bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II study of GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX) with PD-1 blockade antibody and stereotactic body radiation therapy (SBRT) for locally advanced pancreas cancer (LAPC).
Authors: Lee Valerie , Rodriguez Christina , Shupe Ella-Mae , Chen Linda , Parkinson Rose , Durham Jennifer N. , Sugar Elizabeth , Wilt Cara , McIntyre Keith R. , Hacker-Prietz Amy , Weiss Matthew J. , He Jin , Wolfgang Christopher Lee , De Jesus-Acosta Ana , Le Dung T. , Herman Joseph M. , Laheru Daniel A. , Narang Amol , Jaffee Elizabeth M. , Zheng Lei
Published: September 2018

TPS4154

Background: Optimal treatment strategy beyond systemic chemotherapy for LAPC remains undefined. SBRT improves local control, but distant metastasis free survival (DMFS) is only 7.7 months. Checkpoint inhibitors are poor monotherapies in pancreas cancer, but may be primed by SBRT via absocopal effect and GVAX, which induces novel lymphoid infiltrates and increased effector T-cells in tumor microenvironment. Methods: This is a single-arm, single-institution, open-label study for pts with LAPC. Eligibility: surgically unresectable LAPC, predominant adenocarcinoma at diagnosis, with ECOG 0-1, who remain metastases free after 4-8 cycles of FOLFIRINOX or gemcitabine/abraxane based-chemotherapy. Exclusion: those off chemotherapy > 49 days prior to study treatment, prior immunotherapy, active immunosuppressive use, autoimmune disease, HIV, HBV, or HCV infection, and non-oncology vaccines within 28 days of study treatment. Pts receive cyclophosphamide (200mg/m2 IV) and pembrolizumab (200mg IV) on day 1, followed by GVAX (six intradermal injections) on day 2 every three weeks for two cycles, with cycle 2 initiating concurrently with five days of SBRT. If non-metastatic, pts undergo surgical resection, nano-knife, or EUS guided biopsy (if non-surgical). Pts receive two further cycles of chemotherapy, and if remain free of metastases, receive q3 week cyclophosphamide, pembrolizumab, and GVAX for six cycles, then are monitored for two years. The primary endpoint is DMFS. Secondary endpoints include overall survival, surgical resectability, pathologic response, quality of life, and toxicity. Exploratory objectives of peripheral antigen specific t-cell responses, and changes in immune parameters of tumor microenvironment. 11 of 54 pts have been enrolled since July 2016. Clinical trial information: NCT02648282.
TARIBO trial: Cytoreductive nephrectomy in metastatic renal cell carcinoma patients treated with targeted agents.
Authors: Grassi Paolo , Verzoni Elena , Bearz Alessandra , Bracarda Sergio , Bregni Marco , Buti Sebastiano , Cinieri Saverio , De Giorgi Ugo , Fornarini Giuseppe , Galli Luca , Milella Michele , Morelli Franco , Nole Franco , Passalacqua Rodolfo , Sabbatini Roberto , Santini Daniele , Salvioni Roberto , Cappelletti Vera , Ratta Raffaele , Procopio Giuseppe
Published: September 2018

TPS4601

Background: In the cytokine era cytoreductive nephrectomy (CN) has been shown to increase survival in patients (pts) with metastatic renal cell carcinoma (mRCC). Efficacy of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib has been demonstrated. It is unclear if similar survival benefit could be achieved without CN with TKIs since most of pts enrolled into phase III trials had undergone CN. Methods: A total of 270 mRCC pts will be randomized to receiveCN followed by TKIs vs upfront TKIs without CN. Patients will receive pazopanib 800 mg orally daily or sunitinib 50 mg daily, 4 weeks on/ 2 weeks off. The choice of TKI will be done according to investigator’s clinical practice. Primary objective: to compare clinical benefit, as measured by overall survival (OS), provided by CN followed by TKIs vs upfront TKIs in pts with mRCC. Secondary objectives: i) to compare clinical benefit, as measured by progression-free survival (PFS) and response rate (RR) provided by CN followed by TKIs vs upfront TKIs; ii) Safety; iii) Exploratory analyses: evaluation of the predictive role of circulating tumor cells count and circulating tumor DNA at baseline, before and after surgery (in pts undergoing CN), 24 weeks after randomization and at the time of disease progression. Key inclusion criteria: Favorable or intermediate MSKCC or Heng prognostic risk group; histological diagnosis of RCC with a clear-cell component; resectable asymptomatic mRCC with primary tumor in place; up to three different metastatic sites; ≥ 3 metastatic lesions. Key exclusion criteria: Widespread disease ( > or = 4 metastatic organ sites); disease suitable of metastasectomy ( < 3 lesions confined at one organ site). Statistical plan: The sample size was calculated in order to compare 5-year OS between subjects randomized to receive CN followed by TKIs and those randomized to receive upfront TKIs. A total of 191 deaths will yield 80% power to detect a hazard ratio of 1.5 of upfront TKIs vs CN followed by TKIs with an overall type 1 error of 0.05 (two-sided log-rank test). Such a HR corresponds to an increase in the 5-year OS, from an anticipated value of 10% for TKIs to 21.5% for CN followed by TKIs. To date 10/270 pts have been enrolled. Clinical trial information: NCT02535351.
Phase I dose-escalation study of fractionated-dose 177Lu-PSMA-617 for progressive metastatic castration resistant prostate cancer (mCRPC).
Authors: Tagawa Scott T. , Vallabhajosula Shankar , Batra Jaspreet , Christos Paul J. , Jhanwar Yuliya , Goldsmith Stanley J. , Nanus David M. , Beltran Himisha , Molina Ana M. , Faltas Bishoy , Hackett Amy , Sreekumar Jyothi , Babich John , Bander Neil Harrison
Published: September 2018

TPS5093

Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of radiolabeled anti-PSMA antibody J591 revealed 1) targeting and safety [Bander 2003]; 2) safety and prelim efficacy [Milowsky 2004, Bander 2005]; 3) efficacy and initial dose-response [Tagawa 2013]; 4) dose-fractionation allows higher doses, ability to combine with docetaxel, confirmation of dose-response (PSA and overall survival) [ASCO 2010, 2014, 2016]; 5) predictable, reversible myelosuppression is dose-limiting [Tagawa 2013]. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and are widely used for imaging and treatment in Europe. 177Lu-PSMA-617 is the most commonly used, but experience is mostly anecdotal/retrospective and no formal dose-escalation studies have been performed. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function will undergo imaging with 68Ga-PSMA-HBED-CC PET/CT followed by escalating fractionated doses of 177Lu-PSMA-617. Cohort 1 = 3.7 GBq x2 two weeks apart up to 11.1 GBq x2 in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu-PSMA-617, CTC count (CellSearch) changes, tissue and circulating genomic assessment of DNA repair pathways, patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03042468.
Phase III randomized trial of image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) for locoregionally advanced cervical cancer: The INTERTECC-3 trial.
Authors: Mell Loren K. , Sirak Igor , Portelance Lorraine , Wolfson Aaron Howard , Stewart Alexandra J. , Sharma Dayanand , Princ Denis , Mahantshetty Umesh , Nakamura Mitsuhiro , Hirata Kimiko , Kry Stephen F , Wei Lichun , Xu Ronghui , Zakeri Kaveh , Sojourner Elena , Moore Kevin , McHale Michael T. , Saenz Cheryl C. , Yashar Catheryn M. , Mundt Arno James ,   INTERTECC Study Group
Published: September 2018

TPS5600

Background: Cervical cancer is a leading cause of cancer death in women worldwide. Image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) has shown potential to reduce acute toxicity of chemoradiotherapy and improve chemotherapy delivery in phase I and II trials (Mell LK, Sirák I, Wei L, et al. Bone Marrow-sparing IMRT With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2). Int J Radiat Oncol Biol Phys 2017;97:536-545. Mell LK, Saenz CC, Yashar CM, et al. Phase I Trial of Bone Marrow Sparing IMRT With Concurrent Cisplatin and Gemcitabine in Stage IB-IVA Cervical Cancer (abstr.) Int J Radiat Oncol Biol Phys 2016; 96: S14.). Methods: INTERTECC-3 is a randomized phase III trial designed to test the effect of IG-BMS-IMRT on progression-free survival (PFS) for women with unresected FIGO stage IB-IVA cervical carcinoma (clinicaltrials.gov #NCT01554397). It presently involves centers in the U.S., Czech Republic, U.K., India, Japan, and China. Women are randomized 3:2 to either (A) IG-BMS-IMRT or (B) standard chemoradiation, with 6 cycles of concurrent cisplatin (40 mg/m2) weekly in both arms. Secondary objectives are to compare overall survival, treatment-related toxicity, disease recurrence, quality of life, chemotherapy delivery, and radiation quality assurance. Planning objectives require maintaining pelvic marrow and active marrow mean doses < 27 Gy and < 28.5 Gy respectively. Correlative studies involve longitudinal collection of magnetic resonance restriction spectrum imaging and 18F-fluorothydimine positron emission tomography scans to assess imaging biomarkers of treatment response in select patients. 415 women will be enrolled to determine if IG-BMS-IMRT improves the median PFS from 3.2 to 5.0 years with 80% power and alpha = 0.05. INTERTECC-3 opened in the U.S. and Czech Republic in 2016. To date, 17 patients have been randomized. The trial will be activated at additional international sites in late 2017 and 2018. We are seeking to recruit sites who wish to collaborate. Clinical trial information: NCT01554397.
OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel+/- novel agents in platinum-resistant ovarian cancer—Vistusertib (AZD2014).
Authors: Banerjee Susana N. , Lewsley Liz-Anne , Clamp Andrew R. , Gabra Hani , Herbertson Rebecca , Green Clare , Orbegoso Cecilia , Wilson Cheryl , Banerji Udai , Hanif Aishah , McNeish Iain A. , Paul James
Published: September 2018

TPS5609

Background: There is an urgent need to improve outcomes for patients with platinum-resistant and refractory ovarian cancer (PROC). OCTOPUS is an umbrella phase II framework for testing whether the addition of novel targeted agents to weekly paclitaxel (wPxl) improves efficacy in PROC. The first agent to be evaluated is the dual mTORC1/mTORC2 inhibitor, vistusertib (AZD2014), as preclinical studies support targeting the PI3kinase/Akt/mTOR pathway in PROC and the combination of vistusertib and wPxl has shown promising preliminary activity in high grade serous ovarian cancer (HGS) patients in a phase I trial (Banerji et al poster discussion ESMO 2016). This is the first randomised trial of wPxl and a dual mTORC1/2 inhibitor in ovarian cancer. Methods: OCTOPUS is an investigator-initiated, randomised, double-blind, placebo-controlled, multicentre, phase II trial. 140 patients with PROC (histologically confirmed HGS) are randomised 1:1 to receive wPxl (80mg/m2 D1, D8, D15 of 28 day cycle) plus oral vistusertib (50mg BD) or placebo (D1-3, D8-10, D15-17). The primary endpoint is progression-free survival (PFS) based on combined RECIST v1.1/GCIG CA125 criteria. The study is designed to detect a 50% improvement in median PFS from 3.7 months on placebo to 5.55 months on the experimental arm with 90% power, at the 20% 1-sided level of statistical significance (or equivalently with 80% power at the 10% level of statistical significance) using a 3-outcome design. Secondary endpoints include response (based on RECIST 1.1 and GCIG CA125 criteria), overall survival, toxicity and quality of life. Patients whom received prior wPxl for PROC are not eligible. A mandatory pre-treatment biopsy (if technically feasible), archival tissue, and serial blood samples will be collected for translational research studies. 49 patients have been recruited. The study is part of the NIHR CRN Cancer/Astrazeneca Alliance, sponsored by NHS Greater Glasgow and Clyde/University of Glasgow and endorsed by Cancer Research UK (CRUKE/14/052). Clinical trial information: ISRCTN16426935.
Palbociclib versus placebo in combination with letrozole for patients with advanced or recurrent endometrial cancer: The NSGO ENGOT-EN3/PALEO trial.
Authors: Mirza Mansoor Raza , Salutari Vanda , Mendiola Cesar , Sehouli Jalid , Christensen Rene dePont , Bjorge Line , Pignata Sandro , Gil-Martin Marta , Chekerov Radoslav , Nyvang Gitte-Betina , Lorusso Domenica , Barretina-Ginesta Maria Pilar , Marme Frederic , Ronzino Graziana , Rubio M Jesus , Runnebaum Ingo B. , Juhler-Nøttrup Trine , Løhndorf Joan , Auranen Annika
Published: September 2018

TPS5612

Background: Endometrial cancer (EC) patients with advanced or recurrent disease and endometrioid histology have a short progression-free survival (PFS). These malignancies are hormone dependent and endocrine therapy with aromatase inhibitors is well established. Palbociclib is an oral and selective inhibitor of cyclin-dependent kinases CDK4 and CDK6. Studies in breast cancer have demonstrated superiority of letrozole treatment in combination with palbociclib vs. letrozole monotherapy in oestrogen receptor positive (ER+) HER2- advanced disease. The combination is generally well tolerated with an acceptable toxicity profile. This multicenter, prospective, double-blind, placebo-controlled, randomized, phase II trial is evaluating the efficacy of letrozole when combined with palbociclib against letrozole-placebo combination therapy in women with ER+ advanced or recurrent EC. Methods: The primary objective of this trial is to demonstrate superiority of palbociclib against placebo in combination with letrozole, as defined by investigator-assessed progression-free survival (PFS). Key eligibility criteria include: histologically confirmed ER+ EC of endometrioid type; stage 4 or recurrent disease; prior surgery, adjuvant chemotherapy, radiation therapy, hormonal therapy (e.g. megestrol acetate) is permitted; measurable/evaluable disease according to RECIST 1.1. 78 patients will be randomized 1:1 to receive palbociclib 125mg daily or placebo on days 1-21 and letrozole 2.5mg daily on days 1-28 in a 28 days cycle until disease progression, unacceptable toxicity, or withdrawal. Secondary endpoints include PFS in sub-populations, overall response rate, disease control rate, PFS2, time to first subsequent therapy, time to second subsequent therapy, overall survival, safety & tolerability, patient reported outcomes (assessed via EORTC QLQ-C30 and EORTC QLQ-EN24) and PFS in patients with or without retinoblastoma protein-expressing tumors. The following cooperative groups are participating: NSGO (DK, FIN, NOR), MITO (ITA), GEICO (SPA) & NOGGO (GER). Clinical trial information: NCT02730429.
Phase 2, two-group, two-stage, open-label study of avelumab in patients with microsatellite stable, microsatellite instable and POLE-mutated recurrent or persistent endometrial cancer.
Authors: Konstantinopoulos Panagiotis A. , Liu Joyce F. , Barry William Thomas , Krasner Carolyn N. , Buss Mary K. , Birrer Michael J. , Farooq Sarah , Campos Susana M. , Stover Elizabeth , Schumer Susan , Wright Alexi A. , Curtis Jennifer , Peralta Ariana , Whalen Christin , Dizon Don S. , Penson Richard T. , Cannistra Stephen A. , Fleming Gini F. , Matulonis Ursula A.
Published: September 2018

TPS5615

Background: The Cancer Genome Atlas project identified 2 groups of hypermutated endometrial cancers (ECs): an ultramutated group that harbored mutations in the exonuclease domain of polymerase e ( POLE), and a hypermutated group with microsatellite instability (MSI), the majority of which harbored MLH1 promoter methylation. We (Howitt, JAMA Onc 2015) and others have shown that POLE and MSI ECs are associated with higher number of predicted neoepitopes and tumor infiltrating lymphocytes, which is counterbalanced by overexpression of PD-1/PD-L1, suggesting that they may be excellent candidates for PD-1/PD-L1 blockade. Anti-PD-1 therapy has also demonstrated promising activity in mismatch repair deficient colorectal cancers and collectively in non-colorectal cancers (Le, NEJM 2015). Methods: This is an open-label, two-cohort, two-stage, phase 2 trial, of avelumab, a fully human IgG1 antibody directed against PD-L1, in two cohorts: i) a MSI/ POLE cohort including ECs with immunohistochemical (IHC) complete loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) a MSS cohort including ECs with normal IHC expression of all MMR proteins. Key eligibility criteria include measurable disease, no upper limit of prior therapies, and any EC histology. Co-primary objectives include objective response rate and rate of progression-free survival at 6 months. Avelumab is administered at 10 mg/kg as 1-hour IV infusion every 2 weeks until disease progression or unacceptable toxicity; therapy may continue at the investigator’s discretion while awaiting radiologic confirmation of disease progression 4 weeks later. Maximum target enrollment is 70 patients (35 for each cohort). In the first stage, 16 patients will be enrolled in each cohort; if there are at least two objective responses or two patients progression-free at 6 months, accrual will continue to the second stage where 19 more patients will be enrolled for each cohort. Thus far, 16 patients have been enrolled, 13 on the MSS cohort and 3 on the MSI/ POLE cohort. Clinical trial information: NCT02912572.
PEARLY: A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo)adjuvant therapy in patients with early triple-negative breast cancer.
Authors: Kim Gun Min , Jeung Hei-Cheul , Jung Kyung Hae , Kim Se Hyun , Kim Han Jo , Lee Ki Hyeong , Park Kyong Hwa , Lee Ji Eun , Ahn Mi Sun , Kohn Sujin , Lee Sung Sook , Moon Yong Wha , Sohn Joohyuk
Published: September 2018

TPS587

Background: Triple-negative breast cancer (TNBC) is an aggressive tumor with poor prognosis. There are no molecular targets for TNBC, and there is an unmet need to provide new drugs to patients with TNBC. Platinum agents are known to have an anti-tumor activity in TNBC, especially in BRCA-mutated tumor. Addition of carboplatin significantly increased pathologic complete response rates with neoadjuvant chemotherapy in recent randomized studies. There are no data about adjuvant role of carboplatin for TNBC in a randomized trial. Methods: PEARLY is a randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo)adjuvant therapy in patients with triple-negative breast cancer (TNBC). Patients with stage II or III TNBC who need adjuvant or neoadjuvant chemotherapy were included. Any prior systemic therapy for breast cancer was not allowed. Bilateral, metastatic, and inflammatory breast cancer are excluded. A total of 840 patients will be enrolled for 3 years. Patients were randomized 1:1, stratified based on the node positivity (N0 vs N+), institution, treatment setting (neoadjuvant vs. adjuvant), and BRCA mutation status (positive vs. negative). Standard arm treatment consists of doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV every 3 weeks for 4 cycles followed by taxane treatment (paclitaxel 80 mg/m2 IV weekly for 12 doses or docetaxel 75mg/m2 IV every 3 weeks for 4 cycles). Experimental arm added carboplatin AUC5 IV every 3 weeks for 4 cycles during taxane treatment. The primary objective was to evaluate 5-year event free survival (EFS) rate. Secondary objectives included overall survival, distant recurrence free survival, pathologic complete response, and tolerability. The analysis is planned at 248 EFS events, which provides approximately 80% power to detect superiority of standard treatment plus carboplatin versus standard treatment using a log-rank test, assuming a hazard ratio of 0.7 at a two sided alpha of 0.05. Data is expected in 2023. Clinical trial information: NCT02441933.
NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence free interval (IBCRFI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).
Authors: Mamounas Eleftherios P. , Bandos Hanna , White Julia R. , Julian Thomas B. , Khan Atif J. , Shaitelman Simona Flora , Torres Mylin Ann , Vicini Frank , Ganz Patricia A. , McCloskey Susan Ann , Paik Soonmyung , Gupta Nilendu , Li X. Allen , DiCostanzo Dominic J. , Curran Walter John , Wolmark Norman
Published: September 2018

TPS589

Background: This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PAx nodes that are negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease pts, and predictors for the degree of reduction in locoregional recurrence. Methods: Clinical T1-3, N1 IBC PAx nodes (FNA or core needle biopsy) pts complete ≥12 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC BCS or Mx, sentinel node biopsy (≥3 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts receive required systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI RNRT. Statistics: 1636 pts to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 2-2-17 is 534 (32.64%). Contacts: Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org . Support: U10 CA-2166; -180868, -180822; 189867; Elekta Clinical trial information: NCT01872975.
Phase II trial of neoadjuvant (neo) palbociclib (Palbo) plus anastrozole (ana) in endocrine resistant clinical stage 2/3 estrogen receptor positive and HER2 negative (ER+ HER2-) breast cancer (BC).
Authors: Bagegni Nusayba Ali , Gao Feng , Goetz Matthew P. , Northfelt Donald W. , Forero-Torres Andres , Anderson Jill , Vij Kiran R. , Sanati Souzan , Ellis Matthew J , Ma Cynthia X.
Published: September 2018

TPS592

Background: Persistent cell proliferation (Ki67 > 10%) on tumor biopsies as early as 2-4 weeks (wks) on neo endocrine therapy (ET) identifies resistant tumors in ~20% patients (pts) with early stage ER+ HER2- BC who are at high risk of relapse. Palbo plus ET significantly improves progression free survival in pts with ET naïve or resistant advanced ER+ HER2- BC, and is being evaluated in the adjuvant setting. However, biomarkers predictive of palbo sensitivity are unknown. Ki67 analysis of serial tumor biopsies in the neo palbo and ana (NeoPalAna) trial demonstrated that 2 wks of palbo plus ana potently inhibited Ki67 and induced complete cell cycle arrest (CCCA, Ki67≤2.7%) in tumors with high Ki67 post 4 wks ana run-in. This study is therefore aimed to prospectively investigate the biological activity of palbo plus ana in ET resistant ER+ HER2- BC. Methods: The primary objective is to assess the rate of CCCA (central Ki67 ≤2.7%) after 2 wks of neo palbo and ana. Secondary objectives include analysis of tumor biopsies to explore response biomarkers. Key inclusions include women with clinical stage 2/3 ER+ HER2- BC, central Ki67 > 10% after ≥2 wks of any neo ET, adequate organ function. Key exclusions include prior CDK 4/6 inhibitor, treatment of BC except ET, concomitant use of strong CYP3A4 inhibitor. Pts receive palbo (125mg PO daily, days 1-21, 28-day cycle), ana (1 mg PO daily) and goserelin (if premenopausal). Pts with C1D15 Ki67 > 10% will discontinue study. If C1D15 Ki67 ≤10%, pt will receive 4 cycles of treatment, and additional 10-12 days of palbo if counts normalized within 3 wks post C4D28. Following surgery, pts are eligible for 2 years of adjuvant palbo. A sample size of 37 (stage 1, n = 12, stage 2 n = 25) by simon optimal two stage phase II design will be employed to assess whether the rate of CCCA is ≤5% vs ≥20% (90% power, alpha 0.1). Stage 2 will proceed if ≥1 had CCCA in stage 1. If ≤3 of 37 had CCCA, this regimen will be considered ineffective. The study is active and has enrolled 4 pts. Clinical trial information: NCT01723774.
Phase III randomised controlled trial (RCT) comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer (CompARE).
Authors: Mehanna Hisham Mohamed , Sen Mehmet , Chester John David , Sanghera Paul , Paleri Vinidh , Gaunt Piers , Babrah Jaspreet , Hartley Andrew G. J. , Kong Anthony , Al-Booz H , Foran Bernadette , Miles Elizabeth , Robinson Max , Jepson Marcus , Donnovan Jenny , Yap Christina , Firth Charlotte , Gaunt Claire , Bowden Sarah Jane , Forster Martin David
Published: September 2018

TPS6091

Background: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. The CompARE trial is designed to test alternative approaches to intensification of treatment for these patients to improve survival. Methods: CompARE is a pragmatic phase III open-label multicenter RCT with an adaptive multi-arm multi-stage design. Eligible OPC patients include those with; HPV negative, T1-T4, N1-N3 or T3-4, N0 or HPV positive current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. The primary outcome measure is overall survival. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complications and cost-effectiveness. The trial is powered to detect a hazard ratio of 0.69 (an improvement of 10% in OS at 3-years) requiring 128 control events. It is estimated that the study will take 6.5 years to recruit sufficient patients to experience the number of events needed. Planned interim futility analyses using event-free survival (EFS) will be performed when 70 and 114 control EFS events have occurred. Current treatment arms are; (1) control: standard treatment of 3-weekly cisplatin 100mg/m2 or weekly 40mg/m2 with Intensity Modulated Radiotherapy (IMRT) using 70Gy in 35F +/- neck dissection determined by clinical and radiological assessment 3-months post treatment. (3) IMRT 64Gy in 25F + cisplatin 100mg/m2 day 1 of week 1 and week 5 or weekly 40mg/m2+/- neck dissection as per standard treatment. (4) Resection of primary + selective neck dissection followed by standard treatment. (5) One cycle of induction durvalumab 1500mg followed by standard treatment then durvalumab 1500mg every four weeks for a total of 6 months. Recruitment to arm (2) involving induction chemotherapy from the original protocol is suspended. Since July 2015, 42 patients have been randomised with 16 sites open to recruitment. The Data Monitoring Committee last reviewed progress and conduct of the trial in September 2016 and recommended continuation. ISRCTN Number: 41478539, CRUK CRUK/13/026 Clinical trial information: 41478539.
An open-label, single-arm, multi-institutional phase II trial of avelumab for recurrent, metastatic nasopharyngeal carcinoma.
Authors: Sacco Assuntina Gesualda , Messer Karen , Leidner Rom S. , Colevas A. Dimitrios , Nieva Jorge J. , Chau Nicole Grace , Nangia Chaitali Singh , Pinsky Benjamin , Gold Kathryn A. , Daniels Gregory A. , Cohen Ezra E.W.
Published: September 2018

TPS6092

Background: The majority of patients with nasopharyngeal carcinoma (NPC) present with locally advanced disease, with a predilection for early systemic dissemination. For patients who develop recurrent and/or metastatic (R/M) NPC, survival is poor. Following first-line platinum-based regimens, there is no well-defined paradigm for subsequent therapies. Inhibition of PD-L1 with Avelumab is an attractive strategy because Epstein-Barr virus (EBV), the primary causative agent in NPC pathogenesis, universally upregulates PD-L1 expression; proposed mechanisms of upregulation include immune resistance via innate (EBV-induced latent membrane protein-1) and adaptive (Interferon-gamma) mechanisms; increased PD-L1 expression is an independent poor prognostic factor for disease-free survival. Methods: Patients with histologically/cytologically confirmed, EBV-related NPC not amenable to curative intent therapy who received ≥1 prior line of systemic therapy for R/M disease are eligible. Patients must be at least 18 years old, ECOG 0-2, willing to undergo tumor biopsy, have adequate organ and marrow function, and no prior therapy with PD-1/PD-L1 inhibitors. 39 patients will be enrolled across 6 sites. Patients will receive Avelumab 10 mg/kg IV on days 1 and 15 of each 28-day cycle. Treatment will continue until disease progression, unacceptable toxicity, investigator/patient decision. A newly obtained tumor specimen is required at enrollment; optional biopsy at time of progression. EBV plasma DNA titers will be evaluated at baseline, during treatment and at progression, using an EBV BamHI-W DNA PCR. Blood samples at baseline and 12 weeks after treatment initiation will be obtained for correlatives. Primary endpoint is overall response rate (ORR; complete and partial responses) at 6 months per RECIST. A two-stage design will reject H0 (ORR 15%) if the observed ORR is ≥30%, α 0.1, β 0.8, required sample size n = 39. Secondary endpoints include duration of response, progression-free and overall survival. Correlative analyses will evaluate PD-L1 expression, T and B-cell subsets, frequency and clonality. The study has accrued 2 of planned 39 patients. NCT02875613. Clinical trial information: NCT02875613.
Phase ιι (window) preoperative study of olaparib with cisplatin or with durvalumab or alone or no treatment in patients with histologically proven head and neck squamous cell carcinoma who are candidates for surgery (OPHELIA).
Authors: Psyrri Amanda , Papaxoinis George , Economopoulou Panagiota , Kotsantis Ioannis , Kotoula Vassiliki , Tsavaris Onoufrios , Avgerinou Chrysanthi , Fountzilas George
Published: September 2018

TPS6096

Background: Novel agents are often investigated in unselected end-stage cancer patients and their efficacy is evaluated by the classical RECIST criteria making unlikely to fully exploit the antitumor potential of these targeted agents. Olaparib (O) is a potent inhibitor of PARP especially active in tumors that have homologous recombination DNA repair pathway deficiencies. Durvalumab (D) is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, overcoming PD-L1-mediated inhibition of T-cell activation. There is substantial evidence that tumor cells use PARP to repair platinum-induced DNA damage and thus escape apoptosis. In addition, O may complement the antitumor activity of D by increasing DNA damage through repair inhibition. Methods: OPHELIA is an open-label randomized multicenter phase II (window) trial in patients (pts) with head and neck squamous cell carcinoma (HNSCC). Treatment-naive HNSCC pts selected for primary curative study are randomized 3:3:3:1 in 4 neoadjuvant treatment groups: D 1500 mg on day 1 followed by O 600mg daily for 21-28 days (12 pts), cisplatin 60 mg/m2 on day 1 followed by O 75mg daily for 5 days (12 pts), monotherapy with O 600mg daily for 21-28 days (12 pts) and no treatment (5 pts). Preoperative therapy is discontinued 24 to 36 hours before surgery. Tumor biopsies, CT scans, PET and blood specimens are obtained at diagnosis and at surgery. Primary endpoint is the change in the tumor Ki-67 before and after treatment. Secondary endpoints are objective response rate according to RECIST 1.1 criteria, pathologic complete response rate and metabolic response rate assessed by FDG-PET/CT scan. Exploratory endpoints will include tumor and blood biomarkers. Translational correlates will be tested in tumor tissue, plasma and germline DNA and will include mutations in genes associated with DNA repair assessed by next generation sequencing and circulating tumor cells (CTCs) evaluated for DNA repair biomarkers and PD-L1. Trial is open to enrollment. Clinical trial information: NCT02882308.
A phase II study of pembrolizumab and docetaxel for aggressive RAI refractory thyroid carcinomas or salivary gland cancers: The iPRIME study.
Authors: Seiwert Tanguy Y. , De Souza Jonas A. , Vokes Everett E. , Agrawal Nishant
Published: September 2018

TPS6099

Background: Both aggressive, radioactive iodine refractory thyroid cancers as well as high-grade salivary gland cancers respond poorly to chemotherapy, and there is no widely used standard of care. Targeted thearpies as well as cytotoxic chemotherapy (e.g. doxorubicin, or taxanes) are commonly used, but are only modestly effective. Both salivary gland and thyroid cancers have been shown to have tumor infiltrating lymphocytes, tumor inflammation, and PD-L1 expression ( Ayers, AACR 2015). Early data with anti-PD-1 immunotherapy using pembrolizumab (Keynote 28) show activity in ≤10a% of patients in a biomarker selected population (Keynote 28 thyroid and salivary gland cohorts). However, most patients are not PD-L1 positive and were not eligible. Recently synergy of anti-PD-1 checkpoint blockade with cytotoxic chemotherapy was reported in several studies (e.g. Langer et al, Keynote 21G) . Mechanistically chemotherapy may increase tumor inflammation, and eradicate immusupressive myeloid derived suppressor cells (MDSCs). Data suggest a significant increase in the response rate e. g. in KN21G from 29% to 55%. Furthermore the depths of responses and durability improve, including patients with PD-L1 negative tumors. Methods: We hypothesize that the combination of PD-1 checkpoint blockade and cytotoxic chemotherapy will show synergistic activity in aggressive thyroid cancers and salivary gland cancers. Eligible patients will have radioactive iodine refractory, aggressive thyroid cancer (cohort A, N = 25 pts), or progressive salivary gland cancers (cohort B, N = 25 pts). There will be no PD-L1 or other biomarker selection. Patients must have progressed on prior therapy. Patients will receive docetaxel at a dose of 75mg/m2 Q21 days as well as pembrolizumab 200mg flat-dose Q21 days intravenously. The primary outcome of this study is response rate. The addition of pembrolizumab to chemotherapy will increase the response rate from 20% (H0) to 40% (H1). A simon two-stage design will be used for each cohort (cohorts A and B) with an estimate 81% power in each arm. Patient screening and enrollment are expected to begin mid 2017. Clinical trial information: pending.
Objective assessment of physical activity during chemotherapy for breast cancer.
Authors: Melisko Michelle E. , Hadeler Edward Kenji , Nelson Sandahl H , Lunde Audrey , Acerbi Irene , Rugo Hope S. , Majure Melanie Catherine , Chien Amy Jo , Esserman Laura , Hartman Sheri J.
Published: September 2018

TPS6626

Background: Exercise can alleviate side effects of chemotherapy, improve quality of life (QOL), and positively impact disease specific and overall survival. Despite the benefits of physical activity (PA), many patients’ activity levels decrease during chemotherapy. Wearable devices, such as the Fitbit, can provide insight into patterns of activity, and help encourage behavior change. The aims of this study are: 1) determine the feasibility/acceptability of using a Fitbit to measure PA and sleep throughout chemotherapy for breast cancer; 2) describe patterns of PA, sedentary time, and sleep during chemotherapy; 3) explore associations of activity and sleep with QOL. Methods: Non-metastatic breast cancer patients from UCSF and UCSD will be enrolled prior to starting chemotherapy. Eligibility criteria include ability to speak/read English, walk unassisted, and access to internet or Fitbit compatible smart phone. Patients sign informed consent, receive a Fitbit Charge HR and guidance on how to use the device. Patients are instructed to wear the Fitbit throughout their adjuvant or neoadjuvant chemotherapy and 6 months post therapy and to sync the Fitbit at least weekly. Patients complete surveys at start, midpoint, end, and 6 months post chemotherapy. Questionnaires include PROMIS anxiety, depression, physical function, fatigue, cognitive function, social roles, comfort with technology and usefulness of the Fitbit. Fitabase database collects minute level activity, sleep, and heart rate. To assess feasibility, we will evaluate if a participant wears FitBit for at least 10 hour per day for ≥ 80% of the days during chemotherapy. We will use mixed effects regression models to assess patterns of PA and associations between activity and QOL. All models will include activity time and Fitbit wear time and will control for the potential confounding effects of age and other demographic or clinical variables. As of February 6 2017, 48 out of a planned 80 patients are enrolled. Acknowledgment: Athena Breast Health Network investigators and patients; support at UCSD by NCI (U54 CA155435-01) and by gift from Carol Vassiliadis and family; NCI grant K07CA181323 to SH; UCSF M Zion Health Fund Award, GBCTB unrestricted funding and TriValley SOCKS to MM. Clinical trial information: NCT03041545.
COSMOS: MOR208 plus idelalisib or venetoclax in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) previously treated with a Bruton's tyrosine kinase inhibitor (BTKi)—A two-cohort phase II study.
Authors: Wendtner Clemens-Martin , Byrd John C. , Foà Robin , Greil Richard , Hillmen Peter , Jäger Ulrich , Jurczak Wojciech , Kelemen Peter , Laribi Kamel , Munir Talha , Schetelig Johannes , Staber Philipp B. , Stilgenbauer Stephan , Woyach Jennifer Ann
Published: September 2018

TPS7567

Background: Patients (pts) with R/R CLL who discontinue treatment with the BTKi ibrutinib due to progression have a particularly dismal prognosis. A phase I study showed that the Fc-enhanced, humanized, CD19 antibody MOR208 was well tolerated with encouraging single-agent activity in pts with R/R CLL/SLL. In preclinical models, MOR208 showed synergy with idelalisib (an inhibitor of PI3K delta) and venetoclax (an inhibitor of BCL-2), both approved for the treatment of CLL. Methods: This two-cohort, phase II study will investigate MOR208 combined with idelalisib (cohort A) or venetoclax (cohort B) in pts with R/R CLL or R/R SLL and includes a safety run-in phase for each cohort, to be evaluated by an Independent Data Monitoring Committee. Key inclusion criteria: aged ≥18 years, R/R CLL/SLL while receiving a BTKi therapy or intolerance of such therapy, BTKi administered as a single-agent or in combination for at least 1 month as the most recent prior anticancer therapy, ECOG performance status of 0–2, and adequate organ function. Key exclusion criteria: transformed CLL/SLL or Richter’s syndrome, BTKi treatment within 5 days prior to study drug dosing, prior treatment with a CD19-targeted therapy, a PI3K inhibitor (cohort A) or a BCL-2 inhibitor (cohort B). Pts will be treated for a maximum of 24 (28-day) cycles or until disease progression. Treatment will be MOR208 12 mg/kg IV (weekly for the first 3 months, every second week for the next 3 months, and monthly thereafter) in combination with oral idelalisib 150 mg twice-daily or venetoclax administered on a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. Primary endpoint: overall response rate based on independent review; secondary and exploratory endpoints include: progression-free and overall survival, duration of response, safety, pharmacokinetics, MOR208 immunogenicity, quality of life and minimal residual disease negativity. 120 pts per cohort are planned. Clinical trial information: 2015-002915-14.
CheckMate 436: A phase 1-2 study to evaluate safety and efficacy of nivolumab plus brentuximab vedotin in patients with CD30-expressing relapsed/refractory non-Hodgkin lymphomas.
Authors: Barr Paul M. , Carson Kenneth Robert , Brody Joshua , Shustov Andrei R. , Moskowitz Alison J. , Kline Justin Paul , Savage Kerry J. , Kuruvilla John , Campbell Mary S. , Zinzani Pier Luigi , Salles Gilles A. , Masood Aisha , Ansell Stephen Maxted
Published: September 2018

TPS7577

Background: Nivolumab (nivo) is a PD-1 immune checkpoint inhibitor that augments T-cell activation and host anti-tumor responses. PD-1 blockade has shown promise in B- and T-cell non-Hodgkin lymphoma (NHL),1 but many patients (pts) with NHL do not respond or progress after response. Combination therapy using anti-tumor agents with complementary mechanisms of action and low immunosuppressive impact may result in more frequent and durable responses. Brentuximab vedotin (BV) is an anti-CD30 antibodydrug conjugate that induces cell cycle arrest and apoptosis, with activity in a range of NHL tumors.2,3 Tumor cells undergoing BV-induced apoptosis have shown subsequent immune-mediated anti-tumor cytotoxicity.4 Therefore, nivo and BV may synergize if combined for relapsed/refractory (RR) NHL. Methods: CheckMate 436 (NCT02581631) is a phase 12, open-label, international, single-arm study evaluating nivo + BV for CD30-expressing RR NHL (study start: Dec 2015) in pts with RR diffuse large B-cell lymphoma, peripheral T-cell lymphoma (excluding anaplastic large cell lymphoma), and cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome); cohorts with primary mediastinal B-cell lymphoma (PMBL) and mediastinal gray zone lymphoma were made eligible in Sept 2016. Pts with PMBL must be aged ≥15 y (≥18 y for other histologies). All pts must have CD30-expressing disease, defined by CD30 on ≥1% of tumor cells or tumor-infiltrating lymphocytes by immunohistochemistry. In the phase 1 component, 6 pts will receive nivo and BV until disease progression or unacceptable toxicity. In the phase 2 component, ~130 more pts across the 5 histologies will be enrolled and treated at the recommended dose. Primary endpoints: safety, tolerability, and investigator-assessed objective response rate; secondary endpoints: duration of response and complete response (CR), CR rate, and progression-free and overall survival. Accrual is ongoing. References: 1. Lesokhin A et al. JCO 2016;34:2698704 2. Jacobsen E et al. Blood 2015;125:1394402 3. Horwitz S et al. Blood 2014;123:3095100 4. Gardai S et al. Cancer Res 2015;75(15 Suppl):2469 [abstract]. Clinical trial information: NCT02581631.
Early rebiopsy to identify mechanisms and biomarkers of tumor cell survival following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.
Authors: McCoach Caroline Elizabeth , Merrick Dan , Aisner Dara L. , Bunn Paul A. , Camidge D. Ross , Gao Dexiang , Kondo Kimi , Doebele Robert Charles
Published: September 2018

TPS9100

Background: Significant advances in the clinical outcomes of lung cancer patients have been achieved in part due to the identification of targetable driver mutations. The success of targeting oncogenic drivers with TKIs has allowed for improvements in response rates, progression free survival and overall survival. Despite these improvements, patients ultimately relapse. Acquired resistance has been evaluated in post-progression tumor samples and is caused by a variety of mechanisms including secondary resistance mutations, gene copy number gains, gene amplification, or bypass pathway activation. Residual tumor burden with surviving cancer cells are the origin of the ultimate tumor progression. Studies analyzing signaling pathways and other markers of these tumor cells or microenvironmental cells in tumor samples before clinical resistance develops are needed to determine how best to target this compartment. Methods: Eligible patients will have a new diagnosis of advanced NSCLC with an EGFR TKI sensitizing mutation. Additional inclusion criteria include ECOG 0-2, a tumor measurable by RECIST 1.1 and at least 2cm in one dimension, and tumor site that is accessible and safe to biopsy. Patients will undergo a pretreatment target lesion biopsy, begin treatment with an EGFR TKI then receive a second biopsy of the same target lesion after two weeks of therapy. Our primary objective is to identify differences between pretreatment and early treatment tumor samples. To do this we will be using a combination of RNA seq, multiplex protein expression analysis and proximity ligation assays. Secondary objectives include identification of predictive markers that can be used to determine which tumors will undergo epithelial to mesenchymal transition or activate other survival pathways and determination of the success rate and adverse event rate of repeat biopsy. Patients are currently being enrolled at a single academic institution however, additional clinical site openings are pending. Our goal enrollment for this study is 47 patients to achieve 20 paired biopsy samples. We will present updated enrollment and demographic information. Clinical trial information: NCT03042221.
An open-label, uncontrolled, single arm phase II trial of the PI3K inhibitor buparlisib in patients with melanoma brain metastases.
Authors: Meier Friedegund Elke , Forschner Andrea , Garzarolli Marlene , Rauschenberg Ricarda , Beissert Stefan , Garbe Claus , Eigentler Thomas K.
Published: September 2018

TPS9595

Background: The approval of effective BRAF +/- MEK inhibitors and immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma. However, available therapies appear to be less effective on cerebral than extracerebral metastases. Hyperactivation of the PI3K-AKT survival pathway is a prominent feature of melanoma brain metastases (MBM). This trial aims to determine the activity and safety of the PI3K inhibitor buparlisib in patients (pts) with MBM. Methods: The study enrolls adults suffering from MBM not eligible for neurosurgery or/and radiosurgery. Patients must have failed prior treatment with BRAF +/- MEK Inhibitors (BRAF-V600E mutated population) and anti-PD-1 or/and anti-CTLA-4 antibodies (BRAF wild-type population), respectively. Patients are treated with buparlisib 100 mg PO daily until disease progression or unacceptable toxicity. The Simon-Two-Step design for phase 2 studies was used to determine sample size. Assuming a response rate of 12.5% in comparison to historical 10% for chemotherapy 22 (8/14) pts would be required. If there are one or fewer responses in the first 8 pts the study would stop. Prespecified activity goal for the first stage of accrual was met; currently 11/22 pts are enrolled. Clinical trial information: NCT02452294.