Dose-Escalation and Safety Trial of YN968D1
This protocol will be divided into two parts: Part 1 will evaluate the safety and pharmacokinetics of three doses of YN968D1 after a single administration followed by a 28-Day continuous course of therapy; Part 2 will evaluate the safety and preliminary efficacy in an open-label administration of YN968D1 at the MTD or a maximum of 750 mg. All subjects in Part 1 and Part 2 of this study will be permitted to continue therapy with only safety monitoring and bimonthly assessments for progression, if the product is well tolerated and the subject has stable disease or better. Up to 72 subjects will be enrolled in this clinical trial.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Evaluation of the Safety, Pharmacokinetics and Efficacy of Four Doses of YN968D1 in Subjects With Solid Tumors|
- Safety in the first 28-Days of Therapy [ Time Frame: 28-Days after Discontinuation of YN968D1 ] [ Designated as safety issue: Yes ]The primary endpoint is evaluation of safety during the first 28-day cycle of therapy following the initiation of multiple dosing of YN968D1. The safety variables to be evaluated in this study are adverse events, physical examinations, vital signs (specifically including blood pressure), clinical laboratory evaluations including serum chemistry, hematology (including RBC morphology and reticulocyte count), and urinalysis (with detailed sediment analysis, proteinuria, and 24-hour urine for collection for creatinine clearance and protein), and electrocardiograms (ECGs) in triplicate.
- Pharmacokinetic Assessments for AUC, Cmax and Tmax [ Time Frame: Day 1 Single Dose and Day 28 Steady State ] [ Designated as safety issue: No ]In Part 1 of this study, full PK profiles of YN968D1 will be obtained following administration of a single oral dose of YN968D1 on Day 1, and at steady state on Day 35±2. In Part 2 of this study, PK sampling will include a pre-dose and at the 4±1 hour time point on the first day of dosing in the first 28-Day cycle of therapy, and pre-dose on days 2, 7, 14 and 28 of the first 28-Day cycle of therapy
- Tumor Biomarkers for Specific Tumor Types [ Time Frame: Every 28-Days ] [ Designated as safety issue: No ]The primary Pharmacodynamic endpoints will include specific serum tumor markers for the target cancer, levels of endothelial growth factor (VEGF), and detection of EC-derived molecules such as sVEGFR-1, sVEGFR-2, sVEGFR-3, sTie-2 and VCAM-1, as well as PIGF. These biomarkers will be measured at baseline and at the end of every two 28-Day cycles of therapy. For patients that continue on repeat 28-Day cycles after the primary evaluation period, biomarkerts will be assessed after each two 28-Day cycles of therapy.
- Objective Response Rate (RESIST) [ Time Frame: Every 56-Days ] [ Designated as safety issue: No ]Anti-tumoral efficacy will be assessed by best radiographic response based on Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) at baseline (Day -14 to -1) and at the end of two 28-Day cycles of therapy (Part 1 - Day 35±2; or Part 2 56±2 Days). For patients that continue on repeat 28-Day cycles after the primary evaluation period, progression will be assessed after each two 28-Day cycles of therapy.
|Study Start Date:||April 2012|
|Study Completion Date:||May 2015|
|Primary Completion Date:||February 2015 (Final data collection date for primary outcome measure)|
Active therapy arm for safety evaluation
Daily dosing of YN968D1 for treatment of solid tumors
Other Name: Apatinib
Part 1 will include a sequential evaluation of 3 subjects per cohort; cohort 1 at a dose of 100 mg YN968D1, followed by a cohorts 2, 3 and 4 at doses of 250 mg, 500 mg and 750 mg respectively. Initially, each subject will receive one dose of YN968D1 followed by a 7-Day observation period, during which single dose PK assessments and safety monitoring will be performed. If the initial dose is well tolerated, the subject will return on Day 8 and receive 28-Days of continuous YN968D1 oral administration daily. Each subject will subsequently be assessed for safety and disease progression on Day 35±2 and steady state pharmacokinetic sampling will be obtained. Patients may continue on therapy for an additional 28-Day cycles without dose interruption if the therapy is well tolerated. Efficacy assessments (biomarkers) and disease progression (RECIST imaging) will be assessed every two 28-Day cycles. The subjects will be assessed for safety for at least 28-Days after the last dose of YN968D1.
For Part 1 of this study, a Dose Limiting Toxicity (DLT) event is defined as any of the following events that are assessed by the Investigator as probably or possibly related to YN968D1 and occur during or after the initial dose on Day 1 through Day 35 of the first cycle of therapy.
- CTCAE Grade 4 event
- Grade 3 febrile neutropenia (<1,000 neutrophils/mL)
- Grade 3 hematologic toxicity with duration > 7 days
- Grade 3 non-hematologic toxicity (except for nausea, vomiting, diarrhea that continues despite optimal medical management)
If a DLT is experienced in any cohort, the cohort will be expanded to 6 subjects. If two (2) DLTs are experienced in any cohort, the study will be paused until the safety events are evaluated and discussed with the FDA to determine if the trial may continue.
Part 2 of this study will include up to 30 subjects. Each subject will receive a 750 mg dose or the maximum tolerated dose of YN968D1 from part 1 of the study for continuous 28-Day cycles of therapy. If a subject experiences an intolerable side effect a dose reduction or a dose interruption for up to 7-Days is allowed at the discretion of the investigator. Subjects will be evaluated for RECIST (version 1.1) response at the end of the second cycle of therapy on Day 56±3 of the Part 2 study. Safety reporting will be continued for 28-Days from the last dose of study medication.
All subjects in Part 1 and 2 of this trial will be eligible to continue therapy provided they have a least stable disease or better and are, in the opinion of the investigator, adequately tolerating treatment with YN968D1.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01497704
|United States, Utah|
|Huntsman Cancer Institute|
|Salt Lake City, Utah, United States, 84112|
|Korea, Republic of|
|ASAN Medical Center|
|Seoul, Korea, Republic of, 138-736|
|Principal Investigator:||Sunil Sharma, MD, FACP||Huntsman Cancer Institute|
|Principal Investigator:||Yoon-Koo Kang, MD, PhD||Asan Medical Center|