bluuebunny/crossref_metadata_2025 huggingface dataset:
Keynote-200 phase 1b: A novel combination study of intravenously delivered coxsackievirus A21 and pembrolizumab in advanced cancer patients.
Authors: Pandha Hardev S. , Ralph Christy , Harrington Kevin , Curti Brendan D. , Sanborn Rachel E. , Akerley Wallace L. , Gupta Sumati , Rudin Charles M. , Rosenberg Jonathan E. , Kaufman David Ross , Schmidt Emmett V. , Grose Mark , Shafren Darren
Published: September 2018

TPS3108

Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody that has yielded significant solid tumor responses via reversal of tumor induced T-cell suppression. Intravenous (i.v.) CVA21 mono-therapy is generally well tolerated, with low toxicity and can successfully target tumors in patients with melanoma, NSCLC and bladder cancer as confirmed by detection of CVA21 viral RNA in post-treatment tumor biopsies (Pandha et al., 2016). Intratumoral CVA21 replication has the potential to up-regulate numerous key immune checkpoint molecules, including PD-L1 (Andtbacka et al., 2016).The combination of i.v. CVA21+pembrolizumab may translate to a potential enhanced benefit in the clinic. Methods: The Phase Ib KEYNOTE-200 (NCT02043665) Treatment: Primary objectives are to assess dose-limiting toxicities (DLT) of CVA21 in combination with pembrolizumab. Secondary objectives are to assess ORR by irRECIST 1.1 criteria, PFS, and OS. Patients (pts) are infused with CVA21 in 100 mL saline + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = ~80) at a dose of 1 x 109 TCID50 on study days 1,3,5,8,29,and Q3W for 6 additional infusions. Pembrolizumab is given in all cohorts at 200 mg IV Q3W from Day 8 for up to 2 years. Treatment (tx) with CVA21 + pembrolizumab will continue until confirmed CR or PD (whichever comes first) per irRECIST 1.1 or DLT.To date the combination of intravenous CVA21 and pembrolizumab has been generally well-tolerated. At present one gr 3 CVA21-related hyponatremia with no DLT for the combination of CVA21 and pembrolizumab being observed. Enrolment in Cohorts 1 and 2 is complete with tx of pts in Cohort 3 currently underway. Key eligibility: Pts with advanced disease considered appropriate tx with CVA21 + pembrolizumab, lesion(s) accessible for core biopsy, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression. Clinical trial information: NCT02043665.
A phase Ib study combining irinotecan with AZD1775, a selective WEE 1 kinase inhibitor, in RAS/RAF mutated metastatic colorectal cancer patients who progressed on first line therapy.
Authors: Cohen Deirdre Jill , Grabocka Elda , Bar-Sagi Dafna , Godin Robert , Leichman Lawrence P.
Published: September 2018

TPS3627

Background: Mutant KRAS tumors show a dependency on WT-H/N-Ras for activation of ATR/Chk1-mediated G2 DNA damage response (Grabocka, Cell, 2015). We have shown in vitro that the Wee1 kinase inhibitor AZD1775, which acts to abrogate the G2 DNA damage checkpoint and induces replication stress during S-phase, selectively sensitizes RAS/RAF mutant cells to the DNA damaging agent irinotecan. Up to 65% of metastatic colorectal cancers harbor RAS or BRAF mutations and these patients have limited treatment options following first line therapy. Methods: This is an open label, single-arm, phase Ib study using a modified 3+3 dose-escalation schedule with expansion cohort. Primary objective is to determine the MTD of AZD1775 in combination with irinotecan as 2nd-line therapy in patients with metastatic KRAS, NRAS or BRAF mutated colorectal cancer. Up to 18 patients will be enrolled in the dose escalation portion. Standard dose irinotecan is given on day 1 of every 2 week cycle. AZD1775 is administered PO twice daily for 3 to 5 days of each cycle, starting cycle 2. The maximum tolerated dose (MTD) is defined as the highest dose level at which ≤1 of 6 patients experience a dose limiting toxicity. Once the MTD is reached and/or recommended dose for expansion is determined, a dose expansion cohort of 14 patients will be enrolled. Secondary endpoints include characterizing the safety profile at the MTD, obtaining a preliminary estimate of efficacy for the combination (measured by overall response rate, progression-free and overall survival rates), and obtaining pharmacokinetic parameters. Pre- and on-treatment biopsies will be collected from the expansion cohort to determine: adequate target engagement of Wee1, changes in markers of DNA damage, TP53 mutation status, and changes in gene expression profiles in order to identify potential biomarkers of response. At February 2017, 2 patients have been enrolled on this study. Clinical trial information: NCT02906059. [Table: see text]
Perioperative trastuzumab and pertuzumab in combination with FLOT versus FLOT alone for HER2 positive resectable esophagogastric adenocarcinoma: Petrarca—A phase II trial of the German AIO.
Authors: Hofheinz Ralf , zur Hausen Gerrit , Borchert Kersten , Kretzschmar Albrecht , Ebert Matthias Philip , Ettrich Thomas Jens , Koenigsmann Michael , Haag Georg Martin , Hagen Volker A. , Hoehler Thomas , Homann Nils , Kroening Hendrik , Reichardt Peter , Rieger Michael , Teschendorf Christian , Goekkurt Eray , Lindig Udo , Schmiegel Wolff H. , Pauligk Claudia , Al-Batran Salah-Eddin
Published: September 2018

TPS4133

Background: Neoadjuvant or perioperative chemotherapy has become a standard of care for locally advanced, resectable gastric cancer and adenocarcinoma of the GEJ. However, patient’s outcome is still unsatisfactory and 5-year survival, even in prospective trials, has been below 40%. Targeting HER2 with Trastuzumab and Pertuzumab prolonged survival in patients with HER2-positive advanced breast cancer as did Trastuzumab in patients with HER2-positive advanced gastric cancer. This provides a rationale for the evaluation of anti-HER2 treatment for resectable patients. Methods: This is a prospective, multicenter, randomized, investigator initiated phase II trial. Patients with HER2-positive locally advanced adenocarcinoma of the stomach and GEJ (i.e. ≥cT2 any N or any T N-positive) with exclusion of distant metastases are enrolled. HER2 status is centrally assessed. Patients are randomized 1:1 to 4 pre-operative 2-week cycles (8 weeks) of FLOT (Docetaxel 50 mg/m²; Oxaliplatin 85 mg/m²; Leucovorin 200 mg/m²; 5-FU 2600 mg/m²) followed by surgery and 4 additional cycles of FLOT (arm A); or the same therapy in combination with Trastuzumab 8/6 mg/kg and Pertuzumab 840 mg every 3 weeks pre- and postop, followed by a total of 9 additional cycles of Trastuzumab/Pertuzumab monotherapy (arm B). Primary endpoint of the phase II part (n = 100) of the trial is to show numerical improvement of the rate of pathological complete remission to approx. 25% with antibodies compared to approx. 16% with FLOT alone as assessed by a centralized pathology. Main secondary endpoints are safety and tolerability. Once results from phase II become available, study transition into phase III will be evaluated based on de facto results and current medical standards. Recruitment has already started; by February 2017 a total of 19 patients have been randomized. EudraCT: 2014-002695-86 Clinical trial information: NCT02581462.
A phase II, open-label, randomized study to evaluate the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in subjects with unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma.
Authors: Shah Manish A. , Metges Jean-Philippe , Chun Patrick Youngwhan , Smith Victoria , Maltzman Julia D. , Wainberg Zev A.
Published: September 2018

TPS4141

Background: GS-5745 is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. Inhibiting MMP9 is expected to block paracrine signaling and metastasis and to alter the immune microenvironment within the tumor. Results from the ATTRACTION-2 Phase III trial showed the PD-1 inhibitor nivolumab significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in patients with heavily pre-treated advanced gastric or gastroesophageal junction cancer. Preclinical studies indicate that selective inhibition of MMP9 can inhibit immune-suppressive myeloid cell polarization, regulatory T cell generation, desmoplasia, and the destruction of ligands for CXCR3 (a critical chemokine receptor that enables effector T cell trafficking). In combination with a checkpoint inhibitor, CD8+, CD4+ and CD44+ cytotoxic T cells are significantly increased in a checkpoint-refractory model, suggesting that MMP9 inhibition could relieve immune suppression. Methods: This phase 2, open-label, randomized study investigates the efficacy and safety of GS-5745 combined with nivolumab versus nivolumab alone in patients with unresectable or recurrent gastric or gastroesophageal adenocarcinoma. 120 patients will be randomized to either GS-5745 800mg IV + nivolumab 3mg/kg IV, or nivolumab alone. Treatment will be administered every 2 weeks and stratified by PD-L1 status. CT will be performed every 8 weeks to evaluate response. The primary endpoint of the study is ORR; secondary endpoints include PFS, OS, and occurrence of adverse events. Key inclusion criteria: metastatic or inoperable adenocarcinoma of the stomach or GEJ which has progressed after ≥1 prior systemic therapy, ECOG performance status ≤1, RECISTv1.1 measureable disease, archival tissue adequate for PD-L1 evaluation. Exploratory biomarkers correlated with study drug response will also be evaluated. Enrollment opened September 2016. Clinical trial information: NCT02864381.
S1605: Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer.
Authors: Singh Parminder , Catherine Tangen , Lerner Seth P. , McConkey David , Plets Melissa , Lucia M. Scott , Woods Michael , Bivalacqua Trinity , Kassouf Wassim , Bangs Richard Carlton , Thompson Ian Murchie , Black Peter C.
Published: September 2018

TPS4591

Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. Results: If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Conclusion:Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial information: NCT02844816.
Avelumab plus axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma: Phase 3 study (JAVELIN Renal 101).
Authors: Choueiri Toni K. , Rini Brian I. , Larkin James M. G. , Bjarnason Georg A. , Gravis Gwenaelle , Gurney Howard , Lee Jae-Lyun , Keizman Daniel , Haanen John B. A. G. , Tomita Yoshihiko , Uemura Hirotsugu , Albiges Laurence , Schmidinger Manuela , Atkins Michael B. , Mariani Mariangela , Shnaidman Michael , di Pietro Alessandra , Motzer Robert J.
Published: September 2018

TPS4594

Background: The combination of a checkpoint inhibitor with an anti-VEGF agent is a promising treatment strategy for advanced renal cell carcinoma (aRCC). Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in aRCC and other tumor types (eg, Apolo et al. ASCO 2016; Gulley et al. ECC 2015). Axitinib is an anti-VEGF receptor tyrosine kinase inhibitor approved for second-line treatment of aRCC (Rini et al. Lancet 2011) that has also shown clinical activity as a first-line (1L) therapy (Hutson et al. Lancet Oncol 2013). In an ongoing phase 1b study in treatment-naïve patients (pts) with aRCC, avelumab + axitinib administered at standard monotherapy doses showed a tolerable safety profile and encouraging antitumor activity (Larkin et al. ESMO 2016). JAVELIN Renal 101 is a randomized, multicenter, phase 3 study (NCT02684006) comparing avelumab + axitinib vs sunitinib in pts with treatment-naïve aRCC. Methods: The primary objective is to demonstrate superiority of avelumab + axitinib vs sunitinib in prolonging progression-free survival (PFS) in the 1L treatment of pts with aRCC. Eligibility criteria include: aRCC with a clear cell component, ECOG PS ≤1, no prior systemic therapy for advanced disease, and measurable disease per RECIST v1.1. Approximately 583 pts will be randomized 1:1 and stratified based on ECOG PS (0 vs 1) and region (US vs Canada/Europe vs rest of the world). Pts receive either avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID continuously (cycle length 6 weeks) or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off. Treatment is discontinued for unacceptable toxicity or if any other criteria for withdrawal are met. Pts may continue treatment beyond progression (RECIST v1.1) if investigator-assessed clinical benefit is achieved and treatment is well tolerated. PFS is assessed by blinded central review. Secondary efficacy assessments include overall survival, objective response, disease control, duration of response, and time to response. Safety, PK, and biomarker analyses will also be performed. The trial is currently active at 103 sites across 12 countries and as of Feb 2017, more than 40% of patients have been enrolled. Clinical trial information: NCT02684006.
A randomized study of enzalutamide in patients with localized prostate cancer undergoing active surveillance (ENACT).
Authors: Shore Neal D. , Vourganti Srinivas , Silberstein Jonathan L. , Brown Bruce A. , Wilson Samuel , Hollowell Courtney M.P. , Cooperberg Matthew , Shang Gwendoline , Fleshner Neil Eric
Published: September 2018

TPS5097

Background: Prostate cancer (PC) patients (pts) who select active surveillance (AS) are a heterogeneous population with varying risks for disease progression. Studies have estimated that approximately 31–42% of pts electing AS have experienced disease progression (pathological or therapeutic) over 1.8 and 2.3 years. There is no evidence-based pharmacological intervention which has effectively lessened this progression event. Pharmacological intervention with enzalutamide (ENZ), an androgen receptor inhibitor approved for treatment of metastatic castration-resistant PC, may lessen this progression. The aims of this study are to evaluate the efficacy of ENZ versus AS alone for delaying time to progression in pts with clinically localized PC undergoing AS. This study examines the effects of ENZ on progression in a subset of pts with low- or intermediate-risk PC who would otherwise elect an AS protocol. Methods: This is a multicenter, randomized, open-label study (NCT02799745). Eligibility criteria include histologically confirmed prostate adenocarcinoma within 6 months of screening, low or intermediate risk PC (T1c−T2c, prostate-specific antigen [PSA] < 20, N0, M0, Gleason score ≤7 [3+4 pattern only]), Eastern Cooperative Oncology Group status ≤2 and estimated life expectancy > 5 years. Exclusion criteria include any prior PC intervention. Pts will be randomized to receive open-label oral ENZ 160 mg/day once daily or to AS during the 1-year study treatment period. After the first year, all pts will be followed for one additional year with no other intervention. All pts will undergo prostate biopsy at 1 and 2 years. The primary end point is time to PC progression (pathological or therapeutic). Secondary end points include safety, incidence of negative biopsies for cancer at 1 and 2 years, percentage of cancer positive cores at 1 and 2 years, time to PSA progression, incidence of secondary rise in serum PSA, and quality-of-life questionnaires. Exploratory end points include biomarker assessment and genomic analysis. Study enrolment commenced in June 2016, with study completion expected in March 2019. Planned total enrolment is 222 pts from ~60 United States/Canadian sites. Clinical trial information: NCT02799745.
ARIEL4: An international, multicenter randomized phase 3 study of the PARP inhibitor rucaparib vs chemotherapy in germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade ovarian carcinoma.
Authors: Oza Amit M. , Lorusso Domenica , Oaknin Ana , Safra Tamar , Swisher Elizabeth , Bondarenko Igor , Huzarski Tomasz , Klat Jaroslav , Póka Róbert , Viola Luciana Spillari , Tankersley Chris , Maloney Lara , Goble Sandra , Unger Caro , Giordano Heidi , Kristeleit Rebecca Sophie
Published: September 2018

TPS5603

Background: In high-grade epithelial ovarian carcinoma (OC), ≈18% of patients (pts) have tumors with a germline BRCA1 or BRCA2 mutation; ≈7% have tumors with a somatic BRCA1 or BRCA2 mutation (Pennington et al. Clin Cancer Res. 2014;20:764-75). The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is approved in the United States for treatment of pts with OC associated with a deleterious BRCA1 or BRCA2 mutation (germline and/or somatic) who have received ≥2 chemotherapies. Although PARP inhibitors have demonstrated clinical activity in OC in both treatment and maintenance settings, comparison to standard of care (SOC) has only been evaluated in the maintenance setting. Randomized studies are needed to assess the benefit-risk profile of PARP inhibitors vs current SOC as treatment for BRCA1- or BRCA2-mutated, relapsed, high-grade OC. Methods: ARIEL4 (NCT02855944) is evaluating rucaparib vs chemotherapy as treatment for pts with germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade OC (regardless of histology) who have received ≥2 prior chemotherapy regimens. Approximately 345 pts will be randomized 2:1 to receive rucaparib (600 mg BID) (n = 230) or chemotherapy (n = 115) and stratified by progression-free interval after their most recent platinum regimen. Pts with platinum-resistant (progressive disease [PD] 1– < 6 mo after last platinum) or partially platinum-sensitive disease (PD 6– < 12 mo after last platinum) will be randomized to rucaparib or weekly paclitaxel; pts with platinum-sensitive disease (PD ≥12 mo after last platinum) will be randomized to rucaparib or platinum-based therapy (single-agent or doublet at the discretion of the investigator). Pts receiving chemotherapy have the option to cross over to rucaparib upon radiographic disease progression. The primary endpoint is progression-free survival. Secondary endpoints include investigator-assessed objective response rate (ORR) (RECIST version 1.1), ORR/CA-125 response, duration of response, overall survival, and pt-reported outcomes. Safety will be summarized descriptively using standard adverse event reporting. Clinical trial information: NCT02855944.
PAOLA-1: An ENGOT/GCIG phase III trial of olaparib versus placebo combined with bevacizumab as maintenance treatment in patients with advanced ovarian cancer following first-line platinum-based chemotherapy plus bevacizumab.
Authors: Ray-Coquard Isabelle Laure , Harter Philipp , Gonzalez Martin Antonio , Cropet Claire , Pignata Sandro , Fujiwara Keiichi , Marth Christian , Vergote Ignace , Mirza Mansoor Raza , Colombo Nicoletta , Rosenberg Per , Maenpaa Johanna Unelma , Pujade Lauraine Eric
Published: September 2018

TPS5605

Background: Olaparib (Lynparza) is an oral PARP inhibitor indicated in the EU for the maintenance treatment of patients (pts) with platinum-sensitive relapsed BRCA-mutated high grade serous ovarian cancer (HGSOC). Bevacizumab is an anti-VEGF monoclonal antibody indicated in the EU in first line or relapse for the treatment of OC in combination with specific chemotherapeutic agents. Bevacizumab treatment is associated with increasing hypoxia-induced homologous recombination repair deficiencies in tumor cells, and is hypothesized to increase ovarian tumor sensitivity to olaparib. Methods: PAOLA-1 (ENGOT-ov25) is a randomized, placebo-controlled trial evaluating the efficacy and safety of olaparib (tablet formulation) in pts with advanced HGSOC receiving bevacizumab maintenance therapy. Eligible pts are those in complete or partial response following first-line platinum chemotherapy plus bevacizumab, and for whom bevacizumab maintenance therapy is planned. Approximately 762 European and 24 Japanese pts will be randomized 2:1 to olaparib 300 mg twice daily or placebo for up to 24 months. All pts will receive standard maintenance care of bevacizumab (15 mg/kg every three weeks) for up to 15 months. Primary objective: PFS1 according to RECIST 1.1 Secondary objectives: PFS2, OS, Safety, PRO/QoL, TFST, TSST All pts will undergo tumor BRCA testing prior to randomization. Central BRCA testing (tumor) will be performed in five screening platforms in France. Tumor BRCA test results have to be available within two months of sample provision. PFS will be evaluated using a log-rank test stratified by response to first-line treatment and BRCA mutation status. Treatment effect hazard ratio of 0.7 is expected and final PFS1 analysis will be performed after 372 events. The first pt from eight ENGOT groups plus Japan (10 participating countries) was randomized in July 2015. As of 31 January 2017, 549 pts have been randomized. The median period between the provision of a tumor sample and returned BRCA test result is 40 days. Accrual is expected to be complete before July 2017. Clinical trial information: NCT02477644.
Towards omitting breast cancer surgery in select patient groups: Assessment of pathologic complete response after neoadjuvant systemic therapy using biopsies—The MICRA trial.
Authors: Van Der Noordaa Marieke , van Duijnhoven Frederieke , Loo Claudette , van der Vijver Koen , Sonke Gabe S. , Van Der Pol Carmen , Francken Anne Brecht , Vrancken Peeters Marie-Jeanne
Published: September 2018

TPS593

Background: Improvements in systemic treatments for breast cancer patients has led to increasing rates of pathologic complete response (pCR). In addition, the identification of a pCR has been greatly improved with magnetic resonance imaging (MRI). In patients with a pCR, surgical resection of (part of) the original tumor area is performed to confirm the absence or presence of pCR and is not likely to contribute to locoregional control. With the MICRA trial (Minimally Invasive Complete Response Assessment) we aim to omit breast surgery in breast cancer patients achieving pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) using biopsies, thus preventing overtreatment and improving quality of life. Methods: The MICRA trial is a multi-center observational prospective cohort study. In all breast cancer patients receiving NST, a marker is placed in the center of the tumor area before NST. 440 patients with radiologic complete response or partial response (0.1-2.0 cm residual contrast enhancement, ≥30% decrease in tumor size according to RECIST criteria) on contrast enhanced MRI will be included in the MICRA trial. Patients with hormone receptor positive, triple negative and Human Epidermal growth factor Receptor 2 tumors are eligible. After NST, 8 ultrasound-guided biopsies are obtained in the region surrounding the marker, while the patient is under general anesthesia. Immediately hereafter, breast surgery is performed and pathology results of the biopsies and resected specimens are compared. The primary endpoint is specificity of post-NST biopsies. In addition, sensitivity and positive and negative predictive value will be calculated. We will perform a multivariable analysis using data on MRI and ultrasound findings, pre-NST pathology parameters and post-NST biopsy results to determine what the most reliable method is to assess pCR and how many biopsies are needed for this purpose. Conclusion: With the MICRA-trial we aim to select a group of breast cancer patients in whom surgery of the breast after NST can be omitted, by predicting the presence of a pCR on biopsies. Clinical trial information: NTR6120.
A feasibility study of neoadjuvant talazoparib for early-stage breast cancer patients with a germline BRCA pathogenic variant: NCT02282345.
Authors: Litton Jennifer Keating , Scoggins Marion , Whitman Gary J , Barcenas Carlos Hernando , Moulder Stacy L. , Murthy Rashmi Krishna , Abouharb Sausan , Adrada Beatriz , Helgason Thorunn , Schwartz-Gomez Jill , Mittendorf Elizabeth Ann , Thompson Alastair Mark , Arun Banu
Published: September 2018

TPS595

Background: Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a family of enzymes responsible for DNA repair via base excision repair as well as maintenance of genetic stability. BRCA mutation carriers appear to have significant sensitivity to PARP inhibitors, not only from synthetic lethality but also potentially PARP trapping in the metastatic setting. A 2-month window study of talazoparib was reported at ESMO in 2016. In 13 patients treated, the median % tumor shrinkage by ultrasound was 88% (range 30-98%) and the study was halted early to allow for this expansion of neoadjuvant talzoparib as the only treatment prior to surgery to evaluate pathologic response. Primary Objective: Evaluate the rate of pathologic complete response (pCR)/RCB-0 + residual cancer burden (RCB)-I responses in patients with early stage breast cancer and a known BRCA pathogenic variant. Methods: 20 patients with stage I-III breast cancer and a known BRCA mutation will be accrued on this IRB-approved study. Patients will receive 4-6 months of neoadjuvant talazoparib and then proceed to surgery. Radiation, chemotherapy and endocrine therapy will be given when appropriate in teh adjuvant setting. Brief Eligibility Criteria: Patients with an identified BRCA pathogenic variant and diagnosed with a stage I-III breast cancer at least 1 cm in size are eligible. Tumors can have any ER or PR status but HER2 over-expressed cancers were excluded. Prior systemic or radiation therapy for previous breast cancer is excluded, but prior surgical treatment for contralateral DCIS is allowed. Correlative Science: Blood and biopsies prior to initiation of therapy will be collected to evaluate biomarkers of therapy efficacy as well as to initiate patient derived xenograft (PDX) models. Other studies will include: immunohistochemistry, targeted or whole exome sequencing for BRCA pathway mutations and other somatic and germline alterations; RNA sequencing; immune response; transcriptional profiles to assess TNBC subtype, reverse phase protein array (RPPA); generation of PDX models and mammosphere cultures. Clinical trial information: NCT02282345.
JAVELIN head and neck 100: A phase 3 trial of avelumab in combination with chemoradiotherapy (CRT) vs CRT for 1st-line treatment of locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Authors: Lee Nancy Y. , Ferris Robert L. , Beck J. Thaddeus , Harrington Kevin , Haddad Robert I. , Bourhis Jean , Tahara Makoto , Geraldes Margarida , Nuyten Dimitry S. A. , Goldberg Zelanna , Cohen Ezra E.W.
Published: September 2018

TPS6093

Background: Cisplatin + radiotherapy is a standard-of-care treatment for patients (pts) with LA SCCHN. Combining avelumab (fully human IgG1 anti–PD-L1 antibody) and CRT may synergistically activate multiple immune-mediated mechanisms to effect a robust and durable antitumor response and improve long-term disease control. Methods: JAVELIN Head and Neck 100 (NCT02952586) is a global, multicenter, randomized, double-blind, phase 3 trial of avelumab + cisplatin-based CRT vs placebo + CRT as 1st-line treatment for pts with LA SCCHN. The primary objective is to demonstrate superiority of avelumab + CRT in prolonging progression-free survival (PFS) vs CRT alone. Eligible pts have LA SCCHN of the oral cavity, oropharynx, larynx, or hypopharynx; HPV− or non-oropharyngeal HPV+ disease of stage III, IVa, or IVb; or HPV+ oropharyngeal disease T4, N2c, or N3. Pts must be candidates for cisplatin-based CRT. Other eligibility criteria include ECOG PS ≤1 and no prior systemic treatment for advanced disease. Approximately 640 pts will be randomized 1:1 to receive avelumab 10 mg/kg (1-hour IV) + CRT (intensity-modulated RT [70 Gy/35 fractions] + cisplatin 100 mg/m2 [x3]) or placebo + CRT. There will be 3 treatment phases: lead-in (single dose of avelumab or placebo), CRT (concurrent avelumab or placebo + CRT for 7 weeks), and maintenance (avelumab or placebo Q2W for 12 months). The rationale for this design is to induce an immune response during lead-in and CRT phases, followed by maintenance treatment to prolong and support immune memory development. The primary endpoint is PFS per modified RECIST v1.1. Secondary efficacy endpoints include overall survival, objective response, locoregional failure, distant metastatic failure, and duration of response. Other endpoints include safety, pharmacokinetics, immunogenicity, pt-reported outcomes, and biomarker assessments. Treatment will continue for 12 months following initiation of the maintenance phase or until progressive disease, unacceptable toxicity, or any other protocol-defined criterion for withdrawal occurs. Enrollment in this phase 3 trial began in November 2016. Clinical trial information: NCT02952586.
An open-label, randomized phase III study of gilteritinib versus salvage chemotherapy in relapsed or refractory FLT3 mutation-positive acute myeloid leukemia.
Authors: Perl Alexander E. , Cortes Jorge E. , Strickland Stephen Anthony , Ritchie Ellen K. , Neubauer Andreas , Martinelli Giovanni , Naoe Tomoki , Pigneux Arnaud , Rousselot Philippe H. , Röllig Christoph , Baer Maria R. , Larson Richard A. , James Angela Joubert , Chen Caroline , Shu Lei , Hasabou Nahla , Bahceci Erkut
Published: September 2018

TPS7067

Background: FLT3 mutations occur in 30% of patients with acute myeloid leukemia (AML), most often as internal tandem duplications (FLT3-ITD) or point mutations at codon D835. FLT3-ITDs are associated with high relapse rates, short remission duration, and poor overall survival (OS); FLT3-D835 can confer resistance to other tyrosine kinase inhibitors (TKIs). Gilteritinib is a highly selective FLT3/AXL TKI with activity against both FLT3-ITD and FLT3-D835 mutations. A recent phase 1/2 study of gilteritinib (20–450 mg/d) in relapsed/refractory (R/R) AML showed favorable tolerability at doses ≤300 mg/d, and consistent, potent FLT3 inhibition at doses ≥80 mg/d. Patients with FLT3 mutation-positive (FLT3mut+) AML receiving doses ≥80 mg/d had an ORR of 52% (CR/CRp/CRi = 41%, PR = 11%) and longer OS than historic experience in R/R AML with combination cytotoxic chemotherapy or other FLT3 TKIs as monotherapy. Given these results, we initiated a phase 3 trial of once-daily (QD) 120 mg gilteritinib. Methods: This randomized, open-label phase 3 study (NCT02421939) will enroll 369 adults with FLT3mut+ AML in first relapse or refractory to front-line therapy. Patients who have not previously received FLT3 inhibitors, except sorafenib and midostaurin, will be randomized 2:1 to either 120 mg gilteritinib QD or the investigator’s pre-randomization specified salvage chemotherapy choice (LoDAC, Aza, MEC, FLAG-IDA), and stratified by prior chemotherapy response and salvage chemotherapy intensity. Gilteritinib or low-intensity chemotherapy cohorts will receive continuous 28-day treatment cycles until a discontinuation event occurs; the high-intensity chemotherapy cohort will receive ≤2 treatment cycles before response measurement. Primary objective is OS; key secondary objectives are event-free survival and CR rate. Other secondary objectives: leukemia-free survival, remission duration, composite CR rate, subsequent transplantation rate, patient-reported fatigue, and safety. A formal interim analysis is planned when ~50% of planned death events have occurred. Study enrollment began on Oct 23, 2015; as of Jan 20, 2017, 167 subjects have been randomized. Clinical trial information: NCT02421939.
A biomarker-directed phase 2 trial of SY-1425, a selective retinoic acid receptor alpha agonist, in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).
Authors: Cook Rachel J. , Stein Eytan , Steensma David P. , Sekeres Mikkael A. , Bixby Dale L. , Rizzieri David , Jurcic Joseph G. , Vigil Carlos Enrique , Redner Robert , Roboz Gail J. , Savona Michael R. , McKeown Michael R. , Stephens Kristin , Roth David A. , Cortes Jorge E.
Published: September 2018

TPS7071

Background: SY-1425 (tamibarotene) is an orally available, synthetic retinoid approved in Japan for the treatment of relapsed/refractory (R/R) APL. SY-1425 is a more potent and selective retinoic acid receptor alpha (RARα) agonist with improved pharmacologic properties compared to all-trans retinoic acid (ATRA) including increased half-life and lack of metabolism by CYP26A1 resulting in extended relative exposures. SY-1425 binding to RARα relieves pathogenic repression of myeloid differentiation. Super-enhancers associated with RARA and upregulation of RARA expression correlate with increased sensitivity to SY-1425 in vitro and predict for response to SY-1425 with induced differentiation and reduced proliferation in RARA-high PDX AML models, but not in RARA-low models. SY-1425 also induces the RARα target gene DHRS3 in RARA-high AML cell lines. This study is designed to demonstrate pharmacodynamic (PD) and clinical effects of SY-1425 in non-APL AML and MDS patients (pts) positive for the RARA super-enhancer associated biomarker or exploratory RARA pathway biomarker, IRF8. Methods: This study is enrolling pts with R/R AML, R/R higher-risk MDS, newly-diagnosed AML ≥60 yrs unlikely to respond to or tolerate standard therapy, and transfusion dependent lower-risk MDS pts without del 5q who are unlikely to respond to or have failed ESAs. Pts must be biomarker positive based on centralized testing of tumor cells from blood. All pts receive SY-1425 at 6 mg/m2/day PO with continuous twice daily dosing. Primary objectives are to characterize the activity of SY-1425 by ORR in AML and higher-risk MDS pts or transfusion independence in lower-risk MDS pts. Secondary objectives include event-free and relapse-free survival, duration of response, overall survival, hematologic improvement and safety. PD evaluation includes induction of DHRS3 and expression of myeloid differentiation markers. Target enrollment is 80 pts. This trial opened in September 2016. Through a protocol amendment, SY-1425 treatment in combination with azacitidine will also be evaluated. ClinicalTrials.gov identifier: NCT02807558.
A randomized, open-label, phase II study of azacitidine (AZA) in combination with durvalumab in patients (pts) with previously untreated higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) ineligible for hematopoietic stem cell transplantation (HSCT).
Authors: Silverman Lewis R. , Dohner Hartmut , Dombret Herve , Mufti Ghulam J. , Stone Richard M. , Rose Shelonitda , Gerike Torsten , Camus Frederic , Fenaux Pierre
Published: September 2018

TPS7074

Background: Hypomethylating agents (HMAs) induce hematologic response in ~ 50% of higher-risk MDS pts; however, there are few treatment options for nonresponding pts at increased risk of AML progression and death. While older AML pts ineligible for HSCT have similar overall survival (OS) with AZA and chemotherapy (13.3 vs 12.2 months) (Döhner et al. Haematologica 2015;100:P566), there is an opportunity to further improve responses and OS in these pts. Blockade of the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway with immune checkpoint inhibitors is an emerging paradigm in anticancer therapy. PD-L1 is expressed on cells from AML and MDS pts; expression is upregulated on myeloblasts following HMA therapy (Yang et al. Leukemia 2014;28:1280) and during MDS transformation to AML (Ogata et al. Leuk Res 2012;36:1229). Durvalumab (MEDI-4736), a human anti-PD-L1 monoclonal antibody, is well tolerated and induces durable responses in pts with solid tumors (Lutzky et al. JCO 2014;32:3001). This randomized, open-label, phase 2 study evaluates efficacy and safety of subcutaneous (SC) AZA ± durvalumab in pts with higher-risk MDS and older pts with AML. Methods: Eligible MDS pts ( < 20% blasts) aged ≥ 18 years, with IPSS intermediate- or high-risk MDS, and AML pts (≥ 20% blasts) aged ≥ 65 years, are randomized 1:1 to receive either AZA 75 mg/m2 SC for 7/28 days or AZA 75 mg/m2 SC for 7/28 days plus durvalumab 1500 mg IV on day 1 of 28-day cycles. Pts are stratified by cytogenetic risk: intermediate- vs poor-risk AML, and intermediate- vs poor-/very-poor-risk MDS. Primary endpoint is overall response rate per IWG 2006 criteria in MDS pts, and proportion of pts achieving complete response (CR) or CR with incomplete blood count recovery (CRi) per modified IWG 2003 criteria in AML pts. Other endpoints include safety, time to response, overall survival and PD-1/PD-L1 activity. Pts will be followed every 3 months until discontinuation. Target enrollment is 182 pts: 72 MDS pts and 110 AML pts. Enrollment began in June 2016 (ClinicalTrials.gov NCT02775903).
Phase 2 study of the safety and efficacy of INCB050465 in patients with relapsed or refractory (R/R) diffuse large b-cell lymphoma (DLBCL) (CITADEL-202).
Authors: Coleman Morton , Forero-Torres Andres , Ribrag Vincent , Chau Ian , DeMarini Douglas James , Zinzani Pier Luigi
Published: September 2018

TPS7579

Background: Aberrant activation of PI3Kδ is implicated in B-cell malignancies. INCB050465, a highly selective PI3Kδ inhibitor, is demonstrating preliminary efficacy in an ongoing phase 1/2 dose-escalation and expansion study as monotherapy for r/r DLBCL as well as for other r/r B-cell malignancies (ASH 2016; Abstract 4195). This phase 2 study will further evaluate the efficacy and safety of single-agent INCB050465 in pts with r/r DLBCL. Methods: In this phase 2, multicenter, open-label study (NCT02998476), eligible adults will have r/r DLBCL diagnosis, defined as receiving 1–5 prior treatments and be ineligible for high-dose chemotherapy or autologous stem-cell transplant (SCT). Pts will also have ≥1 measurable lesion (nodal ≥2 cm or extranodal > 1 cm in longest dimension); Eastern Cooperative Oncology Group performance status ≤2; adequate hematologic, hepatic, and renal function; no mediastinal large B-cell lymphoma or CNS metastases; no allogeneic SCT ≤6 months, or graft-versus-host-disease after allogeneic SCT, or autologous SCT ≤3 months, before first dose; and no prior treatment with PI3K inhibitors. Pts will be enrolled into 2 groups according to prior treatment with a Bruton’s tyrosine kinase (BTK) inhibitor (Group A [n = 100, no BTK inhibitor] or B [n≤20, received BTK inhibitor]). Both groups will receive INCB050465 20 mg orally QD for 8 wks; then 20 mg QW until disease progression, death, unacceptable toxicity, or consent withdrawal. The primary endpoint is the objective response rate in Group A (complete/partial response per independent review committee based on Lugano criteria). Secondary endpoints will include duration of response, progression-free survival, overall survival, and safety in Group A (these endpoints will be exploratory in Group B). Other exploratory assessments will include pharmacokinetics and association between genetic characteristics and treatment response in both groups. In a planned interim futility analysis of Group A, the study will be terminated if ≤13 of the first 40 treated pts respond (no futility analysis of Group B will be conducted). The study is currently recruiting (estimated completion date, March 2020). Clinical trial information: NCT02998476.
A phase II, open-label, multi-arm study of novel combinations of immunotherapies or DDR inhibitors in platinum-refractory, extensive disease small-cell lung cancer (ED-SCLC): BALTIC.
Authors: Von Pawel Joachim , Vynnychenko Ihor , Jiang Haiyi , Huang Yifan , Dennis Phillip A.
Published: September 2018

TPS8585

Background: The prognosis of platinum-refractory ED-SCLC is poor, with ~95% of pts failing to respond to topotecan, the only approved 2ndline treatment. SCLC is associated with a high mutation load and genomic instability, and data suggest that enhanced DNA repair could be a resistance mechanism. As such, immunotherapies and DNA damage repair inhibitors may be beneficial in this disease setting. Durvalumab (D) is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (T) is a selective human IgG2 mAb against CTLA-4. In a Phase 1b study in NSCLC (NCT02000947), D + T showed encouraging activity and manageable tolerability. AZD1775 is a small-molecule inhibitor of the DNA damage checkpoint kinase WEE1 that potentiates genotoxic chemotherapies and is being developed for the treatment of advanced solid tumors with genetic deficiencies in DNA repair mechanisms. In a Phase 2 study in platinum-refractory p53 mutated ovarian cancer (NCT01164995), AZD1775 + carboplatin showed promising activity and an acceptable safety profile. Methods: BALTIC (NCT02937818) is a Phase 2, open-label, multicenter, multi-arm, exploratory, signal-searching study to assess the preliminary activity of novel treatment combinations in refractory ED-SCLC. Eligible pts will have progressed during, or within 90 days of completing 1st line platinum-based chemotherapy, and have life expectancy ≥8 wks. Each arm is independent and will open sequentially to enroll up to 20 pts. The study will open initially with 2 arms: D 1500 mg + T 75 mg i.v. q4w for 4 doses, followed by D monotherapy 1500 mg i.v. q4w (Arm A); and oral AZD1775 225 mg bid for 2.5 days from Day 1 + carboplatin AUC 5 on Day 1 i.v. q3w (Arm B). Pts will receive treatment until confirmed disease progression or discontinuation. Further arms may be added to assess other combinations once safe and tolerable doses and schedules have been established. The primary endpoint is investigator-assessed ORR (RECIST v1.1). Secondary endpoints include duration of response, disease control rate, time to response, PFS, OS, PK, safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT02937818.
A randomized phase II study of vemurafenib plus cobimetinib continuous versus intermittent in previously untreated BRAF V600-mutation positive patients with unresectable locally advanced or metastatic melanoma.
Authors: Lopez-Martin Jose A. , Berrocal Alfonso , González-Cao María
Published: September 2018

TPS9599

Background: Previous clinical trials have shown that vemurafenib significantly increases PFS and OS in untreated BRAFV600 mutant advanced melanoma patients. Nevertheless, disease progression occurs after a median of 6-7 months since start of vemurafenib. Several mechanisms of acquired resistance to vemurafenib result in reactivation of MAPK pathway. Upfront addition of a MEK inhibitor (MEKi) to vemurafenib delays secondary resistance to BRAFi. The combination of cobimetinib, a MEKi, plus vemurafenib as a continuous administration was approved by FDA in 2,015 in untreated metastatic BRAFV600 advanced melanoma patients based on an increase in PFS and OS achieved in a phase III trial (coBRIM trial). Preclinical models have shown that continuous vemurafenib dosing promotes the clonal expansion of drug-resistant cells, and intermittent dosing could serve to eliminate the fitness advantage of the resistant cells and delay the onset of drug-resistant disease (Das Thakur, Nature 2013). These observations and some clinical case reports support upfront evaluation of alternative dosing regimens of MAPK pathway inhibition. Methods: This is a randomized phase II study to explore the efficacy and safety of two schedules of administration of vemurafenib in combination with cobimetinib (continuous – 28-day cycles with vemurafenib 960 mg PO BID, Days 1-28, and cobimetinib 60 mg PO QD, Days 1-21 – and intermittent – same dose/schedule during first 12 weeks, and then, same doses with the following schedule: vemurafenib 4 weeks on /2 weeks off, and cobimetinib 3 weeks on/ 3 weeks off), in patients with untreated, BRAFV600 mutated, unresectable, measurable (RECIST 1.1), locally advanced or metastatic melanoma. Prior adjuvant immunotherapy is allowed. Primary endpoint is PFS. Secondary endpoints include: OS, ORR, pharmacokinetic and pharmacodynamic profiles and safety. Additional translational research to analyze predictive factors and mechanism of resistance will be explored. The trial is in progress; 56 of up to 116 planned pts have been recruited at the end of December 2016 (enrollment started in June 2015). Clinical trial information: NCT02583516.
FGF controls epithelial-mesenchymal transitions during gastrulation by regulating cell division and apicobasal polarity
Authors: Sun Jingjing , Stathopoulos Angelike
Published: September 2018

To support tissue and organ development, cells transition between epithelial and mesenchymal states. Here we investigated how mesoderm cells change state in Drosophila embryos and whether fibroblast growth factor (FGF) signaling plays a role. During gastrulation, presumptive mesoderm cells invaginate, undergo an epithelial-to-mesenchymal state transition (EMT) and migrate upon the ectoderm. Our data show that EMT is a prolonged process in which adherens junctions progressively decrease in number throughout the mesoderm cells’ migration. FGF influences adherens junction number and promotes mesoderm cell division, which we propose decreases cell-cell attachments to support slow EMT while retaining collective cell movement. We also found that, at the completion of migration, cells form a monolayer and undergo a reverse mesenchymal-to-epithelial transition (MET). FGF activity leads to accumulation of beta-integrin Myospheroid basally and cell polarity factor Bazooka apically within mesoderm cells, thereby reestablishing apicobasal cell polarity in an epithelialized state in which cells express both E-Cadherin and N-Cadherin. In summary, FGF plays a dynamic role in supporting mesoderm cell development to ensure collective mesoderm cell movements as well as proper differentiation of mesoderm cell types.