberger Mario A. , Tran Phuoc T.
Published: September 2018

TPS5094

Background: ORIOLE is a randomized, non-blinded Phase II interventional study evaluating the safety and efficacy of SBRT in biochemically recurrent, oligometastatic, hormone-sensitive prostate cancer at 3 centers in the US. Patients will be stratified by clinical characteristics and randomized 2:1 to SBRT or observation. The primary clinical endpoint is progression at 6 months defined by PSA increase, radiologic or clinical evidence, ADT initiation, or death from any cause. Secondary endpoints include local control at 6 months, SBRT-associated toxicity and quality of life, and ADT-free survival. Imaging and laboratory correlates will characterize, in isolation, the effects of SBRT on oligometastatic disease. Methods: Eligible patients are hormone-sensitive, have undergone prior definitive treatment and recurred with 1-3 asymptomatic bone or soft tissue metastases diagnosed within 6 months, PSA doubling time (PSADT) < 15 months, ECOG performance status ≤ 2, and normal organ and marrow function. Minimization will be used to balance assignment by primary intervention, prior ADT, and PSADT. Accrual of 54 patients provides 85% power to detect a decrease in progression rate from 80% to 40% with type I error = 0.05 using one-sided Fisher’s exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival, ADT free survival, and time to locoregional and distant progression will be calculated based on intention-to-treat. Local control will be assessed using RECIST 1.1 criteria. Withdrawal prior to 6 months will be counted as progression. Adverse events will be summarized and quality of life pre- and post-SBRT will be measured by Brief Pain Inventory. The investigational targeted imaging agent 18F-DCFPyL will be compared to bone scan and CT for identifying oligometastases before SBRT and monitoring disease response following SBRT. Biological alterations induced by SBRT will be investigated using circulating tumor cell analysis, deep sequencing of circulating tumor DNA, and T-cell repertoire profiling. A hereditary cancer assay will inform efforts to advance personalized screening and therapy. Clinical trial information: NCT02680587.
Combination chemotherapy with nintedanib/placebo for patients with advanced or recurrent endometrial cancer: The NSGO ENGOT-EN1/FANDANGO trial.
Authors: Mirza Mansoor Raza , Maenpaa Johanna Unelma , Braicu Elena Ioana , Vergote Ignace , Berton-Rigaud Dominique , Rosenberg Per , Huober Jens Bodo , Denys Hannelore , Joly Lobbedez Florence , Kristensen Gunnar , Reimer Toralf , Kridelka Frederic , Floquet Anne , Knudsen Anja , Aktas Bahriye , Baurain Jean-Francois , Follana Philippe , Juhler-Nøttrup Trine , Jederud Christina , Sehouli Jalid
Published: September 2018

TPS5611

Background: Endometrial cancer (EC) patients with advanced and recurrent disease relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). With the emerging clinical data on anti-angiogenic agents and with promising results of nintedanib in ovarian cancer, it is apparent to explore its role in EC. Nintedanib is a potent, orally available triple receptor tyrosine kinase inhibitor targeting VEGFR 1-3, PDGFR α/β, and FGFR 1-3. This placebo-controlled, multicenter, two-arm, phase 2 trial compares nintedanib versus placebo as concomitant and maintenance therapy in combination with chemotherapy in patients with advanced or recurrent EC. Methods: The primary objective of this trial is to evaluate efficacy of nintedanib against placebo in combination with chemotherapy, defined by PFS. Key eligibility criteria include: histologically confirmed EC, stage 3C 2 or 4 A & B or relapsed after adjuvant therapy for stage 1-3 disease; prior surgery; adjuvant chemotherapy; radiation therapy; hormonal therapy are permitted; measurable/non-measurable disease. 148 patients will be randomized 1:1 to receive nintedanib 200mg twice daily or placebo days 2-21 during chemotherapy (six cycles of Carboplatin (AUC5) and paclitaxel (175mg/m2) every 21 days) and continuously in maintenance phase. Nintedanib/placebo is continued until disease progression, unacceptable toxicity, or withdrawal. Secondary endpoints include PFS in sub-populations, PFS2, disease specific survival, time to first subsequent therapy, time to second subsequent therapy, overall survival, objective response, disease control rate, patient reported outcoms (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24) and safety. Trial is enrolling patients. The following cooperative groups are participating: NSGO (DK, FIN, SWE, NOR), NOGGO (GER), BGOG (BEL), & GINECO (FRA). Clinical trial information: NCT02730416.
ABC trial (A011502): A randomized phase III double blinded placebo controlled trial of aspirin as adjuvant therapy for node positive breast cancer.
Authors: Chen Wendy Y. , Winer Eric P. , Barry William Thomas , Hudis Clifford A. , Openshaw Thomas H. , Visvanathan Kala , Symington Banu , Matyka Carol , Holmes Michelle D.
Published: September 2018

TPS586

Background: In-vitro and in-vivo evidence suggest that aspirin, an inexpensive and widely available drug may have anti-tumor activity via effects on multiple pathways. Multiple epidemiologic studies have reported improved breast cancer survival among regular aspirin users compared to non-users. Furthermore, pooled data from randomized trials of aspirin for cardiovascular disease have also reported a decreased risk of metastatic cancer among aspirin users, especially metastatic adenocarcinoma (RR 0.52 (95% CI 0.35-0.75). In order for aspirin to be considered standard of care, the exact benefits and risks for breast cancer survivors need to be confirmed in a randomized trial. Methods: The primary objective is to compare the effect of aspirin versus placebo upon invasive disease-free survival (iDFS) in stage II-III node-positive HER2 negative breast cancer patients. Secondary objectives include effects on overall survival and cardiovascular disease and to collect toxicity and adherence. A biospecimen repository will be created for future correlative analyses including tumor collection at baseline and blood and urine samples at baseline and 2 years. Questionnaires assessing lifestyle factors associated with inflammation (pain, sleep, stress, and depression) will also be collected at baseline and 2 years. Study design: Subjects will be randomized (1:1) to aspirin 300 mg vs placebo daily for 5 years in a double-blinded fashion. Stratification factors include hormone receptor status (positive vs negative), body mass index ( < or ≥ 30 kg/m2), and stage (II vs III).Subjects will be followed every 6 six months while on study drug and then annually until 10 years from registration. 2936 patients will be enrolled with 80% power to detect HR 0.75. Eligibility: Eligible subjects include patients aged 18-70 diagnosed with a primary invasive stage II or III node positive HER2 negative breast cancer in the past year. Patients who currently use any oral or injectable anticoagulant or those with a prior history of GI bleeding, atrial fibrillation, myocardial infarction, or grade IV hypertension will be excluded. Patients who regular used aspirin over the past year will be excluded. Clinical trial information: NCT02927249.
Anti-PD-L1 durvalumab combined with cetuximab and radiotherapy in locally advanced squamous cell carcinoma of the head and neck: A phase II study.
Authors: Bonomo Pierluigi , Desideri Isacco , Loi Mauro , Mangoni Monica , Sottili Mariangela , Greto Daniela , Scotti Vieri , Meattini Icro , Livi Lorenzo
Published: September 2018

TPS6094

Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by prominent immune escape mechanisms. Potentially, the blockade of immune check points such as the PD-1/PD-L1 axis may stimulate the host T-cell activation against tumor cells and favor the FcγRIIIa-mediated, Cetuximab (CTX) induced antibody dependent cellular cytoxicity (ADCC). Durvalumab (DUR) is a humanized monoclonal IgG1, anti-PD-L1 antibody with promising activity in recurrent/metastatic HNSCC (NCT01693562). The aim of our study is to test the hypothesis that a restored ability of the host immune system via blockade of the PD1/PD-L1 axis through DUR may enhance the antitumor activity of both CTX and radiotherapy (RT) in locally advanced HNSCC, a setting with unmet needs for effective treatment options. Methods: In this open-label, multi-center, single-arm, phase II study, enrolled patients will receive RT (69.9 Gy/2.12 Gy fx in 33 fractions over 7 weeks) with concurrent CTX (400 mg/m2 1 week before RT start followed by 250 mg/m2 q1w) and DUR (1500 mg q4w starting from RT-CTX week 1) followed by adjuvant DUR (to a maximum of 6 months after completion of RT-CTX). Primary endpoint of the study is 2-year progression-free survival (PFS). Assuming a 2-year PFS of 66% based on historical data from RTOG study 0129, the experimental regimen is hypothesized to yield a 12% absolute increase at 2 years, corresponding to a hazard ratio of 0.6 (α = 0.1, power is 0.80 when the 2-year PFS is 78%). The required sample size with this design is 69 patients. A safety run-in is planned after the enrollment of first 12, 24 and 36 patients. Patients affected by high-risk ( > N2a or > T3, any N) larynx, hypopharynx and HPV negative oropharynx or HPV-positive oropharynx ( > N2b, > 10 pack/years) will be eligible. To avoid potential RT-induced chronic loco-regional immunosuppression, protocol-indications will be undertaken to restrict target volumes to sites of gross disease and subclinical high risk lymph node basins excluding areas deemed at very low risk of disease spread. For this purpose, dose-painting intensity modulated radiotherapy (IMRT) is mandatory for this study. Clinical trial information: 2016-004668-20.
A randomized, double-blind phase III study of ibrutinib versus placebo in combination with corticosteroids in patients with new onset chronic graft versus host disease.
Authors: Miklos David Bernard , Jagasia Madan H. , Greinix Hildegard , Ko Bor-Sheng , Jacobsohn David A. , Mokatrin Ahmad , Dubovsky Jason , Horn Biljana , Hauns Bernhard , Styles Lori Appel , Flowers Mary
Published: September 2018

TPS7072

Background: Chronic graft versus host disease (cGVHD) is a common complication of allogeneic stem cell transplantation, with pathophysiology involving alloreactive and dysregulated T and B cells and innate immune populations. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of patients (pts) with CLL/SLL. Ibrutinib recently received breakthrough therapy and orphan drug designation for the treatment of pts with cGVHD who did not respond to one or more lines of systemic therapy. Ibrutinib reduces severity of cGVHD in murine models and recently was shown to achieve an NIH-defined overall response rate of 67% in pts with steroid relapsed/refractory cGVHD (Miklos Blood 2016). Methods: The primary objective of this Phase 3, multicenter, international, randomized, controlled, double-blind study is to evaluate the 24-week response rate of ibrutinib versus placebo in combination with prednisone. Pts with newly diagnosed moderate or severe cGVHD, as per NIH Consensus Development Project Criteria (2014), will be randomized in a 1:1 ratio to receive either oral ibrutinib (arm A) or placebo (arm B) in combination with oral prednisone. Ibrutinib or placebo will be given until unacceptable toxicity, relapse of underlying disease, death, or the need for a new systemic treatment for progressive cGVHD. Eligible study pts (age ≥12 yrs) must require systemic treatment with corticosteroids and have no prior systemic treatment for cGVHD. The primary endpoint is response rate (complete or partial response) at 24 weeks, as per NIH Consensus Development Project Criteria, and must occur in the absence of both new therapy for cGVHD and relapse/return of the underlying disease that was the indication for transplant. Secondary endpoints will assess for additional clinical benefit including corticosteroid dose reduction, improvement of Lee cGVHD Symptom Scale scores, withdrawal of all immunosuppressants, and overall survival. This study is currently enrolling pts. Funding source: Pharmacyclics LLC, an AbbVie Company. Clinical trial information: NCT02959944.