Maximum tolerated dose
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Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors Open
HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with …
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First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced <i>KRAS</i><sup><i>G12C</i></sup> Solid Tumors (KRYSTAL-1) Open
PURPOSE Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRAS G12C . We report results from a phase I/IB study of adagrasib in non–small-cell lung cancer, colorectal cancer, and other solid tumors har…
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Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials Open
Despite more than two decades of publications that offer more innovative model-based designs, the classical 3 + 3 design remains the most dominant phase I trial design in practice. In this article, we introduce a new trial design, the Baye…
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Keyboard: A Novel Bayesian Toxicity Probability Interval Design for Phase I Clinical Trials Open
The primary objective of phase I oncology trials is to find the MTD. The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides bet…
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A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma Open
ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II …
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A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2–Positive Metastatic Breast Cancer Open
Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positi…
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BOIN12: Bayesian Optimal Interval Phase I/II Trial Design for Utility-Based Dose Finding in Immunotherapy and Targeted Therapies Open
PURPOSE For immunotherapy, such as checkpoint inhibitors and chimeric antigen receptor T-cell therapy, where the efficacy does not necessarily increase with the dose, the maximum tolerated dose may not be the optimal dose for treating pati…
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A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor Open
Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients ar…
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Time-to-Event Bayesian Optimal Interval Design to Accelerate Phase I Trials Open
Late-onset toxicity is common for novel molecularly targeted agents and immunotherapy. It causes major logistic difficulty for existing adaptive phase I trial designs, which require the observance of toxicity early enough to apply dose-esc…
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Phase I trial of isatuximab monotherapy in the treatment of refractory multiple myeloma Open
This phase I dose-escalation/expansion study evaluated isatuximab (anti-CD38 monoclonal antibody) monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). Patients progressing on or after standard therapy received intraven…
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A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) Open
( ClinicalTrials.gov Identifier: NCT02028442 ). Trial registration date: 07 January 2014 - Retrospectively registered.
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A utility‐based Bayesian optimal interval (U‐BOIN) phase I/II design to identify the optimal biological dose for targeted and immune therapies Open
In the era of targeted therapy and immunotherapy, the objective of dose finding is often to identify the optimal biological dose (OBD), rather than the maximum tolerated dose. We develop a utility‐based Bayesian optimal interval (U‐BOIN) p…
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Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study Open
Purpose: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile. Patient…
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Safety and Immunogenicity of the PRAME Cancer Immunotherapeutic in Patients with Resected Non–Small Cell Lung Cancer: A Phase I Dose Escalation Study Open
The PRAME immunotherapeutic had an acceptable safety profile. All patients had anti-PRAME humoral responses that were not dose related, and 80% of those treated at the highest dose showed a cellular immune response. The dose of 500 μg was …
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A Phase I Dose-Escalation and Expansion Study of Telaglenastat in Patients with Advanced or Metastatic Solid Tumors Open
Purpose: Glutamine is a critical fuel for solid tumors. Interference with glutamine metabolism is deleterious to neoplasia in preclinical models. A phase I study of the oral, first-in-class, glutaminase (GLS) inhibitor telaglenastat was co…
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Time-to-event model-assisted designs for dose-finding trials with delayed toxicity Open
Summary Two useful strategies to speed up drug development are to increase the patient accrual rate and use novel adaptive designs. Unfortunately, these two strategies often conflict when the evaluation of the outcome cannot keep pace with…
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Phase I Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, Monotherapy in Patients with Advanced Non–Small Cell Lung Carcinoma Open
Purpose: Telisotuzumab vedotin (Teliso-V) is an anti–c-Met–directed antibody–drug conjugate. Here, we present safety and efficacy data from a phase I/Ib study of Teliso-V monotherapy evaluated in once every 2 weeks/once every 3 weeks sched…
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Diffuse optical spectroscopic imaging reveals distinct early breast tumor hemodynamic responses to metronomic and maximum tolerated dose regimens Open
Background Breast cancer patients with early-stage disease are increasingly administered neoadjuvant chemotherapy (NAC) to downstage their tumors prior to surgery. In this setting, approximately 31% of patients fail to respond to therapy. …
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Dose‐finding methods for Phase I clinical trials using pharmacokinetics in small populations Open
The aim of phase I clinical trials is to obtain reliable information on safety, tolerability, pharmacokinetics (PK), and mechanism of action of drugs with the objective of determining the maximum tolerated dose (MTD). In most phase I studi…
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TAS-116 (Pimitespib), an Oral HSP90 Inhibitor, in Combination with Nivolumab in Patients with Colorectal Cancer and Other Solid Tumors: An Open-Label, Dose-Finding, and Expansion Phase Ib Trial (EPOC1704) Open
Purpose: This is a phase Ib trial of TAS-116, an oral HSP90 inhibitor, plus nivolumab for colorectal cancer and other solid tumors. Patients and Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate …
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Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors Open
Purpose: LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with…
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Phase I Clinical Trial of the Wee1 Inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors: A COG Phase I Consortium Report (ADVL1312) Open
Purpose: Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase…
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Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors Open
Purpose: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors. Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG…
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Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization Open
Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for so…
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Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results Open
The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4…
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TITE‐BOIN12: A Bayesian phase I/II trial design to find the optimal biological dose with late‐onset toxicity and efficacy Open
In the era of immunotherapies and targeted therapies, the focus of early phase clinical trials has shifted from finding the maximum tolerated dose to identifying the optimal biological dose (OBD), which maximizes the toxicity‐efficacy trad…
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Toxicity‐dependent feasibility bounds for the escalation with overdose control approach in phase I cancer trials Open
Phase I trials of anti‐cancer therapies aim to identify a maximum tolerated dose (MTD), defined as the dose that causes unacceptable toxicity in a target proportion of patients. Both rule‐based and model‐based methods have been proposed fo…
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Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46) Open
QBiotics Group Limited Brisbane, Queensland, Australia was the sponsor of the study.
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A practical Bayesian design to identify the maximum tolerated dose contour for drug combination trials Open
Drug combination therapy has become the mainstream approach to cancer treatment. One fundamental feature that makes combination trials different from single‐agent trials is the existence of the maximum tolerated dose (MTD) contour, that is…
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Low doses in immunotherapy: Are they effective? Open
Checkpoint inhibitors are versatile immunomodulatory agents, and they are being approved for the treatment of an increasing number of cancers, based on the demonstration of clinical benefits. While they have changed the landscape of treatm…