bluuebunny/crossref_metadata_2025_split huggingface dataset:
ENGOT-en9/LEAP-001: A phase III study of first-line pembrolizumab plus lenvatinib versus chemotherapy in advanced or recurrent endometrial cancer.
Authors: Marth Christian , Vulsteke Christof , Rubio Pérez Maria Jesus , Makker Vicky , Braicu Elena Ioana , McNeish Iain A. , Madry Radoslaw , Ayhan Ali , Hasegawa Kosei , Wu Xiaohua , Dutta Lea , Xu Cindy , Keefe Stephen Michael , Lee John J. , Pignata Sandro 
Published: May 2020

TPS6106 Background: The prognosis for endometrial cancer (EC) can be favorable when diagnosed in early stages, but prognosis and overall survival are poor in patients with advanced or recurrent EC. First-line standard of care for patients with advanced or recurrent EC is paclitaxel and carboplatin chemotherapy; however, there is a need for more effective and tolerable therapies. In the phase Ib/II trial KEYNOTE-146, which assessed the PD-1 inhibitor pembrolizumab (pembro) in combination with the multikinase inhibitor lenvatinib, an objective response rate (ORR) of 38% was observed (N=108) in patients with previously treated advanced EC. ENGOT-en9/LEAP-001 (NCT03884101) is a randomized, open-label, active-controlled, phase III study investigating pembro + lenvatinib vs chemotherapy in patients with newly diagnosed advanced or recurrent EC. Methods: Patients with newly diagnosed advanced (stage III-IV) or recurrent EC not previously treated with antiangiogenic agents; systemic chemotherapy (unless within a chemoradiation regimen); PD-1, PD-L1, or PD-L2 inhibitors; or other T-cell receptor–targeted therapies will be eligible. Patients will be randomized 1:1 to receive pembro 200 mg every 3 wk (Q3W) + lenvatinib 20 mg daily or paclitaxel 175 mg/m2 Q3W + carboplatin AUC 6 Q3W. Randomization will be stratified on the basis of proficient vs deficient mismatch repair (pMMR vs dMMR) status. The pMMR population will be further stratified by prior chemoradiation (yes vs no), measurable disease (yes vs no), and ECOG performance status (0 vs. 1). Patients will continue on treatment for up to 35 cycles of pembro vs 7 cycles of chemotherapy or until initiation of a new anticancer treatment, unacceptable adverse events, or withdrawal of consent. Primary study endpoints are progression-free survival (per RECIST v1.1 by blinded independent central review) and overall survival. Secondary study endpoints are ORR, health-related quality of life, safety and tolerability, and lenvatinib pharmacokinetics. Exploratory endpoints will include disease control rate, clinical benefit rate, and duration of response. Enrollment is ongoing. Clinical trial information: NCT03884101.
Phase III LEAP-010 study: first-line pembrolizumab with or without lenvatinib in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Authors: Siu Lillian L. , Burtness Barbara , Cohen Ezra E.W. , Harrington Kevin Joseph , Licitra Lisa F. , Rischin Danny , Zhu Ying , Lee Chooi Peng , Pinheiro Cecilia , Swaby Ramona F. , Machiels Jean-Pascal H. , Tahara Makoto 
Published: May 2020

TPS6589 Background: The PD-1 inhibitor pembrolizumab is currently approved as first-line monotherapy for patients with R/M HNSCC whose tumors express PD-L1 combined positive score (CPS) ≥1. In a phase 1b/2 trial (NCT02501096) of pembrolizumab plus lenvatinib (multikinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRa, RET, and KIT) in solid tumors, the combination demonstrated promising antitumor activity and a manageable safety profile in patients with HNSCC. LEAP-010 (NCT04199104) is a randomized, double-blind, placebo-controlled, phase 3 study that will evaluate the efficacy and safety of first-line pembrolizumab with or without lenvatinib in patients with PD-L1–positive R/M HNSCC. Methods: Key eligibility criteria include histologically confirmed R/M HNSCC incurable by local therapies, PD-L1–positive tumor (CPS ≥1) as determined by central laboratory, measurable disease as assessed by blinded independent central review (BICR) per RECIST v1.1, and ECOG performance status (PS) 0 or 1. Patients will be randomly assigned 1:1 to pembrolizumab plus lenvatinib or pembrolizumab plus placebo. Randomization will be stratified by PD-L1 status defined by tumor proportion score ( < 50% vs ≥50%), human papillomavirus status for oropharynx cancer (positive vs negative), and ECOG PS (0 or 1). Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles (~2 years) and oral lenvatinib 20 mg or placebo once daily; patients may continue to receive lenvatinib or placebo after pembrolizumab treatment is complete. Treatment will continue until BICR-verified disease progression or unacceptable toxicity. Pembrolizumab retreatment (second course) for 17 additional cycles will be allowed for eligible patients who stop pembrolizumab and subsequently experience BICR-verified disease progression. These patients could have stopped treatment with stable disease, partial response, or complete response or after 35 cycles of pembrolizumab for reasons other than disease progression or toxicity. Tumor imaging assessment will be performed at week 6, then every 6 weeks until 1 year, and thereafter every 9 weeks. Primary end points are objective response rate and progression-free survival, assessed by BICR per RECIST v1.1, and overall survival. Secondary end points are duration of response and safety and tolerability. Recruitment is ongoing; planned enrollment is ~500 patients. Clinical trial information: NCT04199104 .
Single-arm study of bimiralisib in head and neck squamous cell carcinoma (HNSCC) patients (pts) harboring NOTCH1 loss of function (LOF) mutations.
Authors: Johnson Faye M. , Janku Filip , Lee J. Jack , Schmitz Debora , Streefkerk Henk , Frederick Mitchell 
Published: May 2020

TPS6590 Background: Effective targeted therapies are needed for HNSCC that is lethal despite recent advances with immunotherapy. A major challenge to personalize treatment is that most genomic alterations are in tumor suppressors, including NOTCH1 that is mutated in ~20% of HNSCC. We recently published that HNSCC cell lines harboring NOTCH1 LOF mutations undergo cell death in vivo and in vitro following PI3K inhibition, in contrast to PIK3CA mutant cell lines that merely undergo cell cycle arrest when exposed to the same drugs. Based on these results we initiated a novel genomic biomarker-driven phase II clinical trial treating NOTCH1 mutant HNSCC pts with the dual PI3K/mTOR inhibitor bimiralisib (PQR309). Methods: The primary objective is to determine the objective response rate (ORR) of recurrent/metastatic HNSCC harboring NOTCH1 LOF mutations to bimiralisib. Pts who have already received standard platinum chemotherapy and immunotherapy will receive bimiralisib orally twice per wk unless progression or intolerable toxicity occurs. Tumors will be evaluated using RECIST q 6 wks. A Simon’s optimal two-stage design is used. To have 80% power to detect an ORR of 30%, (one-sided α = 0.05, β = 0.20) 10 pts will be enrolled in the first stage. If ≤1 pts respond, the trial will be closed for futility. If ≥2 pts have an OR, the study will enroll an additional 19 pts in the second stage. The null hypothesis (ORR ≤ 10%) will be rejected if ≥ 6 in 29 pts have an OR. Seven pts have enrolled. The algorithm for determining NOTCH1 mutation function is based on the patterns of mutations in HNSCC vs. leukemia where mutations are activating. It may be difficult to determine whether NOTCH1 mutations are homo- or heterozygous due to normal cell contamination. Therefore, levels of activated NOTCH1 in pretreatment tumors may be assessed by IHC with an antibody against activated NOTCH1 (NICD). In parallel with the trial, to further confirm NOTCH1 LOF, we can use site-directed mutagenesis to re-create NOTCH1 mutations from trial pts that will then be introduced into NOTCH1-null cell lines to assay for NICD and growth inhibition with culture on NOTCH1 ligand. All pts will have serial collection of blood for pharmacokinetics and for ctDNA to examine clonal evolution associated with acquired resistance. Samples with high NOTCH1 mutation ctDNA VAF will be analyzed by WES and compared with pretreatment tissue. In the second stage, IHC and WES may be performed on pre- and post- treatment (day 15 and progression) tissue to examine pharmacodynamics and mechanisms of resistance. Clinical trial information: NCT03740100 .
A phase II open-label, multicenter, study to evaluate the efficacy and safety of rivoceranib in subjects with recurrent or metastatic adenoid cystic carcinoma.
Authors: Kang Hyunseok , Ho Alan Loh , Muzaffar Jameel , Bowles Daniel W. , Kim Sung-Bae , Ahn Myung-Ju , Hanna Glenn J. , Worden Francis P. , Yun Tak , Norton Steven , Sankar Neil , Keam Bhumsuk 
Published: May 2020

TPS6597 Background: Adenoid cystic carcinoma (ACC) is a rare salivary gland malignancy, also found in other secretory gland sites (tracheobronchial tree, esophagus, breast, lungs, prostate, uterine cervix and vulva). Initial disease is typically treated with surgical resection and radiation, but recurrent or metastatic disease remain to be a significant challenge. There is no standard systemic therapy option for advanced ACC, although recent studies with tyrosine kinase inhibitors have shown moderate objective response and disease stabilization rates. Rivoceranib (also known as apatinib) is a potent selective inhibitor of VEGFR-2 and has been evaluated in a single arm phase II study of 59 recurrent or metastatic ACC patients in China and has demonstrated an (ORR) of 47.1% and disease control rate of 98.1. Methods: This is a phase II, open-label, multicenter[HGJ3], single arm clinical trial of oral rivoceranib (700 mg daily) in patients with recurrent or metastatic ACC of any anatomic site, not amenable to curative surgery or radiotherapy to confirm activity of rivoceranib. Subjects must have at least one evaluable lesion by RECIST v1.1 and have evidence of disease progression within the 6 months prior to study entry. Fifty-five subjects will be enrolled at 7 US sites and 4 South Korean sites. The primary endpoint is ORR assessed by investigators with a target ORR of 25% to detect a difference of 15% from the historical ORR of 10% at 1-year (this achieves 80% power with a 5% significance level). Secondary endpoints include overall survival, disease control rate, progression free survival at 6, 12 and 24 months and time to progression. Exploratory objectives include correlation between ORR and the presence of MYB/MYB-L1 fusion, pharmacokinetics evaluation, and patient-reported quality of life assessments by FACT-G. This study is open and enrolling at the time of submission. References: 1. Tchekmedyian V, Sherman EJ, Dunn L, et al. Phase II Study of Lenvatinib in Patients With Progressive, Recurrent or Metastatic Adenoid Cystic Carcinoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2019;37:1529-37. 2. Zhu G, Zhang L, Li R, Dou S, Yang W, Zhang C. Phase II trial of apatinib in patients with recurrent and/or metastatic adenoid cystic carcinoma of the head and neck: Updated analysis. Journal of Clinical Oncology 2018;36:6026. Clinical trial information: NCT04119453 .
A phase I clinical trial testing the safety of IL-21-expanded, off-the-shelf, natural killer cells for relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome.
Authors: Vasu Sumithira , Sharma Nidhi , Odonnell Lynn , Bosse Kevin , Lee Dean Anthony 
Published: May 2020

TPS7562 Background: Allogeneic transplantation (Allo-HCT) demonstrates the enduring and potent role of the immune system in the control and eradication of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, patients with relapsed, refractory (R/R) disease or comorbidities are not eligible for Allo-HCT. We sought to develop an allogeneic Natural killer (NK) cell-based immunotherapy approach to induce remission for these patients. The efficacy of haploidentical NK cells expanded ex vivo using a K562 feeder-cell line transfected with IL-21 and 41BBL has been established in R/R AML patients. However, haploidentical donor-derived NK cell manufacturing exceeds three weeks with the possibility of fulminant malignancy rendering patients ineligible for cellular therapy. To address this limitation we established a third-party NK cell bank derived from KIR and HLA-mismatched ‘ideal’ donors that allows scalable, affordable mass-production of large numbers of NK cells suitable for banking and immediate ‘off-the-shelf’ (OTS) administration to a broad population of recipients. Methods: This phase I study follows a 3+3 design to investigate the safety of mIL-21-expanded, third-party, OTS NK cells for treatment of R/R AML and MDS patients. Patients aged ≥18 or ≤80 years are enrolled into two cohorts: those <60 years and able to tolerate intensive chemo will receive Fludarabine 30mg/m2/day (days -6 to -2) and Cytarabine 2g/m2/day (days -6 to -2). Patients >60 years or <60 years and unable/unwilling to tolerate intensive chemo will receive Fludarabine 30mg/m2/day (days -5 to -2) and Decitabine 20mg/m2/day (days -6 to -2). All patients subsequently receive a total of 6 infusions of NK cells administered thrice weekly for two weeks (between days 0-21) and will be followed up to day 56 from first NK cell infusion. Three NK cell dose-levels: 1x107, 3x107 and 1x108 cells/kg/dose will be explored to determine maximum tolerated dose (MTD). 3-18 patients/cohort/dose may be enrolled for MTD determination plus an additional 10 patients/dose in an expansion phase (maximum 28/cohort = 56 total subjects). Primary objective is to determine safety and feasibility of NK cell infusions. Secondary objectives will explore rates of remission PFS, overall survival and measurable residual disease negativity, cell counts, infectious complications, and patients proceeding to transplant. Enrollment in dose level 1 has started. Clinical trial information: NCT04220684 .
Phase Ib study of CPX-351 lower-intensity therapy (LIT) plus venetoclax as first-line treatment for patients with AML who are unfit for intensive chemotherapy (IC).
Authors: Lin Tara L. , Uy Geoffrey L. , Walter Roland B. , Zou Heng , Wang Qi , Faderl Stefan , Cheung Ronald , Pullarkat Vinod A. 
Published: May 2020

TPS7567 Background: CPX-351 (Vyxeos; daunorubicin and cytarabine liposome for injection) is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study in patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML who were fit for IC, CPX-351 significantly improved median survival versus 7+3 cytarabine/daunorubicin and had a comparable safety profile. However, it may not be appropriate to administer CPX-351 at the label dosage in pts unfit for IC. Venetoclax, a BCL-2 inhibitor, has clinical efficacy in combination with low-dose cytarabine in AML pts unfit for IC, and preclinical data suggest a rationale for combining CPX-351 and venetoclax. This study thus evaluates CPX-351 LIT in combination with venetoclax in AML pts unfit for IC. Methods: This is an open-label, multicenter, 2-part, phase 1b study (NCT04038437) to determine the maximum tolerated dose (MTD) and evaluate the safety, efficacy, and pharmacokinetics of CPX-351 LIT plus venetoclax. Key eligibility criteria are shown in the Table. In the dose-escalation phase (3+3 design), up to 24 pts will receive CPX-351 (dose levels: 20, 40, 60, and 75 units/m2) on Days 1 and 3 plus venetoclax 400 mg on Days 2-21 of each cycle to determine the MTD, with each dose escalation confirmed by a safety assessment committee. Pts who achieve complete or partial remission after 1 or 2 cycles may receive up to 4 similar cycles of CPX-351 plus venetoclax. In the expansion phase, an additional 20 pts will be treated at the MTD. All pts are assessed for response by morphology and minimal residual disease testing, and are monitored for safety (until 1 month after end of treatment) and survival (up to 1 year after start of treatment). The study is ongoing and actively enrolling pts. Clinical trial information: NCT04038437 . [Table: see text]
Brentuximab vedotin in combination with nivolumab, doxorubicin, and dacarbazine in newly diagnosed patients with advanced-stage Hodgkin lymphoma (Trial in Progress).
Authors: Friedman Judah D. , Lee Hun Ju , Ho Linda , Flinn Ian 
Published: May 2020

TPS8068 Background: Brentuximab vedotin (BV, ADCETRIS) is approved for the treatment of adults with treatment-naïve Stage III or IV cHL in combination with AVD (Connors 2017). Nivolumab is approved for treatment of adults with relapsed/refractory cHL. Both agents have been well tolerated with promising activity when combined with multi-agent chemotherapy. The combination of BV plus nivolumab was evaluated as a frontline treatment option for patients (pts) with cHL who are over 60 years and ineligible for or declined conventional combination chemotherapy (Friedberg, 2018). The ongoing study reported an ORR of 82% in 11 pts and appears well tolerated in this population. In another trial in 93 patients in the first salvage setting, the combination produced a 67% CR rate (Herrera 2018, Moskowitz 2019) and the majority of patients were able to undergo subsequent stem cell transplant. It is reasonable to expect that the combination of BV, nivolumab, A, and D (AN + AD) will result in high response rates and be well tolerated, with potentially less toxicity. Methods: SGN35-027 (NCT03646123) is a phase 2 study designed to evaluate the efficacy and safety of A+AVD when administered with growth factor prophylaxis in pts with stage III/IV cHL (Part A). Part B will evaluate the combination of AN + AD in a similar patient population. The primary objective of Part B is to estimate the CR rate at EOT in pts with treatment-naïve advanced cHL. Patients in Part B will have Ann Arbor Stage IIB/III/IV cHL or Stage IIA cHL with bulky mediastinal disease. Enrollment is ongoing in both parts of the study. Approximately 50 pts will be enrolled in Part B. All pts will be treated with BV 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2, administered separately by IV infusion on Days 1 and 15 of each 28-day cycle for up to 6 cycles. Efficacy will be assessed by PET/CT scans at C2 and EOT. Disease assessments will be performed periodically during follow up. Disease response and progression will be assessed using Lugano with the incorporation of LYRIC (Cheson 2016). Clinical trial information: NCT03646123 .
POLARGO: Randomized Phase III study of polatuzumab vedotin plus rituximab, gemcitabine, and oxaliplatin (R-GemOx) in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL).
Authors: Haioun Corinne , Matasar Matthew J. , Sancho Juan-Manuel , Viardot Andreas , Hernandez Juana , Perretti Thomas , McMillan Andrew 
Published: May 2020

TPS8070 Background: The antibody-drug conjugate polatuzumab vedotin (pola; POLIVY) targets CD79b on B-cell malignancies. Pola plus bendamustine and rituximab (BR) has significantly improved efficacy vs BR alone in patients (pts) with R/R DLBCL. As a result, pola-BR was approved by the FDA for pts with R/R DLBCL after ≥2 prior therapies. This year, the EU granted conditional marketing authorization for pola-BR in pts with stem cell transplant (SCT)-ineligible R/R DLBCL. A range of therapies are used for R/R DLBCL; one recommended option is R-GemOx. Platinum-based chemotherapies such as oxaliplatin are a preferred salvage therapy. In the POLARGO study, the safety and efficacy of pola-R-GemOx vs R-GemOx alone will be assessed in pts with R/R DLBCL. Methods: POLARGO (MO40598; NCT04182204) is a multicenter, open-label, Phase III study, comprising a safety run-in stage (pola-R-GemOx; n=10) and a randomized controlled trial (RCT) stage (pola-R-GemOx vs R-GemOx alone; expected n=206). Pts must have histologically confirmed R/R DLBCL and ECOG PS of 0–2. Exclusion criteria include prior allogeneic SCT and/or planned autologous/allogeneic SCT, and baseline grade >1 peripheral neuropathy (PN). Pts in the RCT stage will be recruited from 80–90 sites globally. The primary endpoint of the safety run-in stage is the safety and tolerability of pola-R-GemOx (pola, 1.8mg/kg; R, 375mg/m2; Gem, 1000mg/m2; Ox, 100mg/m2) administered in 21-day cycles, with a focus on PN. In the RCT stage, pts will be stratified by number of prior lines of therapy, outcome of last systemic therapy and age, and randomized (1:1) to receive up to eight 21-day cycles of pola-R-GemOx or R-GemOx. The RCT stage primary endpoint is overall survival. Key secondary endpoints are independent review committee-assessed complete response (CR) and objective response rate (ORR; Lugano 2014 criteria). Other secondary efficacy endpoints include investigator-assessed best overall response, CR rate and ORR. Safety and health-related quality of life during treatment will be assessed. PET-CT and CT scans will be obtained at screening, during, and after the treatment period; follow-up will continue for up to 2 years. POLARGO is currently open and recruiting. Acknowledgment: POLARGO is sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing assistance, under the direction of Prof. Haioun, Dr McMillan and Dr Hernandez, was provided by Lucinda Sinclair of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Clinical trial information: NCT04182204 .
GO39775: A multicenter phase I trial evaluating the safety, pharmacokinetics, and activity of BFCR4350A, a FcRH5/CD3 T-cell dependent bispecific antibody, in patients with relapsed or refractory multiple myeloma.
Authors: Cohen Adam D. , Trudel Suzanne , Forsberg Peter A. , Fonseca Rafael , Krishnan Amrita Y. , Spencer Andrew , Berdeja Jesus G. , Hamirani Sarah M. , Li Mengsong , Cooper James , Harrison Simon J. 
Published: May 2020

TPS8551 Background: Multiple myeloma (MM) remains an incurable disease, with estimated median survival of 8–9 months in patients with relapsed or refractory (R/R) disease (Kumar et al. 2014; Usmani et al. 2016). There is no uniform standard of care for R/R MM, and combinations used in later lines have diminishing responses, especially after re-exposure to previously received classes of therapy (Gandhi et al. 2019). New targets and treatment modalities are needed. Fragment crystallizable receptor-like 5 (FcRH5) is expressed on myeloma cells across lines of therapy, and is overexpressed by myeloma cells with 1q21 gain; expression in healthy tissue is restricted to the B-cell lineage, and is retained in plasma cells (Li et al. 2017). BFCR4350A is an IgG-based T-cell-dependent bispecific antibody that was specifically engineered to target the most membrane-proximal domain of FcRH5 on myeloma cells and cluster of differentiation 3 (CD3) on T cells, with dual binding resulting in efficient immune synapse formation and T-cell killing of myeloma cells. BFCR4350A demonstrates potent killing of plasma cells and patient-derived myeloma cells (including those with low levels of FcRH5 expression) in vitro, and complete depletion of bone marrow plasma cells in primates, without severe or prolonged cytokine release (Li et al. 2017). GO39775 (NCT03275103) is an open-label, multicenter Phase I dose-escalation and dose-expansion trial evaluating the safety, pharmacokinetics (PK), and activity of BFCR4350A monotherapy in patients with R/R MM. Methods: Patients must be aged ≥18 years and must have R/R MM for which no established therapies are available or appropriate, or be intolerant to those therapies. Patients with prior CAR-T therapy and/or prior BCMA-directed therapy are not excluded. BFCR4350A is administered by intravenous infusion, and q3w dosing with Cycle 1 single-step or multi-step dosing is being investigated in dose-escalation (Arms A and B, respectively). Enrolment into both arms is ongoing, with patients receiving up to 17 cycles of treatment until disease progression or unacceptable toxicity. Primary objectives are to evaluate safety (including the maximum tolerated dose and dose-limiting toxicities) and to identify a recommended Phase II dose. Secondary objectives include assessment of PK, activity, immunogenicity, and pharmacodynamic biomarkers. Clinical trial information: NCT03275103 .