bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II open-label multicenter study to assess the efficacy and safety of AFM13 in patients with relapsed or refractory CD30-positive peripheral T-cell lymphoma or transformed mycosis fungoides: The REDIRECT study design and rationale.
Authors: Choe-Juliak Cassandra , Alexis Karenza M. , Schwarz Sylvia , Garcia Linta , Sawas Ahmed 
Published: May 2020

TPS3148 Background: AFM13 is a tetravalent, bispecific (anti-CD30/anti-CD16A) recombinant antibody being developed for the treatment of CD30-positive T-cell malignancies and Hodgkin lymphoma. AFM13 selectively kills CD30-positive tumor cells by engaging and activating natural killer cells and macrophages. AFM13 was well tolerated at doses of 0.01 to 7 mg/kg and showed clinical activity in patients with relapsed/refractory (R/R) Hodgkin lymphoma in a Phase 1 study. In an ongoing biomarker Phase 1b/2a study in patients with R/R CD30-positive lymphomas with cutaneous involvement, 4 of 8 patients responded (at different doses) including one CR. Based on these findings, this Phase 2 study (REDIRECT) has been initiated. Methods: This is a Phase 2, open-label, multicenter global study investigating the efficacy and safety of AFM13 in patients with R/R CD30-positive peripheral T cell lymphoma (PTCL) or transformed mycosis fungoides (TMF). AFM13 is administered at 200 mg weekly via an intravenous infusion until disease progression, unacceptable toxicity, investigator discretion or withdrawal of consent. Cohorts A and B include PTCL patients with ≥10%, and ≥1% to <10% CD30 expression by IHC, respectively. Cohort C includes patients with TMF who express ≥1% CD30. Eligible PTCL patients must have received at least 1 prior line of systemic therapy and, if diagnosed with systemic anaplastic large cell lymphoma, must have failed or be intolerant to brentuximab vedotin. Eligible patients with TMF must have received at least 1 prior line of systemic therapy and have exhausted systemic therapies with regular approval for their disease. This global trial started enrollment in Oct 2019. The primary endpoint is objective response rate as confirmed by an Independent Review Committee for all cohorts. The study will also assess investigator-measured efficacy parameters, safety, PK, immunogenicity and QOL. Disease assessment will be done at screening and every 8 weeks for the first 3 assessments, then every 12 weeks thereafter, regardless of any treatment/cycle delays that may occur. ClinicalTrials.gov identifier: NCT04101331. References: Reusch U et al. mAbs. 2014;6(3):728-739. Rothe A et al. Blood. 2015;125(26):4024-4031. Clinical trial information: NCT04101331 .
KITE-439: A phase I study of HPV16 E7 T cell receptor-engineered T cells in patients with relapsed/refractory HPV16-positive cancers.
Authors: Kirtane Kedar , Massarelli Erminia , Hanna Glenn J. , Klebanoff Christopher Austin , Blumenschein George , Bishop Michael Russell , Lee Sylvia , Niu Jiaxin , Adhikary Sabina , Astrow Stephanie H. , Rodriguez Katherine , Chu Rong , Jung A. Scott 
Published: May 2020

TPS3149 Background: Human papillomavirus 16 (HPV16) is the most prominent subtype across invasive head and neck cancers, as well as cervical cancer and other anogenital cancers (Saraiya M, et al. J Natl Cancer Inst. 2015). The HPV16 E7 (E7) viral antigen is important for the survival of HPV-positive tumor cells but is absent from normal human tissue, making it an attractive target for anti-cancer therapy. Preclinical efficacy has been observed with MHC class I-restricted T cell receptor (TCR)-engineered T cells targeting E7 on HPV16-positive tumor cells (Jin BY, et al. JCI Insight. 2018). This Phase 1, first-in-human, open-label, multicenter study (NCT03912831) will evaluate the safety and efficacy of KITE-439, an autologous TCR-engineered T cell therapy targeting E7, in HLA-A*02:01–positive patients with relapsed/refractory HPV16-positive cancers. Methods: A single-patient dose-escalation schema will be used in Phase 1A of the study, enrolling up to 30 patients. Phase 1A will evaluate safety and inform the recommended dose of KITE-439 for Phase 1B. Approximately 45 patients with squamous cell cancer of the head and neck, cervical cancer, and other HPV16-positive tumors will be included in Phase 1B. Patients in Phase 1A and Phase 1B may receive optional bridging therapy followed by cyclophosphamide and fludarabine conditioning chemotherapy. Patients will then receive an infusion of KITE-439 at 1 × 106 up to 1 × 108 TCR-transduced T cells/kg along with daily subcutaneous IL-2 therapy for a maximum of 14 doses post-infusion. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per modified RECIST v1.1 criteria (Eisenhauer EA, et al. Eur J Cancer. 2009). Secondary endpoints for Phase 1B include duration of response, progression-free survival, overall survival, and safety. Patients ≥ 18 years must be HLA-A*02:01–positive and have relapsed/refractory HPV16-positive cancer, an ECOG PS of ≤ 1, and adequate bone marrow and organ function. Key exclusion criteria include a history of stroke, myocardial infarction, or symptomatic deep vein thrombosis/pulmonary embolism, known infection with human immunodeficiency virus, detectable hepatitis C, or detectable hepatitis B. This study is currently open and accruing patients. Clinical trial information: NCT03912831 .
Phase II trial of Voyager-V1 (vesicular stomatitis virus expressing human IFNβ and NIS, VV1), in combination with cemiplimab (C) in patients with NSCLC, melanoma, HCC or endometrial carcinoma.
Authors: Sznol Mario , Lutzky Jose , Adjei Alex A. , Powell Steven Francis , He Aiwu Ruth , Patel Manish , O'Day Steven , Pandya Naimish B. , Kaesshaefer Stephen , Reckner Monica , Brown Cheryl , Diaz Rosa M , Russell Luke , Peng Kah Whye , Wiegert Erol , Gullo Giuseppe , Seebach Frank A. , Lowy Israel , Bexon Alice Susannah 
Published: May 2020

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .
Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.
Authors: Powderly John D. , Chmielowski Bartosz , Brahmer Julie R. , Piha-Paul Sarina Anne , Bowyer Samantha Elizabeth , LoRusso Patricia , Catenacci Daniel V.T. , Wu Christina , Barve Minal A. , Chisamore Michael Jon , Nasrah Nicole , Johnson Dan , Ho William 
Published: May 2020

TPS3163 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects are being enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy (Part 1a) or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of February 4, 2020, Phase 1 dose escalation has been completed and a recommended Phase 2 dose chosen for both FLX475 monotherapy and combination therapy with pembrolizumab. Enrollment into Phase 2 expansion cohorts has been initiated. Clinical trial information: NCT03674567 .
Trial in progress: A phase I/II, open-label, dose-escalation, safety and tolerability study of NC318 in subjects with advanced or metastatic solid tumors.
Authors: Gutierrez Martin , Hamid Omid , Shum Elaine , Wise David R , Balar Arjun Vasant , Weber Jeffrey S. , LoRusso Patricia , Shafi Saba , Rimm David L. , Tolcher Anthony W. , Basudhar Debashree , Dujka Melanie Elizabeth , Heller Kevin N. 
Published: May 2020

TPS3166 Background: Siglec-15 (S15) is a member of the Siglec family (Sialic acid-binding Immunoglobulin Lectins), a distinct subgroup of immunoglobulin (Ig) superfamily proteins involved in discriminating self from non-self-immune regulation (Macauley MS et al. 2014). Nonclinical models demonstrate S15 mediates suppression of T cell proliferation and negatively regulates T cell function. NC318 is a first-in-class monoclonal antibody that blocks S15-mediated immune suppression and prevents tumor growth by normalizing T cell function and restoring anti-tumor immunity in the tumor microenvironment (Wang J et al. 2019). The clinical hypothesis of this study is that NC318 targeting of S15 can improve anti-tumor immune response and provide benefit in multiple oncology indications. Methods: This is a multi-center, first in human, phase 1/2, open-label, non-randomized study to determine the safety and tolerability, define maximum tolerated dose and/or pharmacologically active dose, assess preliminary efficacy, and explore predictive and pharmacodynamic biomarkers of NC318 in subjects with advanced or metastatic solid tumors. Key eligibility criteria included measurable disease based on RECIST v1.1 and consent for collection of biopsies at screening and on treatment (optional for phase 1). Phase 1 used a 3+3 dose escalation design to determine the recommended phase 2 dose (RP2D) and schedule of NC318 while identifying drug related toxicities (DLTs). Phase 2 enrollment is limited to non-small cell lung, ovarian, head and neck, and triple negative breast cancer subjects with PD-L1 tumor proportion scores <50% (additional tumor types are being evaluated for inclusion). Ongoing exploratory analyses include the assessment of predictive biomarkers associated with treatment benefit, and pharmacodynamic markers associated with study drug activity (e.g. evaluation of tumor biopsies and peripheral markers of inflammation). Phase 1 enrollment began October 2018 and completed in August 2019. The RP2D was defined and the phase 2 opened to enrollment October 2019. Clinical trial information: NCT03665285 .
Phase II basket trial of olaparib and durvalumab in patients (pts) with isocitrate dehydrogenase (IDH) mutated solid tumors.
Authors: Chen Eric Xueyu , O'Kane Grainne M. , Mason Warren P. , Knox Jennifer J. , Abdul Razak Albiruni Ryan , Zadeh Gelareh 
Published: May 2020

TPS3167 Background: Somatic IDH mutations are common in low grade gliomas, and rare in other solid tumors with the exception of intrahepatic cholangiocarcinoma (ICA) and certain subtypes of chondrosarcoma. IDH mutations confer a gain-of-function neomorphic activity, such that mutant IDH enzymes preferentially convert αKG to 2-hydroxyglutarate (2HG), resulting in abnormal accumulation of 2HG. 2HG competitively inhibits αKG-dependent dioxygenases, many of which are involved in DNA repair. Preclinical studies show that IDH mutated cancer cells have defective homologous recombination repair and are exquisitely sensitive to poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibition. Methods: This is a single arm phase II basket study (NCT03991832). Pts with IDH mutated solid tumors are divided into three cohorts; A: low-grade glioma; B: cholangiocarinoma; C: all other solid tumors. Pts are treated with olaparib 300 mg twice daily continuously and durvalumab 1500 mg every 4 weeks until progression, intolerable toxicity or consent withdrawal. Radiological assessment is performed after every 2 cycles of study treatments. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, up to 2 lines of systemic therapy for advanced disease, performance status 0 – 2 and adequate organ function. Pts are excluded if they received prior PARP inhibitors and anti-PD-1/PD-L1 antibody. The Simon’s optimal 2-stage design is applied for Cohorts A and B. 10 pts will be enrolled in each of Cohort A and B initially. If 2 or more partial responses (PR) are seen in these 10 pts, additional 19 pts will be enrolled for a total of 29 pts in that cohort. The combination is considered to be of clinical interest for further development if ≥ 6 PRs are seen in each cohort. Cohort C will enroll 20 pts. Archival tumor tissues and serial blood samples will be collected on study. 2HG levels will be measured and correlated with responses. The study was activated in December 2019. 3 pts have been enrolled into Cohort B. Clinical trial information: NCT03991832 .
An open-label, first-in-human, phase I trial of the safety and efficacy of daily PCLX-001.
Authors: Sangha Randeep S. , Sehn Laurie Helen , Kuruvilla John , Weickert Michael , Mackey John Robert , Berthiaume Luc G. 
Published: May 2020

TPS3656 Background: Myristoylation regulates numerous membrane-bound signal transduction pathways important in cancer biology. This modification is catalyzed by N-myristoyltransferases 1 and 2 (NMT1 and NMT2). PCLX-001 is an oral small molecule with high affinity for both NMT proteins (IC50 of 5nM and 8nM, respectively) with high bioavailability and drug-like pharmacokinetic properties. In ex vivo sensitivity screening cell lines of hematologic cancer origin were exquisitely sensitive to PCLX-001, although high sensitivities and cell killing were also seen in some solid tumor lines derived from lung, pancreas, breast, colon, and bladder carcinomas. PCLX-001 demonstrated strong preclinical single-agent antitumor activity and tolerability in vivo in subcutaneous tumor xenograft models derived from lymphoma cell lines, lung cancer cell lines, a breast cancer cell line, as well as in a patient derived xenograft model from a patient with refractory DLBCL. The primary objective of this study is to determine the MTD and/or recommended phase II dose, safety, tolerability, and pharmacokinetics of PCLX-001 as a single agent, in patients with refractory lymphomas and advanced solid tumors. The secondary objective of the study is to evaluate the preliminary single agent anti-tumor activity of PCLX-001 in the patient populations studied. Methods: This is a multicenter, open-label, phase I dose-escalation study of oral PCLX-001 comprised of two parts (dose escalation and dose expansion). Eligible patients will have: histologically-confirmed advanced solid tumor or B-cell lymphomas who have failed prior therapy and/or are not eligible for therapies; ages ≥ 18 years; adequate organ function; life expectancy of at least 12 weeks; and measurable disease. Part A (dose-escalation) patients will be accrued in cohorts of 3 to 6 patients to each dose level, starting at 20 mg daily on a 28 day cycle. Dose escalation will follow a modified Fibonacci design such that the magnitude of escalation decreases as the dose level nears the human equivalent dose of the highest non-severely toxic dose in dogs and then escalate at 1.4 times the previous dose. Dose escalation and determination of the maximum tolerated dose will be based on the occurrence of dose limiting toxicities in cycle 1. Part B will have two single agent expansion cohorts (n = 20 each) in advanced solid malignancies and relapsed/refractory B-cell lymphoma, to determine the preliminary clinical activity of PCLX-001 to determine the recommended phase II dose. The first patient on study is planned for Q3 2020.
A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 and BI 754111 in patients (pts) with advanced solid tumors.
Authors: Tolcher Anthony W. , Hafez Navid , Yamamoto Noboru , Park Jaehong , Grempler Rolf , Lucarelli Anthony G. , Lahmar Mehdi , Wang Bushi , Gounder Mrinal M. 
Published: May 2020

TPS3660 Background: Preclinical data show that the combination of a murine double minute 2–tumor protein 53 (MDM2–TP53) antagonist with anti-PD-1 and anti-LAG3 antibodies produces an anti-tumor effect in multiple tumor types. This Phase Ia/Ib study aims to determine the safety, recommended dose for expansion (RDE), and preliminary efficacy of BI 907828, a MDM2–TP53 antagonist, with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in a variety of TP53 wild-type cancers. Methods: In Phase Ia (dose escalation), ~30 pts with a confirmed diagnosis of any unresectable, advanced/metastatic solid tumor, irrespective of TP53 mutation status, will be enrolled. Pts will receive one dose of BI 907828 every 21 days (Q3W), at a starting dose of 10 mg orally, plus BI 754091 and BI 754111 (240 mg and 600 mg, respectively, Q3W, intravenously). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. The primary endpoint is the maximum-tolerated dose of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle. Secondary endpoints include pharmacokinetics and DLTs in the treatment period (to determine the RDE). In Phase Ib (dose expansion), pts with previously treated, unresectable, advanced/metastatic TP53 wild-type tumors with ≥1 measurable target lesion will be enrolled into four expansion cohorts (1: NSCLC; 2: melanoma; 3: well-differentiated/dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma; 4: hepatocellular carcinoma). The RDE of BI 907828 will be administered with fixed doses of BI754091 and BI 754111 (Q3W). In the NSCLC cohort only, pts will be randomized to one of three arms: RDE of BI 907828 + 240 mg BI 754091 + 600 mg BI 754111 (arm A, 32 pts); 240 mg BI 754091 + 600 mg BI 754111 (arm B, 32 pts); RDE of BI 907828 + 240 mg BI 754091 (arm C, 16 pts). The primary endpoint is objective response (OR, per RECIST 1.1). Secondary endpoints include OR (per iRECIST), disease control (per RECIST 1.1 and iRECIST), progression-free survival (PFS), PFS rate at 12 and 24 weeks (cohort 3), and safety. Phase Ib will include at least 140 evaluable pts (80 pts in cohort 1 and 20 pts each in cohorts 2–4). Clinical trial information: NCT03964233 .
Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC): A phase III study utilizing the German Registry of Incidental Gallbladder Carcinoma Platform (GR)—The AIO/CALGP/ACO-GAIN-Trial.
Authors: Goetze Thorsten Oliver , Bankstahl Ulli Simone , Lang Sven A. , Heeg Steffen , Bechstein Wolf Otto , Schnitzbauer Andreas , Pession Ursula , Reim Daniel , Lorenzen Sylvie , Keck Tobias , Königsrainer Alfred , Piso Pompiliu , Vogel Arndt , Pauligk Claudia , Al-Batran Salah-Eddin 
Published: May 2020

TPS4653 Background: Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20–40%. GBC is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts, while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. Encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even in intrahepatic and extrahepatic cholangiocarcinoma. Especially because data regarding pure adjuvant chemotherapy in BTC`s are conflicting. Methods: This is a multicenter, randomized, controlled, open-label phase III study including pts with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts with resectable/borderline resectable cholangiocarcinomas (ICC/ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator’s choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N=333 patients with GBC or BTC will be included. Recruitment has just started; first patient in was on December 6, 2020. EudraCT number: 2017-004444-38. Clinical trial information: NCT03673072 .