bluuebunny/crossref_metadata_2025_split huggingface dataset:
GBM AGILE: A global, phase II/III adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.
Authors: Buxton Meredith Becker , Alexander Brian Michael , Berry Donald A. , Cavenee Webster K. , Colman Howard , De Groot John Frederick , Ellingson Benjamin M. , Gordon Gary B. , Khasraw Mustafa , Lassman Andrew B. , Li Wenbin , Lim Michael , Mellinghoff Ingo K. , Perry James R. , Sulman Erik P. , Tanner Kirk , Weller Michael , Wen Patrick Y. , Yung W. K. Alfred , Cloughesy Timothy Francis ,   GBM AGILE Investigators
Published: May 2020

TPS2579 Background: Glioblastoma (GBM) is an aggressive brain tumor with few effective therapies and is invariably fatal. Developing new therapies for patients with GBM requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. Industry is wary of developing drugs for GBM due to the high failure rate and high cost of drug development. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase II/III development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research (GCAR), a non-profit organization. GCAR’s mission is to speed the discovery and development of treatments for patients with rare and deadly diseases by serving as sponsor of innovative trials. Methods: GBM AGILE is an international, seamless phase II/III platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs/drug combinations from different pharmaceutical companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, enrolling its first patient in June 2019. Site activation is ongoing in the US, with approximately 40 US planned. The trial received CTA approval from Health Canada in January 2020. Expansion to Europe, China, and Australia is also underway. Clinical trial information: NCT03970447 .
Phase I trial of drug resistant immunotherapy: A first-in-class combination of MGMT-modified γδ t cells and temozolomide chemotherapy in newly diagnosed glioblastoma multiforme.
Authors: Lamb Lawrence S. , Gibbs Shirley , Pillay Thriumaine , Beelen Melissa , Ho William , Nabors Louis B. 
Published: May 2020

TPS3150 Background: Temozolomide (TMZ) transiently upregulates GBM-specific stress-induced NKG2D ligands that are targeted by innate immune effector cells. Leveraging this effect is problematic, however, due to the lymphodepleting effects of TMZ.Genetic modification of ex vivo expanded and activated with an MGMT-expressing lentivector allows simultaneous chemotherapy and γδ T cell therapy that targets the tumor when NKG2DL are maximally expressed. We have termed this Drug Resistant Immunotherapy (DRI). Patient-derived xenograft mouse models of both primary and recurrent GBM treated with DRI have shown a significant survival advantage that were otherwise impervious to either cell therapy or TMZ. These preclinical findings and associated safety data provide the rationale to initiate a Phase I trial of DRI in primary GBM. Methods: This first in human study will evaluate the safety and optimal dosing frequency of the DRI with TMZ (NCT04165941).Eligibility criteria include the following: GBM eligible for resection, ≥18y, adequate organ and marrow function, and KPS≥70. Six to 12patients with newly diagnosed GBM are being enrolled in a 3 + 3 design into 1 of 2 fixed dose levels (DL) of DRI. Following tumor resection and immediately prior to induction chemo/radiotherapy, an apheresis product is collected and γδ T cells expanded in Zoledronic Acid (Novartis) and rhIL-12 (Miltenyi) and transduced with a P140K-MGMT lentivector (Miltenyi Lentigen, Gaithersburg, MD), harvested, and cryopreserved. At initiation of maintenance phase TMZ therapy, patients receive 150mg/m2 intravenous TMZ concurrently with intracranial injection of 1 x 107 γδ T cells (DL1) delivered through a Rickham reservoir previously inserted into the tumor cavity at resection. The patient then receives 4 daily doses of oral TMZ followed by 24d rest. Treatment cycles escalate from 1 to 3 (DL2) DRI doses following a safety observation period and absence of dose limiting toxicity. Maintenance TMZ treatment will continue for 6 cycles. Safety evaluations consist of routine laboratory analyses, clinical measurements (physical exams, vital signs), neurological function and evidence DRI γδ T cell related toxicity. Peripheral blood will be obtained for comprehensive immuno-phenotyping and T cell function analysis. Clinical benefit of DRI will be characterized by evaluating responses (CR, PR, SD and PD) and determining progression-free, median, and overall survival. As of February 2020, enrollment into DL 1 is ongoing. Clinical trial information: NCT04165941 .
A phase Ib study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO).
Authors: Ileana Dumbrava Ecaterina Elena , Suarez-Almazor Maria E. , Painter Jeane , Johanns Tanner , Dougan Michael L. , Cappelli Laura , Bingham Clifton O. , Wang Yinghong , Gupta Sarthak , Warner Blake M , Rahma Osama E. , Naidoo Jarushka , Ott Patrick Alexander , Hafler David A , Kluger Harriet M. , Khosroshahi Arezou , Katsumoto Tamiko R , Kummar Shivaani , Sharon Elad , Tawbi Hussein Abdul-Hassan 
Published: May 2020

TPS3158 Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flares and worsening of pre-existing autoimmune disorders in pts with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, Sjögren's Syndrome and Other Autoimmune Disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345 .
TROPiCS–03: A phase II open-label study of sacituzumab govitecan (SG) in patients with metastatic solid tumors.
Authors: Saxena Ashish , Michel Loren S. , Hong Quan , Hilsinger Karrie , Kanwal Charu , Pichardo Cabilia , Goswami Trishna , Santin Alessandro 
Published: May 2020

TPS3648 Background: Trophoblast cell surface antigen (Trop-2) is highly expressed in many epithelial cancers (non–small-cell lung cancer [NSCLC], endometrial cancer, urothelial carcinoma [UC], and triple-negative breast cancer [TNBC]) and has been linked to aggressive disease and poor prognosis. SG is a Trop-2–directed antibody drug conjugate containing SN-38 (active metabolite of irinotecan) with a 7.5:1 drug-to-antibody ratio and unique hydrolyzable linker that allows for extracellular bystander effect. The phase 1/2 IMMU-132-01 basket study reported clinical activity with SG in patients with multiple tumor types not selected for Trop-2 expression including NSCLC (objective response rate [ORR]: 17%), TNBC (ORR: 33%), and UC (ORR: 31%).1-3 Results from the overall safety population (N=420) from this study found that SG was tolerable, with a predictable and manageable safety profile, and low discontinuation rates due to AEs. Methods: To test a biomarker-enrichment strategy with Trop-2, the TROPiCS-03 (TROP-2 Investigations in Cancer with SG) study was initiated. TROPiCS-03 (NCT03964727) is a multi-cohort, open-label, phase 2 study in patients with metastatic solid tumors - presently NSCLC (adenocarcinoma and squamous cell carcinoma), head and neck squamous cell carcinoma, and endometrial cancer - selected based on elevated Trop-2 expression by a validated IHC assay. Patients receive SG (10 mg/kg IV, days 1 and 8 every 21 days) and continue treatment until lack of clinical benefit or unacceptable toxicity. The primary endpoint is objective response rate (local assessment) and additional endpoints include clinical benefit rate, duration of response, progression-free survival, and safety. Females or males ≥18 years old who are histologically documented to have locally advanced or metastatic (M1, stage 4) solid tumors of the above types are eligible. Patients must have ECOG 0 or 1 and adequate clinical laboratory results to be enrolled. All subjects will have progressed after prior platinum-based chemotherapy and programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) directed therapy. Patients who have previously received topoisomerase I inhibitors and those with known active CNS metastases are excluded. Approximately 160 patients will be enrolled in the trial overall; enrollment in the NSCLC cohort is currently in progress. References: Heist RS et al. J Clin Oncol. 2017;35:2790-7, Bardia A et al., NEJM. 2019;380:741-51.,Tagawa ST et al., Oral presentation; ASCO-GU 2019, San Francisco, CA. Clinical trial information: NCT03964727 .
Phase I study of the antibody-drug conjugate ABBV-321 in patients with non-small cell lung cancer and squamous head and neck cancer with overexpression of the epidermal growth factor receptor.
Authors: Carneiro Benedito A. , Bestvina Christine M. , Shmueli Einat Shacham , Gan Hui Kong , Beck Joseph Thaddeus , Robinson Randy , Fischer JuDee S. , Wong Amber , Ansell Peter J , Jin Janet Yikai , Naumovski Louie , Papadopoulos Kyriakos P. 
Published: May 2020

TPS3649 Background: ABBV-321 (serclutamab talirine) is an epidermal growth factor receptor (EGFR)-targeted antibody-drug conjugate that consists of a humanized immunoglobulin G1 anti-EGFR monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer via a maleimidocaproyl-valine-alanine linker. Once bound, ABBV-321 is internalized, the maleimidocaproyl-valine-alanine linker undergoes proteolytic cleavage, and the cytotoxic PBD is released, causing DNA cross-links and cell death. Preclinical studies have shown cytotoxicity in numerous human xenograft and patient (pt)-derived tumor models. This first-in-human trial is assessing the safety, pharmacokinetic (PK), and preliminary antitumor activity of ABBV-321 in pts with advanced solid tumor types likely to exhibit elevated levels of EGFR. Methods: This is a 2-part, multicenter phase 1 study (NCT03234712) of ABBV-321 monotherapy in pts (≥18 years; Eastern Cooperative Oncology Group performance status 0–1) with advanced solid tumors associated with overexpression of EGFR. EGFR overexpression will be determined by centralized testing using an RNA-based assay. Primary objectives of the completed part 1 (dose escalation) were to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of ABBV-321 and assess the PK and toxicity and safety profile; part 2 (dose expansion) will evaluate safety and PK profile at the RP2D in specific cohorts (NSCLC and HNSCC). Secondary objectives include assessment of preliminary antitumor activity. Pts will receive escalating doses of ABBV-321 until the MTD/RP2D is determined. Dose-limiting toxicities will be assessed during the first cycle of dosing. Adverse events (AEs) will be evaluated per National Cancer Institute Common Terminology Criteria for AEs (version 4.03). Blood samples for PK analysis (ABBV-321, total antibody, unconjugated PBD) will be collected at designated time points throughout the study. The multinational trial is active, with the first pt screened on 1 Feb 2018. The dose-escalation phase has been completed; screening and enrollment for the expansion phase of the study in NSCLC and HNSCC is underway. Clinical trial information: NCT03234712 .
First-in-human phase I study of SY-5609, an oral, potent, and selective noncovalent CDK7 inhibitor, in adult patients with select advanced solid tumors.
Authors: Papadopoulos Kyriakos P. , Sharma Manish , Hamilton Erika Paige , Richardson Debra L. , Hodgson Graeme , Zhou Li , Volkert Angela , Jolin Hina A. , Madigan Catherine , Kelly Michael , Roth David A. 
Published: May 2020

TPS3662 Background: SY-5609 is an oral, noncovalent, highly selective and potent inhibitor of cyclin-dependent kinase 7 (CDK7), a key regulator of 2 biological processes that play critical roles in driving tumor development: transcription and cell cycle control. Evaluation of SY-5609 as a single agent in PDX models from a range of solid tumors, including breast, ovarian, lung and colorectal tumors, revealed robust antitumor activity including complete regressions, and activity in models known to be resistant to standard of care therapy. Models with genetic alterations in RB pathway genes demonstrated deep ( > 90% TGI) and sustained SY-5609-induced tumor regressions following treatment discontinuation, in contrast to models without genetic alteration in RB pathway genes, suggesting that tumor cells with aberrant cell-cycle control may be particularly sensitive to SY-5609 treatment. The study is designed to evaluate the safety, tolerability, and maximum tolerated dose (MTD) of SY-5609, to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and preliminary antitumor activity of SY-5609, and to explore candidate biomarkers predictive of response to SY-5609. Methods: This is a multi-center, open-label Phase 1 trial expected to enroll approximately 60 adult patients with select advanced solid tumors for which standard treatment is no longer effective. The dose escalation phase of the trial is open to adult patients with ovarian, breast, colorectal, or lung cancer, and patients with any solid tumor histology with molecular evidence of deregulated RB cell cycle control. SY-5609 is being administered orally once daily, for each 4-week cycle. Initially, patients will be enrolled into single-patient accelerated titration cohorts; subsequent cohorts will transition to a 3 + 3 design. Following completion of DLT evaluation at a given dose level, additional patients may be enrolled at that dose to further characterize safety, PK, PD, and early clinical activity. Data from this trial will support dose selection for planned evaluations of antitumor activity of SY-5609 as a single agent and in combination. Clinical trial information: NCT04247126 .
Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies.
Authors: Hamilton Erika Paige , Patel Manish R. , Rodon Jordi , Hong David S. , Schram Alison M. , Janne Pasi A. , LoRusso Patricia , Sachdev Jasgit C. , Ou Sai Hong , Buck Elizabeth A , O'Connor Matthew , Waters Nigel , Witt Karsten , Cook Carl 
Published: May 2020

TPS3665 Background: A significant unmet need exists for drugs targeting allosteric ErbB mutations (non-canonical mutations outside the ATP binding site). Current EGFR and HER2 tyrosine kinase inhibitors or mAbs have limited antitumor activity against allosteric mutations, resulting in toxicity before adequate drug exposure (Connell and Doherty, 2017). BDTX-189 is a potent and selective orally available irreversible inhibitor targeting unique oncogenic driver mutations of ErbB kinases in EGFR and HER2, while sparing WT EGFR. Preclinical studies demonstrated antitumor activity across a range of allosteric ErbB mutants, including extracellular domain allosteric mutations of HER2 as well as EGFR and HER2 kinase domain exon 20 insertions (Buck, 2019). This first-in-human trial (NCT04209465) is aimed to determine the recommended phase 2 dose (RP2) and schedule (Phase 1, P1), and evaluate the efficacy (Phase 2, P2) of BDTX-189. P1 primary objective is to determine the RP2 dose and schedule of monotherapy BDTX-189. Secondary objectives include assessment of safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) effects in tumor, and preliminary efficacy. The P2 primary objective is to assess antitumor activity of monotherapy BDTX-189. Methods: The study will enroll patients (pts) ≥18 yrs with histologically or cytologically confirmed locally advanced or metastatic solid tumors with no standard therapy available or for whom standard therapy is unsuitable or intolerable. P1 dose-escalation will use a BOIN design (Yuan, 2016) and will enroll ≤ 88 pts with allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplified or overexpressing tumor; or EGFR exon 19 deletion or L858R mutation. BDTX-189 will be dosed orally (PO) initially QD in 3 wk cycles. Regimen optimization will use PK, PD and safety data and may explore a BID schedule. An expansion cohort of ≤12 pts will further evaluate safety and preliminary efficacy of BDTX-189 prior to P2. P2, utilizing a Simon 2-stage design, will enroll ≤100 pts with NSCLC with EGFR or HER2 exon 20 insertion mutations (cohort 1); breast cancer with an allosteric ErbB mutation (cohort 2); tumors (except breast) with S310F/Y mutation (cohort 3); and other allosteric ErbB mutations not defined in cohorts 1-3 (cohort 4). Assessments include safety, tolerability, DLTs, evaluation of MTD, PK, PD, and preliminary antitumor activity. Enrollment began 1/2020. Clinical trial information: NCT04209465 .
A phase III study of comparing FOLFOX+/-bevacizumab with FOLFOX+/-bevacizumab+ high-dose intravenous vitamin C as first-line therapy in patients with advanced colorectal cancer.
Authors: Wang Feng , Xiao Jian , Zhang Yan-Qiao , Yuan Xianglin , Fang Weijia , Wang Wei , HU Xiaohua , Zhuang Zhixiang , Zhou Fuxiang , Ying Jieer , Yuan Ying , Guo Zeng-qing , Wu XiangYuan , Zou Qing-Feng , He Ming-ming , Guo Ying , Chen Shuang-Zhen , Xu Rui-hua 
Published: May 2020

TPS4115 Background: Previous studies showed that high dose vitamin C especially when administered intravenously might have anti-cancer effect. A recent preclinical study found that human colorectal cancer cells harboring KRAS or BRAF mutations are selectively killed by high dose vitamin C. Our phase I dose-escalation and expansion study has shown that high dose (up to 1.5g/kg) intravenous vitamin C with FOLFOX or FOLFIRI is well tolerated in patients with colorectal or gastric cancer. This trial is a randomized, multicenter, phase Ⅲ study of high dose vitamin C infusion combined with FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line therapy in patients with advanced colorectal cancer. Methods: This study has enrolled patients with histologically confirmed metastatic adenocarcinoma of colorectum, normal G6PD status and no prior treatment for metastatic disease. 432 patients are randomized 1:1 into one of two groups. Patients in the control group are treated with mFOLFOX6 (oxaliplatin 85 mg/m² d1 concurrent with leucovorin 400 mg/m², followed by bolus 5FU 400 mg/m² d1, followed by infusional 5FU 2400 mg/m² over 46 hours) with or without bevacizumab (5mg/kg, d1) every 2 weeks. Patients in the experimental group are treated with vitamin C intravenously (1.5g/kg/day, d1-3) in combination with mFOLFOX6 with or without bevacizumab every 2 weeks. Randomization is stratified by the location of primary site (left-sided or right-sided) and treatment with bevacizumab (with or without). The primary endpoint is progression free survival (assessed by investigator per RECIST v1.1). Secondary endpoints are overall survival, response rate, assessment of treatment-related adverse events, progression free survival and overall survival in RAS or BRAF mutant patients. Genome, microbiome and metabolome are also assessed. Clinical trial information: NCT02969681 .