bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of a digital medicine program in optimizing opioid pain control in cancer patients (SWOG S1916).
Authors: Shen Sherry , Vaidya Riha , Darke Amy , Unger Joseph M. , Sedrak Mina S. , Segarra-Vazquez Barbara , Law Cynthia , Rowland Kendrith M. , Floyd Justin D. , Brant Jeannine M. , O'Rourke Mark Allen , Beck Anna Catherine , Ramsey Scott David , Hershman Dawn L.
Published: May 2020

TPS12126

Background: The undertreatment of pain in patients with advanced or metastatic cancer is well described in cancer research. Overcoming barriers that prevent successful use of opioid analgesics for cancer pain requires a clear understanding of how individuals use oral medications at home. The Proteus Discover is a digital medicine program (DMP) consisting of an FDA-approved ingestible sensor made of dietary minerals co-encapsulated with patients’ medications, a wearable sensor patch, and a mobile device app that enables patients to electronically transmit their medication adherence patterns. Use of the DMP has demonstrated improved clinical outcomes vs. usual care in patients with diabetes and hypertension, shown superiority over directly-observed therapy in tuberculosis and has been studied in the treatment of patients with hepatitis C, HIV, cancer and severe mental illness, but it has not been previously studied with opioids or in monitoring cancer-related pain. Methods: We are conducting a multicenter pilot study at SWOG NCORP sites to test the feasibility of using the DMP to monitor opioid use in the treatment of metastatic cancer pain. Eligible patients must have a diagnosis of metastatic cancer, have a baseline Brief Pain Inventory worst pain score of ≥3, be deemed by their physician to need initiation or up-titration of oxycodone-acetaminophen for pain control, and be able to read English. Primary outcomes include: (1) study accrual of 60 patients within six months of study activation at all participating sites; (2) patient retention defined as ≥50 patients completing the study, and; (3) adherence to the DMP defined as ≥66% of patients wearing the sensor patch for ≥28 days of the 42-day observation period. Secondary outcomes include change in Brief Pain Inventory pain scores, opioid medication consumption, number of safety alert triggers for high consumption, hospital or emergency room visits for pain, activity levels, and frequency of changes to the pain control regimen. The study will enroll patients at six sites; the first patient was enrolled on 1/20/2020. If successful, this study will inform design of a randomized controlled trial of the DMP vs. usual care in optimizing medication utilization and controlling cancer-related pain. Clinical trial information: NCT04194528 .
ECOG-ACRIN tomosynthesis mammographic imaging screening trial (EA1151).
Authors: Pisano Etta , Gatsonis Constantine , Yaffe Martin , Troester Melissa , Gareen Ilana F , Collins Laura C. , Curtis Amarinthia , Cole Elodia , Carlos Ruth , Miller Kathy , Comstock Christopher
Published: May 2020

TPS1597

Background: This randomized trial is intended to determine whether tomosynthesis (TM) should replace the current standard for breast cancer (BC) screening, digital mammography (DM). It is hypothesized that the population of women assigned TM screening for 3-5 rounds will have fewer advanced cancers than the population assigned to DM screening. Methods: 164,946 women, ages 45 to 74 years who present for screening mammography and consent to participate will be enrolled across 150 sites in the US, Canada and abroad. Women will be randomized to TM or DM. The frequency and number of screening examinations over a five year period will vary based on menopausal status and whether they have specific risk factors, including - hormone use, family history of BC, deleterious genes, prior benign breast biopsy with diagnosis of LCIS or atypia any kind, or dense breasts. Blood and buccal cells will be collected from as many enrolled women as are willing to provide the samples. All breast biopsies during the trial will undergo gene expression analysis for the PAM50 and other progression pathways (PAM50-plus). All subjects enrolled will be followed long term for at least eight years. The primary endpoint is the proportion of participants who have an advanced breast cancer diagnosed at any time within 4.5 years of randomization in to the trial. Secondary endpoints include measures of diagnostic and predictive performance; rates of recall, biopsy, and interval cancers, prevalence of breast cancer subtypes, and tumor subtype based on PAM50-plus analysis. As of January 17th 2020, there are 104 sites open and 21,452 women enrolled in the trial. The DSMC last reviewed the trial in June 2019 and suggested that the trial continue as planned. Clinical trial information: NCT03233191.
A multi-stakeholder platform to prospectively link longitudinal real-world clinico-genomic, imaging, and outcomes data for patients with metastatic lung cancer.
Authors: Lu Michael W , Walia Guneet , Schulze Katja , Doral Michelle Yuri , Maund Sophia L. , Gaffey Sarah , Cabili Moran N , Bourla Ariel B. , Green Robert J. , Santos Eric C. , Herbst Roy S. , Chiang Anne C. , Schwartzberg Lee S.
Published: May 2020

TPS2087

Background: Making personalized diagnostics and treatments a reality for every cancer patient necessitates comprehensively capturing the patient journey. Real-world data has shown promise for the future of clinical research and advancing precision medicine. However, certain limitations exist such as data quality management as well as bias and confounding factors associated with retrospective analyses. We present a multi-stakeholder platform to prospectively collect and link real-world clinico-genomic, imaging, and outcomes data to longitudinal blood genomic profiling for lung cancer. Methods: This study is enrolling approximately 1000 patients with metastatic non-small cell lung cancer or extensive-stage small cell lung cancer who will initiate standard-of-care systemic anti-neoplastic treatment, regardless of line of therapy, at 20 community oncology and academic practices within the Flatiron Health network. Relevant clinical data points from both structured and unstructured fields will be collected through the electronic health records via technology-enabled abstraction, eliminating the need for case report forms. Digital pathology and clinical images at standard-of-care visits will be collected. Blood samples for circulating tumor DNA (ctDNA) profiling using FoundationOne Liquid will be collected at three timepoints: enrollment, first tumor assessment, and end of treatment. Tumor tissue samples may be submitted at baseline for genomic profiling using FoundationOne CDx. Overall survival follow-up will occur until death, withdrawal of consent, loss to follow-up, or end of study. The objectives are to evaluate 1) the feasibility of building a scalable, prospective platform and 2) the associations between ctDNA and real-world clinical outcomes, including overall survival. Enrollment is ongoing. Clinical trial information: NCT04180176.
Technology-enabled longitudinal monitoring of patient-reported outcomes (PROs) to individualize care of immune-related adverse events (irAEs) in patients (pts) treated with immune checkpoint inhibitors (ICIs).
Authors: Msaouel Pavlos , Van Alstine Michael L. , Oromendia Clara , Gao Jianjun , Wang Yinghong , Siddiqui Bilal A. , Siefker-Radtke Arlene O. , Shah Amishi Yogesh , Shaw Leah , Lopez Lidia , Laccetti Andrew Leonard , Tannir Nizar M. , Elashoff Michael , Logothetis Christopher
Published: May 2020

TPS2088

Background: ICIs have become the therapeutic standard for many cancers but are associated with unique and diverse irAEs that often occur at home. Appropriately timed and specific interventions are critical to recovery. Thus, there is a need to effectively & efficiently monitor in real time pts treated with ICIs. To improve outcomes, we have activated a clinical trial developed to determine the feasibility and safety of an electronically enabled strategy to remotely monitor symptoms and prompt communication that will guide and inform specific patient-driven “course corrections” in response to potential irAEs. Methods: This is an adaptive prospective trial that uses a mobile irAE-specific PRO application we developed to monitor and alert the care team in real time when severe symptoms are reported. In parallel with the mobile symptom collection, serum and urine biomarkers are collected at baseline, first tumor restaging, and upon the development of irAEs. Optional stool microbiome analyses are also performed. To facilitate the generalizability of our inferences, we are using broad inclusion criteria: ECOG performance status ≤3; any line of ICI given as standard of care or as part of therapeutic clinical trials; elderly pts are included. Because the relationship between PROs and irAEs is currently undefined, we designed our trial to use adaptive symptom thresholds that will notify the healthcare team of suspicion for irAEs. The mobile application will use these dynamic thresholds to determine whether or not to alert the healthcare team. The positive and negative predictive value of each symptom for identifying subsequent irAEs will be assessed at scheduled interim analysis time points. The care teams’ responses to the alerts, and all of the clinical outcomes for the pts over time will be collected as part of the trial. The primary goal of the trial is the assessment of the predictive power of the mobile PRO symptom collection in combination with serum and urine markers to identify grade 2 or higher adverse events that require intervention (e.g., dose modifications, hospitalizations, and therapeutic interventions) within two weeks of symptom onset. Effective remote monitoring of irAEs will leverage our understanding of ICI toxicity and empower pts to be effective partners in their care. The trial has currently enrolled 17 pts towards the enrollment target of 100 pts. Clinical trial information: PA19-0095 .
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 .
Phase II study of durvalumab plus total neoadjuvant therapy (TNT) in locally advanced rectal cancer: The GEMCAD-1703 DUREC trial.
Authors: Capdevila Jaume , Macias Declara Ismael , Riesco Martinez Maria Carmen , Maurel Joan , Hernando Jorge , Alonso Vicente , Suárez Begoña Graña , Gallego Plazas Javier , Losa Ferran , Vera Ruth , Melian Marcos , Navalpotro Begona , Acosta Daniel , Diez Marc , Garcia-Alvarez Alejandro , Garcia-Albeniz Xabier , Fernandez-Martos Carlos
Published: May 2020

TPS4122

Background: In clinical stages II and III (cT3-4 and/or N+), preoperative chemoradiotherapy (CRT) or short-course radiation followed by total mesorectal escision (TME) have been the standard of care for the last 15 years. Induction chemotherapy (CT) before CRT (strategy known as TNT) results in fewer toxic effects and improved compliance. TNT may release tumor-neoantigens with platinum-based induction CT, and radiotherapy has the potential ability to induce an immunogenic cell death and counteract an immune-suppressive tumor microenvironment that provides the rationale for combining with immunotherapies. In addition, the presence of tumor infiltrating lymphocytes has been demonstrated in patients with rectal cancer treated with neoadjuvant CRT, reinforcing the rational for immune check-point inhibitors in this setting. We hypothesize that combining TNT with durvalumab (an optimized monoclonal antibody directed against programmed cell death-1 ligand 1) would improve outcome. Methods: DUREC is a multicenter, single-arm, open-label, phase Ib/II study for patients with magnetic resonance (mr) image middle or distal third, mrT3c-d/T4/N2 rectal adenocarcinoma. Treatment: Patients will receive 6 cycles of modified FOLFOX6 prior to CRT (capecitabine with 50.4 Gy in 28 fractions) and TME, combined with durvalumab 1500 mg every 4 weeks during induction CT, CRT and waiting period until surgery. To assess the tolerability and toxicity profile we plan to perform a run-in treatment phase including the first 6 patients in the study, holding recruitment until all of them will be operated and 30-days post-surgery period completed. If ≤ 2 durvalumab-related dose-limiting toxicities (DLTs) are observed, recruitment will continue. The primary objective is pathological complete response (pCR) rate. Secondary endpoints include toxicity, tumor regression grade, R0 resections, clear circumferential margins, surgical complications, NAR score, disease-free survival and a biomarker program on tumor tissue, blood samples and stool microbiota. Statistical design: 58 evaluable patients (assuming a P0 of 16% and a P1 of 30%, with 0.1 alpha and 0.1 beta); Study started recruitment on December 2019. Clinical trial information: 2018-004835-56 .
Randomized phase III trial to evaluate omentum preserving gastrectomy for patients with resectable advanced gastric cancer: JCOG1711 (ROAD-GC).
Authors: Yamada Takanobu , Yoshikawa Takaki , Sato Yuya , Machida Ryunosuke , Mizusawa Junki , Katayama Hiroshi , Tokunaga Masanori , Nishida Yasunori , Hihara Jun , Watanabe Masaya , Choda Yasuhiro , Nunobe Souya , Fujita Junya , Kaji Masahide , Fukushima Norimasa , Ito Seiji , Boku Narikazu , Terashima Masanori
Published: May 2020

TPS4646

Background: Standard surgery for resectable advanced gastric cancer is D2 (standardized extended lymph node dissection) gastrectomy with omentectomy. The reason why omentectomy has been performed is as follows; (1) principal surgery for gastrointestinal cancers is en-block resection of mesothelium including regional lymph nodes. Omentum is a part of the mesothelium of the stomach. (2) Cancer cells implanted into the peritoneal cavity aggregated in the milky-spot of the omentum and formed peritoneal dissemination in an animal model. (3) By special staining, micrometastasis detected in the omentum. There is some arguments for this theory. (1) no prospective study showed survival benefit of omentectomy as compared with omentum preservation. (2) anatomically, milky-spot is found not only in the omentum but also in other mesothelium or Douglas pouch. (3) JCOG1001 phase III study showed no survival benefit of bursectomy against non-bursectomy although bursa is a part of mesothelium of the stomach. (4) Anti-immunity is accelerated by antigen presentation by macrophage in the milky-spot of the omentum. Preservation of the omentum may have several benefits; (1) decrease in blood loss and operation time, (2) preservation of physical function by omentum such as reaction to peritonitis and prevention of adhesion, and (3) overcoming difficulties in laparoscopic omentectomy and avoidance of organ injury during surgery. Methods: The study is multicenter randomized phase III trial designed to confirm non-inferiority of omentum preservation to omentectomy for resectable advanced gastric cancer. Patients aged 20-79 years, histologically proven gastric adenocarcinoma, clinical subserosal/serosal invasion, and expected R0 (curative) resection are randomly assigned (1:1) during surgery to either omentum preservation or omentectomy. Total or distal gastrectomy with D2 dissection is performed in both arms. Laparoscopic gastrectomy is not allowed. Intraoperative photographs of the dissected field are centrally reviewed for all patients for quality control. The primary endpoint is relapse-free survival (RFS) and the secondary endpoints are overall survival, blood loss, operation time, and adverse events. Sample size was set at 1050 considering expected 3-year RFS of 77% in both arms with non-inferiority margin of 5%, one-sided alpha of 5%, and power of 80%. Planned accrual and follow up period are 6.5 years and 3 years respectively. The trial was activated in March 2019, and 177 patients are enrolled as of January 2020. Clinical trial information: UMIN000036253 .
POF (paclitaxel/oxaliplatin/5-FU/leucovorin) versus SOX/CAPOX/FOLFOX as a postoperative adjuvant chemotherapy for curatively resected stage III gastric cancer: Study protocol for a randomized controlled trial, FNF-014 trial.
Authors: Su Liyu , Li Chunxiang , Huang Feng , Chen Lu chuan , Cai Lisheng , Li Jiayi , Zhao Shen , Lin Rongbo ,   FNF Independent Investigations Group
Published: May 2020

TPS4647

Background: Postoperative chemotherapy (S-1, CAPOX, or Docetaxel/S-1) is a standard treatment for stage II/III gastric cancer in Asia. With regard to single agent or doublet, the need for improvement has consistently been pointed out because of the relatively poor outcome for patients with stage III gastric cancer. Triplet (FLOT) has shown significant survival benefits in perioperative setting. POF, our regiment similar to FLOT, demonstrated priority to doublet (FOLFOX) in advanced setting (2019 ASCO-GI). We conducted a randomized, multicenter, phase III study to compare triplet to doublet regimens for patients with stage III gastric cancer. Methods: This is currently enrolling patients (n = 544) with pathologic stage III gastric cancer after D2 lymph node dissection. Patients are randomized 1:1 and stratified by tumor stage (IIIA, IIIB, or IIIC, AJCC 8th) into POF or SOX/CAPOX/FOLFOX (chosen by the clinicians). SOX: oxaliplatin 130 mg/m2 on day 1, oral S-1 80mg/m2 divided by two on days 1 to 14 every 21 days for 8 cycles. CAPOX: oxaliplatin 130 mg/m2 on day 1, oral capecitabine 1000 mg/m2 twice daily on days 1 to 14 every 21 days for 8 cycles. FOLFOX: oxaliplatin 85 mg/m2, levo-leucovorin 200 mg/m2, and 5-FU 400 mg/m2 bolus on day 1, then 5-FU 2400 mg/m2 continuous infusion over 46 hours, every 14 days for 12 cycles. Three doublets were chosen by the clinicians. POF: paclitaxel 135 mg/m2, followed by FOLFOX omitted 5-FU bolus, every 14 days for 12 cycles. Eligibility criteria: patients aged 18-70 years, primary histologically proven gastric adenocarcinoma (including adenocarcinoma of the gastroesophageal junction) of stage III with no evidence of metastatic disease, R0 resection with D2 lymph node dissection, good performance status (ECOG PS ≤1). Subjects must be able to take orally, and without other concomitant medical conditions that required treatment, initially treated with curative surgery followed by chemotherapy within 42 days. Life expectancy estimated more than 6 months. Adequate organ function. All patients provided written informed consent prior to treatment. Key exclusion criteria: patients with other primary malignancies, gastrointestinal bleeding. The primary end point is 3-year disease-free survival. Secondary end points are 3-year overall survival, 5-year overall survival, 5-year disease-free survival, and adverse events. Clinical trial information: NCT03788226 .
Trial in progress: A phase I study of AMG 199, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy, targeting MUC17 in patients with gastric and gastroesophageal junction (G/GEJ) cancer.
Authors: Chao Joseph , Buxó Elvira , Cervantes Andrés , Dayyani Farshid , Rocha Lima Caio Max Sao Pedro , Greil Richard , Van Laarhoven Hanneke W.M. , Lorenzen Sylvie , Heinemann Volker , Kischel Roman , Shitara Kohei , Lordick Florian
Published: May 2020

TPS4649

Background: Prognosis for advanced G/GEJ cancer is poor and new treatment modalities are urgently needed. MUC17 is a transmembrane protein overexpressed and differentially localized on the cell membrane of G/GEJ cancer cells; expression and localization in normal cells is much more limited. AMG 199 is an HLE BiTE immune therapy designed to engage CD3-positive T cells to MUC17-positive G/GEJ cancer cells, mediate redirected tumor cell lysis, and induce T cell activation and proliferation. A clinical trial is being conducted for this novel and targeted immune therapy agent in patients with MUC17-positive G/GEJ cancer. Methods: This is a first-in-human phase 1, open-label, dose escalating study (NCT04117958) evaluating AMG 199 in patients with MUC17-positive G/GEJ cancer. Key eligibility criteria include metastatic or locally advanced unresectable MUC17-positive (as determined by IHC using a central laboratory assay) gastric adenocarcinoma or gastroesophageal junction adenocarcinoma ineligible for curative surgery and relapsed or treatment-refractory following ≥2 lines including a platinum, a fluoropyrimidine, taxane or irinotecan, and an approved vascular endothelial growth factor receptor antibody or tyrosine kinase inhibitor. Patients eligible for human epidermal growth factor receptor 2 (HER2) directed therapy should have received an approved HER2 targeting antibody. Primary endpoints include: dose-limiting toxicities, treatment-emergent or -related adverse events, vital signs, electrocardiogram (ECG), and laboratory changes. Secondary endpoints include: pharmacokinetics of AMG 199, objective response, duration of response, time to progression, 6-month and 1-year progression-free survival, and 1-year and 2-year overall survival. The dose exploration (n = 30) will estimate the maximum tolerated dose and/or recommended phase 2 dose; this will be followed by a dose expansion (n = 40) and evaluation of the benefit/risk profile of AMG 199. The study began enrolling patients in January 2020 and is ongoing. This is the first clinical trial to investigate MUC17 as a potential anti-tumor target. For more information, please contact Amgen Medical Information: medinfo@amgen.com . Clinical trial information: NCT04117958 .
An exploratory study of fruquintinib as second-line treatment for patients with advanced or metastatic biliary tract cancer.
Authors: Li Qiu , Zhang Pengfei
Published: May 2020

TPS4657

Background: Biliary tract cancer (BTC) is a relatively uncommon but highly fatal malignancy and most patients with BTC are diagnosed at advanced stages. Currently, no standard second-line treatment has been established following recurrence from the first-line treatment. VEGF is highly expressed in more than 50% of BTC, which indicates anti-angiogenesis might be a potentially effective method to improve the outcome in BTC. Fruquintinib is a novel small molecule tyrosine kinase inhibitor targeting VEGFR1, VEGFR2, and VEGFR3 and is currently being evaluated in clinical trials for multiple cancers including lung cancer, gastric cancer and colorectal cancer, and showed strong anti-tumor activity. However, the effect and safety of fruquintinib has not been investigated in the setting of second-line treatment for BTC. Methods: The study is a multicenter, single-arm, phase 2 trial of fruquintinib (5 mg, po, for 3 weeks, followed by 1 week off, 4 weeks for a cycle) for patients with advanced or metastatic BTC who have failed to first-line chemotherapy. The primary endpoint is progression-free survival (PFS) with the null hypotheses of 8 weeks, and the median PFS≥15 weeks as evidence of the study drug activity (α=0.05, 80% power, one-sided). The number of patients required to complete the study is 27. Allowing for 20% expulsion rate, the study needs 33 patients. The secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety and quality of life (QoL). Meanwhile, the study also set an exploratory objective to evaluate the mutation status of related genes in plasma (cfDNA) and tumor tissue and explore the interplay between mutation patterns with efficacy. Major eligibility requirements: Age ≥18 years; Histologically or cytologically confirmed diagnosis of advanced or metastatic biliary tract adenocarcinoma; First-line chemotherapy failed (tumor progression or intolerable adverse events); No less than 3 months of expected survival; ECOG PS≤1; At least one measurable lesion according to RECIST 1.1 criteria; Adequate organ function. Eligible patients with advanced or metastatic BTC refractory to first-line chemotherapy will be enrolled at 7 medical centers in China. The study is open and actively enrolling at time of submission. Clinical trial information: NCT04156958 .
An exploratory study of sorafenib plus toripalimab for unresectable hepatocellular carcinoma with portal vein tumor thrombus.
Authors: Yang Yu , Li Qiu
Published: May 2020

TPS4658

Background: Portal vein tumor thrombosis (PVTT) is common among advanced hepatocellular carcinoma ( HCC), resulting in poor prognosis. As the standard first-line treatment, the efficacy of Sorafenib is not satisfactory in HCC with PVTT. Although immune checkpoint inhibitors have made a breakthrough in treatment of advanced HCC, objective response rate (ORR) of anti-PD-1 monoclonal antibody monotherapy is only 17-20%. Recently, PD-1/PD-L1 inhibitors combined with anti-angiogenesis therapy have shown good efficacy in the clinical studies. However, the data on immunotherapy for HCC with PVTT are still limited. Toripalimab is the first Chinese-produced anti-PD-1 monoclonal antibody marketed. We designed the study to evaluate the efficacy and safety of Sorafenib plus Toripalimab as the first-line treatment for unresectable HCC with PVTT. Methods: The study is a multicenter, single-arm, phase Ib/II trial. The primary objectives are 6-month progression-free survival (PFS) rate and safety. Secondary objectives include ORR, disease control rate, PFS, overall survival. The escalation stage includes two dose cohorts: Sorafenib 400 mg po qd or 400 mg bid combined with Toripalimab 240 mg iv d1 q3w. 6-12 patients are estimated to evaluate the dose-limiting toxicity within the first 42 days of administration. In the expansion stage, patients are treated with the recommended dose based on the escalation stage, until progressive disease or intolerable toxicity. Assuming Sorafenib plus Toripalimab can improve the 6-month PFS rate to 40% (Sorafenib:20%, β = 0.2, α = 0.05) and dropout is 10%, this stage need 39 patients. A total of 45-51 patients are enrolled. Major eligibility requirements include: unresectable HCC with diagnoses confirmed histologically or cytologically, or confirmed clinically in accordance with Chinese guideline for HCC diagnosis and treatment (v2017); radiographic evidence of PVTT; age ≥18 and < 75 years; at least one measurable lesion according to RECIST 1.1; a predicted life expectancy ≥ 3 months; ECOG PS≤1, Child-Pugh class A or B (≤7); no any prior systemic anti-cancer treatment; adequate organ function. Patients with hepatitis B treated with antiviral therapy (viral load < 100 IU/mL) or patients with chronic hepatitis C can be included. The study is open and actively enrolling at time of submission. Clinical trial information: NCT04069949 .