bluuebunny/crossref_metadata_2025_split huggingface dataset:
A first-in-human phase I single-agent dose-escalation, food effect and dose expansion study of oral ONC206 in recurrent and rare primary central nervous system neoplasms.
Authors: Theeler Brett James , Jung Jinkyu , Burton Eric , Gonzalez Javier , Leeper Heather , Wu Jing , Nduom Edjah , Zaghloul Kareem , Ray-Chaudhury Abhik , Quezado Martha , Raffeld Mark , Allen Joshua E. , Prabhu Varun Vijay , Stogniew Martin , Oster Wolfgang , Yuan Ying , Aldape Kenneth D. , Penas-Prado Marta , Armstrong Terri , Gilbert Mark R. 
Published: May 2020

TPS2576 Background: Blockade of the dopamine receptor D2 (DRD2) has emerged as a therapeutic target in neuro-oncology. ONC201, a first-generation imipridone that antagonizes DRD2, has demonstrated clinical activity in Diffuse Midline Gliomas, H3K27M-mutant (DMGs). Treatment options beyond surgical resection and radiation therapy are limited for most recurrent and rare primary CNS neoplasms. DRD2 blockade holds promise as a therapeutic target in multiple primary CNS cancers. ONC206 is a next generation imipridone and a chemical analog of ONC201 that possesses favorable drug properties such as oral bioavailability, robust stability, and blood-brain barrier penetrance. ONC206 exhibits enhanced allosteric inhibition of DRD2 and nanomolar affinity/potency as a DRD2 antagonist with complete antagonism and specificity for DRD2. ONC206 demonstrated broad spectrum anti-cancer efficacy in vitro across most solid tumor types tested in a panel of > 1000 human cancer cell lines with nervous system tumors emerging as most responsive. In addition to its broad-spectrum activity in vitro, ONC206 efficacy has been demonstrated in xenograft mouse models. Methods: This is an open label, dose escalation, and food effect Phase I study of ONC206at the National Cancer Institute, Neuro-Oncology Branch. Adult patients 18 years and older with recurrent, primary CNS neoplasms will initially be accrued to the dose escalation portion of the study and evaluated for toxicity. Eligible diseases include recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, and rare primary CNS neoplasms in the NCI-CONNECT program: DMGs, ependymomas, medulloblastomas, and other rare CNS tumor types. The primary endpoint is to determine DLT during the first cycle (28 days). Dose escalation will proceed according to a standard 3+3 design. Both once weekly and more frequent dosing of ONC206 will be explored in the dose escalation scheme. After the MTD is established, food effect will be determined in a dedicated cohort using a balanced, single-dose, two-arm, two-period crossover design. Secondary endpoints will include objective response rate by RANO criteria, overall and progression-free survival, and disease control rate. Exploratory analysis of DRD2 and DRD5 expression, DRD2 dimerization, expression of MYC and N-MYC in tumor tissue in relation to clinical outcomes will also be performed.
A phase I study of AK112, a bispecific antibody that targets PD-1 and VEGF co-expressing T cells, in patients with advanced solid tumors.
Authors: Coward Jermaine , Lemech Charlotte Rose , Mislang Anna Rachelle Austria , Parakh Sagun , Underhill Craig , Nagrial Adnan , Jin Xiaoping , Li Baiyong , Wang Zhongmin Maxwell , Kwek Kon Yew , Xia Yu 
Published: May 2020

TPS3155 Background: AK112 is a humanized IgG1 bispecific anti-PD-1/VEGF antibody. VEGF blockade potentiates PD-1 inhibition by, inter alia, opposing the immunosuppressive effects of VEGF-A, which include suppression of dendritic cell activity and enhancement of checkpoint molecule expression on CD8+ T cells and proliferation of regulatory T cells. Combination therapies involving PD-(L)1 and VEGF inhibitors have been approved for the treatment of selected patients with metastatic non-small cell lung carcinoma, advanced renal cell carcinoma and advanced endometrial carcinoma. A supplemental Biologics License Application has been submitted for an anti-PD-L1 + anti-VEGF combination for the first-line treatment of unresectable hepatocellular carcinoma. Given the strong correlation between VEGF and PD-1 expression in the tumor microenvironment, the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificities and synergistically produce enhanced antitumor activity compared to co-administration of anti-PD-(L)1 and anti-VEGF therapies. Methods: This is a Phase 1a/1b, first-in-human, multicenter, open-label study in patients with advanced or metastatic solid tumor that is refractory/relapsed to standard therapies. The primary objective is to assess safety, tolerability and DLTs; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose of AK112. Antitumor activity, PK and immunogenicity of AK112 will be studied as secondary objectives. As exploratory endpoints, tumor tissue samples may be evaluated for PD-L1 expression, mRNA expression profile and biomarkers (e.g. CD8+, FoxP3, Granzyme B, apelin and EPHB4). PD-1 receptor occupancy on circulating T-cells and serum VEGF level may also be measured as indications of target engagement. The dose-escalation phase will evaluate 5 dose levels of AK112 (up to 20 mg/kg Q2W IV) using a 3+3+3 study design. Additional subjects (up to 18 subjects) may be enrolled at any dose level not exceeding the MTD for additional PK, PD and safety evaluations to determine the optimal dose level for the dose-expansion phase. Cohorts 1 and 2 have been completed and enrollment to Cohort 3 began in January 2020. The dose-expansion phase will be performed in patients with selected advanced solid tumors who had no prior exposure to drugs targeting T-cell co-stimulation or immune checkpoint pathways. Clinical trial information: NCT04047290 .
A phase II study of olaparib in combination with pembrolizumab in patients with previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) and/or homologous recombination repair deficiency (HRD): KEYLYNK-007.
Authors: Yap Timothy A , Dhawan Mallika Sachdev , Hendifar Andrew Eugene , Maio Michele , Owonikoko Taofeek Kunle , Quintela-Fandino Miguel , Shapira Roni , Saraf Sanatan , Qiu Ping , Jin Fan , Gozman Alexander , Levine Douglas A 
Published: May 2020

TPS3156 Background: The anti-PD-1 antibody pembrolizumab (pembro) has improved clinical outcomes in multiple previously treated advanced solid tumors. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (ola) has shown antitumor activity as monotherapy in previously treated advanced cancers with BRCA1/ BRCA2 mutations (BRCAm), other HRRm, and ovarian cancer with HRD phenotype. Antitumor activity of PD-(L)1 plus PARP inhibition was reportedly higher than expected with either agent alone in patients (pts) with recurrent ovarian cancer regardless of BRCAm or HRD status and in pts with BRCAm breast cancer. KEYLYNK-007 (NCT04123366) evaluates antitumor activity and safety of ola plus pembro in pts with advanced solid tumors with HRRm and/or HRD. Methods: This phase 2, nonrandomized, multicenter, open-label study plans to enroll ~300 pts aged ≥18 y with histologically/cytologically confirmed, previously treated, advanced solid tumors with HRRm and/or HRD per Lynparza HRR-HRD assay (Foundation Medicine, Inc., Cambridge, MA, USA) and ECOG PS 0-1. Pts will be grouped by biomarker status: (1) BRCAm; (2) HRRm without BRCAm; (3) HRD positive without HRRm (loss of heterozygosity score ≥16 per Lynparza HRR-HRD assay). Pts will receive ola 300 mg BID + pembro 200 mg IV Q3W (35 cycles) until PD, unacceptable AEs, intercurrent illness, investigator decision, withdrawal, or pregnancy. Tumor imaging assessment by blinded independent central review (BICR) per RECIST v1.1 or Prostate Cancer Working Group (PCWG)-modified RECIST v1.1 for prostate cancer will occur Q9W for 12 mo, then Q12W until PD, start of new anticancer treatment, withdrawal, pregnancy, or death. AEs will be monitored throughout the study and for 30 days after final dose (90 days for serious AEs) and graded by NCI CTCAE v5. The primary endpoint is ORR (RECIST v1.1 or PCWG-modified RECIST v1.1 by BICR). Secondary endpoints include DOR, PFS (RECIST v1.1 or PCWG-modified RECIST v1.1 by BICR), OS, and safety. ORR will be analyzed by the Clopper-Pearson method; and DOR, PFS, and OS by the Kaplan-Meier method. Clinical trial information: NCT04123366 .
AGEN1181, a clinical stage Fc-engineered anti-CTLA-4 antibody with improved therapeutic potential for the treatment of patients with advanced malignancies.
Authors: O'Day Steven , Ramamurthy Chethan , Bullock Andrea J. , El-Khoueiry Anthony B. , Ohanjanian Lernik , Wijatyk Anna , Ortuzar Feliu Waldo Ignacio , Shapiro Irina , Ancukiewicz Marek , Chand Dhan , Buell Jennifer , Gordon Michael S. 
Published: May 2020

TPS3157 Background: AGEN1181 is a novel Fc-optimized anti-CTLA4 antibody, currently being evaluated in an ongoing multi-center, open-label, phase 1 study in all advanced solid tumors as mono-therapy and combination with anti-PD-1 antibody, AGEN2034 (NCT03860272). AGEN1181 is Fc-engineered to harness a novel mechanism for enhanced FcγR-dependent functionality relative to first-generation CTLA-4 antibodies. In pre-clinical models, AGEN1181 enhances T cell priming, depletion of intratumoral regulatory T cells (Treg) and improved memory formation compared to first-generation anti-CTLA-4 antibodies. Most notably, AGEN1181 demonstrates improved binding to FcyRIIIA and superior T cell responsiveness in populations that only express the low affinity FcγRIIIA receptor relative to first-generation IgG1 CTLA-4 antibodies. The combination of AGEN1181 and AGEN2034 further enhances T cell activation and effector function. Methods: This phase 1 study is an open-label, multi-center dose-escalation designed to evaluate the safety, tolerability, dose limiting toxicity (DLT) PK, and pharmacodynamic profiles of patients with refractory advanced solid tumors who did not receive an anti-CTLA4 previously. The study is being conducted in 3 arms; with patients assigned using a standard 3+3 dose escalation design in the mono-therapy arms with AGEN1181 and an accelerated design in the combination with AGEN2034 arm. AGEN1181 is administered as IV infusion as mono-therapy on Day 1 of every 3 weeks (0.1,0.3,1,2,4 mg/kg), every 6-weeks (1,2,4 mg/kg) in parallel cohorts and every 6-weeks (0.1,0.3,1,2,4 mg/kg) in combination with AGEN2034 (3mg/kg Q2Weeks) until disease progression or unacceptable toxicity (maximum 2 years). All 3 Arms are open and enrolling patients. The study is expected to enroll approximately 80 evaluable patients with solid tumors. Dose reductions are not allowed in the event of AGEN1181-related toxicities. Currently 3 cohorts have been completed, first cohort in the combination arm and the fourth cohort in the monotherapy arm are enrolling. Preclinical and clinical assessment of AGEN1181 supports continued development as a potential therapy for refractory or relapsed advanced solid tumors. Clinical trial information: NCT03860272 .
First-in-human phase Ib study of ATRC-101, an engineered version of a patient-derived antibody targeting a tumor-restricted ribonucleoprotein complex.
Authors: Benjamin Jonathan Eliot , Higgins Nicholas , Millward Carl , Defalco Jeff , Manning-Bog Amy , Aydin Iraz T , Zhang Danhui , Lippow Shaun , Scholz Alexander , Leung Yvonne , Zhu Yanhong , Sedello Anna , Rogers Zane , Dhawan Ish , Emerling Daniel , Robinson William H. , Serafini Tito , Greenberg Norman 
Published: May 2020

TPS3168 Background: ATRC-101 is a fully human, engineered IgG1 version of an antibody discovered through a a target-agnostic screen to identify patient-derived antibodies that bind selectively to public tumor antigens. The parental antibody was identified from B cells in the active immune response of a patient receiving checkpoint therapy for Stage IV non-small cell lung cancer (NSCLC). A fluorescently conjugated version of ATRC-101 binds selectively to human tumor specimens including a majority of NSCLC, acral melanoma, breast, colorectal, and ovarian cancer samples. No reactivity of toxicological significance is found across a wide range of normal human tissues. ATRC-101 displays dose-dependent, single-agent activity in syngeneic mouse tumor models, including the EMT6 breast cancer model, which displays a T cell-excluded microenvironment often observed in human tumors, and in which checkpoint inhibitors targeting the PD-1 axis exhibit limited activity. Dosing with ATRC-101 in the EMT6 model causes marked changes in the tumor microenvironment, including a shift from the M2 to the M1 macrophage phenotype and infiltration of T cells. ATRC-101 does not appear to act via NK cell-driven ADCC; instead, activity in vivo is dependent both on Fc region interactions with Fc receptors, likely on myeloid rather than lymphoid cells, and on the presence of CD8+ T cells. ATRC-101 binds to a target that is a ribonucleoprotein (RNP) complex containing polyadenylate-binding protein 1 (PABP-1) bound to poly(A)RNA. Whereas both PABP-1 and poly(A)RNA are ubiquitously expressed at high levels in normal tissues and have been localized intracellularly, the ATRC-101 target is detected extracellularly on tumor cells grown in vivo. The basis for the tumor-selectivity of ATRC-101 as well as the extracellular localization of the target is under investigation. Ascending doses of ATRC-101 were well tolerated in multiple non-clinical safety studies. Methods: ATRC-101-A01 is an open-label, 3+3, Phase 1b safety study in patients with acral melanoma, NSCLC, breast, ovarian, and colorectal cancers. Participants are accruing in the first dose cohort. ATRC-101 is administered every 21 days up to 24 months or until disease progression. The primary objective of the trial is to determine the safety and tolerability of ATRC-101. Secondary objectives are to characterize the pharmacokinetic profiles of ATRC-101 and to assess antitumor activity as determined by RECIST 1.1 and lymphocytic infiltration in the tumor microenvironment. Clinical trial information: NCT04244552 .
EV-202: A phase II study of enfortumab vedotin in patients with select previously treated locally advanced or metastatic solid tumors.
Authors: Bruce Justine Yang , Pusztai Lajos , Braiteh Fadi S. , Gorla Seema Rao , Wu Chunzhang , Baranda Joaquina 
Published: May 2020

TPS3647 Background: Nectin-4, a transmembrane cell adhesion protein, is highly expressed in urothelial carcinoma (UC), breast cancer (BC), non-small cell lung cancer (NSCLC), and gastroesophageal cancers (GEC); targeting Nectin-4 on these tumors may provide a novel treatment approach. Enfortumab vedotin (EV), an investigational human monoclonal antibody-drug conjugate, binds to Nectin-4 and upon internalization releases MMAE resulting in cell cycle arrest and cell death. Recently, EV received accelerated approval by the FDA for the treatment of adults with locally advanced/metastatic UC who previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Use of EV in this study is investigational. Methods: This open-label phase 2 study (NCT04225117) will assess the efficacy and safety/tolerability of EV in patients (pts) with previously treated locally advanced/metastatic malignant solid tumors. Adult pts (~240) with histologically or cytologically confirmed disease and an ECOG ≤1 will be enrolled into 1 of 6 tumor-specific cohorts (Table), with ~40 pts each. While Nectin-4 expression is not required for enrollment, it is being tested retrospectively. Patients with active CNS metastases, grade ≥2 preexisting sensory or motor neuropathy, grade ≥3 immunotherapy-related hypothyroidism or panhypopituitarism, ongoing grade >3 immunotherapy-related AEs requiring high-dose steroids, or a history of uncontrolled diabetes mellitus within 3 months of the study will be excluded. All pts will receive EV 1.25 mg/kg IV on Days 1, 8, and 15 of each 28-day cycle until treatment discontinuation criteria are met; dose reductions/interruptions will be permitted. For all cohorts, the primary endpoint is investigator-assessed confirmed objective response rate (RECIST v1.1); secondary endpoints include duration of response, disease control rate, progression-free and overall survival, and safety/tolerability of EV. This study is recruiting as of February 2020. Clinical trial information: NCT04225117 . [Table: see text]
A phase I, open-label, dose-escalation trial of BI 1701963 as monotherapy and in combination with trametinib in patients with KRAS mutated advanced or metastatic solid tumors.
Authors: Gort Eelke , Johnson Melissa Lynne , Hwang Jimmy J. , Pant Shubham , Dünzinger Ulrich , Riemann Kathrin , Kitzing Thomas , Janne Pasi A. 
Published: May 2020

TPS3651 Background: Activating mutations of KRAS drive many types of cancer. Activation of KRAS relies on guanine nucleotide exchange factors, such as SOS1, to mediate exchange of GDP for GTP. BI 1701963 is a small-molecule protein–protein interaction inhibitor that prevents the interaction between KRAS and SOS. Binding of BI 1701963 to the catalytic site of SOS1 inhibits binding of SOS1 to RAS–GDP, thereby hindering the exchange from RAS–GDP (inactive form) to RAS–GTP (active form). In preclinical studies this has been shown to lead to cytostasis in cancer cells addicted to KRAS signaling. Methods: NCT04111458 is a first-in-human trial of BI 1701963 in patients aged ≥18 years with tumors harboring KRAS mutations. Primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase II dose of BI 1701963 as monotherapy and in combination with trametinib, based on dose-limiting toxicities (DLTs). Secondary objectives are to evaluate safety, tolerability, pharmacokinetics/-dynamics and preliminary efficacy. The study will have two arms (mono- and combination therapy), and be divided into dose escalation (Part A), confirmation (Part B) and expansion (Part C, combination only) phases. Inclusion criteria include activating KRAS mutation, ≥1 evaluable lesion (RECIST 1.1), ECOG PS ≤1 and adequate organ function. Exclusion criteria include history of: RAS, MAPK or SOS1 targeting therapies; retinal vein occlusion; retinal pigment epithelial detachment; and decreased cardiac function. Parts B and C will be conducted in patients with advanced NSCLC. Treatment will continue until confirmed clinical benefit, defined toxicities, or withdrawal of consent. The primary endpoints are: Part A, the MTD, and the number of patients with DLTs during Cycle 1; Part B (monotherapy), the number of patients with DLTs; Part C, objective response (OR, RECIST 1.1). Starting doses of BI 1701963 in Part A will be 50 mg once daily (QD) orally (monotherapy) and 100 mg QD (combination, once proved safe as monotherapy) and will be escalated until the MTD is reached. The starting dose of trametinib will be 1 mg QD, escalated to the MTD or a max. of 2 mg QD. Dose cohorts will include ≥3 patients, with two therapeutic relevant doses (TRDs) established in each arm. In Part B, patients will be randomized to groups receiving one of the TRDs. If an OR is observed at a TRD in the combination arm, additional patients will be recruited into expansion cohorts receiving the relevant dose. As of Feb 11, 2020 three patients have been treated. Clinical trial information: NCT04111458 .
A phase I, open-label, multicenter, first-in-human study of the safety, tolerability, pharmacokinetics, and antitumor activity of TPX-0022, a novel MET/CSF1R/SRC inhibitor, in patients with advanced solid tumors harboring genetic alterations in MET.
Authors: Hong David S. , Sen Shiraj , Park Haeseong , Heist Rebecca Suk , Gadgeel Shirish M. , Zimmerman Zachary Franklin , Bazhenova Lyudmila 
Published: May 2020

TPS3663 Background: Alterations in the MET gene, including amplifications, chromosomal translocations, and activating mutations (kinase domain [KD] or exon 14 [Δex14]), occur across various tumors and may function as oncogenic drivers. SRC family kinases function as a key downstream node for MET signaling. CSF1R is a receptor tyrosine kinase associated with tumor progression and suppression of the immune response in the tumor microenvironment. TPX-0022 is a type I kinase inhibitor with a novel macrocyclic structure that potently inhibits MET, CSF1R and SRC to simultaneously target oncogenic MET signaling, its key downstream mediators, and the tumor microenvironment. Methods: This is a multicenter phase 1 first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of TPX-0022 in adults with advanced solid tumors harboring genetic alterations in MET. TPX-0022 will be administered orally in continuous 28-day cycles. The primary endpoint is the incidence of DLTs and determination of recommended phase 2 dose (RP2D). Secondary endpoints include ORR by blinded independent central review, intra-cranial response rate, PFS and OS (dose expansion only). In the dose escalation portion, ~30 subjects age ≥18 with solid tumors harboring MET gene amplifications, Δex14, fusions or KD mutations as determined by local tissue-based or liquid biopsy will be enrolled in a 3+3 design. Intrasubject dose escalation will also be allowed. Once the RP2D has been determined, a food effect sub-study will be conducted and ~80 subjects will be enrolled in a dose expansion portion of the study into the following cohorts: I: non-small cell lung cancer (NSCLC) Δex14 (MET therapy naïve), II: NSCLC Δex14 (MET therapy pre-treated), III: MET amplified NSCLC, gastric, or hepatocellular carcinoma, IV: solid tumors with MET KD mutations or fusions. Correlative studies will include analysis of circulating cell-free DNA to identify genomic alterations that may predict activity of TPX-0022 as well as circulating protein biomarkers such as s-MET, HGF, CSF1 and serum cytokines. The study is open and enrolling in the dose escalation portion at the time of submission. Clinical trial information: NCT03993873 .