bluuebunny/crossref_metadata_2025 huggingface dataset:
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 .
DREAMM-5 platform trial: Belantamab mafodotin in combination with novel agents in patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Biswas Swethajit , Holkova Beata , Jackson Nicola , Netherway Thelma , Paul Sofia , Ferron-Brady Geraldine , Yeakey Anne , Shelton Chris , Montes de Oca Rocio , Ahlers Christoph Matthias , Ballas Marc S. , Paul Elaine Marie , Gupta Ira , Opalinska Joanna , Luptakova Katarina
Published: May 2020

TPS8552

Background: Single-agent belantamab mafodotin (GSK2857916), a B-cell maturation antigen targeting immunoconjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile (DREAMM-2, NCT03525678, Lancet Oncol.2020). A platform trial design allows efficient evaluation of belantamab mafodotin in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4 inducible T-cell costimulatory (ICOS) agonist, and a gamma-secretase inhibitor. The unique, multimodal mechanisms of action (MoAs) of belantamab mafodotin, in combination with MoAs of these agents, has the potential to achieve synergistic effects in MM, to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04162210) utilizes a master protocol with separate sub-studies comprised of sequential dose exploration (DE) and cohort expansion (CE) phases, to identify promising, effective belantamab mafodotin combinations when compared with a shared belantamab mafodotin monotherapy control arm (CE phase only). DE phases consist of multiple dosing cohorts with belantamab mafodotin combinations where patients are assigned to treatment slots by predetermined algorithmic approach (modified toxicity probability interval; N≤10 per cohort). Recommended phase 2 doses (RP2D) will be based on dose-limiting toxicities, safety, and pharmacokinetics. Interim analyses, based on overall response rate (ORR), determine if a RP2D is moved forward to a CE phase (N≥35 per cohort). Patients in the CE (stratified by number of prior therapies) will be randomized equally to open sub-studies. Eligible patients will have received ≥3 prior therapy lines which must include ≥1 immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. The primary objectives are to identify RP2D for each combination (DE phase) and ORR (≥partial response, CE phase). Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GlaxoSmithKline (207495). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04162210 .
A phase Ib/II study of niraparib plus temozolomide plus atezolizumab versus atezolizumab as maintenance therapy in extensive-stage small cell lung cancer (TRIO-US L-06).
Authors: Cummings Amy Lauren , Kim David Dae-Young , Rosen Lee S. , Garon Edward B. , Wainberg Zev A. , Slamon Dennis J. , Goldman Jonathan Wade
Published: May 2020

TPS9084

Background: Maintenance therapy is a promising therapeutic approach for extensive-stage small cell lung cancer (ES-SCLC), especially in light of IMpower 133 (Horn NEJM 2018). SCLC models of poly (ADP-ribose) polymerase (PARP) protein 1 and 2 inhibition suggested synergy with temozolomide (TMZ) (Wainberg AACR 2016). Combining PARP inhibition and TMZ with atezolizumab after first-line therapy for ES-SCLC may improve disease control. Methods: This is a phase 1b/2, randomized, open-label study of TMZ plus niraparib, a PARP inhibitor, with atezolizumab versus atezolizumab as maintenance therapy in adult patients with ES-SCLC after completion of platinum-based first-line chemotherapy. The primary outcome for phase 1b is the RP2D of TMZ in combination with niraparib, and for phase 2, progression-free survival (PFS). Secondary endpoints include safety, objective response rate, and overall survival. Exploratory endpoints include adverse events and patient-reported outcomes, including health-related quality of life. Phase 1b participants are required to have an advanced and incurable solid malignancy. Part one of phase 1b includes an accelerated lead-in of 12 participants treated in cohorts of 6 with an initial dose level of niraparib 200 mg po daily in 28-day cycles and low-dose TMZ 40 mg po daily on days 1-5 of each cycle. Part two includes a safety lead-in of 6 patients receiving standard-of-care atezolizumab, to which R2PD niraparib and TMZ will be added. For phase 2, participants are required to have ES-SCLC with a complete response or partial response per RECIST 1.1 following 4 to 6 cycles of platinum-based chemotherapy and ability to proceed to randomization within 7 weeks after day 1 of the last cycle of prior chemotherapy. Prophylactic WBRT is allowed prior to study. 52 participants will be stratified by a history of brain metastases and randomized 1:1 to atezolizumab with or without RP2D niraparib plus TMZ. There will be no cross-over between arms. To date, cohort 1 had two DLTs. Enrollment to dose level -1 and an intermediate dose have been completed without a DLT. The atezolizumab safety lead-in begins enrollment in March 2020. Clinical trial information: NCT03830918.
A phase II randomized study of telaglenastat, a glutaminase (GLS) inhibitor, versus placebo, in combination with pembrolizumab (Pembro) and chemotherapy as first-line treatment for KEAP1/NRF2-mutated non-squamous metastatic non-small cell lung cancer (mNSCLC).
Authors: Skoulidis Ferdinandos , Neal Joel W. , Akerley Wallace L. , Paik Paul K. , Papagiannakopoulos Thales , Reckamp Karen L. , Riess Jonathan W. , Jenkins Yonchu , Holland Sacha , Parlati Francesco , Shen Yijing , Whiting Sam H. , Rizvi Naiyer A.
Published: May 2020

TPS9627

Background: Mutational activation of the KEAP1/NRF2 pathway occurs in >20% of NSCLC patients (pts). KEAP1/NRF2 activation protects tumor cells from diverse forms of oxidative stress and promotes tumor growth and survival. In pts w/ advanced NSCLC, mutation of the KEAP1/NRF2 pathway is associated w/ dramatically reduced survival and poor outcomes following standard-of-care therapy. These tumors have increased dependence on GLS-mediated conversion of glutamine to glutamate due to upregulation of NRF2 target genes involved in glutamine metabolism. Telaglenastat (CB-839), an investigational, first-in-class, potent, oral GLS inhibitor, has demonstrated preclinical activity in KEAP1/NRF2-mutated NSCLC cell lines and xenograft models. This study will evaluate the safety and efficacy of telaglenastat + standard-of-care pembro and chemotherapy as 1L therapy for KEAP1/NRF2-mutated non-squamous mNSCLC (NCT04265534). Methods: This phase II, randomized, multicenter, double-blind study will enroll ~120 pts with histologically or cytologically documented stage IV non-squamous NSCLC w/ KEAP1 or NRF2 mutation, no prior systemic therapy for mNSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, and no EGFR, ALK, ROS, or other actionable mutation w/ available approved therapy in 1L setting. KEAP1 or NRF2 mutations will be determined by next generation sequencing (NGS), and study-provided liquid biopsy NGS will be available. Pts will be randomized 1:1 to receive telaglenastat (800 mg BID PO) or placebo, in combination with pembro, carboplatin, and pemetrexed at standard doses on day 1 of each 21-day cycle. Pts will be stratified by STK11/LKB1 mutational status and M stage of cancer (M1a-b vs M1c). The study will include an initial safety run-in period (n=12; 1 cycle). Co-primary endpoints are safety and investigator-assessed progression-free survival (RECIST v1.1). Secondary endpoints include overall response rate, duration of response, overall survival, and efficacy analysis in the subgroup of pts w/ biochemical confirmation of KEAP1/NRF2 pathway activation. Findings of this novel NGS biomarker-selected study will inform the efficacy and safety profile of telaglenastat + standard-of-care chemoimmunotherapy for 1L treatment of KEAP1/NRF2-mutated, non-squamous mNSCLC. Clinical trial information: NCT04265534 .
Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE).
Authors: Percent Ivor John , Reynolds Craig H. , Konduri Kartik , Whitehurst Matthew Thomas , Nidhiry Emmanuel A. , Yanagihara Ronald H. , Nagasaka Misako , Schreeder Marshall T , Uyeki James , Azzi Georges , Pachipala Krishna Kishore , Comer Jason C. , Lerner Rachel E. , Leal Ticiana , Alvarez Delia , Neuteboom Saskia T.C. , Reddinger Natasha , yan xiaohong , Shazer Ronald L. , Waterhouse David Michael
Published: May 2020

TPS9635

Background: Sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and split (VEGFR2/KIT) family receptor tyrosine kinases (RTKs), as well as MET. Inhibition of TAM RTKs may promote the depletion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) and repolarize tumor associated macrophages towards the pro-inflammatory M1 phenotype. Inhibition of the split RTKs may reduce immunosuppressive regulatory T cells in addition to MDSCs within the TME. Given these pleiotropic immune-stimulating effects, sitravatinib may reverse resistance to checkpoint inhibitor therapy (CIT) and augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study (MRTX-500) demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on or after CIT. Methods: Global, randomized, open-label, Phase 3 study of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have progressed on or after CIT. Pts must have also received platinum-based chemotherapy either in combination with CIT or prior to CIT. Pts are randomized (1:1) to receive oral sitravatinib 120 mg once daily in continuous 28-day cycles combined with nivolumab IV 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m2 IV every 3 weeks. Patients are stratified based on number of prior treatment regimens in the advanced setting, ECOG performance status, and presence of brain metastases. Key eligibility criteria include duration of treatment of CIT of at least 4 months, discontinuation of prior treatment with CIT < 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is overall survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will review safety at regular intervals and efficacy at a planned interim analysis based on OS. Enrollment is ongoing. Clinical trial information: NCT03906071 .
TRIDENT-1: A global, multicenter, open-label Phase II study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements.
Authors: Doebele Robert Charles , Lin Jessica Jiyeong , Nagasaka Misako , Zhu Viola Weijia , Gabrail Nashat Y. , Bazhenova Lyudmila , Anderson Peter Meade , Solomon Benjamin J. , Dudek Arkadiusz Z. , Pippas Andrew William , Shirinian Mihran , Baik Christina S , Stopatschinskaja Shanna , Camidge D. Ross , Cho Byoung Chul , Drilon Alexander E.
Published: May 2020

TPS9637

Background: Repotrectinib is a next-generation ROS1/TRK inhibitor with > 90-fold greater potency than crizotinib against ROS1 and > 100-fold greater potency than larotrectinib against TRK. Preclinical studies demonstrated inhibitory activity of repotrectinib against ROS1 resistance mutations, including the solvent-front mutation (SFM) G2032R. In the phase 1 portion of the study, repotrectinib was found to be well tolerated with encouraging antitumor activity including a 91% confirmed overall response (cORR) in TKI-naïve ROS1+ NSCLC pts. In ROS1+ NSCLC pts who received 1 prior chemo and 1 prior TKI, the cORR was 57% at the clinical dose of 160 mg QD or above. Intra-cranial (IC) activity was observed in ROS1+ NSCLC pts with measurable CNS disease (100% IC-ORR in TKI-naïve and 75% IC-ORR in patients with 1 prior TKI). Encouraging antitumor activity was observed in pts with NTRK+ solid tumors. Methods: A global phase 2 study was initiated and is actively enrolling. The primary endpoint for the Phase 2 study is cORR assessed by BICR (Blinded Independent Central Review) using RECIST v1.1, in each expansion cohort in pts with advanced solid tumors that harbor a ROS1 or NTRK1/2/3 gene fusion. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), IC-ORR, IC-PFS, and quality of life assessments. All pts need to have RECIST 1.1 measurable disease confirmed by BICR and ECOG performance score ≤1. Repotrectinib is administered at 160 mg QD for 14 days and, if tolerated, the dose can be increased to 160 mg BID. Approximately 320 pts (≥12 years old) will be enrolled into 6 defined expansion cohorts, depending on the status of previous treatment with TKIs and cancer types (see table below). Clinical trial information: NCT03093116 . [Table: see text]
Development and Validation of Criteria for Sparing Confirmatory Tests in Diagnosing Primary Aldosteronism
Authors: Wang Kanran , Hu Jinbo , Yang Jun , Song Ying , Fuller Peter J , Hashimura Hikaru , He Wenwen , Feng Zhengping , Cheng Qingfeng , Du Zhipeng , Wang Zhihong , Ma Linqiang , Yang Shumin , Li Qifu
Published: May 2020

Context

The Endocrine Society Guidelines for the diagnosis of primary aldosteronism (PA) suggest that confirmatory tests (CFT) are not required when the following criteria are met: plasma aldosterone concentration (PAC) is >20 ng/dL, plasma renin is below detection levels, and hypokalemia is present. The evidence for the applicability of the guideline criteria is limited.

Objective

To develop and validate optimized criteria for sparing CFT in the diagnosis of PA.

Design and Setting

The optimized criteria were developed in a Chinese cohort using the captopril challenge test, verified by saline infusion test (SIT) and fludrocortisone suppression test (FST), and validated in an Australian cohort.

Participants

Hypertensive patients who completed PA screening and CFT.

Main Outcome Measure

Diagnostic value of the optimized criteria.

Results

In the development cohort (518 PA and 266 non-PA), hypokalemia, PAC, and plasma renin concentration (PRC) were selected as diagnostic indicators by multivariate logistic analyses. The combination of PAC >20 ng/dL plus PRC <2.5 μIU/mL plus hypokalemia had much higher sensitivity than the guideline criteria (0.36 vs 0.11). The optimized criteria remained superior when the SIT or FST were used as CFT. Non-PA patients were not misdiagnosed by either criteria, but the percentage of patients in whom CFT could be spared was higher with the optimized criteria. In the validation cohort (125 PA and 81 non-PA), the sensitivity of the optimized criteria was also significantly higher (0.12 vs 0.02).

Conclusions

Hypertensive patients with PAC >20 ng/dL, PRC <2.5 μIU/mL, plus hypokalemia can be confidently diagnosed with PA without confirmatory tests.
Expression of SOAT1 in Adrenocortical Carcinoma and Response to Mitotane Monotherapy: An ENSAT Multicenter Study
Authors: Weigand Isabel , Altieri Barbara , Lacombe Amanda M F , Basile Vittoria , Kircher Stefan , Landwehr Laura-Sophie , Schreiner Jochen , Zerbini Maria C N , Ronchi Cristina L , Megerle Felix , Berruti Alfredo , Canu Letizia , Volante Marco , Paiva Isabel , Della Casa Silvia , Sbiera Silviu , Fassnacht Martin , Fragoso Maria Candida B V , Terzolo Massimo , Kroiss Matthias
Published: May 2020

Context

Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells.

Objective

To investigate SOAT1 protein expression as a marker of treatment response to mitotane.

Patients

A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens.

Setting

Retrospective study at 12 ACC referral centers.

Main outcome measure

Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS).

Results

Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different.

Conclusions

SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.
Diversification As a Strategy of Risk Reduction in Credit Load of Enterprises of Defense Industry Complex
Authors: Basov A.
Published: May 2020

Diversification can be used as a strategy to neutralize the risk of insolvency of the defense industry if it is considered as a diversification of independent sources of incoming cash flows. At the same time, the directions for obtaining new sources of cash flows are determined based on the possibilities of developing the company's resources within the framework of its resource model, with which the company is going to overcome competitors.
A cost–benefit analysis of hospital diagnostic imaging services in public hospital units in Greece
Authors: Zarakovitis Dimitrios A , Tsoromokos Dimitrios , Tsaloukidis Nikolaos , Lazakidou Athina
Published: May 2020

This study involved a financial analysis of five Greek public hospital units in the sixth health region from 2012–15. Geographical information systems can be used for the rational management of diagnostic imaging examinations as they allow users to exchange large volumes of financial data very quickly and their statistics allow users to estimate a number of financial indicators. The data include the cost of radiology departments, total cost, revenue, number of magnetic resonance imaging exams and number of hospital beds. Statistical Package for the Social Sciences analysis shows a strong linear correlation between the number of magnetic resonance imaging exams and hospital beds. The majority of hospital units display an overtime revenue increase of magnetic resonance imaging exams in 2012–14. In 2013–15 the cost of radiology departments (a major part of the total cost for the majority of hospital units) decreased by 2–76%.
Learning when to give up (or not)
Authors: Hancock Dave
Published: May 2020

Admitting an initiative is failing and deciding when to discontinue pursuing it can be difficult. The dilemma of knowing when to cut your losses has been studied by academics, as Dave Hancock explains
New tax rules make electric vehicles an attractive option
Authors: Harvey Jonathan
Published: May 2020

Jonathan Harvey, a tax specialist at chartered accountants MHA MacIntyre Hudson, provides a guide to tax changes introduced on 6 April 2020 to encourage the uptake of more environmentally-friendly cars
Parental requests for access to children's records
Authors: Birch Rachael
Published: May 2020

Dr Rachel Birch, Medicolegal Consultant at Medical Protection advises on handling a dilemma with regard to the disclosure of a child's medical records
Acute pancreatitis in canine patients
Authors: Welsh Louise
Published: May 2020

Canine acute pancreatitis (AP) is now commonly seen in veterinary practice. AP can be challenging to manage and patients may require intensive nursing care. This article aims to explain the pathophysiology of the disease, some of the common clinical findings, diagnostic testing available and treatment required by these patients. It will focus on the specific nursing care: analgesia and nutrition. The use of early enteral nutrition (EN) is now a well-established treatment method in human medicine for patients with pancreatitis, and should be considered in veterinary patients also. The benefits of EN over parenteral nutrition (PN) and suggested routes of administration will be discussed.
How to get the most from blood samples: a guide to producing diagnostic blood smears
Authors: Jones Marie , Arnfield David , Barber Paul
Published: May 2020

The production of high-quality diagnostic blood smears is a skill often overlooked in first opinion veterinary practices despite their usefulness in providing diagnostic information that would otherwise be omitted from results generated from automated analysers. Well made, well stained diagnostic blood smears can instantly provide vital information regarding the health of the patient and even provide a diagnosis. However, making quality blood smears is open to intraspecific and interspecific observer error and therefore this article aims to provide best practice guidelines along with a comprehensive troubleshooting guide to aid veterinary clinicians, nurses, technicians and students in the production of diagnostic blood smears.
Más sobre el lugar de las mujeres en la campaña norte de Buenos Aires. San Vicente, 1869-1895
Authors: Contente Claudia
Published: May 2020

Nos proponemos explorar la complejidad del trabajo femenino en el norte de la provincia de Buenos Aires y su evolución entre dos años extremos: 1869 y 1895, que corresponden a los dos primeros censos nacionales argentinos. Nos basaremos en las cédulas censales de San Vicente, una zona rural representativa, y en proceso de urbanización que, en aquel momento, recibía un importante fl ujo migratorio. Analizaremos la evolución de las actividades productivas del conjunto de la población, prestando particular atención a las tareas femeninas y sus características según el estado civil y nacionalidades a fi n de detectar los cambios producidos durante ese periodo de importantes transformaciones sociales y económicas.
A távmunka menedzselésének problémái a HR-menedzser és a pszichológus szemszögéből
Authors: Gulyás László , Turcsányi Enikő
Published: May 2020

Nowadays there are more and more atypical work-foim, one of them is teleworking, which has more and more significant part of labour market of both USA and EU. According to the forecast, the number of this type of workers will grow rapidly. Parallel this, human and organizational problems will arise because of typical character of this type of work. One author of this paper is psychologist, the other one is HR-manager, both of them investigate the human and organisational problems arising from teleworking, from their point of view.
A kukoricapiac és a bioetanol termelés hazai persektívái
Authors: Czagány László
Published: May 2020

The EU's grain intervention system brought the Hungarian corn producers into a favorable situation. In the last years record breaking quantities of corn were produced, and a large part of it was offered for intervention procurement. More than 90% of the Union's intervention corn stocks are in Hungary. The European Commission decided on a gradual abolishment of the corn intervention. Hungarian corn producers, however, will not see a decline in their market position, because volume of ethanol fuel production is expected to rise in the coming years, with a substantial demand for raw material. Experts think, that Hungarian development plans are exaggerated, because they are not validated by either corn production capacity, or prospective demand for ethanol fuel.
A környezeti piac néhány munkaerőpiaci és logisztikai összefüggése az elmúlt évtizedben
Authors: Gál József
Published: May 2020

Environmental market is much more than environmental protection. We must survey it in its economical, sociological etc. aspects. In my paper I try to find some interesting connecting points how to meet labour market, logistics of material, people and knowledge. Number of employees in this sector is increasing fluently, but you can see big gap among different parts of Europe. We know pollution and environmental protection do not stop at frontiers of countries, therefore must understand flows and find common solutions.