bluuebunny/crossref_metadata_2025 huggingface dataset:
DSP-0390, an oral emopamil binding protein (EBP) inhibitor, in patients with recurrent high-grade glioma: A first-in-human, phase 1 study.
Authors: Reardon David A. , Narita Yoshitaka , Arakawa Yoshiki , Goldlust Samuel A. , Ansstas George , Mei Jian , Dow Edward , Seki Masataka , Furuta Yudai , Song Gregory , Colman Howard
Published: June 2022

TPS2077

Background: The brain’s cells are fully dependent on their own de novo biosynthesis of cholesterol as the blood-brain barrier prevents its uptake from the circulation. In normal glial cells, proper regulation of cholesterol synthesis depends on its cell density and is turned off when the cell density exceeds a certain level. On the other hand, gliomas maintain high levels of cholesterol synthesis to support abnormal growth under any condition. Upregulation of cholesterol synthesis genes is associated with decreased survival in patients with glioblastoma (GBM). Therefore, gliomas are potentially sensitive to cholesterol synthesis inhibition. DSP-0390, an investigational small molecule, is an inhibitor of EBP, an enzyme in one of the last and crucial steps of cholesterol biosynthesis. By inhibiting de novo cholesterol synthesis, cytotoxicity can be induced more selectively against hyperproliferative GBM cells. DSP-0390 has shown significant antitumor activity in orthotopic xenograft models of human GBM (data on file). Methods: DSP-0390 will be evaluated in a phase 1 study in patients with recurrent, high-grade glioma (NCT05023551). Key eligibility criteria: age ≥18 years; Karnofsky Performance Status score ≥70%; and adequate renal, hepatic, and hematologic function. Patients must not have multifocal disease, leptomeningeal metastasis or extracranial metastasis, abnormal electrocardiograms, or significant cardiovascular disease. In Dose Escalation, 21–30 patients with World Health Organization (WHO) grade III or IV malignant glioma who progressed after ≥1 prior therapy will be enrolled. Dose level enrollment will be guided by a Bayesian Logistic Regression Model until identification of the maximum tolerated dose or recommended dose for expansion. Dose Expansion for clinical activity will enroll approximately 20–40 patients with WHO grade IV GBM who progressed after primary therapy and have measurable disease. Patients will receive oral DSP-0390 once daily. Study endpoints include safety (treatment-emergent adverse events [AEs], serious AEs, and dose-limiting toxicities), efficacy (6-month progression-free survival [PFS], objective response, PFS, duration of response, and 12-month overall survival), pharmacokinetics (PK), and pharmacodynamic biomarkers. This study is currently recruiting in the United States and Japan. Clinical trial information: NCT05023551.
ZENYTH-ESO: Master protocol to assess the safety and recommended phase II dose of next generation NY-ESO-1-specific TCR T-cells in HLA-A*02 patients with synovial sarcoma and myxoid/round cell liposarcoma [Substudy 3, GSK4427296].
Authors: Araujo Dejka M. , Ladle Brian H. , He Kai , Powers Benjamin , McGillivray Amanda , Mitrica Ionel , Liu Wenlei , Patel Nitin , D'Angelo Sandra P.
Published: June 2022

TPS2681

Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing an affinity-enhanced T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapy, GSK4427296, utilizes the same TCR as lete-cel, as well as an epigenetic reprogramming process (Epi-R) developed by Lyell Immunopharma to alter the phenotypic T-cell profile of the manufactured product, and is intended to increase the proportion of cells with properties of durable stemness. T cells with properties of durable stemness are able to proliferate, persist, and self-renew with anti-tumor functionality. A first-time-in-human master protocol (NCT04526509) is underway to evaluate the safety, tolerability, and recommended phase II dose (RP2D) of next generation NY-ESO-1 TCR T-cell therapies. Substudy 3 is added to this master protocol to assess GSK4427296 in patients with advanced synovial sarcoma (SS) or myxoid/round cell liposarcoma (MRCLS). Methods: This substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage, aiming to dose 10 participants at the RP2D. Key inclusion criteria: age ≥18 years; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation or MRCLS with a translocation involving DDIT3 and/or FUS and/or EWSR1 genes; and anthracycline-based therapy receipt/completion/intolerance. Key exclusion criteria: prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene or allogenic stem cell/solid organ transplant; and central nervous system metastases. Primary endpoints: safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints: investigator-assessed overall response rate, duration of response, maximum transgene expansion (Cmax), Tmax, and AUC(0-t). Analyses will be descriptive. The master protocol is open for recruitment. Clinical trial information: NCT04526509.
Phase 1/2 dose escalation study of NUV-422, a potent inhibitor of cyclin-dependent kinases 2, 4, and 6, in recurrent or refractory (r/r) high-grade gliomas (HGG) and solid tumors.
Authors: Wen Patrick Y. , Rodon Ahnert Jordi , Powderly John D. , Colman Howard , Matheny Shannon L. , Golsorkhi Anthony A. , Bihani Teeru , Zhang Yan , Kaley Thomas Joseph
Published: June 2022

TPS3173

Background: CDKs that govern the G1-S transition of the cell cycle (CDK2, CDK4 and CDK6) are deregulated in many cancers. CDK2 expression, in particular, is associated with worse overall survival in glioblastoma (GB), disease-free recurrence in prostate cancer, and resistance to approved CDK4/6 inhibitors (CDK4/6i) in breast cancer. These provide rationale for inhibition of CDK2/4/6 as a potential novel therapeutic strategy in these cancers. NUV-422 is a potent (low nM) small molecule CDK2/4/6i with limited activity against CDK1, a target potentially associated with toxicities in other CDKi. Preclinical studies have shown that NUV-422 has favorable blood-brain barrier penetration, inhibited growth of multiple glioma cell lines in vitro, and exhibited antitumor activity in GB xenograft models. NUV-422 also exhibited antitumor activity in multiple patient-derived xenograft (PDX) models of HR+ HER2- mBC resistant to CDK4/6i, and PDX models of prostate cancer resistant to anti-androgens. Methods: NUV-422-02 (NCT04541225) is a phase 1/2, first in human, open label, multicenter study to evaluate single-agent NUV-422 (given orally) in patients with advanced solid tumors (r/r HGG, r/r HR+ HER2- mBC, or r/r mCRPC). The Ph 1 dose escalation will use a 3+3 design to evaluate safety, tolerability, and PK of NUV-422 and establish the recommended phase 2 dose (RP2D). Ph 1 also includes a randomized surgical substudy to characterize PK and pharmacodynamics (PD) of preoperative NUV-422 in resected GB tumor tissue. After the RP2D is identified, parallel enrollment into phase 2 expansion cohorts will begin. Cohort 1 will evaluate isocitrate dehydrogenase wild type (IDH-WT) GB. Cohort 2 will evaluate HR+ HER2- mBC (without active brain metastases); Cohort 3 will evaluate mCRPC; and Cohort 4 will evaluate HR+ HER2- mBC with active brain metastases. The Ph 2 primary endpoint is objective response rate. Secondary efficacy endpoints include clinical benefit rate, duration of response, progression-free survival, and overall survival. Response assessments will be based on response criteria appropriate to the tumor type (HGG [RANO]; HR+HER2- mBC [RECIST 1.1 or RANO-Brain Metastases]; mCRPC [RECIST 1.1, PCWG3, prostate-specific antigen decrease]). Blood, urine, or tumor tissue will be obtained to assess safety, PK, PD, and for additional exploratory analyses to characterize NUV-422 mechanism of action. Enrollment was initiated in December 2020, and dose escalation is ongoing. The NUV-422 program will also be expanded in 2022 to include additional studies in mBC and mCRPC in combination with standard of care treatments. Clinical trial information: NCT04541225.
NSAB C-14: CORRECT-MRD II—Second colorectal cancer clinical validation study to predict recurrence using a circulating tumor DNA assay to detect minimal residual disease.
Authors: Salem Mohamed E. , Huggins-Puhalla Shannon Leigh , George Thomas J. , Allegra Carmen Joseph , Palomares Melanie R. , Baehner Frederick L , Wolmark Norman
Published: June 2022

TPS3632

Background: Patients (pts) with stage II and III colon cancer (CC) have unique post-operative decisions regarding adjuvant chemotherapy (ACT). There is a subset of stage II pts with defined clinicopathologic features associated with poor prognosis who may benefit from ACT, although more discriminating and objective predictors of benefit are needed. In addition, there may be a subset of Stage III CC pts who could tolerate a de-escalation of ACT or who may require intensification of ACT to improve clinical outcome. Detectable ctDNA after resection of early-stage solid tumors has been associated with very high risk of recurrence, suggesting ctDNA is evidence of minimal residual disease (MRD). Several studies are ongoing to investigate the role of ctDNA in the optimal management of pts with CC using different assay technologies. Methods: This is a prospective, observational, multicenter study in the United States and Canada of 750 pts who have undergone complete surgical resection for stage II or III CC, have FFPE tissue available from the primary resection sufficient for a novel bespoke MRD assay, and are willing to provide serial whole blood specimens for ctDNA analysis. Subjects are asked to provide study specimens at baseline, pre-recurrence follow-up, and clinical recurrence (if applicable) study visits. ctDNA will be analyzed with an NGS-based MRD assay that identifies somatic genetic alterations from DNA derived from the pt’s tumor tissue, subtracts germline variants, and detects a subset of these tumor-specific (bespoke) ctDNA in the pt’s blood. The primary objective is to validate the association of post-definitive therapy and pre-recurrence follow-up ctDNA positivity with recurrence-free interval (RFI). Further objectives are to assess the: sensitivity and specificity of ctDNA positivity for subsequent clinical recurrence; contribution of post-surgery baseline, post-adjuvant therapy, and pre-recurrence follow-up ctDNA results on RFI; time from positive ctDNA to clinical recurrence in subjects who had a positive ctDNA result; and compare the Oncotype Colon Recurrence Score estimate of 3 yr recurrence risk with the observed 3 yr recurrence rate. The primary analysis will use a Cox proportional hazards regression applied to the RFI with ctDNA result (positive or negative) measured at post-surgical baseline (or end of ACT if ACT was used) and serially after that as a single, time-dependent covariate. Protocol: 16-002/NSABP C-14. Support: NSABP Foundation. Clinical trial information: 05210283.
SEAMARK: Randomized phase 2 study of pembrolizumab + encorafenib + cetuximab versus pembrolizumab alone for first-line treatment of BRAF V600E-mutant and microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC).
Authors: Kopetz Scott , Bekaii-Saab Tanios S. , Yoshino Takayuki , Chung Chin-Hee , Zhang Xiaosong , Tabernero Josep
Published: June 2022

TPS3634

Background: Among patients with MSI-H/dMMR CRC, BRAF mutations occur in approximately 30%. MSI-H/dMMR and BRAF mutations are both associated with poor prognosis; in patients who have both biomarkers, poor prognosis is thought to be driven by the BRAF mutation. Pembrolizumab is indicated for the treatment of patients with MSI-H/dMMR unresectable or metastatic CRC (mCRC). The BRAF inhibitor encorafenib, in combination with cetuximab, is indicated for previously treated patients with BRAF V600E-mutant mCRC. Currently, there are no first-line treatment options indicated specifically for patients with both MSI-H/dMMR and BRAF V600E-mutant mCRC. To assess the safety and efficacy of combining pembrolizumab with encorafenib + cetuximab, the SEAMARK study (NCT05217446) will evaluate this combination vs pembrolizumab alone in patients with previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC. Methods: SEAMARK is an open-label, multicenter, randomized, phase 2 study. Approximately 104 patients (randomized 1:1; stratified by Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0 vs 1) will receive either pembrolizumab + encorafenib + cetuximab or pembrolizumab. Enrolled patients must be aged ≥16 or ≥18 years (per country-specific regulations) and have previously untreated BRAF V600E-mutant MSI-H/dMMR mCRC; measurable disease (Response Evaluation Criteria in Solid Tumors v1.1); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients who received prior treatment with BRAF/EGFR inhibitors or immune checkpoint inhibitors, or who have brain metastases (unless radiologically stable) or RAS mutation (or unknown RAS status), will be excluded. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include safety and tolerability, overall survival, objective response rate, duration of response, and quality of life. Enrollment will begin in April 2022. Clinical trial information: NCT05217446.
TALENTop: A multicenter, randomized study evaluating the efficacy and safety of hepatic resection for selected hepatocellular carcinoma with macrovascular invasion after initial atezolizumab plus bevacizumab treatment.
Authors: Sun Hui-Chuan , Shen Feng , Liu Lianxin , Huang Zhi-Yong , Song Tianqiang , Kuang Ming , Xiang Bang-De , Bai Xueli , Zhu Xiaodong , Zhou Jian , Fan Jia
Published: June 2022

TPS4175

Background: Hepatocellular carcinoma (HCC) patients with macrovascular invasion are consistently considered to be at an advanced stage of disease. The combination therapy of atezolizumab (atezo) plus bevacizumab (bev) has been the new standard-of-care for those patients. In patients responding to systemic therapy, hepatic resection may provide additional benefit. Here we propose a phase 3 study to investigate whether hepatic resection following atezo/bev can bring more benefits for HCC patients with macrovascular invasion when compared with atezo/bev alone. Methods: This is a multicenter, open-label, two-arm, randomized study designed to evaluate the efficacy and safety of surgical resection plus peri-operative atezo/bev compared with regular systemic atezo/bev (Q3W, every three weeks) in HCC patients with macrovascular invasion and without extrahepatic metastasis. Initially eligible patients have enrolled into induction phase, during which they receive 3 cycles of atezo/bev and 1 cycle of atezo alone as primary systemic therapy. Patients who are assessed as partial response or stable disease (RECIST v1.1 criteria) and considered suitable for R0 hepatic resection are randomized in a 1:1 ratio to either Arm A, hepatic resection with post-operative atezo/bev for 1 year (or until loss of clinical benefit or intolerable toxic effects), or Arm B, continuing atezo/bev for 1 year (or until loss of clinical benefit or intolerable toxic effects). The primary endpoint of this study is time-to treatment failure (TTF), defined as time from randomization to the first documented treatment failure (i.e., tumor recurrence or metastasis [Arm A], disease progression [Arm B] according to RECIST v1.1, or death from any cause). We hypothesize that hepatic surgery with peri-operative atezo/bev will improve the TTF from 5.8 months to 9.2 months, with the hazard ratio of 0.63. With 2-sided significance level of 0.05, the sample size for randomization will be 198. The study, registered with clinical trial ID of NCT04649489, started enrollment in Apr 2021. As of Jan 2022, 65 patients have been enrolled and 15 patients have been randomized. Research funding: Shanghai Roche Pharmaceuticals Ltd. Clinical trial information: NCT04649489.
Randomized controlled trial of the efficacy of lymph node dissection on stage IIICr of cervical cancer (CQGOG0103).
Authors: He Misi , Zhong Lin , Wang Haixia , Tang Ying , Zhou Qi , Zou Dongling
Published: June 2022

TPS5604

Background: In FIGO 2018, allowing assessment of retroperitoneal lymph nodes by imaging and/or pathological findings and, if deemed metastatic, the case is designated as stage IIIC (with r and p notations). Patients with lymph node metastases have lower overall survival (OS), progression free survival (PFS), and survival after recurrence, especially those who have unresectable macroscopically positive lymph nodes. Retrospective analysis suggests that there may be a benefit to debulking macroscopic nodes that would be otherwise difficult to sterilize with standard doses of radiation therapy. No prospective study reported that resecting macroscopic nodes before Concurrent chemoradiation therapy (CCRT) would improve PFS or OS of cervical cancer. The CQGOG0103 study is a national, prospective, multicenter and randomized clinical study evaluating lymph node dissection on stage IIICr of cervical cancer. Methods: Eligible patients are histologically confirmed cervical squamous cell carcinoma, adenocarcinoma, adeno-squamous cell carcinoma. Stage IIICr (confirmed by CT/MRI/PET/CT) and the short diameter of image-positive lymph node ≥15mm. 452 patients will be equally randomized to receive either CCRT (Pelvic EBRT/Extended-field EBRT + cisplatin (40mg/m2) or carboplatin (AUC = 2) every week for 5 cycles + brachytherapy) or Open/minimally invasive pelvic and para-aortic lymph node dissection followed by CCRT. Randomization is stratified by status of para-aortic lymph node. The primary endpoint is PFS. Secondary endpoints are OS and surgical complications. The sample size calculation of 346 patients provides 80% power to detect a difference in survival at the two-sided 5% significance level using the log-rank test, considering a 20% reduction, a total of 452 patients are required. This study began in January 2021 and will be accrued within 4 years. Enrollment is ongoing.
A phase 3, randomized, open-label study of the anti-Globo H vaccine adagloxad simolenin/obi-821 in the adjuvant treatment of high-risk, early-stage, Globo H-positive triple-negative breast cancer.
Authors: Rugo Hope S. , Cortes Javier , Xu Binghe , Huang Chiun-Sheng , Kim Sung-Bae , Melisko Michelle E. , Nanda Rita , Sharma Priyanka , Schwab Richard , Hsu Pei
Published: June 2022

TPS611

Background: Adagloxad simolenin (A-S) is an anti-Globo H immunogen comprised of the carbohydrate tumor antigen Globo H, covalently linked to keyhole limpet hemocyanin, a carrier protein that deploys T cells to enhance the humoral response. Administration of A-S in combination with the immune adjuvant OBI-821 serves as an anti-tumor associated carbohydrate antigen vaccine intended to generate anti-Globo H humoral responses in patients with Globo H-expressing tumors. Methods: Study OBI-822-011, a phase 3 study, was initiated in 2018. Following feedback from investigators and advisors the study design was changed from a double-blind, placebo-controlled study to an open-label, standard of care (SOC) study. The revised protocol includes patients who have recovered from surgery and completed all planned neoadjuvant and/or adjuvant multiagent chemotherapy and/or radiation therapy. SOC in the A-S/OBI-821 arm is concomitant therapy of capecitabine or immune checkpoint inhibitor. In the SOC arm patients will receive SOC therapy consisting of observation alone, or adjuvant capecitabine alone, or immune checkpoint inhibitor alone. The key protocol changes included a change from open-label to standard of care, providing unblinding and reconsent guidelines for patients enrolled into the study prior to the protocol amendment, allowing concurrent adjuvant single agent chemotherapy, revising the stratification algorithm from a non-hierarchical to a hierarchical structure and aligning the stratification factors with prognostic factors more representative of the study population, revising the eligibility criteria, number and frequency of assessments to reduce patient burden, revising the interim analysis timepoints for futility, and removed an interim analysis for superiority. Study Objectives: Primary Objective: To determine the effect of A-S/OBI-821 treatment on improving IDFS in the study population. Secondary Objectives: To determine the impact of A-S/OBI-821 treatment on Overall survival (OS), Quality of life (QoL), Breast cancer-free interval (BCFI), Distant disease-free survival (DDFS) in the study population; To determine the safety and tolerability of A-S/OBI-821 in the study population. Key Exploratory Objectives: Beyond the safety, efficacy, and QoL endpoints of this trial, exploratory endpoints will evaluate the relationship between aberrant Globo H expression and baseline characteristics, including tumor pathology and immune factors. Conclusion: An estimated 668 subjects will be enrolled, treated for up to 2 years, and followed until occurrence of 187 events (invasive disease recurrence or death) or 3 years from last subject randomized. Survival follow-up is for 5 years from randomization of last subject. Clinical trial information: NCT03562637.
NANORAY-312: A phase III pivotal study of NBTXR3 activated by investigator’s choice of radiotherapy alone or radiotherapy in combination with cetuximab for platinum-based chemotherapy-ineligible elderly patients with locally advanced head and neck squamous cell carcinoma.
Authors: Le Tourneau Christophe , Hoffmann Caroline , Takacsi-Nagy Zoltan , Liem Xavier , Salas Sébastien , Debard Anais , Finzi Laetitia , Farber Leonard A , Gogishvili Miranda , Kristesashvili Giorgi , Makharadze Tamta , Yom Sue S.
Published: June 2022

TPS6110

Background: Elderly patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are largely underrepresented in clinical trials (CT). Broad access to CTs in this population is challenging due to an increased prevalence of comorbidities and ageing-related conditions. However, as population-age increases, more and more elderly patients are diagnosed with LA-HNSCC although many are not eligible to receive standard cisplatin-based concurrent chemoradiation (CRT). CRT-related toxicities, treatment burden and compliance are a concern. NBTXR3, a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of radiotherapy without additional toxicity to surrounding healthy tissue. NBTXR3 has been shown to prime the adaptive immune response in cancer models. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas. In a Phase I trial of NBTXR3 + RT alone in elderly LA-HNSCC patients, the combination was shown to be safe and an Objective Response Rate (ORR) of 85.4% and CRR of 51.2% was reported at ASTRO 2021. A pivotal randomized phase III study was initiated and is now recruiting. Methods: NANORAY-312 [NCT04892173] is a global, open-label, randomized (1:1), 2-arm, Investigator's choice Phase III (Pivotal Stage) study to investigate the efficacy and safety of NBTXR3/RT±cetuximab versus RT±cetuximab in treatment-naïve, platinum-ineligible, elderly patients with LA-HNSCC. 500 patients will be enrolled. Eligible patients are ≥65 years with at least one measurable (RECIST 1.1) biopsy-confirmed T3-4 (AJCC v8) SCC of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx which is amenable for intratumoral injection. For patients with oropharyngeal cancer, human papilloma virus (HPV) status must be known. In addition to the primary tumor, a single accessible LN in the neck is eligible for intranodal injection. The primary objective is PFS. The key secondary endpoint is OS. Other secondary endpoints include ORR, safety and tolerability and quality of life. Enrollment began in January 2022 and is ongoing. Clinical trial information: NCT04892173.
Neoadjuvant HER2-targeted therapy +/- immunotherapy with pembrolizumab (neoHIP): An open-label randomized phase II trial.
Authors: McArthur Heather L. , Leal Jorge Henrique S. , Page David B. , Abaya Christina DiLauro , Basho Reva K , Phillips Michelle , Chan David , Hool Hugo , Park Dorothy J. , El-Masry Mary , McAndrew Philomena , Sikaria Swati , Spring Laura , Bardia Aditya , Tighiouart Mourad , Dadmanesh Farnaz , Giuliano Armando E. , Shiao Stephen Lawrence
Published: June 2022

TPS624

Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxics; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: 174 patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer will be randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts receive TH-K. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion including radiotherapy per local clinical standard. Pts whose tumors are hormone-receptor positive will receive hormone therapy per local standard-of-care. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Clinical trial information: NCT03747120.
Emotion and symptom-focused engagement (EASE): A multisite randomized controlled trial of an intervention for individuals with acute leukemia.
Authors: Fitzgibbon Kyle , Malfitano Carmine , Rydall Anne , Hannon Breffni , Richardson Harriet , Schimmer Aaron David , Zimmermann Camilla , Rodin Gary
Published: June 2022

TPS7072

Background: Acute leukemia (AL) is characterized by rapid symptom onset requiring urgent hospitalization and initiation of intensive treatment with high mortality. Despite this, there is scant research on its psychological and physical impacts and even less on interventions to alleviate them [Bryant 2016]. We conducted a longitudinal study showing substantial physical and psychological distress in these patients [Rodin 2013; Zimmermann 2013; Nissim 2013; Nissim 2014; Gheihman 2016; Rodin 2018a; Shaulov 2019]. Despite this distress, we observed a lack of referrals for specialized psychosocial and palliative care. Based on these findings, we developed an integrated psychosocial and early palliative care (symptom control) intervention, Emotion And Symptom-focused Engagement (EASE), for AL [Rodin 2015]. In a subsequent randomized phase II trial of EASE in patients newly diagnosed with AL, we demonstrated its feasibility and found preliminary evidence that it reduces physical and psychological distress compared to usual care [Rodin 2020]. EASE includes: i) an 8-week manualized psychotherapy intervention tailored to AL to prevent and treat psychological symptoms through: supportive counselling and trauma-focused cognitive-behavioural therapy; and emotional assessment and affect modulation; ii) 4-week systematic screening of physical symptoms with automatic referrals to palliative care for the management of moderate to severe symptoms. Methods: We are conducting a multi-centre randomized controlled phase III trial of 266 AL patients comparing EASE to usual care in collaboration with the Canadian Cancer Trials Group at Princess Margaret Cancer Centre, Sunnybrook Health Sciences, Kingston Health Sciences and the Ottawa Hospital in Ontario, Canada. Patients are newly diagnosed with acute myeloid leukemia or acute lymphoblastic leukemia and randomized within two weeks of hospital admission for induction chemotherapy with curative intent. Patients randomized to EASE will receive psychological support from a trained mental health clinician for 8 weeks and will be assessed for physical symptoms twice weekly until discharged from hospital. Moderate to severe physical symptoms will trigger a referral to a symptom-control team for symptom management. The symptom-control team consists of a physician and nurse with expertise in symptom control and other professionals as needed. All participants will be assessed for physical symptom severity, psychological distress, quality of life and satisfaction with care at baseline, 4, 8, 12 weeks, 6 and 12 months. Hypotheses will be tested using multilevel modeling (MLM) with maximum likelihood estimation, conducted as intention-to-treat analyses. The DMC last reviewed the trial in April 2021 and suggested that the trial continue as planned. Clinical trial information: NCT04224974.
A phase 1b study to evaluate safety, tolerability, pharmacokinetics, and efficacy of SER-155 in adults undergoing hematopoietic stem cell transplantation to reduce the risk of infection and graft versus host disease (NCT04995653).
Authors: Ponce Doris M. , Lombardo Mary-Jane , Ford Christopher B. , Peled Jonathan U. , Van Den Brink Marcel R. M. , Tejura Bindu
Published: June 2022

TPS7074

Background:In patients undergoing allogeneic hematopoietic stem cell transplantation (HCT), loss of gastrointestinal microbial diversity is associated with risk of bloodstream infections (BSI), acute graft-versus-host disease (aGvHD), and death. SER-155 is a cultivated investigational microbiome therapeutic rationally designed to improve clinical outcomes in patients undergoing HCT by restoring colonization resistance to pathobionts, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a Phase 1b study to evaluate the efficacy, safety, and pharmacokinetics (PK) of SER-155 in adults undergoing HCT. Methods:This study will enroll approximately 70 subjects ≥ 18 years in an open-label Cohort 1 (n = 10) followed by a double-blind, placebo-controlled Cohort 2 (n = 60) randomized 1:1 to SER-155 or placebo and stratified by conditioning regimen intensity. Exclusion criteria include history of severe colitis of any etiology or active inflammatory bowel disease or total colectomy, transplant using umbilical cord blood or ex vivo T-cell therapy, receipt of fecal microbiota transplant or any live microbial therapeutic within 3 months prior to screening, and evidence of relapse or progression of hematologic malignancy (minimal residual disease is allowed). Following screening, subjects in both cohorts will receive 2 treatment courses (before and after HCT), each comprised of microbiome conditioning with oral vancomycin or placebo followed by SER-155 or placebo, and a conditional 3rd treatment course if the subject receives antibiotics (Table). Safety outcomes will be followed through 52 weeks post HCT. The primary endpoint is to evaluate the incidence and severity of adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints include rates of BSI, gastrointestinal infections, aGvHD, febrile neutropenia and overall survival in placebo vs SER-155 arms. Microbiome related endpoints include engraftment of SER-155 bacterial strains in the gastrointestinal tract (PK endpoint) and fecal microbiome diversity, composition and metabolites. Clinical trial information: NCT04995653. [Table: see text]
KITE-363: A phase 1 study of an autologous anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (R/R) B-cell lymphoma (BCL).
Authors: Nastoupil Loretta J. , Dahiya Saurabh , Miklos David Bernard , Reagan Patrick Michael , Ulrickson Matthew , Jung A. Scott , Kloos Ioana , Dong Jinghui , Chou Justin , Murakami Jodi , Rodriguez Katherine , Nahas Myrna
Published: June 2022

TPS7579

Background: One mechanism by which B-cell tumors can resist the effects of CD19-targeted CAR T-cell therapy is through CD19 antigen escape (Neelapu et al. ASH 2019). Recent analyses in large B-cell lymphoma (LBCL) demonstrated that approximately one-third to two-thirds of relapses after infusion of CAR T-cell therapy were CD19 negative (Plaks et al. Blood. 2021; Spiegel, Dahiya et al. Blood. 2021; Spiegel et al. Nat Med. 2021). KITE-363 is an autologous CAR T cell transduced with a bicistronic vector with resultant expression of a CD19 CAR with a CD28 costimulatory domain and a CD20 CAR with a 41BB costimulatory domain. In preclinical studies, KITE-363 recognized and eliminated tumor cells expressing CD19 and/or CD20. KITE-363 CAR T-cell therapy has the potential to rescue CD19-negative relapsing patients with BCL as well as prevent CD19 antigen escape by minimizing selective pressure through upfront therapeutic dual targeting. This Phase 1, first-in-human, open-label, multicenter study (NCT04989803) will evaluate the safety and preliminary efficacy of KITE-363 in patients with R/R BCL. Methods: The Phase 1 design includes a 3+3 dose-escalation portion (1A), with 5 planned CAR T-cell levels, and a dose expansion portion (1B). Patients may receive optional corticosteroid bridging therapy following leukapheresis. Patients will then receive conditioning chemotherapy (cyclophosphamide and fludarabine) on Day ‒5 to Day ‒3 followed by KITE-363 infusion on Day 0. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per Lugano criteria (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete response rate, time to next treatment, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells in blood and cytokines in serum. Eligible adult patients have histologically confirmed BCL, including LBCL, indolent non-Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma (HL), and BCL, unclassifiable (with features intermediate between diffuse LBCL and classical HL), that is R/R after ≥2 lines of therapy (patients with LBCL may have primary refractory disease). Other key inclusion criteria are adequate bone marrow and organ function and ECOG performance status 0‒1. Key exclusion criteria are central nervous system (CNS) involvement from lymphoma, active infection including hepatitis B and C, and clinically significant CNS disorder. This study is currently open and accruing patients. Clinical trial information: NCT04989803.
A phase 1/2 study of BLU-945 in patients with common activating EGFR-mutant non–small cell lung cancer (NSCLC): SYMPHONY trial in progress.
Authors: Shum Elaine , Elamin Yasir Y , Piotrowska Zofia , Spigel David R , Reckamp Karen L. , Rotow Julia K , Tan Daniel Shao-Weng , Lim Sun Min , Kim Tae Min , Lin Chia-Chi , Kato Terufumi , Parepally Jagan , Albayya Faris , Louie-Gao Melinda , Weinig Tessa , Zalutskaya Alena , Goto Koichi
Published: June 2022

TPS9156

Background: Although EGFR-targeted therapies have improved outcomes in patients with EGFR-mutant ( EGFRm) NSCLC, such as EGFR ex19del and L858R, resistance to these drugs is inevitable. BLU-945 is an investigational next-generation EGFR tyrosine kinase inhibitor (TKI) designed to suppress common activating and on-target resistance EGFR mutations, such as C797S and T790M. Preclinically it has shown activity as monotherapy in osimertinib-resistant patient-derived xenograft (PDX) models. In addition, BLU-945 has > 450-fold selectivity for C797S and T790M mutants over wildtype, advantageous for combinations with complementary EGFR-targeting agents, such as osimertinib. These combinations have shown enhanced activity in PDX models. The SYMPHONY trial (BLU-945-1101; NCT04862780) is an international, open-label, first-in-human, phase 1/2 study designed to evaluate safety, tolerability, and antitumor activity of BLU-945 as monotherapy and in combination with osimertinib in patients with EGFRm NSCLC. Methods: Key eligibility criteria include adults with pathologically confirmed metastatic NSCLC with an activating EGFR mutation, Eastern Cooperative Oncology Group performance status 0–1, and previous treatment with ≥1 EGFR-targeted TKI. Patients with asymptomatic brain metastases who are on stable doses of corticosteroids are eligible. Tumors with additional known driver alterations, including EGFR exon 20 insertions and other kinase drivers, are excluded. Primary endpoints are maximum tolerated dose, recommended phase 2 dose (RP2D) and safety (phase 1); and overall response rate (ORR) by RECIST 1.1 (phase 2). Key secondary endpoints include ORR, duration of response (DOR), pharmacokinetics (PK), and pharmacodynamics (PD; phase 1); and DOR, progression-free survival, overall survival, CNS efficacy, PK, and safety (phase 2). Phase 1 dose escalation will be done using Bayesian optimal interval design; ̃85 patients will receive BLU-945 monotherapy and ̃18 will receive combination BLU-945 and osimertinib. In the phase 2 dose expansion, patients will receive BLU-945 at the RP2D of the monotherapy in 3 groups based on EGFR mutational profile: T790M and C797S (n≈37), T790M, but not C797S (n≈12), and C797S, but not T790M (n≈12). In a combination group, BLU-945 plus osimertinib will be administered at RP2D of the combination to n≈24 patients, ≥12 with both T790M and C797S mutations. Patients may receive treatment until disease progression or unacceptable toxicity. Recruitment has started and approximately 30 sites will be open for enrollment across North America, Europe, and Asia. Clinical trial information: NCT04862780.
Randomized phase 2 study evaluating efficacy and safety of inupadenant in combination with chemotherapy in adults with metastatic non–small cell lung cancer (mNSCLC) who progressed on immunotherapy.
Authors: O'Brien Mary E.R. , Cheema Parneet K. , Grohé Christian , Costa Enric Carcereny , Girard Nicolas , Chiappori Alberto , Ross Sally , Rossetti Maura , Dubois Frederic , Lager Joanne J. , Srivastava Shouryadeep , Velcheti Vamsidhar
Published: June 2022

TPS9158

Background: In cancer, the accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression mainly via the high affinity A2A receptor (A2AR), causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. This results in increased tumor cell survival and immune escape (Blay 1997; Merighi 2003; Muller-Haegele 2014). Therefore, inhibiting A2AR could reverse immunosuppression and re-establish immune surveillance in the tumor microenvironment. Inupadenant is an antagonist of the A2AR with potent inhibition of A2AR even at the high concentrations of adenosine present in the tumor microenvironment. Ongoing clinical studies have established inupadenant as a molecule with a favorable safety profile with preliminary evidence of clinical activity in multiple tumor types, including durable PRs in patients who have exhausted standard treatment options (Buisseret 2021). The standard treatment for patients without a driving mutation who progress on first-line IO is a platinum-based doublet chemotherapy regimen. Carboplatin plus Pemetrexed (C+P) is the preferred chemotherapy in nonsquamous mNSCLC. Study A2A-005 will evaluate the efficacy of inupadenant in combination with C+P as a second-line therapy in adult patients with nonsquamous mNSCLC (post-IO). A successful outcome from study A2A-005 will help address a high unmet need for this patient population and could lead to new therapeutic options. Methods: This is a 2-part study. The first part is an open label dose-finding part to determine the safety and recommended Phase 2 dose (RP2D) of inupadenant in combination with C+P (N = 40). In Part 2, 150 patients will be randomized 1:1 to inupadenant or placebo, both in combination with C+P. Tumor response will be determined according to RECIST 1.1 criteria and safety findings will be reviewed by the Safety Review Committee (for Part 1) and the Data Monitoring Committee (for Part 2). Key eligibility criteria include 1) mNSCLC of nonsquamous pathology, 2) have received only 1 line of anti-PD-(L)1 therapy in the metastatic setting, without concomitant chemotherapy, and have progressed (IO/IO combination therapy is allowed), 3) have measurable disease as defined by RECIST v1.1 criteria and 4) Eastern Cooperative Oncology Group status ≤1. Primary endpoints are RP2D (for Part 1) and PFS (for Part 2). Secondary endpoints include change in tumor size, ORR, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. The study will be conducted in approximately 11 countries in North America and Europe. Clinical trial information: EudraCT 2021-005487-22.
DETECTION phase II/III trial: Circulating tumor DNA–guided therapy for stage IIB/C melanoma after surgical resection.
Authors: Lee Rebecca , Rothwell Dominic G. , Jackson Richard , Smith Nigel , Wong Stephen Q , Kelso Noel , Burghel George , Hewitt Chelsee , Clarke Harry , Mitchell Jackie , Jones Kate , Muinonen-Martin Andrew , Turajlic Samra , Corrie Philippa Gail , Marais Richard , Middleton Mark R. , Dawson Sarah-Jane , Sandhu Shahneen , Dive Caroline , Lorigan Paul
Published: June 2022

TPS9603

Background: Circulating tumor DNA (ctDNA; the tumor derived fraction of circulating free DNA in the blood) is a well recognized, minimally-invasive biomarker of tumor burden/progression in many cancers. We have previously shown in retrospective and prospective cohorts of patients with melanoma that ctDNA analysis of serial blood samples following curative intent surgery can identify minimal residual disease (MRD) or molecular relapse. The majority of patients with resected stage II melanoma do not recur, therefore better strategies to identify high risk patients are required. Furthermore, a consistent finding in studies of immune therapy in stage IV melanoma is that patients with small volume disease have the best outcome. We aim to test whether early relapse can be identified by ctDNA analysis and acted upon in a clinically relevant timeframe, and if early treatment of molecular recurrence with immune therapy improves outcomes for patients with resected stage IIB/C melanoma. Methods: We designed a phase II/III multicenter study across 21 UK and 4 Australian sites with a tumor informed approach employed for ctDNA detection. Droplet digital assays for BRAF/NRAS/TERT promoter mutations were validated for sensitive ctDNA detection across two accredited clinical testing laboratories. Patients with stage IIB/C melanoma, BRAF/NRAS/TERT promoter mutant cutaneous melanoma, ECOG 0/1, adequate organ function, with complete resection (including sentinel lymph node biopsy) performed within 12 weeks and radiological/clinical disease-free status confirmed within 4 weeks prior to registration, no prior immune/targeted therapy will be followed up with blinded ctDNA sampling in addition to clinical follow-up. Patients with ctDNA detected will be randomised 1:1 in a double blind fashion to continue routine follow-up with investigators choice treatment if they develop disease recurrence, or unblinded and treated with nivolumab 480mg IV Q4-weekly. Primary objectives include i) whether MRD/molecular relapse following curative intent surgery can be identified earlier than clinical relapse, ii) whether early treatment of molecular recurrence with nivolumab improves overall survival. 1050 patients are planned to be enrolled. The study opened in the UK in November 2021 and will open in Australia in Spring 2022. Clinical trial information: NCT04901988.
Capturing uveal melanoma (UM) global practice patterns and clinical outcomes in the collaborative ocular melanoma natural history (OMNi) study (NCT04588662).
Authors: Sacco Joseph J. , Orloff Marlana M. , Patel Sapna Pradyuman , Conway Max , Lim Li-Anne , Fog Lotte S. , Sia David , McKenzie John , McKay Daniel , O'day Roderick , Isaacs Timothy , Shoushtari Alexander Noor , Sullivan Ryan J. , Kin Sarah , Gwadry-Sridhar Femida Hussein , Joshua Anthony M. , Carvajal Richard D.
Published: June 2022

TPS9610

Background: Geographical differences in the management of primary UM, surveillance for recurrence, and care of metastatic disease have emerged based upon local expertise, treatment availability and insurance coverage. We have initiated accrual to OMNi (NCT04588662), an ambispective database developed to provide contemporary real-world data of UM, capturing its natural history and serving as a virtual biospecimen repository. The overall objectives of OMNi are to characterize regional/international UM management practice patterns and associated clinical outcomes in an effort to inform best practice recommendations. Methods: OMNi utilizes the Pulse Infoframe Healthie platform, a globally compliant platform which enables the structured collection of data mapped to Observational Medical Outcomes Partnership. The data fields created permit longitudinal capture of data including baseline patient and tumor characteristics, treatment of primary lesion and outcomes, surveillance patterns, time to disease recurrence, treatment of recurrent disease with outcomes, and survival. Inclusion criteria include a diagnosis of uveal melanoma and the ability to provide written informed consent for participation in the prospective registry or an institutional waiver by the IRB/ethics committee for retrospective data collection without written informed consent. We have initiated data collection at 3 US and 3 Australian centers, with 184 patients enrolled to date. Based upon feasibility assessment, we anticipate retrospective data entry for ̃2,000 patients and annual recruitment of ̃700 patients once all centers are active. Data collected in this OMNi collaboration, which will include additional US, UK and Australian sites, will facilitate new insights, hypothesis testing, as well as clinical trial development and conduct, and through a governance structure, will be made accessible for research. The OMNi dataset can serve and aid in interpretation of clinical trial outcomes in the real-world, facilitate cutting-edge research, and accelerate the development of diagnostics and therapeutics. Clinical trial information: NCT04588662.
Joan Heath interviews Suzanne Cory and Joan Steitz: a female perspective of science in the swinging ‘60s
Authors: Heath Joan , Cory Suzanne , Steitz Joan
Published: June 2022

Prompted by the occasion of International Women's Day, Joan Heath and DMM reunited Professors Suzanne Cory and Joan Steitz via Zoom to discuss their extraordinary careers and joint experiences in science. They also delve into past and present challenges for women in science, and discuss the role of scientists in a post-pandemic world.
Ετερότητα και ένταξη
Authors: Αναλυτή Δήμητρα-Σταυρούλα
Published: June 2022

Η ετερότητα και η ένταξη είναι το βασικό θέμα της μελέτης και συγκεκριμένα η σχέση των Ρομά με την εκπαίδευση. Με την έρευνα , μελετώνται τρεις διαδοχικές γενιές και η εξέλιξη της σχέσης τους με την εκπαίδευση. Η σχέση αυτή διερευνήθηκε σε συνάρτηση με παραμέτρους που επηρεάζουν την εκπαίδευση όπως η ηλικία, το φύλο, ο γάμος ,ο αριθμός Τα στοιχεία που συγκεντρώθηκαν, ταξινομήθηκαν στατιστικά και εν συνεχεία ερμηνεύθηκαν κοινωνιολογικά.