A Study To Test The Effect Of Apatinib On P450 Enzymes

Phase 1

• Conditions: Cytochrome P450 Interaction
• Interventions: Drug: Apatinib; Drug: Nifedipine GTIS; Drug: Warfarin Potassium

• Registration Number: NCT03245307
• Lead Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Brief Summary

Apatinib, an oral inhibitor of vascular endothelial growth factor receptor 2（VEGFR-2）, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of Apatinib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe drugs in the presence and absence of Apatinib. The probes used included Nifedipine (CYP3A specific), warfarin (CYP2C9 specific).

Detailed Description

This open-label study consists of a drug interaction phase that (part A) and a drug-continuation phase (part B). Patients will receive CYP450-probe drugs, and PK assessments will be performed before apatinib-administration and aſter once-daily administration of apatinib for 5 days (the predicted time point when steady-state plasma apatinib concentrations will have been achieved).

Study Timeline

• Status Verified: 2017-07
• Study First Submitted: 2017-07-17
• Study First Submitted QC: 2017-08-07
• Study First Posted: 2017-08-10
• Study Start: 2017-08-22
• Last Update Submitted: 2018-02-06
• Last Update Posted: 2018-02-07
• Primary Completion: 2018-04-30
• Study Completion: 2018-09-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of advanced solid tumors.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Adequate bone marrow, renal, lung, and liver function.
• A female subject must not be pregnant and will agree not to become pregnant during the trial

Exclusion Criteria

• Primary carcinoma of liver
• Any major surgery, chemotherapy, hormone therapy, investigational drugs, or radiotherapy within the last 28 days.
• Poorly controlled hypertension.
• A prior history of cardiovascular disease, arrhythmias, or significant ECG abnormalities, and corrected QT (QTc) prolongation defined as a QTc interval greater than or equal to 450 msec(male) or 470 msec(female).
• Arterial or venous thrombi (including cerebrovascular accident).
• Current use of therapeutic anticoagulation (low molecular weight heparin, oral anticoagulant agents).
• Active brain metastases.
• A history of bleeding problems.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treament	Warfarin Potassium	In phase A, subjects receiving a single 30 mg oral dose of Nifedipine controlled-release tablets and wash-out for 2 days,a single 3 mg oral dose of warfarin tablets and wash-out for 12 days, then apatinib 750 mg once daily with a single 30 mg oral dose of Nifedipine controlled-release tablets co-administered on day 6 ,a a single 3 mg oral dose of warfarin tablets co-administered on day 9.
Treament	Nifedipine GTIS	In phase A, subjects receiving a single 30 mg oral dose of Nifedipine controlled-release tablets and wash-out for 2 days,a single 3 mg oral dose of warfarin tablets and wash-out for 12 days, then apatinib 750 mg once daily with a single 30 mg oral dose of Nifedipine controlled-release tablets co-administered on day 6 ,a a single 3 mg oral dose of warfarin tablets co-administered on day 9.
Treament	Apatinib	In phase A, subjects receiving a single 30 mg oral dose of Nifedipine controlled-release tablets and wash-out for 2 days,a single 3 mg oral dose of warfarin tablets and wash-out for 12 days, then apatinib 750 mg once daily with a single 30 mg oral dose of Nifedipine controlled-release tablets co-administered on day 6 ,a a single 3 mg oral dose of warfarin tablets co-administered on day 9.

Primary Outcome Measures

Name	Time	Method
Area under the plasma concentration versus time curve (AUC) of warfarin or nifedipine	1 year	AUC0\~t of warfarin and nifedipine in the absence or in presence of apatinib will be defined

Secondary Outcome Measures

Name	Time	Method
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Day 1 to 21 ( Phase A）	to assess safety and tolerability of apatinib combined with warfarin or nifedipine in patients with advanced solid tumors. The vital signs, ECG, laboratory values and adverse events (AE and SAE) were judged according to NCI-CTCAE V4.0 criteria

Trial Locations

Locations (1)

Chinese Medical University First Hospital; 🇨🇳 Shenyang, Liaoning, China