bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of larotrectinib for children with newly diagnosed solid tumors and relapsed acute leukemias harboring TRK fusions: Children’s Oncology Group study ADVL1823.
Authors: Laetsch Theodore Willis , Ludwig Kathleen , Barkauskas Donald A. , DuBois Steven G. , Ronan Joan , Rudzinski Erin R. , Memken Amanda , Sorger Joel , Reid Joel M. , Bhatla Teena , Nesin April , Crompton Brian D. , Church Alanna J. , Fox Elizabeth , Weigel Brenda 
Published: May 2020

TPS10560 Background: In children, fusions of the NTRK1/2/3 genes (TRK fusions) occur in soft tissue sarcomas, including infantile fibrosarcoma (IFS), congenital mesoblastic nephroma, high- and low-grade gliomas, secretory breast carcinoma, and papillary thyroid cancer. Rarely, TRK fusions also occur in Ph-like acute lymphoblastic leukemia and acute myeloid leukemia. Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion solid tumors in patients with no satisfactory alternative treatments or whose cancer has progressed following initial treatment. In children, larotrectinib demonstrated a 94% overall response rate (ORR) with a 12-month progression free survival rate of 75% (1). Methods: Patients <30 years with any newly diagnosed unresectable solid tumor or relapsed/refractory acute leukemia with TRK fusions are eligible. TRK fusions must be locally identified in a CLIA/CAP laboratory and are confirmed centrally using a targeted RNA sequencing panel. Patients with high-grade gliomas are excluded. Patients receive larotrectinib 100 mg/m2/dose BID (max of 100 mg/dose) continuously in 28-day cycles. Patients with solid tumors who achieve CR will discontinue larotrectinib at the completion of at least 12 total cycles of therapy and 6 cycles after achieving CR. Those whose tumors become surgically resectable may undergo on study resection and discontinue therapy if an R0/R1 (IFS) or R0 (other tumors) resection is obtained. All other patients will receive 26 cycles in the absence of unacceptable toxicity or progressive disease. The primary endpoint is the ORR to larotrectinib according to RECIST 1.1 in children with IFS. The study uses a Simon 2-stage minimax design, and the regimen will be considered of sufficient interest if 16 of 21 (76%) patients with IFS demonstrate response. Patients with other solid tumors and leukemias will be analyzed in separate cohorts as secondary objectives. Correlative studies include serial sampling of circulating tumor DNA and neurocognitive assessments. This is the first Children’s Oncology Group study to assign frontline therapy based on the presence of a molecular marker independent of histology, and the first clinical trial to evaluate larotrectinib for the treatment of leukemia. Enrollment began in October 2019 (NCT03834961). 1. Tilburg CMv, DuBois SG, Albert CM, et al: Larotrectinib efficacy and safety in pediatric TRK fusion cancer patients. Journal of Clinical Oncology 37:10010-10010, 2019 Clinical trial information: NCT03834961.
Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with pembrolizumab in patients with advanced/metastatic breast or non-small cell lung cancer (NSCLC): A phase Ib, multicenter, study.
Authors: Borghaei Hossein , Besse Benjamin , Bardia Aditya , Mazieres Julien , Popat Sanjay , Augustine Bincy , D'amelio Anthony Michael , Barrios Daniel , Rugo Hope S. 
Published: May 2020

TPS1100 Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and potent topoisomerase I inhibitor. In a phase II trial in patients (pts) with heavily pretreated, metastatic HER2+ breast cancer (BC), T-DXd had a confirmed objective response rate (cORR) of 60.9% (112/184) and median progression-free survival (PFS) of 16.4 mo (Modi N Engl J Med 2019); these results led to the recent FDA approval for HER2+ unresectable or metastatic BC after ≥ 2 prior anti-HER2 based regimens. For HER2-low BC and HER2-expressing/mutated NSCLC, no HER2-directed therapies have been approved. In a phase I trial of T-DXd in pts with HER2-low BC or HER2-expressing/mutated NSCLC, cORR was 44.2% (19/43) (Modi SABCS 2018), and 55.6% (10/18) (Tsurutani Thorac Oncol 2018), respectively. In preclinical models, T-DXd combined with an anti–PD-1 antibody was more effective than monotherapy with either agent (Iwata Mol Cancer Ther 2018). Here we describe a phase Ib study of T-DXd in combination with pembrolizumab in pts with locally advanced/metastatic HER2-expressing BC or HER2-expressing/mutated NSCLC (DS8201-A-U106; NCT04042701). Methods: This is an open-label, multicenter, nonrandomized, multidose, 2-part study in adult (aged ≥18 y) pts in the United States and Europe. In part 1 (dose escalation), pts received T-DXd 3.2 or 5.4 mg/kg IV q3w and pembrolizumab 200 mg IV q3w to determine the recommended dose for expansion (RDE). The RDE will be given to 4 cohorts (part 2): 2 cohorts with BC (HER2+ [IHC 3+ or IHC 2+/ISH+] with progression on prior T-DM1; and HER2-low [IHC 1+ or IHC2+/ISH-] with progression on prior standard treatments) and 2 cohorts with NSCLC (anti–PD-1, –PD-L1, and -HER2 treatment naive either HER2-expressing [IHC ≥ 1+] or HER2-mutated). Enrollment began in February 2020 with approximately 115 to 133 pts planned to be enrolled at 5 sites for part 1 and expanding to 25 sites for part 2. The primary endpoint in part 1 is dose-limiting toxicities. The part 2 primary efficacy endpoint is cORR by independent central review (ICR) per RECIST 1.1. Additional endpoints include duration of response, disease control rate, and progression-free survival by ICR, overall survival, safety, and pharmacokinetics. Clinical trial information: NCT04042701 .
SGNLVA-001: A phase I open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer.
Authors: Beckwith Heather Christine , Medgyesy Diana Cristina , Abraham Jame , Nanda Rita , Tkaczuk Katherine H. R. , Krop Ian E. , Pusztai Lajos , Modi Shanu , Mita Monica M. , Specht Jennifer M. , Hurvitz Sara A. , Han Hyo S. , Kalinsky Kevin , Wilks Sharon , O'Shaughnessy Joyce , Hart Lowell L. , Rugo Hope S. , Mitri Zahi Ibrahim , Garfin Phillip M. , Burris III Howard A. 
Published: May 2020

TPS1104 Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Clinical trial information: NCT01969643 .
Phase II trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies.
Authors: Tolaney Sara M. , Cicin Irfan , Betancourt Rafael , Chan Arlene , Kaen Diego , Kaufman Peter A. , Delaloge Suzette , Liu Qianying , Cartot-Cotton Sylvaine , Amrate Amele , Pelekanou Vasiliki , Cuff Katharine Ellen 
Published: May 2020

TPS1107 Background: Endocrine therapy (ET) targeting ER signaling is the mainstay of care for ER+ metastatic BC. There remains an unmet need in patients (pts) whose tumors become resistant to currently available ET. Selective ER degraders (SERDs) were developed to overcome resistance to existing ER-directed therapies by both competitively antagonizing and degrading ERs, while exploiting continued dependence of the tumor on ER signaling. SAR439859 is a potent SERD with robust preclinical ER degrading activity. In a Phase I dose escalation trial, SAR439859 demonstrated a favorable safety profile with no dose-limiting toxicities across all doses (20–600 mg QD). ER occupancy generally exceeded > 87% with plasma concentrations > 100 ng/mL. Overall response rate was 6.3% and clinical benefit rate was 50% (Campone. SABCS 2019. P5-11-02). The recommended Phase II monotherapy dose was 400 mg QD. Methods: This international, prospective, open-label, randomized Phase II study (NCT04059484; ACT16105) assesses safety and efficacy of SAR439859 in pts with ER+ (> 1%)/HER2- metastatic or locally advanced BC progressing on ≥ 6 months of continuous ET (0–2 lines in the metastatic setting). Prior CDK inhibitors are allowed. Exclusion criteria include Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, life expectancy < 3 months, > 1 chemotherapy or targeted therapy in the metastatic setting, concomitant illness and factors potentially affecting SAR439859 absorption. Pts are randomized 1:1 to SAR439859 400 mg QD orally or physician’s choice of endocrine monotherapy (fulvestrant, tamoxifen, aromatase inhibitor). Pts receive 28-day cycles until unacceptable toxicity, progression, death, investigator decision or pt request. Stratification factors include visceral metastases, prior CDK4/6 inhibitors, and ECOG PS. Primary endpoint is progression-free survival (RECIST v1.1). Secondary endpoints include overall survival, response rate, duration of response, clinical benefit, pharmacokinetics, quality of life and safety. Target enrollment: n = 282; current enrollment: n = 9. Funding: Sanofi Clinical trial information: NCT04059484 .
A phase II trial of atezolizumab (anti-PD-L1) with carboplatin in patients with metastatic triple-negative breast cancer (mTNBC).
Authors: Lander Eric Michael , Lehmann Brian David , Shah Payal D , Dees Elizabeth Claire , Ballinger Tarah Jean , Pohlmann Paula Raffin , Santa-Maria Cesar Augusto , Shyr Yu , Mayer Ingrid A. , Park Ben Ho , Pietenpol Jennifer A. , Abramson Vandana G 
Published: May 2020

TPS1112 Background: Patients with metastatic triple negative breast cancer (mTNBC) have limited treatment options. Recent studies with a PD-L1 inhibitor and taxane based chemotherapy have demonstrated an increase in median progression free survival (PFS) in mTNBC. While taxanes target microtubules, platinum agents directly alkylate DNA and may generate additional neoantigens to enhance anti-tumor immunity via immune checkpoint inhibition. In this study, we are evaluating the combination of carboplatin with and without atezolizumab in patients with mTNBC. Serial biopsies are poised to help elucidate biological differences in responders and nonresponders. As optimal timing of adding checkpoint inhibition to chemotherapy is debatable, the randomized, crossover design will give insight into whether priming mTNBCs with DNA damaging chemotherapy results in cellular and immune changes that lead to a greater likelihood of response. Methods: This is a randomized phase II multicenter study at seven sites within the Translational Breast Cancer Research Consortium (TBCRC). Patients with mTNBC, ECOG 0-1, and 0-1 prior regimens for mTNBC are eligible. 106 patients will be randomized 1:1 to receive atezolizumab 1200 mg plus carboplatin AUC 6 (n = 53; Arm A) or carboplatin AUC 6 alone (n = 53; Arm B) every 3 weeks until intolerable toxicity or disease progression occurs. Patients receiving carboplatin alone have the option to cross over to atezolizumab upon progression (Arm Bx). Patients will undergo clinical assessment every cycle, and tumor assessment every 3 cycles with CT scan of the chest, abdomen, and pelvis and bone scan. Core biopsies of a metastatic lesion are performed at baseline and at progression. The primary endpoint is median progression free survival (PFS) with 95% confidence intervals based on RECIST 1.1. The sample size of 106 with 1:1 randomization is powered to detect a 1.5-month difference in PFS between arms (α = 0.10, β = 0.20). Secondary endpoints include overall response rate (ORR), duration of response (DOR), clinical benefit rate, and overall survival. The PFS, ORR, and DOR will also be measured by irRECIST to account for delayed effects of atezolizumab on tumor burden. The quantification of tumor infiltrating lymphocytes (TILs) will study the prognostic effects of TILs on PFS in patients receiving atezolizumab. Biopsy-derived PD-L1 expression by IHC and RNA-seq will assess treatment-induced changes, define triple-negative subtypes, and evaluate for resistance mechanisms. To date, 89 of 106 patients are enrolled. Clinical trial information: NCT03206203 .
Safety and activity of autologous T cells with enhanced NY-ESO-1–specific T-cell receptor (GSK3377794) in HLA-a*02+ previously-treated and -untreated patients with advanced metastatic/unresectable synovial sarcoma: A master protocol study design (IGNYTE-ESO).
Authors: D'Angelo Sandra P. , Blay Jean-Yves , Chow Warren Allen , Demetri George D. , Thistlethwaite Fiona , Sen Shiraj , Abdul Razak Albiruni Ryan , Haanen John B. A. G. , Noujaim Jonathan Christopher , Johnson Melissa Lynne , Laetsch Theodore Willis , Chiou Victoria L. , Pearce Laura , Faitg Thomas H. , Ji Ran , Johnson Laura A. , Shalabi Aiman M. , Thornton Katherine Anne , Mackall Crystal , Van Tine Brian Andrew 
Published: May 2020

TPS11571 Background: T cells modified to target NY-ESO-1 have shown encouraging activity in HLA-A*02+ patients with NY-ESO-1–positive synovial sarcoma. NY-ESO-1 is a cancer/testis antigen that is expressed across multiple tumor types and highly expressed in synovial sarcoma. NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR able to recognize NY-ESO-1 epitope in complex with HLA-A*02. Ongoing trials are evaluating GSK3377794 in multiple solid tumors and multiple myeloma. Methods: This study (NCT03967223) uses a Master Protocol design that allows investigation of GSK3377794 in multiple tumor types under the same protocol in separate substudies. The first two are single-arm substudies in patients with advanced metastatic or unresectable synovial sarcoma: treatment-naïve (1st line [1L], substudy 1; n = 10 planned) and progressing after anthracycline-based chemotherapy (2L+, substudy 2; n = 55 planned). Patients must be aged ≥10 years, have adequate organ function, ECOG performance status 0–1, measurable disease, and no central nervous system metastases. Excluded prior treatments include gene therapy with an integrating vector or NY-ESO-1–specific T cells, vaccine or targeting antibody, or allogeneic stem cell transplant. Patients will undergo leukapheresis and manufacture of GSK3377794; lymphodepletion then GSK3377794 infusion, followed by safety and disease assessments; and long-term follow-up for 15 years (under a separate protocol). The primary objective of substudy 2 is overall response rate per RECIST v1.1 by central independent review. Secondary objectives include time to response, duration of response, disease control rate, progression-free survival, overall survival, plus safety and tolerability. Exploratory objectives include assessment of the correlation of T-cell persistence with safety, clinical responses, and infused T-cell phenotype. Evaluation of quality of life and daily functioning of patients will also be assessed. Enrollment began in December 2019. These data are presented on behalf of the original authors with their permission. A similar presentation (P453) was presented at the SITC Annual Meeting, National Harbor, MD, USA, Nov 6–10, 2019. Funding: GlaxoSmithKline (208467) Clinical trial information: NCT03967223 .
BMX-HGG: Phase II trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.
Authors: Peters Katherine B. , Cohen Adam Louis , Butowski Nicholas A. , Villano John L. , Giglio Pierre , McGranahan Tresa , Zhang Chi , Cloughesy Timothy Francis , Herndon James Emmett , Healy Patrick , MacLeod David , Penchev Sara , Silberstein David , Batinic-Haberle Ines , Spasojevic Ivan , Gad Shayne , Radoff David , Barboriak Daniel , Crapo James 
Published: May 2020

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .
IPAX-1: Phase I/II study of 131I-iodo-phenylalanine combined with external radiation therapy as treatment for patients with glioblastoma multiforme.
Authors: Pichler Josef , Wilson Rosalind 
Published: May 2020

TPS2578 Background: Many tumor types, including glioblastoma multiforme (GBM), overexpress the L-type amino transporter 1 (LAT-1). 131I-iodo-phenylalanine (131I-IPA) is a small-molecule amino acid derivative taken up by LAT-1 with designated orphan status in the United States and European Union for the treatment of GBM. In preclinical research, combining 131I-IPA with external radiation therapy (XRT) yielded additive cytotoxic effects (Israel et al. Nucl Med Biol 2011). Tumor accumulation of 131I-IPA was shown in a proof-of-principle study (Baum et al. Nucl Med Mol Imaging 2011) and confirmed with single dosing of 2–7 GBq 131I-IPA in combination with XRT in patients with recurrent GBM (Verburg et al. Nuklearmedizin 2013). The 131I-IPA + XRT as Treatment for Patients with Glioblastoma Multiforme (IPAX-1) study evaluates the safety, tolerability, dosing schedule, and preliminary efficacy of 131I-IPA in combination with second-line XRT in patients with recurrent GBM. Methods: IPAX-1 is a multi-center, open-label, phase 1/2, dose-finding study recruiting patients with previously confirmed histological diagnosis of GBM and evidence of first recurrence. Other key inclusion criteria are history of GBM standard therapy, at least 6 months since end of first-line XRT, pathologically increased amino acid tumor uptake shown by molecular imaging, and current indication for repeat radiation. Participants receive intravenous 131I-IPA either as a single fraction (1f) followed by XRT, or as three equal fractions (3f) at weekly intervals followed by XRT commencing between the first and second 131I-IPA administration. The 1f regimen (n = 5) evaluates single administration of 2 GBq 131I-IPA. The 3f regimen is used to assess dose escalation, starting with 2 GBq (3 × 0.66 GBq; n = 5) and increasing in 2 GBq increments (n = 3 per activity level). The highest total dose planned is 8 GBq. XRT delivery is in 18 fractions (2 Gy each) on consecutive working days over 4 weeks. The study’s primary aim is to assess the safety and tolerability of 131I-IPA + XRT. Secondary objectives include evaluating the maximum tolerated dose of 131I-IPA, feasibility of fractionated administration, radiation absorbed dose to tumor and biodistribution; and exploring the antineoplastic effect of combination therapy. IPAX-1 enrollments began in July 2019; the study will enroll up to 44 patients and is currently recruiting at five sites in Europe and Australia. Clinical trial information: NCT03849105 .