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Proposal 1572

Title of the Proposed Research

Research to evaluate the relation of toxicity and the relative dose intensity in phase I trials beyond cycle 1 of Molecular Targeted Agents (MTAs)

Lead Researcher

Kan Yonemori, MD., PhD

Affiliation

Department of Breast and Medical Oncology National Cancer Center Hospital, National Cancer Center, Japan

Funding Source

None

Potential Conflicts of Interest

None

Data Sharing Agreement Date

19 January 2017

Lay Summary

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials, so called the “recommended phase 2 dose (RP2D)”. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. Recently, the emergence of molecularly targeted agents (MTA) and other new biological drugs are rapid. Nonetheless, regardless of drug type (ex. cytotoxic, molecular targeted, immune-modulator) or administration route (ex. oral, iv, im) or schedule (ex. weekly, bi-weekly, daily) or mode of action (ex. Taxanes, VEGFR TKI, PD-1 antibody) or differences of toxicity, the RP2D is generally determined by the same procedure. However, cytotoxic agents and MTAs show different biological activity should be handled differently.

RP2D is generally based on the maximum tolerated dose (MTD) in a phase I trial that is determined based on dose limiting toxicity in the first cycle. MTAs are a newer class of therapeutic agent administered daily with or without short term rest until progression or unacceptable toxicity develops, and treatment duration of MTAs is generally longer than that of cytotoxic drugs. Therefore, some MTAs require dose modification in treatment beyond cycle 1, due to persistent low grade toxicities and as a result, dose intensity is decreased. We hypothesize that on determining the RP2D, the traditional method of using only the cycle one toxicity data is insufficient.

Therefore, the main purpose of our research is to evaluate the relation of toxicity and the relative dose intensity in phase I trials of MTAs using the data of not only the first cycle but also the second and the later courses in the phase I trial. By doing that, we plan to develop a novel method for dose modification in clinical trials and examine the utility of our proposed method for determining the MTD.

With this new method to estimate RP2Ds in MTAs and a dose modification method, we hypothesize that the true RP2D will be calculated and therefore find the ideal dose delivery level, which can be used in a broad range of phase I trials.

Study Data Provided

GSK-MET111516: An Open-label, Randomized, Two-way Balanced Crossover Study to Investigate the Bioavailability of two forms of GSK1363089 in Subjects with Solid Tumors
GSK-SIR113221: A Phase 1, Double-Blind, Randomized Clinical Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of SRT501 in Subjects with Colorectal Cancer and Hepatic Metastases
GSK-MET111647: A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of GSK1363089 (Formerly XL880) Administered Orally to Subjects With Solid Tumors
GSK-BEX104510: A phase I, dose-escalation, open label, multicenter study of Iodine-131 anti-B1 antibody for intermediate- and high-risk B-cell chronic lymphocytic leukemia
GSK-BEX104512: Phase I, Dose-Escalation Study of Iodine-131 Anti-B1 Antibody for Patients with Previously Treated Non Hodgkin’s Lymphoma With More Than 25% Bone Marrow Involvement
GSK-PIK111051: A Phase I Open-Label, Dose-Escalation Study of the Phosphoinositide 3-Kinase Inhibitor GSK1059615 in Patients with Solid Tumors or Lymphoma
GSK-PLK107427: A Phase I Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of [GSK461364], a Polo-like Kinase 1 (PLK1) Inhibitor, in Adult Subjects with Advanced Solid Tumor or Non-Hodgkins Lymphoma
EISAI-E7080-J081-103: An Open Label Phase I Dose Escalation Study of E7080 Administered to Patients With Solid Tumors
GSK-MET111648: A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of GSK1363089 (Formerly XL880) Administered Orally Daily to Subjects with Solid Tumors
LILLY-I4T-IE-JVBM: Phase I Study of Weekly Anti-Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) Monoclonal Antibody IMC-1121B in Patients with Advanced Solid Tumors Who Have Not Responded to Standard Therapy
BI-1200.1: Dose Escalation Study of Oral Treatment With BIBW 2992 in Patients With Advanced Solid Tumors
BI-1200.2: Dose Escalation Study of BIBW 2992 in Patients With Advanced Solid Tumors
BI-1200.3: Dose Escalation Study of Oral Treatment With BIBW 2992 in Patients With Advanced Solid Tumours
BI-1200.4: Dose Escalation Study of Continuous Once-daily Oral Treatment With BIBW 2992 in Patients With Advanced Solid Tumors
BI-1200.17: BIBW 2992 in Patients With Advanced Solid Tumors
GSK-AKT106757: An Open-label Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the AKT Inhibitor GSK690693 given on Various Schedules in Subjects with Solid Tumors or Lymphoma
GSK-393229/027: A Multi-Center Study to Examine the Pharmacokinetics, Whole Body and Organ Dosimetry, and Biodistribution of Fission-Derived Iodine I 131 Tositumomab for Patients With Previously Untreated or Relapsed Follicular or Transformed Follicular Non-Hodgkin's Lymphoma
GSK-FAK113581: A Phase I, Randomized, Single-Blind, Placebo-Controlled Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Food Effect Following Single Oral Doses of the Focal Adhesion Kinase Inhibitor, GSK2256098, in Healthy Subjects
GSK-P3K112826: A Phase I Open-Label, Dose-Escalation Study of the Phosphoinositide 3-Kinase Inhibitor GSK2126458 in Subjects with Solid Tumors or Lymphoma
GSK-GZL116987: A study to evaluate the pharmacokinetics, safety and tolerability, immunogenicity, and pharmacodynamics of GSK2800528 in healthy subjects.

Statistical Analysis Plan

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