A Study To Test The Effect Of Apatinib On P450 Enzymes

A Single-center, Open-Label, Drug Interaction Study to Determine the Effects of Apatinib on the Metabolism of CYP3A4/5 and CYP2C9 Probe Drugs in Patients With Solid Tumors

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).

Study Overview

• Status: Unknown
• Conditions: Cytochrome P450 Interaction
• Intervention / Treatment: Drug: Apatinib; Drug: Nifedipine GTIS; Drug: Warfarin Potassium

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 Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China
      • Recruiting
      • Chinese Medical University First Hospital
      • Contact: Yunpeng Liu; Phone Number: 86024-83282802; Email: cmu_trial@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treament; 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.

Drug: Apatinib; Apatinib at a dosage of 750mg will be administered daily from day 9 of phase A; Drug: Nifedipine GTIS; Nifedipine at a dosage of 30mg will be administered at day 1 and day 14 of phase A; Other Names: Nifedipine; Drug: Warfarin Potassium; Nifedipine at a dosage of 3mg will be administered at day 3 and day 16 of phase A; Other Names: warfarin

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	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	Day 1 to 21 ( Phase A）

Collaborators and Investigators

• Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2017
• Primary Completion (Anticipated): April 30, 2018
• Study Completion (Anticipated): September 30, 2018

Study Registration Dates

• First Submitted: July 17, 2017
• First Submitted That Met QC Criteria: August 7, 2017
• First Posted (Actual): August 10, 2017

Study Record Updates

• Last Update Posted (Actual): February 7, 2018
• Last Update Submitted That Met QC Criteria: February 6, 2018
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Antineoplastic Agents; Membrane Transport Modulators; Protein Kinase Inhibitors; Calcium-Regulating Hormones and Agents; Anticoagulants; Reproductive Control Agents; Calcium Channel Blockers; Tocolytic Agents; Warfarin; Apatinib; Nifedipine
• Other Study ID Numbers: HR-APTN-DDI-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No