A5059144177- PI3K/AKT/mTOR signaling in cancer
- Protein Kinase Regulation and GTPase Signaling
- Chronic Myeloid Leukemia Treatments
- Advanced Breast Cancer Therapies
- Cancer Treatment and Pharmacology
- Colorectal Cancer Treatments and Studies
- Chronic Lymphocytic Leukemia Research
- Statistical Methods in Clinical Trials
- Health Systems, Economic Evaluations, Quality of Life
- Pancreatic and Hepatic Oncology Research
- Hepatocellular Carcinoma Treatment and Prognosis
- Lung Cancer Treatments and Mutations
- HER2/EGFR in Cancer Research
- Melanoma and MAPK Pathways
- CAR-T cell therapy research
- Cancer, Hypoxia, and Metabolism
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Cancer Immunotherapy and Biomarkers
- Angiogenesis and VEGF in Cancer
- Optimal Experimental Design Methods
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Pharmacogenetics and Drug Metabolism
- Meta-analysis and systematic reviews
Bayer (Germany)
2013-2025
Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, efficacy profiles regorafenib in patients with advanced solid tumors.Patients aged 18 years or older tumors refractory to standard treatment were recruited. was administered orally for 21 days on/seven off repeating cycles, until discontinuation...
In a phase I dose-escalation study, regorafenib demonstrated tolerability and antitumour activity in solid tumour patients. The study was expanded to focus on patients with metastatic colorectal cancer (CRC). Patients received oral 60–220 mg daily (160 the extension cohort) cycles of 21 days on, 7 off treatment. Assessments included toxicity, response, pharmacokinetics pharmacodynamics. Thirty-eight heavily pretreated CRC (median 4 prior lines therapy, range 0–7) were enrolled phases; 26 160...
Aim: We report results of a first-in-human study pasotuxizumab, PSMA bispecific T-cell engager (BiTE R ) immune therapy mediating killing tumor cells in patients with advanced castrationresistant prostate cancer.Patients & methods: assessed once-daily subcutaneous (SC) pasotuxizumab.All SC developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed.Results: A total 47 received pasotuxizumab (SC: n = 31, 0.5-172 μg/d; cIV: 16, 5-80 μg/d).The maximum tolerated...
BackgroundMetastatic colorectal cancer (mCRC) is commonly treated with 5-fluorouracil, folinic acid, and oxaliplatin or irinotecan. The multitargeted kinase inhibitor, regorafenib, was combined chemotherapy as first- second-line treatment of mCRC to assess safety pharmacokinetics (primary objectives) tumor response (secondary objective).Patients methodsForty-five patients were every 2 weeks 5-fluorouracil 400 mg/m2 bolus then 2400 over 46 h, acid mg/m2, either 85 irinotecan 180 mg/m2. On...
Abstract Purpose: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. Patients Methods: Adults with solid tumors or aggressive non–Hodgkin lymphoma who were refractory to had exhausted all available therapies received monotherapy as 30-minute intravenous, once-weekly infusion, escalating doses (5, 10, 15, 22.5, 30 mg in 21-day cycles) until MTD was determined. Results: Thirty-seven patients ≥ 1 dose,...
5034 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is promising therapeutic target in mCRPC, pasotuxizumab x CD3 BiTE that mediates tumor cell killing. Methods: NCT01723475 was first-in-human, multicenter, dose-escalation study patients (pts) with refractory to standard therapy. Pts received as continuous intravenous infusion cohorts of 3–4 pts. Dose-escalation followed reassessment methodology design. The primary objective determine safety maximum...
Abstract Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: solid tumors were receive oral (twice daily 2-days-on/5-days-off) weekly (90 mg/m2) or monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives assess safety, establish MTD BAY,...
The CONSORT (CONsolidated Standards Of Reporting Trials) 2010 statement is the standard guideline for reporting completed randomised trials. Dose-finding Extension (DEFINE) extends guidance (with 21 new items and 19 modified items) to early phase dose-finding trials with interim dose escalation or de-escalation strategies. Such generally focus on safety, tolerability, activity, recommending dosing scheduling regimens further clinical development. These are often inadequately reported,...
SummaryEarly phase dose-finding (EPDF) trials are key in the development of novel therapies, with their findings directly informing subsequent clinical phases and providing valuable insights for reverse translation. Comprehensive transparent reporting these studies is critical accurate interpretation, which may improve expedite therapeutic development. However, quality design characteristics results from EPDF often variable incomplete. The international consensus-based CONSORT-DEFINE...
Dual agent dose-finding trials study the effect of a combination more than one agent, where objective is to find Maximum Tolerated Dose Combination (MTC), doses two agents that associated with pre-specified risk being unsafe. In Phase I/II setting, dose both safe and active, Optimal Biological (OBD), optimizes criterion based on safety activity. Since Oncology treatments are typically given over multiple cycles, activity outcome can be considered as late-onset, potentially occurring in later...
3007 Background: The ATR kinase is a key regulator of the DNA damage response (DDR) machinery, activated by and replication stress. BAY 1895344 novel, potent, selective inhibitor with anti-tumor activity in preclinical models DDR defects. Methods: Pts advanced metastatic solid tumors resistant or refractory to standard treatment, without defects, received BID, 3 days (d) on/4 d off continuously 3-weekly cycles. Results: As December 20, 2018, 18 pts colorectal (4), breast (3), prostate (2),...
Background: The use of ‘backfilling’, assigning additional patients to doses deemed safe, in phase I dose-escalation studies has been used practice collect information on the safety profile, pharmacokinetics and activity a drug. These help ensure that maximum tolerated dose is reliably estimated give determine recommended II dose. Methods: In this article, we study effect employing backfilling trial estimation duration study. We consider situation where only one cycle follow-up for...
SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 provides guidance clinical trial protocol writing. However, neither the original nor its extensions adequately cover features of early phase dose-finding trials. The Dose-finding Extension (DEFINE) statement is a new guideline that recommendations essential items should be provided in protocols these It details to guidance, incorporating 17 and modifying 15 existing items. purpose this promote transparency,...
124 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is promising therapeutic target in mCRPC. Pasotuxizumab x CD3 BiTE immune therapy that mediates killing of tumor cells by T cells. Methods: NCT01723475 was first-in-human, multicenter, dose-escalation study patients (pts) with refractory to standard therapy. Pts received continuous IV infusion pasotuxizumab cohorts 3–4 pts. Dose-escalation followed reassessment methodology. The primary objective...
The Northwick Park incident has focused the attention on risk of healthy volunteers participating in Phase I First-in-Man (FiM) studies irrespective biologicals or small molecules being applied. However, only few data safety receiving FiM trials are available. This study reports single dose performed with at Bayer in-house ward Wuppertal from 2000 to 2005.From 2005, 24 escalation were performed. Twenty oral formulations and four intravenous formulations. 1,094 young male subjects included...
3585 Background: Regorafenib is an oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, B-RAF). resulted in a 74% disease control rate (PR+SD) phase I study patients (pts) with refractory metastatic colorectal cancer (CRC). A III monotherapy trial relapsing CRC pts ongoing. Methods: The Ib 11656 investigated the safety, PK, efficacy sequentially administered regorafenib combination mFOLFOX6 (FOLFOX) or FOLFIRI (oxaliplatin 85...
This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor AKT1/2, aimed to evaluate the safety, pharmacokinetics, maximum tolerated dose 1125976 in patients with advanced solid tumors. Oral escalation was investigated continuous once daily (QD) treatment (21 days/cycle) twice (BID) schedule. A expansion 28 hormone receptor-positive metastatic breast cancer, including nine harboring AKT1E17K mutation, performed at recommended...
300 Background: REG is a novel oral inhibitor of multiple kinases involved in angiogenesis, oncogenesis, and tumor microenvironment. A multicenter, open-label, single-arm phase I dose-escalation study evaluated given with continuous schedule established 100 mg once daily as the maximum tolerated dose. This explored safety PK this dose an expanded cohort advanced HCC pts. Methods: Adults treatment-refractory (Child Pugh [CP] or B) received until progression, unacceptable toxicity,...
7538 Background: PTEFb/CDK9-mediated transcription of short-lived anti-apoptotic survival proteins and oncogenes like MCL-1 MYC plays a critical role in variety cancers. VIP152 (formerly BAY 1251152), potent highly selective CDK9 inhibitor, has been evaluated Phase 1 dose-escalation study patients with advanced cancer. The maximum tolerated dose was 30 mg once weekly administered consecutive 21-day cycles, based on neutropenia as the dose-limiting toxicity (JCO 2018;36:2507; NCT02635672)....
An objective of phase I dose‐finding trials is to find the maximum tolerated dose; dose with a particular risk toxicity. Frequently, this assessed across first cycle therapy. However, in oncology, course treatment frequently consists multiple cycles In many cases, overall toxicity for given not fully encapsulated by observations from cycle, and hence it advantageous include outcomes later trials. Extending follow up period trial naturally extends total length which undesirable. We present...