A Pharmacokinetic Interaction Study Between Apatinib Mesylate and Transporter Pgp Substrate Digoxin in Advanced Solid Tumor Subjects

Study Overview
=================
Brief Summary
-----------------
Apatinib, an oral inhibitor of vascular endothelial growth factor receptor 2#VEGFR-2#, Induces Transporter Pgp function in vitro. This study in patients with advanced cancer evaluated the effect of Apatinib on Transporter Pgp function by comparing the pharmacokinetics of Transporter Pgp-specific probe drugs in the presence and absence of Apatinib. The probes used Substrate Digoxin.

Official Title
-----------------
A Single Arm, Open and Fixed Sequence Study to Investigate the Pharmacokinetic Effects of Apatinib Mesylate on Transporter Pgp Substrate Digoxin in Advanced Solid Tumor Subjects

Conditions
-----------------
Advanced Solid Tumor

Intervention / Treatment
-----------------
* Drug: Apatinib Mesylate
* Drug: Digoxin tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1. Histologically or cytologically confirmed diagnosis of advanced solid tumors. 2. ECOG PS score: 0-1; 3. Expected survival ≥ 3 months; 4. Major organs must function normally, meeting the following criteria: Hematology HB≥100 g/L; ANC≥1.5×109/L; PLT≥90×109/L; Blood biochemistry: TBIL≤ 1.25×ULN; ALT and AST≤2.5×ULN; ALP≤2.5×ULN; Serum Cr ≤ 1.5 × ULN or endogenous CrCl ≥ 60 mL/min (Cockcroft-Gault formula); Albumin > 30 g/L; K+>3.0mmol/L; 5. Able to understand and sign an informed consent form (ICF). Exclusion Criteria: Primary liver cancer; gastric cancer; Active brain metastasis (medically uncontrolled), carcinomatous meningitis, spinal cord compression; Presence of clinically symptomatic third space fluid; Uncontrolled hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg despite optimal pharmacological treatment); Uncontrolled clinically significant heart disease, including but not limited to the following: (1) >2 NYHA 2 congestive heart failure; (2) left ventricular ejection fraction (LVEF) < 50% (3) heart rate <60 (4) Grade II or greater myocardial ischemia or myocardial infarction(5) QTc interval ≥ 450 ms in males and ≥ 470 ms in females; Abnormal coagulation function; Prior radiotherapy, systemic chemotherapy (< 6 weeks if chemotherapy including nitrosoureas or mitomycin), hormone therapy, surgery or target therapy within 4 weeks before the study drug administration, or any unresolved AEs > CTC-AE Grade 1; History of psychotropic substance abuse, alcoholism or drug abuse; Use of study drugs in other clinical trials within 4 weeks prior to the first dose； Use of a potent CYP3A4 inhibitor or inducer within 2 weeks prior to the first dose; Use of any prescription or over-the-counter medication, vitamin products or herbs within 2 weeks before taking the investigational drug; Other factors that may lead to the termination of the participation in the study at the discretion of the investigators.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treament<br>In phase A, subjects receiving a single 0.25 mg of digoxin orally and wash-out for 5 days, then apatinib once daily will be conducted on D5 through D16 ； In addition, a single dose of 0.25 mg digoxin (in combination with apatinib) will be orally administered in fasting conditions on D12； | Drug: Apatinib Mesylate<br>* Apatinib at a dosage of will be administered daily from on D5 through D16<br>Drug: Digoxin tablet<br>* Digoxin at a dosage of 0.25mg will be administered at day 1 and day 12<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameter: Cmax of digoxin | Peak Plasma Concentration (Cmax) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetics parameter: AUC of digoxin | Area under the plasma concentration versus time curve (AUC) of digoxin | through study completion, an average of 16 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameter: Tmax of digoxin | Time of maximum observed concentration (Tmax) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetics parameter: T1/2 of digoxin | Half time (T1/2) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetic parameters CL/F of digoxin | Total body clearance for extravascular administration (CL/F) of digoxin | through study completion, an average of 16 days | 
| Pharmacokinetics parameter: Vz/F of digoxin | Volume of distribution (Vz/F) of digoxin | through study completion, an average of 16 days | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | An adverse event is any untoward medical occurrence in a patient or clinical study participant criteria | through study completion, an average of 16 days |