bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 first-in-human study of ABBV-184 monotherapy in adult patients with previously treated acute myeloid leukemia or non-small cell lung cancer.
Authors: Avigdor Abraham , Peterlin Pierre , Yuda Junichiro , Moskovitz Mor Tal , Gabrail Nashat Y. , Moshe Yakir , Quesnel Bruno , Henner William R , Reilly Edward B. , Huang Donghui , Kovalenko Maria , Parikh Apurvasena , Jaryno Stacy , Leibman Rachel S , Freise Kevin J , Saada-Bouzid Esma , Shimizu Toshio
Published: June 2021

TPS2674

Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive therapeutic target in cancer, due to its broad expression in solid tumors and hematologic malignancies but limited expression in normal tissues. Elevated survivin expression is associated with an increased invasive phenotype and worse clinical outcomes. ABBV-184 is a first-in-class T-cell receptor (TCR)/anti-cluster of differentiation 3 (CD3) bispecific molecule. It is composed of a soluble TCR that binds to a survivin-derived peptide bound to the class I MHC allele HLA-A2:01 expressed on tumor cells and to the CD3 receptor on T cells. Preclinical data have demonstrated that treatment with ABBV-184 results in T-cell activation, proliferation, and redirected cytotoxicity of HLA-A2:01–positive target cell lines. This first-in-human trial evaluates ABBV-184 monotherapy in patients with previously treated acute myeloid leukemia (AML) or non-small cell lung cancer (NSCLC). Methods: Patients (≥18 years, Eastern Cooperative Oncology Group performance status ≤2, HLA-A2:01 restricted genotype) with relapsed or refractory AML or NSCLC are currently enrolling in this phase 1 multicenter, open-label trial (NCT04272203), which includes parallel dose-escalation and dose-expansion phases for both diseases. Primary objectives are to determine the recommended phase 2 dose (RP2D) of ABBV-184 (dose escalation) and to assess its preliminary efficacy (dose expansion). Secondary objectives include safety, tolerability, pharmacokinetics (PK), and immunogenicity assessments (dose escalation and dose expansion) and duration of response (dose expansion). Patients will receive intravenous infusion of ABBV-184 once weekly. Dose escalation of ABBV-184 is guided by a Bayesian optimal interval design and the RP2D will be determined on the basis of clinical safety, PK, and pharmacodynamic data. For patients with AML, disease assessment is performed according to modified European LeukemiaNet-International Working Group criteria. For patients with NSCLC, response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune RECIST. Treatment can continue until disease progression or intolerable toxicity. Biomarker assessments will include longitudinal profiling of peripheral blood immune cells and cytokines, analysis of HLA-A2 and survivin levels on AML bone marrow blasts and NSCLC tumor biopsies, and retrospective correlations of biomarker data with antitumor activity. Enrollment initiated in Sep 2020, with 7 patients enrolled as of Jan 2021. Clinical trial information: NCT04272203.
BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Grothey Axel , Yaeger Rona , Ciardiello Fortunato , Desai Jayesh , Kim Tae Won , Maughan Tim , Van Cutsem Eric , Wasan Harpreet Singh , Yoshino Takayuki , Edwards Michelle L. , Golden Adele , Gollerkeri Ashwin , Tabernero Josep
Published: June 2021

TPS3619

Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). 1L tx options for BRAFV600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR, or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cetux is approved for tx of BRAFV600E mCRC after prior therapy. In BEACON CRC, enco + cetux resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAFV600E mCRC (median follow-up: 12.8 months); 57.4% of pts had grade 3/4 adverse events (AEs); 9% discontinued due to AEs. Given the poor prognosis of pts with BRAFV600E mCRC and based on the efficacy and tolerability of enco + cetux from BEACON CRC, BREAKWATER will evaluate efficacy and safety of enco + cetux ± chemotherapy in tx-naive pts with BRAFV600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have BRAFV600E mCRC (determined using tumor tissue or blood); ECOG performance status 0/1; and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen; those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 6 January 2021. Clinical trial information: NCT04607421. [Table: see text]
EORTC 1707 VESTIGE: Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1)—An open-label randomized controlled phase II study.
Authors: Smyth Elizabeth Catherine , Peeters Ellen , Knoedler Maren Kristina , Giraut Anne , Wagner Anna Dorothea , Moehler Markus H. , van Grieken Nicole C.T. , Nilsson Magnus , Mauer Murielle E. , Lordick Florian
Published: June 2021

TPS4156

Background: Gastroesophageal adenocarcinoma (GEA) patients with metastatic lymph nodes (ypN+) or a microscopically incomplete surgical resection (R1) following neoadjuvant chemotherapy are at high risk of disease recurrence. Current practice is to continue with the same perioperative chemotherapy used prior to surgery, despite these suboptimal outcomes. Adjuvant immunotherapy with nivolumab has shown efficacy in poor risk GEA patients following chemoradiotherapy and surgery in the CheckMate 577 trial, and nivolumab and ipilimumab have demonstrated activity in advanced GEA. We hypothesise that high risk (ypN+ and/or R1) post resection GEA patients who are treated with nivolumab and ipilimumab will have better disease free survival than patients who continue with standard post-operative chemotherapy. Methods: VESTIGE is an ongoing, international, open label randomized phase II study designed to evaluate the efficacy of adjuvant nivolumab plus ipilimumab versus standard post-operative chemotherapy in high risk (ypN+ and/or R1) post resection GEA patients. Eligible patients (n=240) will be randomised 1:1 to receive post-operative adjuvant chemotherapy (identical regimen as pre-operatively) or nivolumab 3mg/kg IV q2w plus ipilimumab 1mg/kg IV q6w x 1 year. Key inclusion criteria include ypN+ and/or R1 status following neoadjuvant chemotherapy plus surgery and an adequate pre-specified surgical resection. The primary endpoint of the study is disease free survival, with secondary endpoints of overall survival, safety, toxicity and quality of life. Since start of recruitment in August 2019, the trial has recruited 85 of 240 patients at 18 sites in the Czech Republic, France, Germany, Israel, Italy, Norway, Poland, Spain, and United Kingdom. The VESTIGE translational research programme includes collection of pre-treatment biopsies, post-chemotherapy resection specimens and serial liquid biopsy on treatment to explore biomarkers predictive of immune checkpoint blockade efficacy. Clinical trial information: NCT03443856.
Camrelizumab combined with ablation and chemotherapy for pancreatic cancer with liver metastases: A single-arm, phase II, prospective clinical study.
Authors: Li Zhiwei , Li Qingwei , Ma Zhigang , Ma Yue , Su Dan , Lou Changjie , Wang Guangyu , Liu Chao , Zhang Yanqiao
Published: June 2021

TPS4169

Background: Pancreatic cancer represents one of the most aggressive tumors and the majority of patients receive a diagnosis of metastatic disease, mainly in the liver, leading to poor prognosis and survival. Currently, chemotherapy has been the treatment of choice for fit patients with pancreatic cancer liver metastases (PCLM), reaching a median survival of about 5 to 7 months. In addition, local ablation of the metastatic tumors, by increasing neoantigen exposure and transforming the immune microenvironment to reduce the progression of liver metastases, might increase the survival benefit of patients. Camrelizumab, an anti-PD-1 monoclonal antibody, has obtained preliminary results in metastatic pancreatic cancer. Therefore, this study aims to explore the effectiveness and safety of camrelizumab combined with ablation and chemotherapy in the treatment of PCLM. Methods: In this single-arm, prospective, phase II study, 34 patients with histological or cytological diagnosis of PCLM, ECOG performance score of 0-1, no prior chemotherapy or the interval of adjuvant chemotherapy ≥6 months, plan to be enrolled. The enrolled patients first received ablation surgery of liver metastases, then chemotherapy (the standard regimen for advanced pancreatic cancer, determined by the investigator) combined with camrelizumab (200 mg, iv, q3w) is administered 1 week after ablation. If the patient has multiple metastatic tumors, the ablation needs to be performed in stages. The treatment regimens will continue until the disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint is 6-month progress-free survival (6-month PFS) rate (per RECIST v1.1 by researcher). Secondary endpoints are objective response rate, disease control rate, progression-free survival, overall survival and safety. On the basis of a threshold 6-month PFS rate of 25%, targeting an expected 6-month PFS rate of 44% and assuming 18 months follow-up, 80% power and a one-sided α = 0.05, this design requires 34 evaluable patients to be accrued over 2 years. Clinical trial information: NCT04420130.
A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI study) (NCT03483038).
Authors: Rogers Sherise C. , Ramnaraign Brian Hemendra , Hitchcock Kathryn , Hughes Steven J. , Lee Ji-Hyun , Fan Z. Hugh , Allegra Carmen Joseph , Trevino Jose , El-Far Ahmad , Turk Anita Ahmed , Russell Karen Bullock , DeRemer David L. , George Thomas J.
Published: June 2021

TPS4170

Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. NCT03483038. NALIRIFOX regimen components given intravenously (IV) every 14 days. Clinical trial information: NCT03483038. [Table: see text]
AUREA study: Atezolizumab (Atezo) combined with split-dose gemcitabine plus cisplatin (s-GC) in locally advanced or metastatic urothelial cancer (LA/mUC): A SOGUG study.
Authors: Gomez De Liano Lista Alfonso , Anguera Georgia , Esteban Emilio , Fernandez Calvo Ovidio , García-Carbonero Iciar , Garcia del Muro Xavier , González Maeso Iria , Lorente-Estelles David , Martínez Ortega Esther , Pinto Alvaro , Puente Javier , de Velasco Guillermo
Published: June 2021

TPS4589

Background: First-line cisplatin-based chemotherapy (70 mg/m2) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky´s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression ≥5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age > 70 years, PS ECOG 0-2, creatinine Clearance >30 and <60 mL/min per Cockroft-Gault formula or by 24-hour urine collection. Other reasons for cisplatin ineligibility as considered by investigator, including those uncovered by Galsky´s criteria, will be allowed, prior discussion with PI. Exclusion criteria include prior systemic therapy for LA/mUC (adjuvant/neoadjuvant allowed if finished > 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078.
A phase I/II study of bintrafusp alfa and NHS-IL12 in combination with docetaxel in adults with metastatic castration sensitive (mCSPC) and castration-resistant prostate cancer (mCRPC).
Authors: Atiq Mohammad O. , Bilusic Marijo , Karzai Fatima , Cordes Lisa M. , Strauss Julius , Abdul Sater Houssein , Redman Jason , Floudas Charalampos S. , Hodge James W. , Gameiro Sofia , Figg William Douglas , Schlom Jeffrey , Dahut William L. , Gulley James L. , Madan Ravi Amrit
Published: June 2021

TPS5096

Background: Immune checkpoint inhibition is successful in a small subpopulation of men with prostate cancer. This could be related to barriers to immune response in the tumor microenvironment. Immunocytokines present an opportunity to specifically target the pleiotropic tumor microenvironment impacting immune cells beyond T-cells. NHS-IL12 is an immunocytokine that carries IL-12 (shown to impact natural killer and myeloid cells) and binds to necrotic tissue with exposed histones. Phase 1 studies have indicated immune and even PSA responses in prostate cancer to NHS-IL12 (Strauss J, CCR 2019). Preclinical data has demonstrated synergy with docetaxel, which is standard therapy in both mCSPC and mCRPC. Further synergy has been shown with a novel first-in-class bifunctional fusion protein (bintrafusp alfa) composed of the extracellular domain of human TGF-β receptor II (TGFβRII), which effectively functions to sequester or “trap” all three TGF-β isoforms (Lind H, JITC 2020), fused to a monoclonal antibody against PD-L1. This study will examine the potential of a novel combination of chemotherapy, checkpoint inhibition, and immunocytokines in metastatic prostate cancer. Methods: The study will evaluate safety of NHS-IL12 with docetaxel at escalating doses followed by the addition of bintrafusp alfa in all metastatic patients. Once safety of the combination is established, patients will enroll in 2 cohorts with either mCSPC or mCRPC. Eligible patients include mCSPC (≤134 days of starting ADT) and mCRPC (must have been previously treated with abiraterone or enzalutamide), with good performance status (ECOG of ≤ 2). Patients with brain metastases or who are immunocompromised are excluded. For mCSPC, the primary endpoint will evaluate the increase in the proportion of patients who have a PSA less than 0.2 ng/mL 7 months after the start of ADT, which is based on the prognostic value of PSA less than 0.2 ng/mL at 7 months in mCSPC (Harshman L, JCO 2017). The secondary endpoint is biochemical and radiographic time to progression. The primary endpoint for the mCRPC patients will evaluate progression free survival with secondary endpoints examining the percentage of patients with a 50% PSA decline from baseline and radiographic response rates per RECIST. Exploratory analysis will analyze changes in immune cell subsets after treatment as well as immune status of the tumor microenvironment. Clinical trial information: NCT04633252.
Identifying androgen receptor (AR) and genomic characteristics that define populations of patients with mHSPC who benefit from early PARP inhibition therapy with talazoparib.
Authors: Kasparian Saro , Burnham Leanne , Kittles Rick , Sun Zj , Bedell Fornati , Tran Justin , Li Min , Dorff Tanya B.
Published: June 2021

TPS5097

Background: A minority of men with mCRPC, those with DNA repair mutations, can benefit from PARP inhibitor therapy. In addition to DNA repair, PARP is used by cancer cells to interact with other cellular mechanisms including androgen receptors (AR). The next generation PARP inhibitor talazoparib can, in addition to inhibiting DNA repair, trap PARP, preventing it from carrying out its other functions. As progression in mHSPC is based on AR escape mechanisms, we predict that early exposure to PARP inhibition will delay progression. In addition, AR characteristics and function vary by ethnic populations. AR expression is inversely related with the number of polymorphic CAG repeats. As African American (AfrAm) men commonly have shorter CAG repeats in their AR, they may experience different response duration, but have been under-represented in clinical trials. Furthermore, CAG repeats may be associated with greater signaling through pathways such as wnt and Myc, which is associated with aggressive disease. Thus, studying intensified up-front therapy in a diverse prostate cancer population is a critical unmet need. Methods: 70 subjects will be treated with ADT + abiraterone + talazoparib. Outreach by our Division of Health Equities and accrual at community satellites located near diverse populations will be enlisted to accrue a target of 30% African American. Talazoparib will be dosed at 1mg daily (0.75 mg in renal insufficiency). LHRH and abiraterone formulations will be left to physician’s choice. PSA and safety labs will be checked every 4 weeks for the first 12 weeks. Imaging will be performed every 12 weeks for the first year then every 24 weeks if PSA is decreasing, or 12 weeks if rising. Data safety monitoring for toxicity after every 10 subjects have been accrued. Diversity of accrual will be evaluated after 30 subjects are enrolled; amendments will be made if the diversity goal is not achieved. Tissue genomics and ctDNA will be measured at baseline; ctDNA will be repeated after 4 weeks and at castration resistance. Endpoints: Primary: PSA nadir at 7 months has been found to be associated with overall survival and is achieved by 55% of men with mHSPC with ADT + abiraterone. With 70 subjects there is 97% power to confirm improved nadir rate of 75%, and 83% power to determine a nadir rate >70%. Secondary endpoints include objective response by RECIST 1.1 for subjects with measurable disease. radiographic progression free survival. Correlative objectives include comparing outcomes in subsets of men with high vs low number of AR CAG repeats, men with genomic alterations, and the change in ctDNA alteration fractions from baseline to 4 weeks and at progression. Progress: The trial is open to accrual as of Feb 2021. Sponsor: Pfizer/ Prostate Cancer Foundation RFP Clinical trial information: NCT04734730.
A randomized phase III, two-arm trial of paclitaxel, carboplatin, and maintenance letrozole versus letrozole monotherapy in patients with stage II-IV, primary low-grade serous carcinoma of the ovary or peritoneum.
Authors: Nickles Fader Amanda , Gien Lilian Tran , Miller Austin , Covens Al , Gershenson David Marc
Published: June 2021

TPS5601

Background: Low-grade serous carcinoma of the ovary or peritoneum (LGSOC) is a rare subtype of epithelial carcinoma. Differences in epidemiology, pathogenesis, disease presentation, and clinical outcomes have been characterized between women diagnosed with LGSOC and those with the p53-driven high-grade serous carcinoma (HGSOC). Ultimately, patients with LGSOC should be treated differently than those with HGSOC. Several studies suggest that LGSOC is relatively chemoresistant and that most tumors robustly express estrogen and progesterone receptors. Recently, retrospective reports suggest that utilization of the aromatase inhibitor, letrozole, as monotherapy or in addition to platinum/taxane-based chemotherapy in those with primary advanced-stage LGSOC results in preliminarily promising survival outcomes. Methods: This study is a two-arm, randomized, open-label, Phase III clinical trial. The primary objective is to assess whether letrozole monotherapy (2.5 mg po daily) is non-inferior to carboplatin (AUC 5-6) and paclitaxel (175 mg/m2) followed by letrozole maintenance therapy with respect to progression free survival in women with primary, Stage II-IV LGSOC who have undergone an attempt at maximal surgical cytoreduction. Secondary endpoints include incidence of adverse events, objective response rate in those with measurable disease after surgery, response duration, overall survival, and adherence to letrozole maintenance therapy. Study subjects must have undergone a bilateral salpingo-oophorectomy, and p53 IHC testing of tumors is required to rule out those with aberrant p53 expression commonly observed in HGSOC tumors. Study strata include residual disease status and country of enrollment. Four hundred and fifty patients will be enrolled in the United States, Canada and South Korea through the NRG Oncology trials network. Correlative aims include analyzing the association of ER/PR tumoral expression with aromatase inhibitor therapy response and determining ESR1 mutational status in those who develop letrozole resistance. The study includes two interim analyses; at 20% information time, a futility analysis will be conducted, and at 40% information time, both efficacy and futility will be assessed. This is one of the first randomized trials performed in women with primary, advanced LGSOC, and the study is open with 71 patients enrolled at the time of abstract submission. Clinical trial information: NCT04095364.
ALEXANDRA/IMpassion030: A phase 3 study of standard adjuvant chemotherapy with or without atezolizumab in patients with early-stage triple-negative breast cancer.
Authors: Saji Shigehira , McArthur Heather L. , Ignatiadis Michail , Bailey Andrew , El-Abed Sarra , Brandao Mariana , Metzger Otto , Lai Catherine , Guillaume Sebastien , Fumagalli Debora , Agbor-tarh Dominique , Seiller Aicha , Altarcheh Xifro Rosa , Honvault Vanessa , Viale Giuseppe , DuFrane Carter , Barata Teresa , Winer Eric P. , Gelber Richard D. , Piccart-Gebhart Martine J.
Published: June 2021

TPS597

Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. Because TNBC does not currently have specific targeted agents approved for use in the early setting, it is treated primarily with chemotherapy. TNBC may be more immunogenic than other subtypes of breast cancer. Atezolizumab (an anti–PD-L1 antibody), in combination with nab-paclitaxel has been approved in >70 countries for the treatment of PD-L1-positive unresectable locally advanced or metastatic TNBC based on the results of the randomized phase 3 IMpassion130 trial. The phase 3 IMpassion031 study, evaluating atezolizumab in combination with chemotherapy (nab-paclitaxel followed by doxorubicin and cyclophosphamide) in comparison to placebo plus chemotherapy as neoadjuvant treatment demonstrated a statistically significant and clinically meaningful improvement in pCR in both PD-L1 positive and PD-L1 negative tumors. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial currently investigating the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane adjuvant chemotherapy versus chemotherapy alone in early stage TNBC. Methods: ALEXANDRA/IMpassion030 will randomize 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients are stratified by type of surgery, nodal status, and centrally assessed PD-L1 status. Adjuvant chemotherapy consist of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks or the same chemotherapy regimen (T-EC/AC) given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab. The primary endpoint is invasive disease-free survival (iDFS) and secondary endpoints include, iDFS in the PD-L1 selected tumour status (IC1/2/3) and node-positive subpopulations, overall survival, safety, patient functioning and health related quality of life (HRQoL). Tumor tissue and blood samples will be collected for biomarker research. The first site was activated on May 4 2018, and approximately 373 sites in 30 countries are currently participating in this trial. This trial is sponsored by F. Hoffmann-La Roche Ltd and conducted in partnership with the Breast International Group, Frontier Science and Technology Research Foundation, Institute Jules Bordet and Alliance Foundation Trials. Clinical trial information: NCT03498716.
V2 Trial: A phase I study of venetoclax and CPX-351 for young patients with relapsed/refractory acute leukemia.
Authors: Agresta Laura , O'Brien Maureen Megan , O'Brien Eric Justin , Norris Robin Elizabeth , Breese Erin Haag , Burns Karen Cristly , Mizukawa Benjamin , Ryan Thomas D , Desai Pankaj B , Vinks A.a. , Grimes H. Leighton , Absalon Michael , Perentesis John Peter
Published: June 2021

TPS7052

Background: Despite significant advances in therapy for acute myeloid leukemia (AML), 30-40% of young patients will relapse, after which prognosis is poor. In young patients, curative-intent salvage therapy involves intensive re-induction followed by hematopoietic stem cell transplant. Recently, the COG Phase II study of CPX-351 (liposomal cytarabine:daunorubicin, Vyxeos™) in pediatric patients with AML in first relapse (NCT02642965) demonstrated a CR/CRi rate of 81.3%. Separately, our first-in-pediatrics CPX-351 Phase I (NCT01943682) showed 48% in a heavily pre-treated pediatric cohort with multiply relapsed and refractory (R/R) AML. Our integrated pilot study of single cell RNA sequencing (scRNA-seq) done before, during, and after CPX-351 showed p53 targets over time with enrichment for genes regulating apoptosis (ex.: FAS, BAX), suggesting blasts may be primed for apoptosis following CPX-351. Venetoclax is a small molecule inhibitor of the anti-apoptotic protein BCL-2, a regulator of apoptotic balance in some leukemias. Based on our preclinical data, we developed a Phase I study to investigate venetoclax with CPX-351 for the treatment of young patients with R/R acute leukemias. Methods: The V2 Trial (NCT03826992) is a single-institution Phase I study to evaluate the safety and tolerability of venetoclax with CPX-351 in patients ages 1-39 years with R/R acute leukemias. Inclusion diagnoses include AML, mixed phenotype acute leukemia (MPAL), KMT2A-rearranged acute lymphoblastic leukemia (ALL), and T-ALL. Exclusion criteria include CNS status 3, bone marrow failure syndromes, and prior cardiotoxic exposures above acceptable risk thresholds. Subjects receive a single course of CPX-351 at the FDA approved adult dose on Days 1, 3, 5 with concurrent daily venetoclax. In the dose exploration phase, venetoclax dosing is 400 mg daily (or allometrically-scaled equivalent) for 21 (Dose Level 0) or 14 days (Dose Level -1) using a rolling 6 design. Primary endpoints are determination of the recommended phase 2 dose of venetoclax in combination with CPX-351 and description of toxicities. Secondary endpoints include estimations of CR/CRp/CRi +/- MRD negativity in the context of a phase I study and evaluation of therapy-related cardiac dysfunction. Correlative studies include analysis of venetoclax pharmacokinetics with concomitant CPX-351. At the initial dose level, DLT were encountered and the study is now continuing enrollment at Dose Level -1. Clinical trial information: NCT03826992.
A phase 3, randomized, double-blind, placebo-controlled study of ruxolitinib plus parsaclisib in patients with JAK- and PI3K-inhibitor treatment-naïve myelofibrosis.
Authors: Yacoub Abdulraheem , Erickson-Viitanen Susan , Zhou Feng , Assad Albert
Published: June 2021

TPS7058

Background: Ruxolitinib (JAK1/JAK2 inhibitor) significantly improves outcomes in patients with myelofibrosis (MF); however, a subset of patients may experience a suboptimal response. Recent phase 2 data showed that addition of PI3Kδ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub. EHA2020. S216). This phase 3, randomized, double-blind study (INCB 50465-313; NCT04551066), evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naïve to Janus kinase (JAK) and PI3K inhibitor therapies. Methods: Eligible patients are aged ≥18 years with a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) risk category of at least Intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin; total symptom score ≥10 at screening, ECOG PS 0–2, and life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF ≤3 months of first study dose and/or lack of recovery from all toxicities related to previous therapies to grade ≤1, have recent history of inadequate bone marrow reserve (eg, platelet count = 50×109/L) or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg QD or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×109/L vs 50 to = 100×109/L inclusive). Treatment will begin on Day 1, with starting ruxolitinib dose level determined by baseline platelet count, and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to crossover to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at Week 24 for patients who received ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability for ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Sites are opening across the United States, Europe, Asia, and New Zealand. Clinical trial information: NCT04551066.
A phase III clinical trial of adjuvant chemotherapy versus chemoimmunotherapy for stage IB-IIIA completely resected non-small cell lung cancer (NSCLC) patients nadim-adjuvant: New adjuvant trial of chemotherapy versus chemoimmunotherapy.
Authors: Calvo Virginia , Domine Manuel , Sullivan Ivana , Gonzalez-Larriba Jose-Luis , Ortega Ana Laura , Bernabé Reyes , Sala Maria Angeles , Campos Begona , De Castro Javier , Martín-Martorell Paloma , Bosch-Barrera Joaquim , Mielgo Xabier , Vilà Laia , Casal Joaquin , Ros Silver , Martinez Aguillo Maite , Padilla Airam , Sandiego Sergio , Aires Machado Jonathan , Provencio-Pulla Mariano
Published: June 2021

TPS8581

Background: The results of current studies are considered acceptable evidence to support the hypothesis of efficacy of the proposed combination of immunotherapy with chemotherapy (CT-IO) in patients with NSCLC stages Ib-IIIA candidates for adjuvant treatment. Methods: This is an open-label, randomised, two-arm, phase III, multi-centre clinical trial. Primary objective and endpoint: The primary objective is disease free survival (DFS) defined time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time Sample size: 210 patients NSCLC stages Ib-IIIA (Experimental Arm (Adjuvant Chemotherapy-Inmunotherapy + maintenance adjuvant Inmunotherapy): 105 patients, Control Arm (Adjuvant Chemotherapy): 105 patients Treatment Patients randomised to the experimental arm will receive Nivolumab 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 4 cycles every 21 days (+/- 3 days) as adjuvant treatment followed by maintenance adjuvant treatment for 6 cycles with Nivolumab 480 mg Q4W (+/- 3 days). Patients randomized to the control arm will receive Paclitaxel 200mg/m2 + Carboplatin AUC5 for 4 cycles every 21 days (+/- 3 days) followed by 2 observation visits. Total trial duration: 6.5 years, 3.5 years of recruitment, 1 year of adjuvant treatment or observation and 2 years of follow up. The start date was January 2021. The estimated primary completion date is June 2027. Clinical trial information: NCT04564157.
Blood-based biomarker analysis in high PD-L1 expressing NSCLC treated with PD-1/PD-L1 based therapy with or without the addition of platinum-based chemotherapy.
Authors: Fidler Mary J. , Villaflor Victoria Meucci , Rao Amol , Halmos Balazs , Bertino Erin Marie , Osarogiagbon Raymond U. , Carbone David Paul
Published: June 2021

TPS9126

Background: Immunotherapy directed against the programmed death-1 / ligand-1 (PD-1/L1) axis has revolutionized the treatment of advanced non-small cell lung cancer (aNSCLC). Tumor PD-L1 is currently the only biomarker validated for predicting patient response to front line PD-1/L1 directed immunotherapy, yet 20% of patients with ≥50% PD-L1 expression die within six months of starting therapy (Reck et al. 2016). Blood-based agents such as autoantibodies and circulating inflammatory biomarkers have stratified patient outcomes on anti-PD-1/L1 immunotherapy in preliminary studies (Tarhoni, Kollipara et al. 2019; Tarhoni, Fidler et al. 2019). Moreover, a serum-based proteomic test that uses mass spectrometry and machine learning to provide three classifications (Good, Intermediate and Poor) has stratified non-treatment naïve aNSLCC patients treated with nivolumab based on their outcomes (Mueller et al. 2020) and identified a subset of patients who progressed rapidly. This study will evaluate these blood-based biomarkers as predictors of response and early progression in patients with >50% PD-L1 positive aNSCLC treated with immunotherapy regimens. Methods: This is a prospective, observational, multicenter study (NCT04676386) designed to assess biomarkers (serum and plasma) as predictive of early progression in 390 patients with aNSCLC treated with anti-PD 1/PD-L1 immunotherapy with or without platinum-based chemotherapy. Key eligibility criteria are treatment naïve aNSCLC with tumor biopsy PD-L1 tumor proportion score > 50%, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and ability to consent to participate. Prior to enrollment, tumor specimens will be tested for PD-L1 expression according to participating centers’ standard operating procedures. For each treatment cohort of 195 patients, enrollment will proceed in sub-cohorts to ensure a population with 20% patients with ECOG PS2 and a total of 40 patients with squamous cell carcinoma per treatment arm. Patients will be followed for a maximum of 3 years. Blood draw for biomarker assessment will be performed prior to treatment initiation, start of 3rd cycle and investigator assessed progression. Biomarker analysis will be performed retrospectively. As a secondary objective, this study will evaluate proteomic test performance in predicting early overall survival (OS) and rapid progression, and in stratifying patient survival and response. Exploratory analyses will correlate baseline and serial circulating protein analytes and autoantibodies with the proteomic test, response measures (RECIST 1.1) and toxicities. Enrollment opened in February 2021. Clinical trial information: NCT04676386.
NCT04552223: A phase II study of nivolumab plus BMS-986016 (relatlimab) in patients with metastatic uveal melanoma (UM) (CA224-094).
Authors: Lutzky Jose , Feun Lynn G. , Magallanes Norma , Kwon Deukwoo , Harbour J. William
Published: June 2021

TPS9590

Background: Uveal melanoma (UM) is a rare disease but 50% of patients will eventually develop metastatic disease, for which not effective therapy is available. Liver-directed therapies, immunotherapy, targeted therapy and chemotherapy have limited activity [1]. Lymphocyte activation gene 3(LAG-3) is an immune checkpoint receptor associated with decreased T-cell effector function and tumor escape. Preclinical models have shown that dual inhibition of LAG-3 and PD-1 blockade generates synergistic anti-tumor activity [2]. Recent preclinical data indicates that uveal melanoma CD8+ T cells express the checkpoint receptor LAG3 to a greater extent than PD1 or CTLA4 [3,4]. Therefore, LAG3 is a potential candidate for checkpoint inhibitor immunotherapy in UM. Relatlimab is a human LAG-3-specific antibody isolated from immunized transgenic mice which binds to a defined epitope on LAG-3 with high affinity and specificity and potently blocks the interaction of LAG-3 with its ligand, MHC Class II. Methods: This is an open-label, single arm, single site investigator-initiated phase II study, NCT04552223. Based on Simon two-stage minimax design, 13 patients will be enrolled in Stage 1. If at least one response is noted, the study will proceed to Stage 2 and enroll an additional 14 patients. The null hypothesis will be rejected if 4 or more responses are observed among 27 patients. This design achieves 5% type I error and 80% power when the true ORR is 20%. The trial opened to accrual in December 2020. As of February 15, 2021 four patients had been enrolled the first stage of accrual. Main eligibility criteria include patients with biopsy proven metastatic uveal melanoma, previously untreated with PD-1, CTLA-4 and/or LAG-3 blocking antibodies and in good performance status. Enrolled patients are treated in the outpatient setting. Nivolumab 480 mg is mixed in the same bag with relatlimab 160 mg and administered intravenously over 60 minutes every 4 weeks until disease progression or intolerable toxicity for up to 24 months. The primary endpoint is best objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), median duration of response (mDOR), and adverse events (AEs). Correlative studies will evaluate pre- and post-treatment characteristics of T cells in the tumor microenvironment and blood. Clinical trial information: NCT04552223.
Phase I/II trial of intratumoral administration of hu14.18-IL2, with local radiation, nivolumab, and ipilimumab in subjects with advanced melanoma.
Authors: Albertini Mark R. , Morris Zachary Scott , Hank Jacquelyn A , Ranheim Erik , Zuleger Cindy L , McDowell Kimberly , Quale Renae M , Monson Molly , Clements Erin , Koehn Tamara , Neuman Heather B. , Weber Sharon M. , Racz Jennifer , Henry Mary Beth , Reinstad Emily , Kim KyungMann , Gillies Stephen D. , Sondel Paul M.
Published: June 2021

TPS9591

Background: We are studying an intratumoral (IT) in situ vaccine strategy using the GD2-reactive hu14.18-IL2 immunocytokine (hu-IC) to convert the injected tumor into a site of enhanced tumor antigen presentation, as has been shown in mice. Hu-IC is a humanized monoclonal antibody (mAb) covalently linked to two molecules of IL-2 at the Fc region. The hu14.18 mAb recognizes GD2, a disialoganglioside found in tumors of neuroectodermal origin. We previously studied intravenous (IV) hu-IC and reported immune activation and reversible toxicities (1). Surgery to resect recurrent stage III or stage IV melanoma combined with 3 courses of IV hu-IC resulted in prolonged tumor-free survival in some patients (2). Murine GD2+ tumor models showed enhanced antitumor activity and recruitment of T cells using hu-IC IT versus IV (3). In these models, the combination of radiation therapy (RT) followed by IT hu-IC dramatically potentiates the antitumor response and enhanced response to immune checkpoint blockade (4). Biological samples (blood and tumor) will be interrogated to identify biological mechanisms and develop biomarkers for future testing. Methods: This outpatient phase I/II trial uses a 3 + 3 design to determine maximum tolerated or maximum administered dose of IT hu-IC (planned dose level: 2 mg/m2/day; de-escalation dose level: 1 mg/m2/day) when given alone (Phase 1A: 3-12 patients), after RT (Phase 1B: 6-12 patients), after RT and in combination with nivolumab (Phase 1C: 6-12 patients), and after RT and in combination with nivolumab and ipilimumab (Phase 1D: 31-34 patients). The trial will evaluate safety, antitumor activity, and immunologic endpoints and includes an expanded Phase II cohort (Phase 1D). The IT injections (once daily x 3 days) are delivered every 21 days for 4 cycles and can then continue every 28 days for up to 13 cycles if there is response/stable disease and residual injectable tumor. Key inclusion criteria: 1) histologically proven, malignant melanoma that is advanced (Stage IV) or surgically incurable; 2) at least 1 (preferably 2) sites of disease amenable to safe repeated IT injections; and 3) must have received or declined at least one FDA approved therapy, either in the adjuvant setting or for metastatic disease, with an impact on survival. Two subjects have been accrued into Phase IA as of 2-4-2021. References: (1)King DM, et al. J Clin Oncol 22:4463-4473, 2004. (2)Albertini MR, et al. Can Imm Imm 67(10):1647-1658, 2018. (3)Yang RK, et al. J of Imm 189:2656-2664, 2012. (4)Morris ZS et al. Can Res 76:3929-3941, 2016. Clinical trial information: NCT03958383.
Current and Future Management of HER2-Positive Metastatic Breast Cancer
Authors: Martínez-Sáez Olga , Prat Aleix
Published: June 2021

Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 20% of breast cancers, conferring an aggressive tumor behavior but also an opportunity for targeted therapies. In the advanced setting, the prognosis of patients suffering from this disease has greatly improved after the introduction of new anti-HER2 drugs beyond trastuzumab. For most patients, a taxane combined with trastuzumab and pertuzumab in the first-line setting, followed by trastuzumab-emtansine in second line, should be considered the standard of care today. However, chemo-free anti-HER2 strategies in hormone receptor-positive, HER2-positive breast cancer could also be considered in selected patients. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In addition, new compounds and combinations are showing promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, active drugs such as pertuzumab and trastuzumab-emtansine are moving to early-stage, many biomarkers, including quantification of HER2 itself, are being explored to improve patient selection, and patient populations with specific needs are emerging, such as those with brain metastasis. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer.
Examination of the Igls Criteria for Defining Functional Outcomes of β-cell Replacement Therapy: IPITA Symposium Report
Authors: Landstra Cyril P , Andres Axel , Chetboun Mikael , Conte Caterina , Kelly Yvonne , Berney Thierry , de Koning Eelco J P , Piemonti Lorenzo , Stock Peter G , Pattou François , Vantyghem Marie-Christine , Bellin Melena D , Rickels Michael R
Published: June 2021

Context

The Igls criteria were developed to provide a consensus definition for outcomes of β-cell replacement therapy in the treatment of diabetes during a January 2017 workshop sponsored by the International Pancreas & Islet Transplant Association (IPITA) and the European Pancreas & Islet Transplant Association. In July 2019, a symposium at the 17th IPITA World Congress was held to examine the Igls criteria after 2 years in clinical practice, including validation against continuous glucose monitoring (CGM)-derived glucose targets, and to propose future refinements that would allow for comparison of outcomes with artificial pancreas system approaches.

Evidence acquisition

Utilization of the criteria in various clinical and research settings was illustrated by population as well as individual outcome data of 4 islet and/or pancreas transplant centers. Validation against CGM metrics was conducted in 55 islet transplant recipients followed-up to 10 years from a fifth center.

Evidence synthesis

The Igls criteria provided meaningful clinical assessment on an individual patient and treatment group level, allowing for comparison both within and between different β-cell replacement modalities. Important limitations include the need to account for changes in insulin requirements and C-peptide levels relative to baseline. In islet transplant recipients, CGM glucose time in range improved with each category of increasing β-cell graft function.

Conclusions

Future Igls 2.0 criteria should consider absolute rather than relative levels of insulin use and C-peptide as qualifiers with treatment success based on glucose assessment using CGM metrics on par with assessment of glycated hemoglobin and severe hypoglycemia events.