Ongoing Clinical Trials最新文献

{"title":"Abstract OT2-04-05: Phase II trial of pre-operative stereotactic ablative radiotherapy (SABR) in early-stage breast cancer","authors":"C. Liveringhouse, R. Diaz, K. Ahmed, Marie Catherine Lee, B. Czerniecki, C. Laronga, N. Khakpour, R. Weinfurtner, M. Rosa, M. Montejo","doi":"10.1158/1538-7445.SABCS18-OT2-04-05","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-04-05","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79607558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT2-07-09: A phase Ib study of neratinib, pertuzumab, and trastuzumab with paclitaxel in patients with metastatic and locally advanced breast cancer","authors":"A. Al-Awadhi, M. Kono, An Marx, Tanya W. Moseley, J. Willey, Huiying Sun, M. Fu, G. Whitman, V. Valero, N. Ueno, B. Lim","doi":"10.1158/1538-7445.SABCS18-OT2-07-09","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-07-09","url":null,"abstract":"Background: Neratinib, a potent irreversible pan-ErbB tyrosine kinase inhibitor that blocks signal transduction through HER1, HER2, and HER4, has demonstrated activity against metastatic HER2-positive breast cancer (HER2+ BC) in patients pretreated with trastuzumab. The FDA recently approved neratinib as an adjuvant treatment for HER2+ BC patients who have received trastuzumab for at least 1 year. Preclinical data demonstrate that trastuzumab-resistant BC cells remain sensitive to neratinib. Also, neratinib enhances responses to trastuzumab possibly by increasing trastuzumab9s internalization, immune-mediated action, and other mechanisms. Taken together, these findings provide the rationale for adding neratinib to the standard of care combination of trastuzumab and pertuzumab with paclitaxel to enhance anti-HER2 efficacy in advanced HER2+ BC. Here, we report on the phase Ib portion of an ongoing phase Ib/II trial of this drug combination. Trial Design: Patients with metastatic or locally advanced HER2+ BC will be enrolled in the phase Ib portion of the trial. Neratinib is given orally in 3-week cycles. The initial neratinib dose of 80 mg daily is increased to 120, 160, and 200 mg daily after safety assessments of each dose level. Other agents are administered as per the standard of care. Patients continue therapy with per-protocol dose escalation and de-escalation according to toxicity until the maximum tolerated dose (MTD) of neratinib is reached. The target maximum dose-limiting toxicity rate is 20%. All patients receive 4 cycles of the combination therapy. If patients do not have disease progression or excessive toxicity, they may receive 2-4 additional cycles at the treating physician9s discretion. During therapy, patients undergo blood tests every week and have clinical visits and restaging scans every 3 weeks. Because gastrointestinal toxicity, mainly diarrhea, is anticipated, patients receive prophylactic antidiarrheal medication (e.g., loperamide, budesonide) beginning with the first dose of neratinib. Eligibility Criteria: Eligible patients must have histologically confirmed metastatic or locally advanced HER2+ BC (BC may be inflammatory or non-inflammatory and have any hormone receptor status); an ECOG performance status score of 0 or 1; and adequate hematologic and organ function, including adequate cardiac function (as indicated by a left ventricle ejection fraction of ≥50%). Specific Aims: 1- To determine the MTD of neratinib in combination with paclitaxel, pertuzumab, and trastuzumab. 2- Pharmacodynamic markers will be measured on biologic specimens. Neratinib-induced changes in pEGFR and/or HER2 expression will be analyzed and compared between dose levels. Statistical Methods: The Bayesian modified toxicity probability interval is used to determine dose adjustment. Accrual: The target enrollment for the phase Ib cohort is 20 patients. The trial has enrolled 3 patients since its activation in January 2018. This trial is supported by","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"30 5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82979732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT1-01-03: The WinPro study: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer","authors":"Emma Carson, D. Segara, A. Parker, S. O'toole, A. Coates, B. Mann, G. Lindeman, W. Tilley, E. Lim","doi":"10.1158/1538-7445.sabcs18-ot1-01-03","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-ot1-01-03","url":null,"abstract":"Background There is bidirectional interplay between PR and ER in human breast cancers (Lim et al, Endo Rel Can 2016). There is evidence for a reprogramming of ER chromatin binding sites with 470 genes differentially regulated by dual treatment with estrogen plus progestogen compared to estrogen alone in breast cancer cell lines (Mohammed et al, Nature 2015). Functionally, there was an additive anti-cancer effect with the addition of natural progesterone to endocrine therapy in preclinical breast cancer models. Trial Design This is a phase II multi-site, randomised, open-label, three-arm, study in 200 postmenopausal women with early-stage ER+, PR+, HER2-negative breast cancer. Eligible patients will be randomised 1:1:1 to receive 14 days of intervention with either letrozole 2.5mg PO daily (arm 1), letrozole 2.5mg + prometrium 300mg PO daily (arm 2) or tamoxifen 20mg + prometrium 300mg PO daily (arm 3), between diagnosis of breast cancer and definite surgery. Australian Clinical Trials Registry: ACTRN1261800092813 Eligibility Criteria Inclusion Criteria a) Histologically confirmed ER+ and PR+ breast cancers (≥10% positive staining cells) b) HER2/CEP17 ratio of c) Tumour size ≥1cm on ultrasound and/or mammogram d) Aged ≥18 years Exclusion Criteria a) Currently on hormone therapies (HRT and OCP) b) Locally advanced/inoperable and inflammatory breast cancer c) Clinical evidence of metastatic disease d) Received other preoperative systemic therapies e) Nut allergy (prometrium contains peanut oil) f) Prior history of uterine cancer, deep vein thrombosis, pulmonary embolism or clotting disorder g) Women who are pregnant/breast feeding Specific Aims a) Primary Endpoint The geometric mean suppression of the centrally assessed proliferation marker Ki67, after two weeks of intervention, compared with baseline. This will be obtained by comparing the mean difference in Ki67 staining between pre and post-treated samples in each intervention arm. b) Secondary Endpoint Safety and tolerability of combination therapy (NCI-CTCAE v4.0) c) Translational Endpoints 1. Define a gene set as a predictive biomarker for a reduction in Ki67 2. Evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumors following intervention 3. Evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumors following intervention Statistical Methods The IMPACT study reported a geometric mean reduction in Ki67 after 2 weeks of preoperative tamoxifen of 59.5% and anastrazole of 76% (Dowsett et al, JNCI 2007). This allows estimation of power to detect differences between Arm 1 and either Arm 2 or Arm 3 with a p-value of 0.025. For the third possible comparison of Arm 2 vs Arm 3, there is no prior evidence, therefore this as a purely exploratory comparison. With a total trial recruitment of 200 and allowing 4% dropouts, this would give 80% power to detect an improvement in Ki67 suppression from 76% in the letrozole alone control arm to 92% in either exp","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82374933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT1-12-03: RESCUE: Reaching for Evidence-baSed Chemotherapy Use in Endocrine sensitive breast cancer - A prospective health care study on risk assessment by the clinicomolecular test EndoPredict®and long-term patient outcome in early luminal breast cancer","authors":"J. Ettl, J. Blohmer, C. Denkert, M. Keller, E. Klein, R. Kronenwett, P. Neuser, S. Paepke, C. Schade-Brittinger, K. Schnuppe, M. Untch, M. Wittenberg, M. Kiechle","doi":"10.1158/1538-7445.SABCS18-OT1-12-03","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT1-12-03","url":null,"abstract":"Background: In node negative and 1-3 positive nodes breast cancer patients with hormone receptor positive (HR+), HER2-negative (HER2-) early-stage breast cancer the indication for chemotherapy is based on clinical and pathologic risk stratification (tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67). For further decision-making, the EndoPredict test, which combines a molecular signature with the clinical risk factors tumor size and nodal status, stratifies patients into “low risk\" or “high risk” groups. Level I-B- evidence demonstrates, that EndoPredict predicts the 10 year cumulative risk of relapse and metastases in patients with HR+/HER2- primary breast cancer with endocrine treatment. Aim: In the RESCUE-Trial we document distant metastasis-free survival (DMFS), disease free survival (DFS) and overall survival (OS) events in patients who had an EndoPredict test. The primary objective is to show that 10-year DMFS of patients tested as “low risk” by EndoPredict and treated with adjuvant endocrine therapy alone is >90 %. Secondary endpoints among others include DMFS, DFS, OS in patients with EPclin “low risk” versus “high risk”. Also the proportion of patients whose treatment was concordant and non-concordant with EndoPredict test results, will be analyzed for survival. The prognostic performance of classical prognostic factors (like tumor size, nodal status, grading, quantitative ER, progesterone receptor and Ki67 level) with respect to survival will also be assessed. Eligibility: Patient with HR+/HER2- primary invasive breast cancer stage I/II and T1 to T3 with 0 to 3 positive lymph nodes will be eligible, if they had an EndoPredict test within three months before inclusion. Methods: The EndoPredict test results, tumor board decision and anti-tumor therapy will be assessed. After one year, annually (for 10 years), patients will be evaluated for treatment compliance, recurrence, metastases, and survival. The primary endpoint will be analyzed by a Kaplan-Meyer estimate for which a one-sided lower 95 % confidence interval will be given. Several secondary endpoints will be assessed in three interim analyses after completion of the 1st, 3rd, 5th year and then finally after 10 years. Accrual: Start of accrual is planned for July 2018. At least 26 sites in Germany and one site in Switzerland will be active. Sponsor: The study is sponsored by the North-Eastern-German Society of Gynecological Oncology (NOGGO) e.V. Contact Information: For further information, contact NOGGO via studies@noggo.de or the leading physician Dr. Johannes Ettl via johannes.ettl@tum.de. Citation Format: Ettl J, Blohmer J-U, Denkert C, Keller M, Klein E, Kronenwett R, Neuser P, Paepke S, Schade-Brittinger C, Schnuppe K, Untch M, Wittenberg M, Kiechle M. RESCUE: Reaching for Evidence-baSed Chemotherapy Use in Endocrine sensitive breast cancer - A prospective health care study on risk assessment by the clinicomolecular test EndoPredict® and long-ter","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"06 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85944706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT3-03-02: A phase 2, open-label, single-arm, multi-center study of talazoparib for neoadjuvant treatment of germlineBRCA1/2mutation patients with early-stage triple-negative breast cancer (TNBC)","authors":"J. Litton, F. Symmans, K. Gogineni, M. Saltzman, M. Telli, L. Usha, J. Chakrabarti, I. C. Tudor, R. Quek, A. Czibere","doi":"10.1158/1538-7445.SABCS18-OT3-03-02","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-03-02","url":null,"abstract":"Background: Approximately 15% of all breast cancers are triple negative and deleterious BRCA1/2 mutations are found in ˜11% of unselected TNBC. In the phase 3 EMBRACA trial (NCT01945775), the poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib was superior to chemotherapy in prolonging progression-free survival in BRCA1/2 mutation patients with advanced breast cancer. A recent pilot study (NCT02282345) of 20 patients, explored the feasibility of neoadjuvant talazoparib in BRCA1/2 mutation patients; pathologic complete response (pCR) was reported at 53% with 6 months of single agent talazoparib. Trial Design: This phase 2, single-arm, open-label, multi-center study has a Simon 2-stage design. Eligible pts have stage I-III invasive TNBC (ER and PR Funding: This study is sponsored by Pfizer, Inc. Citation Format: Litton J, Symmans F, Gogineni K, Saltzman M, Telli ML, Usha L, Chakrabarti J, Tudor IC, Quek RG, Czibere A. A phase 2, open-label, single-arm, multi-center study of talazoparib for neoadjuvant treatment of germline BRCA1/2 mutation patients with early-stage triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-03-02.","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83630423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT3-08-01: A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer","authors":"A. Chung, J. Ensor, Jorge Darcourt, A. Belcheva, T. Patel, Jenny C. Chang, P. Niravath","doi":"10.1158/1538-7445.SABCS18-OT3-08-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT3-08-01","url":null,"abstract":"Triple negative breast cancer (TNBC) is an aggressive disease that currently lacks an efficacious form of therapy. Although chemotherapy is the current standard of care for metastatic TNBC, the 5-year prognosis remains grim with a high rate of disease recurrence. Cancer relapse is thought to be initiated by chemotherapy-resistant breast cancer stem cells (BCSCs). These BCSCs give rise to a diverse clonal population that results in a heterogeneous cancer, which complicates targeted therapeutic strategies. Our previous studies revealed that BCSCs utilize inducible nitric oxide synthase (iNOS)-derived nitric oxide to promote their proliferation, migration, and self-renewal capacity. In an effort to target the BCSC population, we found that iNOS inhibition with NG-monomethyl-L-arginine (L-NMMA) sensitized BCSCs to docetaxel in vivo in TNBC xenograft models, leading to decreased BCSC viability and tumor burden. These findings suggest that BCSC resist conventional therapy in a nitric oxide-dependent manner and that combination of L-NMMA with docetaxel will effectively target BCSCs to prevent further relapse. A phase Ib/II clinical trial was conducted to determine the maximum tolerated dose, recommended phase 2 dose (R2PD), dose-limiting toxicities (DLTs), and efficacy of the L-NMMA and docetaxel combination in TNBC patients with chemotherapy-refractory locally advanced or metastatic disease. For the phase Ib portion of the study, a standard Bayesian continual reassessment method is being used to investigate 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg) and two dose levels of docetaxel (75 and 100 mg/m2). Sixteen patients have been recruited to date, and based on current pharmacokinetics, pharmacodynamics, and safety data, the RP2D is expected to be docetaxel 100 mg/m2 (Day 1) and L-NMMA 20 mg/kg (Days 1-5) every 3 weeks. Two and three patients received 15 mg/kg L-NMMA + 75 mg/m2 docetaxel and 17.5 mg/kg L-NMMA + 100 mg/m2 docetaxel, respectively. Of these 5 patients, one partial responder completed 8 cycles before discontinuing treatment due to taxane-associated neuropathy. Among the five patients treated at the RP2D, only one taxane-associated DLT occurred. The overall response rate for patients treated at the higher doses was 22.2%. Early results of the phase Ib/II trial indicate the safety, tolerability, and promising activity of the first-in-class pan-NOS inhibitor L-NMMA in combination with chemotherapy in the treatment of chemotherapy-refractory TNBC. Citation Format: Chung AW, Ensor JE, Darcourt J, Belcheva A, Patel T, Chang JC, Niravath PA. A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-08-01.","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"112 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88070736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT3-02-05: CORALLEEN: A phase 2 clinical trial of chemotherapy or letrozole plus ribociclib as neoadjuvant treatment for postmenopausal patients with luminal B/HER2-negative breast cancer","authors":"J. Gavilá, C. Saura, M. Oliveira, E. Ciruelos, X. Gonzàlez, L. Peña, B. Heras, M. Muñoz, P. Fernandez, P. Villagrasa, V. Ortega, R. Lopez, Pamela Céliz, T. Pascual, A. Prat","doi":"10.1158/1538-7445.sabcs18-ot3-02-05","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-ot3-02-05","url":null,"abstract":"Background: Dysregulation of cyclin D-CDK4/6-Rb pathway is associated with endocrine resistance in hormone receptor–positive (HR+) breast cancer. Recently, a CDK4/6 inhibitor has shown unprecedented efficacy in metastatic disease, leading to its regulatory approval. Several others are currently in clinical development for the management of HR+ breast cancer in the early and advanced settings. However, it is vital to gain insights into the molecular and biological effects of this class of agents and could identify patients who can benefit the most, delaying or avoiding the use of chemotherapy.The neoadjuvant setting provides an ideal scenario to carry out these investigations. Hence, we propose to conduct an exploratory study to evaluate the biological effects and the efficacy of ribociclib in patients with primary luminal B tumors. We hypothesize that the combination of ribociclib plus letrozole may offer clinical benefit in the preoperative setting. Methods: This is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable HR+/HER2-negative Luminal B breast cancer designed to evaluate the clinical benefit of ribociclib plus letrozole. Eligibility includes stage I-III operable breast cancer, Luminal B by PAM50, ECOG 0-1. They will be randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy: four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens will be collected for molecular characterization and evaluation of response (decrease in Ki67, change to ROR low disease) The primary endpoint is the rate of Residual Cancer Burden (RCB) per MD Anderson Cancer Center procedures. A rate of RCB 0 and 1 score at surgery, with a rank between 20% to 25% with 47 evaluable patients by group of treatment will offer a precision between 11.5% and 12.4%, respectively (95%CI). Ninety-four patients will be enrolled in 21 sites across Spain. The trial was activated in July 2017. As of June 2018, 78 patients have been recruited. Citation Format: Gavila J, Saura C, Oliveira M, Ciruelos E, Gonzalez X, de la Pena L, Bermejo de las Heras B, Munoz M, Fernandez P, Villagrasa P, Ortega V, Lopez R, Celiz P, Pascual T, Prat A. CORALLEEN: A phase 2 clinical trial of chemotherapy or letrozole plus ribociclib as neoadjuvant treatment for postmenopausal patients with luminal B/HER2-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-05.","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89146122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT2-07-06: Antibody-coupled T cell receptor (ACTR) engineered autologous T cells in combination with trastuzumab for the treatment of HER2-positive malignancies","authors":"Katie O'Callaghan, John H. Shin, A. Cheung, Tooba A. Cheema, Casey Judge, A. Ranger, Heather A. Huet, S. Ettenberg, J. Sachs, M. Vasconcelles, Greg T. Motz","doi":"10.1158/1538-7445.SABCS18-OT2-07-06","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-07-06","url":null,"abstract":"Antibody-Coupled T cell Receptor (ACTR) is an autologous engineered T cell therapy developed to combine with tumor-targeting antibodies to exert potent anti-tumor immune responses and tumor cell killing. The ACTR construct is composed of the extracellular domain of CD16 fused to CD3ζ signaling and T cell co-stimulatory domains. ACTR-expressing T cells are universal in that they can be paired with a therapeutic antibody to target specific antigens on tumors. Unum has two ACTR constructs, ACTR087 and ACTR707, currently in clinical testing. ACTR087 and ACTR707 are being tested in combination with rituximab in subjects with CD20+ B cell lymphoma in two separate trials (NCT02776813 and NCT03189836, respectively). Preliminary data with ACTR087 + rituximab has demonstrated clinical proof-of-concept and a dose-response relationship in subjects with relapsed/refractory B cell lymphoma. ACTR087 is also being tested in combination with a novel BCMA-targeting antibody in subjects with multiple myeloma (NCT03266692). While T cell therapies, such as chimeric antigen receptor (CAR) T cells, have demonstrated clinical activity in hematological cancers, the therapeutic potential of this approach has yet to be established in solid tumors. Challenges associated with targeting solid tumors with CAR-T cells include tumor antigen heterogeneity and antigen expression on normal tissues. HER2 is a well-established therapeutic target that is over-expressed in a number of cancer indications. HER2 is also expressed at low levels on normal epithelial cells, creating a risk for on-target/off-tumor toxicities of HER2-targeted CAR-T cells. Here we present nonclinical studies demonstrating that ACTR T cells in combination with trastuzumab have antigen density-dependent activity on HER2-expressing tumor cell lines, while trastuzumab-based CAR-T cells do not. We observed that ACTR + trastuzumab had robust activity against HER2-amplified tumor cells and more modest activity against non-amplified tumor cells, whereas HER2-targeting CAR-T cells had comparable activity against HER2-amplified and non-amplified tumor cells. On normal human primary cells, ACTR + trastuzumab had minimal activity in comparison to HER2 CAR-T cells, suggesting that ACTR + trastuzumab may exhibit a superior clinical therapeutic index. Furthermore, the activity of ACTR T cells against HER2-amplified tumor cells was titratable with antibody concentration, allowing for control of ACTR activity by modulation of trastuzumab concentration. Together, these data demonstrate the specificity of the ACTR T cell therapeutic approach to target HER2-amplified tumors and support clinical testing in combination with trastuzumab. A phase 1, multicenter, single-arm, open-label dose escalation study, ATTCK-34-01, is proposed to evaluate ACTR T cells in combination with trastuzumab in subjects with advanced HER2-positive malignancies. The primary study objectives are to assess the safety and tolerability of the combination, and ","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79544334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT2-08-01: Personalized breast cancer screening in a population based study: Women Informed to Screen Depending On Measures of risk (WISDOM)","authors":"I. Acerbi, Yiwey Shieh, L. Madlensky, J. Tice, E. Ziv, M. Eklund, Amie M. Blanco, D. DeRosa, B. Tong, D. Goodman, L. Nassereddine, N. Anderson, H. Harvey, T. Layton, H. Park, Antonia Petruse, S. Stewart, J. Wernisch, L. Risty, B. Koenig, S. Sarrafan, R. Firouzian, C. Kaplan, R. Hiatt, B. Parker, Neil S. Wenger, Vivian Lee, D. Heditsian, S. Brain, A. Fiscalini, A. Borowsky, H. Anton-Culver, A. Naeim, A. Kaster, M. Talley, L. V. Veer, Andrea Z. LaCroix, L. Esserman, Wisdom Study, Advocate Partners","doi":"10.1158/1538-7445.sabcs18-ot2-08-01","DOIUrl":"https://doi.org/10.1158/1538-7445.sabcs18-ot2-08-01","url":null,"abstract":"","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77151247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract OT2-07-01: DETECT V/CHEVENDO – Comparison of dual HER2-targeted therapy with trastuzumab plus pertuzumab in combination with chemo- or endocrine therapy in addition with CDK4/6 inhibition in patients with HER2-positive and hormone-receptor positive metastatic breast cancer","authors":"Sabrina Krause, T. Friedl, T. Fehm, T. Romashova, P. Fasching, A. Schneeweiss, V. Müller, F. Taran, A. Polasik, M. Tzschaschel, A. D. Gregorio, F. Meier-Stiegen, W. Janni, J. Huober","doi":"10.1158/1538-7445.SABCS18-OT2-07-01","DOIUrl":"https://doi.org/10.1158/1538-7445.SABCS18-OT2-07-01","url":null,"abstract":"Background: Metastatic breast cancer (MBC) is usually an incurable disease and maintenance of quality of life (QoL) is one of the main aims of therapy. In patients with HER2-positive MBC taxane-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab and pertuzumab,is the standard of care. Adverse events are well-known side effects of any cytostatic treatment and can seriously impact the patients9 QoL. The synergistic combination of dual HER2-targeted therapy with trastuzumab and pertuzumab plus endocrine therapy might offer a better treatment option for these patients. First clinical trials suggest an additional benefit when a CDK4/6 inhibitor is added to the combination of endocrine therapy and anti HER2 treatment. DETECT V is a randomized phase III study comparing the safety and efficacy of trastuzumab plus pertuzumab and the CDK 4/6 inhibitor ribociclib in combination with either endocrine therapy or chemotherapy. Trial design: Patients with HER2 positive and hormone-receptor positive MBC are 1:1 randomized to receive trastuzumab and pertuzumab combined with endocrine therapy and ribociclib or to chemotherapy with trastuzumab and pertuzumab followed by maintenance therapy with trastuzumab, pertuzumab, endocrine therapy and ribociclib. Chemotherapy and the endocrine agents can be chosen from a variety of available regimens according to the physicians discretion. Specific aims: The primary objective of this study is to compare safety and tolerability in both arms, as assessed by the occurrence of AEs during the treatment period. Secondary endpoints are progression free survival, overall survival, quality-adjusted survival using the quality-adjusted time without symptoms and toxicity (Q-TWiST) method. A translational program is included investigating detection and phenotyping of circulating tumor cells (CTC)-and the assessment of marker expression on CTCs in order to validate an endocrine responsiveness score. Present accrual and target accrual: The DETECT V trial started 2015 in the Dept. of Gynecology, University of Ulm and at the up to 120 sites in Germany. Until June 2018 97 patients with HER2-positive, hormone-receptor positive metastatic breast cancer have been enrolled. A sample size of 270 patients is planned. Contact information: Jens Huober, University of Ulm, Dept of Gynecology, Breast Center, jens.huober@uniklinik-ulm.de Sabrina Krause, University of Ulm, Dept of Gynecology, sabrina.krause@uniklinik-ulm.de Citation Format: Krause S, Friedl T, Fehm T, Romashova T, Fasching PA, Schneeweiss A, Muller V, Taran F-A, Polasik A, Tzschaschel M, De Gregorio A, Meier-Stiegen F, Janni W, Huober J. DETECT V/CHEVENDO – Comparison of dual HER2-targeted therapy with trastuzumab plus pertuzumab in combination with chemo- or endocrine therapy in addition with CDK4/6 inhibition in patients with HER2-positive and hormone-receptor positive metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cance","PeriodicalId":19476,"journal":{"name":"Ongoing Clinical Trials","volume":"564 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77255540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}