bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 3, single arm, open-label study evaluating ovarian suppression following 3-month leuprolide acetate for injectable suspension in combination with endocrine therapy in premenopausal subjects with HR+, HER2-negative breast cancer (OVELIA).
Authors: Tooker Ryan , Hamilton Erika P. , Lynch Kerlin , Atkinson Stuart , Turncliff Ryan 
Published: June 2022

TPS608 Background: In US clinical practice, GnRH agonists are widely used to suppress ovarian function in pre/perimenopausal patients with breast cancer that is moderate-to high-risk for recurrence. Despite extensive use of leuprolide acetate (LA) for ovarian suppression, regulatory approval for this indication has not been established in the US. Additionally, existing three month formulations may not reliably provide ovarian suppression, as demonstrated by escapes in estradiol (E2). An extended-release LA product with a 3-month dosing period specifically developed for ovarian suppression in patients with breast cancer could fill this unmet need. TOL2506 is a 3-month, extended-release formulation of 30 mg of LA. This combination of active drug and in situ polymeric extended release technology is expected to deliver higher exposure to drug than the currently available 3-month (22.5 mg) formulations of LA marketed for advanced prostate cancer and potentially reduce escapes in E2 over the dosing period. Methods: TOL2506A (OVELIA) is a phase 3, single arm, open-label study evaluating the effectiveness of TOL2506 to suppress ovarian function in premenopausal women with HR+, HER2-negative breast cancer. Approximately 250 subjects will be enrolled, with 30% aged 40 years or younger. Subjects must be premenopausal women, age 18-49, with a diagnosis of Stage I, II, or III HR+, HER2-negative breast cancer (ER > 1% and/or, PR > 1%, HER2-negative per ASCO CAP guidelines), who are candidates for ovarian suppression with endocrine therapy. For subjects receiving chemotherapy, premenopausal status will be determined, and confirmed by central lab hormone testing, prior to initiating chemotherapy. Male subjects with HR+, HER2-negative breast cancer may also be eligible, but will be evaluated for safety analyses only. Eligible subjects will enter the 48 week treatment period in 2 groups: those receiving tamoxifen concurrently with TOL2506 or those who initiate therapy with an aromatase inhibitor (AI; letrozole, anastrozole, or exemestane) beginning 6 weeks after the first administration of TOL2506, if E2 < 20 pg/mL has been achieved. After Week 12, subjects will be allowed to switch from receiving an AI to receiving tamoxifen or from tamoxifen to AI at the Investigator’s discretion. Subjects will receive 4 doses of TOL2506 every 12 weeks over the 48 week study duration. Achievement of ovarian suppression will be defined as ≥ 90% of subjects with luteinizing hormone (LH) levels < 4 IU/L at Week 6. Secondary endpoints include suppression of LH, E2 (< 20 pg/mL for tamoxifen cohort and < 2.72 pg/mL for AI cohort) and absence of menses at weeks 6, 12, 24, 36, and 48. Clinical trial information: NCT04906395.
TIRA study: A phase III, multicenter, randomized controlled study of toripalimab plus radical chemoradiotherapy with or without concurrent cisplatin in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.
Authors: Xu Cheng , Ma Jun 
Published: June 2022

TPS6101 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) suffer a high risk of distant metastasis and require guideline-recommended multimodality therapy. However, cisplatin-based concurrent chemotherapy leads to a high incidence of severe toxicities and low patient compliance, consequently limiting survival improvement. Toripalimab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), has a novel anti-cancer mechanism and mild toxicity spectrum. Robust evidence showed that given toripalimab + gemcitabine-cisplatin (GP) chemotherapy regimen, the median progression-free survival could be markedly improved in patients with recurrent and metastatic NPC. Besides, PD-1 antibody + radiotherapy is also regarded as a promising therapeutic strategy due to the synergistic effect. Therefore, we hypothesized that the de-intensification strategy using toripalimab + induction chemotherapy (IC) followed by radiotherapy alone would obtain equivalent survival and low toxicity in patients with LA-NPC compared with toripalimab + IC followed by concurrent chemoradiotherapy. Methods: TheTIRA study is a multicenter, randomized, controlled, open-label, phase III study. Since August 2021, we have been recruiting high-risk LA-NPC patients (stage III-IVa, except T3-4N0M0 & T3N1M0) from 12 Chinese centers. Our target sample size is temporarily set at 494 patients with 247 for each arm. Patients will be 1:1 ratio randomized to the experimental or control arm. Patients in the experimental arm will receive induction-concurrent toripalimab (240 mg, d1, Q3W × 6 cycle) with IC (gemcitabine 1000 mg/m2, d1 & d8 + cisplatin 80 mg/m2, d1, Q3W × 3 cycle) + intensity-modulated radiotherapy (IMRT, 70 Gy in 33 fractions), and thereafter adjuvant toripalimab (240 mg, d1, Q3W × 11 cycle). Patients in the controlled arm will receive an additional concurrent cisplatin (100 mg/m2, d1, Q3W × 2 cycle). The primary endpoint is the 3-year failure-free survival. Secondary endpoints include 3-year overall survival, 3-year distant metastasis-free survival, 3-year locoregional recurrence-free survival, quality-of-life assessment according to the systems of the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy, and safety profile. Exploratory analysis will be performed for potential biomarkers of survival prediction including PD-L1 expression and tumor-infiltrating lymphocytes. Clinical trial information: NCT04907370.
A phase II study evaluating the efficacy of niraparib and dostarlimab (TSR-042) in recurrent/metastatic head and neck squamous cell carcinoma.
Authors: Karivedu Vidhya , Riaz Muhammad Kashif , Mathews Maria , Kurtzweil Nicky , Monroe Ilaina , Romano Audrey , Wise-Draper Trisha Michel 
Published: June 2022

TPS6105 Background: Despite improvement in outcomes with checkpoint (PD-1) inhibitors in some patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (RM HNSCC), overall survival (OS) remains poor, necessitating novel therapy combinations. Fanconi Anemia (FA) and FA-related DNA repair pathways alterations have been associated with cumulative tumor mutational burden (TMB) due to genomic instability. High TMB is associated with improved response to PD-1 inhibitors. DNA pathway repair mutations have been reported in 17% of sporadic HNSCC. Ataxia-Telangiesctasia Mutated (ATM) loss has been reported in 60% of human HNSCC biopsies and FA-related defects were reported in 15-21% of human HNSCC biopsies and cell lines. Poly (ADP-ribose) polymerase (PARP) inhibition has already demonstrated efficacy as a single agent in multiple cancers which harbor a DNA repair defect. Preclinical data also showed PARP inhibitor (PARPi) upregulates PD-L1 expression in cancer lines and animal models via inactivation of glycogen synthase kinase 3 (GSK3β). Importantly, blockade of PD-1 re-sensitized PARPi treated cells to induce T-cell mediated cytotoxicity. Combination of PARPi and anti-PD-1 therapy significantly increased therapeutic efficacy in vivo compared to single agent. Therefore, we hypothesized that the combination of a PARPi (niraparib) and PD-1 blockade (dostarlimab) in our ongoing phase II study would enhance overall response (OR) and survival in R/M HNSCC pts (NCT04313504). Methods: Eligible pts must have a confirmed histopathology of non-cutaneous RM HNSCC not amenable to local therapy, progressive disease (PD) after at least one line of platinum-based chemotherapy and/or immunotherapy, age>18, ECOG <2, no prior therapy with PARPi and adequate bone marrow, liver, and renal function. Seven of 14 pts have been enrolled in the first stage of the study. If 8 or more pts develop either stable disease (SD), partial (PR) or complete response (CR), 9 additional patients will be accrued for a total of 23 patients. Pts will receive 200 mg PO niraparib daily in 28-day cycles along with dostarlimab 500mg (Q3W) for 4 doses followed by 1000mg (Q6W) until PD or unacceptable toxicity. An interim analysis will be performed to assess efficacy and safety after 14 patients become evaluable. Tumor response will be assessed per RECIST v1.1. Primary endpoint is best OR including SD, PR, and CR; Secondary endpoints include adverse events determined by CTCAE v5.0, progression free survival and OS. Integrated tissue analysis includes DNA pathway repair defects and TMB. Additional exploratory analyses including peripheral and immune cell activation will be performed on tissue and plasma samples. Clinical trial information: NCT04313504.
A phase 1b/2 study of nanatinostat and valganciclovir in patients with advanced Epstein-Barr virus positive (EBV+) solid tumors and in combination with pembrolizumab in patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC).
Authors: Colevas A. Dimitrios , Siu Lillian L. , Lim Darren Wan-Teck , Gao Bo , Rojkjaer Lisa , Katkov Afton , Katz Yisrael , Ma Brigette 
Published: June 2022

TPS6107 Background: Epstein-Barr virus (EBV) is linked to the development and pathogenesis of nasopharyngeal carcinoma (NPC). Most patients present with advanced stage disease at diagnosis (Li 2014); first-line chemoradiation is commonly followed by recurrence and poor prognosis emphasizing the need for new treatment options. Targeting EBV in NPC represents a novel therapeutic approach. EBV is predominantly latent in NPC; pre-clinical studies demonstrated that induction of the viral lytic phase by histone deacetylase inhibitors (HDACi) renders EBV+ tumor cells susceptible to the cytotoxic activity of ganciclovir (GCV) (Hui 2016). Nanatinostat (Nstat), a potent Class-I HDACi, induces the expression of the lytic BGLF4 protein kinase in EBV+ tumor cells, which activates the nucleoside analog GCV via phosphorylation. Phosphorylated GCV becomes incorporated into the cellular DNA causing chain termination and apoptosis. The all-oral combination of Nstat and valganciclovir (VGCV), a pro-drug of GCV, has demonstrated favorable safety and preliminary efficacy in a phase 1/2 study in patients with recurrent EBV+ lymphoma (NCT03397706). This phase 1b/2, open-label, multicenter study will evaluate the safety, tolerability, pharmacokinetics, and preliminary activity of Nstat + VGCV in patients with advanced EBV+ solid tumors. Additionally, the combination of pembrolizumab together with Nstat + VGCV will be evaluated in recurrent/metastatic NPC (RM-NPC) patients. NPC frequently exhibits high PD-L1 expression levels; however, PD-1 inhibitors resulted in limited response rates ranging from 20-30% in the RM-NPC setting. Methods: Phase 1b utilizes a 3+3 dose escalation design to determine the recommended Phase 2 dose (RP2D) of Nstat + VGCV in patients with EBV+ RM-NPC. In Phase 2, up to 60 patients with EBV+ RM-NPC will be randomized 1:1 to receive Nstat + VGCV at the RP2D with or without pembrolizumab to evaluate safety, tolerability, overall response rate, and potential pharmacodynamic markers of drug activity, including plasma EBV DNA levels. Additionally, patients with EBV+ solid tumors other than RM-NPC will receive Nstat + VGCV at the RP2D in a separate Phase 1b dose expansion cohort. Patients eligible for the phase 1b dose escalation and phase 2 will have EBV+ RM-NPC with 1-3 prior lines of platinum-based chemotherapy and no available curative therapies. Patients with advanced EBV+ non-NPC solid tumors (gastric cancer, lymphoepithelioma-like carcinoma, leiomyosarcoma) and no curative therapies are eligible for the phase 1b expansion cohort. All patients must have measurable disease per RECIST v1.1 and adequate bone marrow, liver, and renal function. Enrollment began in January 2022. Clinical trial information: NCT05166577.
NHS-Galleri Trial Design: Equitable study recruitment tactics for targeted population-level screening with a multi-cancer early detection (MCED) test.
Authors: Swanton Charles , Neal Richard D , Johnson Peter W. M. , Dur Christina Clarke , Hamilton Stephanie A , Zhang Nan , Kumar Harpal , Sasieni Peter 
Published: June 2022

TPS6606 Background: Cancer is a leading cause of premature death globally. Early detection can reduce cancer mortality by reducing the number of cancers diagnosed at a late stage. A blood-based MCED test (Galleri) was developed that can detect cancer signals and predict cancer origin with a single blood draw. The NHS-Galleri trial is a randomized controlled trial (RCT) assessing the clinical utility of this MCED test in a targeted screening population alongside current screening programs. Screening adherence is lower among certain individuals (eg, those with lower socioeconomic status), despite healthcare being free at the point of access in England. NHS-Galleri utilizes innovative strategies to optimize equity in study recruitment, with the goal of enrolling a representative sample. Methods: This pragmatic, blinded RCT is currently enrolling 140,000 asymptomatic participants by inviting ̃1.3 million residents aged 50-77 in select postcodes of England via the NHS DigiTrials service. Regions were selected to include areas of high cancer mortality, socioeconomic deprivation, and ethnic diversity; eligible participants will be identified from these regions. A variety of methods are employed to enroll a representative study population (defined as including a reasonable number of participants from all socioeconomic statuses and all major ethnic minority groups). These methods include the use of mobile phlebotomy clinics that facilitate access in economically deprived areas, monitoring of participant representativeness by postcode with dynamic adjustment of enrollment, providing interpreters and wheelchair accessibility, and targeted local campaigns. Blood will be collected at 3 annual visits (baseline, year 1, year 2) unless cancer is diagnosed. After baseline blood collection, participants will be randomized 1:1 to the intervention (blood sample analyzed by the MCED test) or control (blood sample stored for potential future MCED testing) arm. Only participants in the intervention arm with “cancer signal detected” will have results returned and be referred for investigations and possible treatment. Participants in the intervention arm without “cancer signal detected” and all in the control arm will remain blinded and return for annual visits. All participants will be reminded to continue guideline-based screening and report unusual/concerning symptoms to a doctor. The primary study objective is a significant reduction in the absolute numbers of stage III & IV cancers diagnosed in the intervention versus control arm 3.5 years after randomization. Cancer-specific mortality will be assessed during trial follow-up. Exploratory endpoints include assessing the primary objective by participant age, gender, socioeconomic status, and ethnicity. Clinical trial information: ISRCTN91431511.
CELESTIMO: A phase III trial evaluating the efficacy and safety of mosunetuzumab plus lenalidomide versus rituximab plus lenalidomide in patients with relapsed or refractory follicular lymphoma who have received ≥ 1 line of systemic therapy.
Authors: Nastoupil Loretta J. , Morschhauser Franck , Scholz Christian W. , Bishton Mark , Yoon Sung-Soo , Giri Pratyush , Wei Michael C. , Knapp Andrea , Li Chi-Chung , Bottos Alessia , Li Haocheng , Purev Enkhtsetseg , Bartlett Nancy L. 
Published: June 2022

TPS7588 Background: Despite significant progress with first-line immunochemotherapy, most patients with follicular lymphoma (FL) will eventually relapse with increasing refractoriness and decreasing duration of response to subsequent therapy lines (Rivas-Delgado et al. 2019). Mosunetuzumab (M) is a CD20xCD3 bispecific antibody that engages and redirects T-cells to eliminate malignant B cells (Sun et al. 2015). In an ongoing, pivotal Phase I/II trial of M monotherapy, patients with relapsed/refractory (R/R) FL who have received ≥2 prior treatment lines achieve deep and durable responses (NCT02500407; Budde et al. ASH 2021). Preliminary data from a Phase Ib study have suggested favorable safety and promising activity of M in combination with lenalidomide (Len), a potent immunomodulatory agent that has shown additive/synergistic activity with an anti-CD20 antibody in R/R indolent lymphoma (Leonard et al. 2019), in patients with R/R FL who have received ≥1 prior therapy (NCT04246086; Morschhauser et al. ASH 2021). The chemotherapy-free M-Len combination may represent a promising outpatient therapy option for future management of patients with R/R FL. The randomized, multicenter Phase III study has been initiated. Methods: CELESTIMO (NCT04712097) is a randomized, multicenter, open-label Phase III study evaluating the efficacy and safety of M-Len versus rituximab plus Len (R-Len) in patients with previously treated R/R FL. Patients must have histologically documented CD20+ FL (Grades 1–3a) requiring systemic therapy and have received ≥1 prior line of systemic therapy. Patients are randomized (1:1) to receive M-Len (M intravenously [IV] on Days [D] 1, 8 and 15 of Cycle [C] 1 [21-day cycle] and D1 of C2–12 [28-day cycles], plus Len orally [PO] on D1–21 of C2–12) or R-Len (R IV on D1, 8, 15 and 22 of C1 then on D1 of C3, 5, 7, 9, and 11, plus Len PO on D1–21 of C1–12 [all 28-day cycles]), and stratified by disease progression within 24 months of initial treatment (yes/no), number of prior lines of therapy (1 versus ≥2), and refractoriness to anti-CD20 therapy (refractory/non-refractory). The primary endpoint is progression-free survival (PFS) assessed by independent review committee; secondary endpoints include investigator-assessed PFS, complete and objective response, overall survival, and safety. Biomarkers predictive of response to M-Len and R-Len will also be investigated as exploratory endpoints. The study started recruitment in 2021 and plans to enroll ̃400 patients from approximately 16 countries and 150 sites globally. Clinical trial information: NCT04712097.
A phase I study of duvelisib in combination with oral azacitidine (CC-486) in relapsed lymphoid malignancies.
Authors: Saeed Hayder , Sahakian Eva , Maharaj Kamira Karen , Mo Qianxing , Zhang Ling , Makanji Rikesh J , Isenalumhe Leidy Lismeri , Gaballa Sameh , Chavez Julio C. , Shah Bijal D. , Bello Celeste M. , Pinilla-Ibarz Javier , Sokol Lubomir 
Published: June 2022

TPS7594 Background: Phosphoinositide 3-kinase (PI3K) inhibitors have shown promising activity in lymphoid malignancies such as mature T cell lymphoma, diffuse large B cell lymphoma, and mantle cell lymphoma. Duvelisib’s PI3K-δ and PI3K-γ activity in T cell lymphoma is promising as a single agent (Horwitz, Koch et al. 2018). While the safety profile can generally be managed, certain autoimmune adverse events may limit its adaptation in clinical practice. Azacitidine, a pyrimidine nucleoside analog of cytidine, is active in T cell lymphoma (Saillard, Guermouche et al. 2017) as well as in DLBCL (Martin, Bartlett et al. 2018). Hypomethylators could enhance the activity of PI3K inhibitors through increasing PTEN expression (Spangle, Roberts et al. 2017), and upregulation of tumor suppressor genes (Zuo, Liu et al. 2011). Duvelisib’s immune mediated adverse events may be related to shifts in T cell differentiation towards Th17 phenotype and decreases in T reg differentiation that found to be more pronounced in patients with higher immune related toxicity (Gadi, Kasar et al. 2019). Studies have shown that T regs can be induced from Cd4+CD25- T cells using DNA methyltransferase inhibition with azacitidine (Fagone, Mazzon et al. 2018). Thus, the intermittent administration of azacytidine can potentially restore the balance by increasing T regs to decrease the autoimmune toxicity while maintaining Th17 phenotype that enhances tumor killing as shown in myelodysplastic syndrome (Jia, Yang et al. 2020). Methods: This is a 3+3 phase I dose escalation study designed to determine the maximum tolerated dose (MTD) of CC-486 in combination with duvelisib in patients with lymphoid malignancies. The MTD is defined as the highest dose with an observed incidence of dose limiting toxicity (DLT) in no more than one out of six patients treated at a particular dose level. Secondary endpoints include best overall response, disease control rate and duration of response. Exploratory end points will be biomarker driven with focus on the composition of different T cell compartments during the administration of the combination. Efficacy biomarkers will include measuring the phosphorylation of AKT in peripheral CD3+ T cells. Oral duvelisib will be given continuously with the dose escalation maintained during the first 2 cycles while CC-486 schedule will be 14 days on/14 days off. The first cohort of patients are enrolled, and are in the DLT testing period. Clinical trial information: NCT05065866.
Trial in progress: A phase 1b study evaluating the safety, tolerability, and preliminary anti-tumor activity of NT-I7 (efineptakin alfa), a long-acting human IL-7, post-tisagenlecleucel in subjects with relapsed/refractory large B-cell lymphoma.
Authors: Ghobadi Armin , Budde L Elizabeth , Galal Ahmed , Stermer Kristina , Austin TaShara Lynn , Fan Jean , DiPersio John F. 
Published: June 2022

TPS7596 Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy with tisagenlecleucel (Kymriah) is standard of care (SOC) for patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). CAR-T expansion is a strong predictor of response to this therapy. NT-I7 (efineptakin alfa) is a first in-class, long-acting human IL-7 previously shown clinically in solid tumor studies to increase the number and functionality of T-cells in peripheral blood and within tumors. In a CD19+ lymphoma xenograft mouse model that received anti-CD19 universal CAR-T infusion, NT-I7 treatment prolonged survival and enhanced CAR-T gene expression of functional markers, proliferation, persistence, and tumor killing. We hypothesize that NT-I7 administration after tisagenlecleucel SOC for subjects with r/r LBCL may increase expansion and persistence of CAR-T, leading to increased tumor response rate and improved clinical outcomes without safety concerns. Methods: This phase 1b study consists of a dose-escalation phase followed by a dose expansion. In dose escalation, subjects receive tisagenlecleucel infusion on Day 0 and a single dose of NT-I7 on Day 21, at 7 dose levels (DLs 1-7): 60, 120, 240, 360, 480, 600, and 720 μg/kg. DLs 1 and 2 will enroll 1 subject each, followed by a 3+3 design for the remaining DLs. Up to 42 subjects will be enrolled for the dose-escalation phase and up to 15 subjects in the dose-expansion phase, treated at the recommended phase 2 dose (RP2D). Eligible subjects are ≥18 years of age with biopsy-proven diagnosis of r/r LBCL after ≥2 lines of systemic therapy, including diffuse LBCL (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Subjects must be eligible for tisagenlecleucel as SOC. Subjects who have received prior CD19-directed therapy are ineligible. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) and/or RP2D for NT-I7 with this regimen. Secondary objectives are to explore the anti-tumor activity of this regimen for r/r LBCL. The effect of NT-I7 after tisagenlecleucel infusion on the safety profile regarding Grade ≥3 Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) will also be evaluated. Exploratory objectives are to assess pharmacokinetic parameters of tisagenlecleucel with NT-I7 administration, and correlative studies will evaluate the effects of this regimen not limited only to the expansion of lymphocytes and serum cytokines. As of January 3, 2022, 2 subjects have received NT-I7 in the dose-escalation phase at DL1 and DL2. Clinical trial information: NCT05075603.