A Pharmacokinetic Interaction Study Between Apatinib and Rosuvastatin or Metformin in Solid Tumor Subjects.

Open-Label, Fixed-Sequence Study in Solid Tumor Subjects to Investigate the Pharmacokinetic Interaction Between Apatinib and Transporter Substrates Rosuvastatin and Metformin.

The primary objective of the study was to assess investigate the pharmacokinetic effects of Apatinib on Rosuvastatin or Metformin.

The secondary objective of the study was to assess the safety of Apatinib alone or Rosuvastatin/Metformin alone or concomitant medication.

Study Overview

• Status: Completed
• Conditions: Solid Tumor, Adult
• Intervention / Treatment: Drug: Apatinib in arm1; Drug: Rosuvastatin; Drug: Apatinib in arm2; Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hebei
    • Shijiazhuang, Hebei, China, 050035
      • The Fourth Hospital of Hebei Medical University

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:

Subjects must meet all of the following criteria to enter the study:

1. Age: 18-70 years old (Include both values);
2. Patients with histopathologically or cytologically confirmed advanced solid tumor(except primary gastrointestinal tumors or metastatic gastrointestinal tumors and primary hepatocellular tumors) , not necessary to have measurable lesions;
3. The standard systemic treatment plan for tumors is ineffective, or intolerable, or there is no recurrence and metastasis after adjuvant chemotherapy and radiotherapy after surgery;
4. ECOG PS score: 0-1;
5. Expected survival ≥ 3 months;
6. Adverse reactions caused by the subject receiving other treatments have recovered (recovered to ≤ grade 1 according to NCI-CTCAE 5.0, except for hair loss), more than 4 weeks after receiving radiotherapy or surgery or receiving other cytotoxic drugs or cell growth inhibitor.

7. Major organs must function normally, meeting the following criteria:

   I. Haematology (no blood transfusion or blood products within the last 14 days, not corrected with G-CSF or other hematopoietic colony-stimulating factors):

   1. HB≥100 g/L;
   2. ANC≥1.5×109/L;
   3. PLT≥90×109/L;

   II. Blood biochemistry:

   1. TBIL≤ 1.25×ULN;
   2. ALT and AST≤2.5×ULN;
   3. ALP≤2.5×ULN;
   4. Serum Cr ≤ 1.5 × ULN or endogenous CrCl ≥ 60 mL/min (Cockcroft-Gault formula);
   5. Albumin > 30 g/L;

   III. Urine protein inspection:

   a. Urinary routines suggest that urine protein <++. If urinary protein ≥ ++, the quantification of urinary protein in 24 hours should be ≤1.5 g;

8. Agree to abstinence or take effective contraception during the study and for at least 8 weeks after the last study drug administration
9. Sign the ICF voluntarily, have good compliance, corporate with follow-up visits, and follow the study requirements.

Exclusion Criteria:

Subjects meeting any one of the followings will be excluded in this study:

1. Patients with gastrointestinal diseases that affect the use or absorption of drugs, such as gastric cancer or intestinal cancer, unable to swallow, chronic diarrhea, intestinal obstruction, large stomach or total gastrectomy, or within 6 months before the first medication Patients with abdominal fistula, gastrointestinal perforation or abdominal abscess;
2. Active (without medical control) brain metastases, cancerous meningitis, spinal cord compression patients, or imaging CT or MRI examination at screening to find diseases of the brain or pia mater
3. Presence of clinically symptomatic third space fluid (e.g. large pleural fluid or ascites) that cannot be controlled by drainage or other methods;
4. Patients with hypertension, or patients with a history of hypertension
5. Patients with NYHA Class III-IV cardiac insufficiency or left ventricular ejection fraction (LVEF) < 50% by echocardiography; uncontrolled arrhythmias (QTc interval ≥ 450 ms in males and ≥ 470 ms in females);
6. During the study period, patients should be used drugs that may lead to prolonged QTc interval (such as antiarrhythmic drugs, quinidine, disopyramide, procainamide, sotalol, amiodarone, etc.)
7. Patients with abnormal coagulation function (INR > 1.5 or prothrombin time (PT) > ULN + 4 s or APTT > 1.5 ULN)
8. Patients with clinically significant bleeding or clear bleeding tendency within 3 months prior to the first dose, such as coughing up blood, hemoptysis, GI bleeding, hemorrhagic gastric ulcer, or baseline fecal occult blood (FOB) ++ and above. Gastroscopy is required for patients with FOB (+) and no surgical resection of primary gastric tumor. In case of ulcerative gastric cancer, patients are not enrolled due to a risk of acute gastrointestinal hemorrhage;
9. Events of arterial/venous thrombosis within 6 months prior to the first dose, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, brain infarction), deep vein thrombosis, and pulmonary embolism;
10. Known hereditary or acquired hemorrhage and thrombophilia (such as hemophilia, coagulopathy, thrombocytopenia, hypersplenism, etc.);
11. Patients treated with anticoagulants or vitamin K antagonists such as warfarin, heparin or similar drugs;
12. Have undergone major surgery or with severe traumatic injury, fracture, or ulcer within 4 weeks prior to the first dose; There is no previous wound healing.
13. Use of study drugs in other clinical trials within 4 weeks prior to the first dose;
14. Drugs that is CYP3A inhibitor, or the transporter BCRP or MATE1 inhibitor, or drugs that affect gastric acid secretion, or Chinese herbal medicines within 2 weeks before the first dose; use the drug that is metabolic enzyme CYP3A inducer within 4 weeks before the first dose
15. Infectious disease screening (hepatitis B virus surface antigen, hepatitis C virus antibody, Treponema pallidum antibody and human immunodeficiency virus antibody) positive
16. History of immunodeficiency, with acquired, congenital immunodeficiency disease, or history of organ transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Assess PK effects of Apatinib on Rosuvastatin; Participant will be administered a single oral dose of rosuvastatin 10 milligram (mg) on Day 1 and Day 7 and Apatinib at a dose of 250 mg once daily from Day 4 until Day 9.	Drug: Apatinib in arm1; Apatinib will be administered at a dose of 250 mg once daily from Day 4 to Day 9.; Drug: Rosuvastatin; Rosuvastatin will be administered as a single oral 10 milligram (mg) dose on Day 1 and Day 7.
Experimental: Assess PK effects of Apatinib on Metformin; Participant will be administered a single oral dose of metformin 500 milligram (mg) on Day 1 and Day 6 and Apatinib at a dose of 250 mg once daily from Day 3 until Day 7.	Drug: Apatinib in arm2; Apatinib will be administered at a dose of 250 mg once daily from Day 3 to Day 7.; Drug: Metformin; Metformin will be administered as a single oral 500 mg on Day 1 and Day 6.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax)	The Cmax is the maximum observed concentration	Up to Day 10
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC [0-last])	The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.	Up to Day 10
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity])	The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time	Up to Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 35 or 37 days in two groups.

Collaborators and Investigators

• Sponsor: Jiangsu HengRui Medicine Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2020
• Primary Completion (Actual): August 22, 2021
• Study Completion (Actual): August 22, 2021

Study Registration Dates

• First Submitted: May 27, 2020
• First Submitted That Met QC Criteria: June 9, 2020
• First Posted (Actual): June 11, 2020

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: July 21, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Protein Kinase Inhibitors; Rosuvastatin Calcium; Metformin; Apatinib
• Other Study ID Numbers: HR-APTN-I-010

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