bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant HER2-targeted therapy ± immunotherapy with pembrolizumab (neoHIP): An open label randomized phase II trial.
Authors: McArthur Heather L. , Leal Jorge , Shiao Stephen Lawrence , Carter Meredith , Basho Reva K , Phillips Michelle , Chan David , Hool Hugo , Park Dorothy J. , El-Masry Mary , McAndrew Philomena , Sikaria Swati , Spring Laura , Bardia Aditya , Tighiouart Mourad , Dadmanesh Farnaz , Giuliano Armando E. , Sanchez Katherine , Page David B. 
Published: June 2023

TPS634 Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxics; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: Patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer are being randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts received T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts received THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts received TH-K. After enrollment of 22 pts to arm C, a prespecified interim efficacy analysis was conducted, and enrollment to this arm was subsequently terminated. Enrollment to the other arms continues with 32/58 pts enrolled to arm A and 33/58 pts enrolled to arm B as of 2/14/2023. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion per local clinical standard. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Clinical trial information: NCT03747120 .
The FOR ME (Fostering Opportunities in Research through Messaging and Education) study: Developing a culturally sensitive narrative intervention to promote equity in clinical trials.
Authors: Hippalgaonkar Neha , Nguyen Ryan Huu-Tuan , Carnahan Leslie , Henderson Vida , Cohn Eliza Brumer , Mersha Tigist , Salum Kauthar , Williams Ana , Khosla Paramjeet Grewal , Murphy Anne Marie , Coleman Lolita , Brent Beluah , Hoskins Kent 
Published: June 2023

TPS6653 Background: Black women are more likely to die from breast cancer than women of any other race/ethnicity. Contributing factors to this inequity include structural and socioeconomic determinants of health, differential access to novel therapies, tumor biology and comorbidities. In 2020, only 7.2% of enrollees in clinical trials that led to approval of 3 novel drugs for breast cancer were Black. Underrepresentation of patients from racial/ethnic minority groups in clinical trials is a contributing factor to health disparities. The first aim of this study is to conduct multiple qualitative methods with multi-level stakeholders to identify barriers, facilitators, and intervention priorities that would assist Black breast cancer patients to make informed decisions about participating in clinical trials. Secondly, we aim to create a culturally sensitive, narrative intervention designed to support decision making and motivate Black breast cancer patients to participate in clinical trials. Aim 3 will pilot a study to determine acceptability of the intervention among patients and assess whether it increases clinical trial participation in a safety net oncology practice. Methods: Community-based participatory research approaches are guiding our research methodologies. First, we are conducting interviews and story circles with Black women with breast cancer, community partners and advocates, and oncologists and clinical trials office staff. These interviews will identify themes to inform intervention content. Next, interviews and focus groups will invite feedback on the educational/motivational content of the intervention and will be used to develop a culturally sensitive script and storyboards. A video production company will produce the narrative intervention. Finally, focus groups and interviews with participant cohorts will provide feedback on the completed intervention. Black women diagnosed with breast cancer will view the intervention in an oncology clinic. Using a pretest/posttest design, we will analyze the acceptability of the intervention and its effect on intention to participate in clinical trials. We will then conduct a quasi-experimental study in a safety net oncology practice to determine whether the rate of clinical trial participation among Black breast cancer patients increases following implementation of the intervention as a standard component of new patient education. Recruitment started in July 2022, and currently, 14 of 30 interviews with patients are completed. Aim 1 interviews with patients, oncologists, clinical trial staff, and advocates are expected to finish by April 2023, and results will be presented.
Phase 1 study of ziftomenib (KO-539) in combination with venetoclax or venetoclax/azacitidine or standard induction cytarabine/daunorubicin (7+3) chemotherapy for the treatment of patients with acute myeloid leukemia.
Authors: Zeidan Amer Methqal , Fathi Amir Tahmasb , Issa Ghayas C. , Erba Harry Paul , Ahsan Julie , Corum Daniel , Tomkinson Blake E. , Kozlek Tom , Leoni Mollie , Wang Eunice S. 
Published: June 2023

TPS7079 Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) represent a high unmet need. Ziftomenib is a potent and selective inhibitor that targets the menin-mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A) interaction driving leukemogenesis in these subtypes. An ongoing Phase 1/2 study (KO-MEN 001) has demonstrated meaningful clinical activity and tolerability with ziftomenib monotherapy in R/R AML. In preclinical testing, ziftomenib combined with venetoclax induced synergistic lethality in KMT2A-r and NPM1-m human AML cell lines and patient-derived cells. Moreover, treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2A-r AML xenografts. Therefore, administration of ziftomenib in combination with standard-of-care (SOC) therapies may provide additional clinical benefit for patients with newly diagnosed or R/R NPM1-m and KMT2A-r menin-dependent AML. Methods: KOMET-007 (KO-MEN-007, NCT# ) is a 2-part dose escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with non-intensive chemotherapy (NIC) and intensive chemotherapy (IC) in patients with NPM1-m and KMT2A-r AML. During Phase 1a, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts ( NPM1-m and KMT2A-r) using a rule-based approach (n = 6 per cohort/dose level) to select ziftomenib doses for expansion/validation in Phase 1b. The Phase 1b portion will also evaluate zifto/ven/aza in newly diagnosed AML ( KMT2A-r and NPM1-m) and zifto/ven in R/R AML ( NPM1-m only). The overall primary objectives are to establish the minimum biologically effective, dose limiting toxicities, and recommended Phase 2 dose of ziftomenib combined with NIC and IC backbones in each genetically defined cohort. Additional secondary endpoints include preliminary antileukemic efficacy (including MRD-negative responses and number of patients able to transition to subsequent allogeneic stem cell transplant), pharmacokinetic, and pharmacodynamic data. Exploratory end points include biomarkers for efficacy and resistance, pharmacodynamic biomarkers and activity in isolated myeloid sarcoma. Clinical trial information: NCT04067336 .
A phase I study of MEK inhibitor selumetinib in combination with azacitidine in patients with higher-risk chronic myeloid neoplasia.
Authors: Roloff Gregory , Patel Anand Ashwin , Pettit Kristen M , Thirman Michael J. , Larson Richard A. , Nawas Mariam , Kosuri Satyajit , Drazer Michael William , Fulton Noreen , Weiner Howard , Stock Wendy , Liu Hongtao , Odenike Olatoyosi 
Published: June 2023

TPS7084 Background: Myelodysplastic syndrome (MDS), Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes present significant clinical challenges for patients deemed transplant ineligible, and who are relapsed or refractory to conventional therapies. RAS-pathway activating mutations in myeloid malignancies are associated with a proliferative phenotype and contribute to disease progression. Cooperation between RAS-dependent signaling and epigenetic dysregulation provides the basis for rationally designed combination studies. Selumetinib (AZD6244) is a potent, selective, orally bioavailable, and non-ATP competitive small molecule inhibitor of MEK1/2, downstream of RAS. Methods: This is an investigator-initiated, Phase I, open-label dose-escalation study of selumetinib in combination with azacitidine for patients with higher risk MDS, MDS/MPNs, and myelofibrosis. The trial will enroll patients with high-risk myeloid neoplasms that meet disease-specific criteria for MDS or MPNs and who require treatment. This phase I study follows a 3+3 dose-escalation design, with three planned dose levels across two different cohorts (A and B). The dose of azacitidine 75 mg/m2 will remain stable, with three planned selumetinib dose levels (50 mg, 75 mg, and 100mg, respectively) across the two cohorts. Azacitidine will be given on days 1-7 followed by selumetinib from days 7-21 of 28 day cycles. Cohort A includes subjects with MDS with relapsed/refractory disease requiring therapy and MDS/MPN overlap syndromes; Cohort B includes subjects with myelofibrosis refractory or intolerant to JAK inhibitor therapy or ineligible for ruxolitinib treatment given baseline cytopenias (thrombocytopenia < 50,000/uL, anemia < 9 g/dL, and/or red cell transfusion dependent). The trial has an enrollment goal of 18 to 24 subjects, and treatment will continue indefinitely if the patient continues to derive benefit. Dose escalation will proceed independently within both cohorts. Cohort A is nearing completion of enrollment and cohort B is actively enrolling. The primary objective is to determine the maximum tolerated dose of selumetinib in combination with azacitidine. Select secondary and exploratory objectives include describing the preliminary clinical response rates and observing relationships between the presence of RAS activating mutations, RAS pathway activation, and clinical response. Clinical trial information: NCT03326310 .
Phase 1b clinical study of IRAK 1/4 inhibition for low-risk myelodysplastic syndromes refractory/resistant to prior therapies.
Authors: Garcia-Manero Guillermo , Yan Lucy , Dummer Wolfgang 
Published: June 2023

TPS7085 Background: Chronic stimulation of both interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to cause a bone marrow proinflammatory environment responsible for persistent cytopenia in patients with low-risk (LR)-MDS. IRAK1 and IRAK4 are serine/threonine kinases that are critical for the downstream signaling of IL-1R and most TLRs resulting in the production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis leading to bone marrow inflammation and cell death. Thus, IRAK1/4 inhibition is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow allowing the restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases and inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 healthy volunteer study (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the trial supported the advancement of R289 into further studies. An open-label Phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The current study (NCT05308264) includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria will include prior treatment for MDS that concluded <4 weeks prior to study treatment. Dose Escalation Phase: Dose escalation will utilize a 3+3 design to determine the maximum tolerated dose (MTD). R289 tablets can be taken orally with or without food. Dose limiting toxicity (DLT) will be assessed at each dose level. The DLT evaluation period will be 28 days. After completion of the DLT evaluation period, patients who do not experience DLTs may remain on treatment at their respective dose level if they continue to demonstrate clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled; the primary endpoint of the study will be the safety and tolerability of R289. The secondary endpoints will include an assessment of preliminary efficacy and characterization of the pharmacokinetics of R289. R289 will be administered to all patients at a dose not to exceed the MTD determined in the Dose Escalation Phase. The trial is currently recruiting at 8 US sites. Clinical trial information: NCT05308264 .
A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.
Authors: Bewersdorf Jan Philipp , Verstovsek Srdan , Derkach Andriy , Masarova Lucia , Pemmaraju Naveen , Stein Eytan M. , Mauro Michael J. , Rampal Raajit , Bose Prithviraj 
Published: June 2023

TPS7086 Background: Patients (pts) with myelofibrosis (MF) have a reduced life-expectancy compared to age-matched controls. Several oral Janus Kinase (JAK) inhibitors such as ruxolitinib (RUX) have been approved by the US FDA based on improvements in symptom burden and spleen volume reduction compared to physician’s choice of best available therapy. However, duration of response to these agents is generally time-limited and treatment with JAK inhibitors is not considered to have disease-modifying potential. Additionally, median overall survival after RUX discontinuation is only 11-14 months. Thus, novel mechanism-based therapies for pts with disease progression on RUX are needed. JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A, which is also upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D have also been implicated in MF pathogenesis. Finally, we and others have shown that combination of the CDK4/6 inhibitors and RUX had synergistic effects in murine models of MF (Rampal et al., CCR 2021) providing the preclinical rationale for this trial. Methods: This multicenter, phase I dose-escalation trial (NCT05714072) evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. Among the currently FDA-approved CDK4/6 inhibitors, abemaciclib was chosen for combination therapy due to less myelosuppressive effects compared with other CDK4/6 inhibitors. Inadequate response to RUX is defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms, as defined by the presence of one symptom score ≥5 or two symptom scores ≥3 using the screening MPN-SAF TSS. Following a conventional “3+3” dose-escalation design, pts will be treated with increasing doses of abemaciclib and stable doses of RUX (10mg or 15mg BID). The primary endpoint is to determine the maximum tolerated dose of RUX + abemaciclib. Secondary endpoints include measures of efficacy. Exploratory endpoints include changes in allele fraction of driver mutations, gene expression profiling, and clonal architecture to identify biomarkers of response, mechanisms of resistance, and to assess for any disease-modifying effects of the combination therapy. This trial is open to enrollment at Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center. Clinical trial information: NCT05714072 .
waveLINE-006: A phase 2 study of the safety and efficacy of zilovertamab vedotin as monotherapy or in combination in patients (pts) with aggressive and indolent B-cell malignancies.
Authors: Zinzani Pier Luigi , Mayer Jiri , Benjamini Ohad , Berkovits Alejandro , Glimelius Ingrid , Stevens Don A. , Chaudhry Arvind , Muzaffer Demir Ahmet , Garcia Sanz Ramón , Seog Kim Won , Li Fei , Halka Janusz , Marin-Niebla Ana , Ozcan Muhit , Paszkiewicz-Kozik Ewa , Santoro Armando , Ren Yixin , Ogbu Uzor , Marinello Patricia , Jurczak Wojciech 
Published: June 2023

TPS7595 Background: ROR1 is a transmembrane protein expressed in hematologic malignancies. Zilovertamab vedotin (ZV) is an antibody-drug conjugate comprising a humanized IgG1 monoclonal anti-ROR1, a proteolytically cleavable linker, and the antimicrotubule agent monomethyl auristatin E. Nemtabrutinib is a reversible inhibitor of Brutons tyrosine kinase (BTK). The combination of ZV and a BTKi has the potential for improved responses in B-cell malignancies. The waveLINE-006 study (NCT05458297) is designed to investigate safety and efficacy of ZV as monotherapy or in combination with nemtabrutinib in pts with B-cell malignancies. Methods: Eligible pts are ≥18 years old with biopsy-proven and/or histologically confirmed mantle cell lymphoma (MCL), Richters transformation (RT), chronic lymphocytic leukemia (CLL), or follicular lymphoma (FL), relapsed or refractory (R/R) disease, ECOG performance status of 0 to 2, and adequate organ function (table). Approximately 275 pts will be enrolled in 6 cohorts (A-F; see table). In cohorts A and B, patients will receive ZV 2.5 mg/kg IV Q3W. In cohort C, 30 patients will be enrolled in a safety run-in phase of ZV in combination with nemtabrutinib, then an additional 15 patients will receive the RP2D of the combination. Patients in cohort D (schedule optimization) will be randomized 1:1 to receive ZV 2.5 mg/kg IV Q3W (arm 1) or ZV 2.0 mg/kg IV Q2/3W (arm 2). Patients in cohorts E and F (efficacy expansion) will receive the dose and schedule of ZV determined during schedule optimization. Each recipient of ZV or nemtabrutinib will receive the assigned intervention until disease progression, unacceptable toxicity, or other discontinuation criteria are met. Tumor scans will be performed at baseline, then Q12W up to week 108, then Q24W thereafter. Adverse events (AEs) will be monitored and will be graded per NCI CTCAE version 5. The primary end points are the safety and tolerability of ZV alone (cohort D) and in combination with nemtabrutinib (cohort C), and the objective response rate of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C). The secondary end points are the duration of response of ZV alone (cohorts A, B, D, E, and F) and in combination with nemtabrutinib (cohort C) and the safety and tolerability of ZV alone (cohorts A, B, E, and F). Clinical trial information: NCT05458297 . [Table: see text]
MagnetisMM-6: An open-label, multicenter, randomized phase 3 study of elranatamab + daratumumab + lenalidomide (EDR) versus daratumumab + lenalidomide + dexamethasone (DRd) in transplant ineligible (TI) patients with newly diagnosed multiple myeloma (NDMM).
Authors: Grosicki Sebastian , Yeh Su-Peng , Huang Jeffrey S.Y. , Byun Ja Min , DiRienzo Christine , Viqueira Andrea 
Published: June 2023

TPS8065 Background: Elranatamab, a humanized bispecific antibody targeting B cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, has shown promising efficacy and acceptable safety in clinical studies, as monotherapy (MagnetisMM-3, NCT04649359) and in combination with daratumumab (MagnetisMM-5, NCT05020236), in the treatment of patients with relapsed/refractory multiple myeloma (RRMM). Despite recent advances in the treatment of NDMM, MM remains incurable and more effective treatment options are needed. The aim of the MagnetisMM-6 study (NCT05623020) is to evaluate EDR versus DRd for TI patients with NDMM. Methods: MagnetisMM-6 is an ongoing, open-label, 2-arm, multicenter, randomized phase 3 study estimated to enroll ~646 patients. There are 2 parts: Part 1 evaluates the safety and recommended phase 3 dose (RP3D) of EDR: Part 2 evaluates the efficacy and safety of EDR at RP3D vs DRd in TI patients with NDMM. TI is defined as age ≥65 or age < 65 with comorbidities impacting the possibility of transplant. The primary endpoints of Part 2 are minimal residual disease (MRD) at 12 mo and progression-free survival. Secondary endpoints include overall and sustained MRD negativity rates, duration of MRD negativity, objective response rate, complete response (CR) rate, time to response, duration of response, duration of CR, overall survival, safety, quality of life, immunogenicity, and pharmacokinetics. Part 1 includes TI patients with NDMM as well as patients with RRMM who have received 1−2 prior lines of therapy including ≥1 immunomodulatory drug and ≥1 proteasome inhibitor. Part 2 includes only TI patients with NDMM. Key inclusion criteria are: ≥18 y; a diagnosis of MM (according to International Myeloma Working Group [IMWG] criteria); an ECOG performance status ≤2; and measurable disease based on IMWG criteria (serum M-protein ≥0.5 g/dL, urinary M-protein excretion ≥200 mg/24 hr, or involved serum free light chain [FLC] ≥100 mg/L and abnormal serum immunoglobulin κ:λ FLC ratio [ < 0.26 or > 1.65]). Key exclusion criteria are: smoldering MM; monoclonal gammopathy; Waldenström’s macroglobulinemia; plasma cell leukemia; active, uncontrolled bacterial, fungal, or viral infections; previous systemic treatment for MM (NDMM patients only); previous treatment with a BMCA-directed therapy or anti-CD38-directed therapy ≤6 mo of the first dose of study treatment (RRMM patients only); or stem cell transplant ≤3 mo of the first dose of study treatment or active graft versus host disease (RRMM patients only). As of February 2023, the study is open and enrolling at 9 sites in 5 countries. Clinical trial information: NCT05623020 .