A Drug-drug Interaction Study Of Fluzoparib (SHR3162) on Patients With Recurrent Ovarian Cancer

A Phase I, Multi-center Study to Determine the Effect of Fluzoparib on Pharmacokinetics of Caffeine, S-Warfarin, Omeprazole, Midazolam, Repaglinide and Bupropion in Patients With Recurrent Ovarian Cancer

Primary objective: To evaluate the pharmacokinetic effects of fluzoparib on caffeine, S-warfarin, omeprazole, midazolam, repaglinide and bupropion in patients with recurrent ovarian cancer.

Secondary objective: To evaluate the safety of single dose of fluzoparib, caffeine, S-warfarin, omeprazole, midazolam, repaglinide and bupropion or fluzoparib in combination with caffeine, S-warfarin, omeprazole, midazolam, repaglinide and bupropion in patients with recurrent ovarian cancer.

Study Overview

• Status: Completed
• Conditions: Recurrent Ovarian Cancer
• Intervention / Treatment: Drug: fluzoparib

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410013
      • Hunan Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

1. Patients are willing to participate this research and sign informed consent forms (ICFs)
2. Patients must be ≥ 18 years of age at the date of signing the informed consent;
3. Patients with histologically diagnosed relapsed high grade (or middle and low differentiation) serous ovarian cancer, fallopian tube cancer or primary peritoneal cancer confirmed by pathology; ovarian endometrioid adenocarcinoma ≥ grade II; mixed type tumor: high grade serous type or endometrioid component ≥ grade II should be more than 50%;
4. Patients with platinum sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer achieved complete or partial remission after platinum containing chemotherapy (carboplatin and cisplatin only). Platinum sensitive defined as having disease progression greater than 6 months after completion of their last dose of platinum chemotherapy. Patient must have received, at least 4 cycles of a platinum based chemotherapy regimen for the last chemotherapy course
5. ECOG Performance Status of 0-1
6. Patients must have a life expectancy of at least 3 months

7. Patients must have normal organ and bone marrow function measured prior to administration of study treatment as defined below:

   HB≥100g/L； ANC≥1.5×109/L； PLT≥100×109/L or 1x UN TBIL≤1.5×ULN； ALT和AST≤3×ULN； Cr≤1.5×ULN； Albumin>30g/L；

8. Agree to abstain from sex or use effective non-drug contraceptives from screening to at least 6 months after the last study drug administration (female subjects are also required to abstain or use effective non-drug contraceptives two weeks prior to study entry)

Exclusion Criteria:

Inclusion Criteria:

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

1. Patients are willing to participate this research and sign informed consent forms (ICFs)
2. Patients must be ≥ 18 years of age at the date of signing the informed consent;
3. Patients with histologically diagnosed relapsed high grade (or middle and low differentiation) serous ovarian cancer, fallopian tube cancer or primary peritoneal cancer confirmed by pathology; ovarian endometrioid adenocarcinoma ≥ grade II; mixed type tumor: high grade serous type or endometrioid component ≥ grade II should be more than 50%;
4. Patients with platinum sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer achieved complete or partial remission after platinum containing chemotherapy (carboplatin and cisplatin only). Platinum sensitive defined as having disease progression greater than 6 months after completion of their last dose of platinum chemotherapy. Patient must have received, at least 4 cycles of a platinum based chemotherapy regimen for the last chemotherapy course
5. ECOG Performance Status of 0-1
6. Patients must have a life expectancy of at least 3 months

7. Patients must have normal organ and bone marrow function measured prior to administration of study treatment as defined below:

   HB≥100g/L； ANC≥1.5×109/L； PLT≥100×109/L or 1x UN TBIL≤1.5×ULN； ALT和AST≤3×ULN； Cr≤1.5×ULN； Albumin>30g/L；

8. Agree to abstain from sex or use effective non-drug contraceptives from screening to at least 6 months after the last study drug administration (female subjects are also required to abstain or use effective non-drug contraceptives two weeks prior to study entry)

Exclusion Criteria:

Subjects who do meet any of the following criteria will not be allowed to enter the study:

1. Patients with previously (within 5 years) or at the same time with other incurable malignant tumors, except for cured skin basal cell carcinoma, cervical carcinoma in situ and breast cancer with no recurrence for more than 5 years after radical operation
2. 3 months prior treatment with any poly adenosine diphosphate ribose polymerase inhibitor (PARPi)
3. Patients with central nervous system metastasis
4. Serous cavity effusion (including pleural effusion, ascites and pericardial effusion) with clinical symptoms and requiring symptomatic treatment; note: Patients with symptomatic serous cavity effusion can be included in the group if there is no disease, patients with symptomatic serous cavity effusion can be included in the group if they are treated with symptomatic treatment (anti-cancer drugs can not be used for serous cavity effusion treatment), and patients can be included in the group if judged by researchers
5. Pre-existing duodenal stent, recent or existing bowel obstruction, and/or any gastrointestinal disorder or defect that would interfere with absorption of study drugs
6. There are clinical cardiac symptoms or diseases that can not be well controlled, such as: (1) NYHA grade 2 or above cardiac insufficiency, (2) unstable angina pectoris, (3) acute myocardial infarction within one year, (4) clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention, (5) QTc > 470ms
7. Patients with abnormal coagulation function (INR > 1.5 or PT > ULN + 4 seconds), bleeding tendency or receiving thrombolytic or anticoagulant therapy
8. Contraindications of midazolam (allergic to benzodiazepine, myasthenia gravis, schizophrenia, severe depression patients)
9. Warfarin contraindications (liver and kidney dysfunction, severe hypertension, coagulation dysfunction with bleeding tendency, active ulcer, trauma, threatened abortion, recent surgery)
10. Patients with contraindications to repaglinide and bupropion (patients with type I diabetes, including insulin-dependent IDDM and C-peptide negative diabetes, diabetic ketoacidosis with or without coma, patients with anorexia nervosa or bulimia, patients with a history of severe epilepsy; patients with sudden abstinence or withdrawal of sedatives); patients with diabetes other than the above Abnormal control
11. Not recovered from the previous adverse events before the first medication (previous treatment adverse events, excluding hair loss and fatigue, recovered to ≤ 1 level)
12. Other clinical trial drugs were taken within 4 weeks before the first medication;
13. CYP1A2, CYP3A4, CYP2C9, CYP2C19 inducers or CYP1A2, CYP3A4, CYP2C9 and CYP2C19 inhibitors or P-gp inhibitors were taken within 4 weeks before the first medication (for group A); CYP3A4, cyp2c8 and CYP2B6 inducers were taken within 4 weeks before the first medication or CYP3A4, cyp2c8 and CYP2B6 inhibitors or transporter OATP1B1 were taken within 2 weeks (or 5 half lives)/ P-gp inhibitor (for group B)
14. Prior treatment with chemotherapy, radiation, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or experimental drugs within 14 days prior to day 1
15. Alcoholics within 3 months before the first medication (drinking 14 units of alcohol per week: 1 unit = 285 ml of beer, or 25 ml of spirits, or 100 ml of wine), and smokers within 3 months before the first medication (smoking ≥ 5 cigarettes per day);
16. Ingestion of grapefruit or grapefruit products within 7 days before the first medication, or ingestion of food or drink containing caffeine, xanthine or alcohol within 72 hours before the first medication; strenuous exercise within 4 days before the first medication; or other factors affecting drug absorption, distribution, metabolism and excretion
17. Patients with history of immunodeficiency, including HIV positive, other acquired or congenital immunodeficiency diseases, or organ transplantation
18. Syphilis infection or active hepatitis (hepatitis B reference: HBsAg positive and HBV DNA ≥ 500 IU / ml; hepatitis C reference: HCV antibody positive and HCV copy number > upper limit of normal value)
19. Patients with active infections requiring antimicrobial therapy (e.g. antibiotics, antiviral drugs, antifungal drugs);
20. According to the judgment of the researchers, there are concomitant diseases (serious diabetes, thyroid diseases, etc.) that seriously endanger the safety of patients or affect the completion of the study
21. Patients with history of drug allergy, or allergic to apatinib or ingredients
22. The researcher judges other situations that may affect the clinical research and the judgment of research results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: fluzoparib; Experimental: group A Intervention: Drug: fluzoparib, caffeine, vitamin K, warfarin, omeprazole, and midazolam; Experimental: group B Intervention: Drug: fluzoparib, repaglinide and bupropion	Drug: fluzoparib; Group A: Caffeine, vitamin K, warfarin, omeprazole, and midazolam with or without fluzoparib Group B: Repaglinide and bupropion with or without fluzoparib; Other Names: caffeine, vitamin K, warfarin, omeprazole, midazolam, repaglinide and bupropion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics parameters of caffeine, S-warfarin, omeprazole, midazolam, repaglinide, bupropion and hydroxybupropion	Peak Plasma Concentration (Cmax)	DAY1, DAY22
Pharmacokinetics parameters of caffeine, S-warfarin, omeprazole, midazolam, repaglinide, bupropion and hydroxybupropion	Area under the plasma concentration versus time curve (AUC)	DAY1, DAY22

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics parameters of caffeine, S-warfarin, omeprazole, midazolam, repaglinide, bupropion and hydroxybupropion	Half life (t1/2)	DAY1,DAY 22
Number of Participants With Treatment-Related Adverse Events	Safety: Laboratory indicators, 12-lead electrocardiogram (ECG), physical examination, vital signs, adverse events (NCI-CTC AE 5.0), etc.	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Jiangsu HengRui Medicine Co., Ltd.
• Investigators: Principal Investigator: Jing Wang, Ph.D., Hunan Cancer Hospitol

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2021
• Primary Completion (Actual): October 26, 2022
• Study Completion (Actual): July 15, 2023

Study Registration Dates

• First Submitted: January 14, 2021
• First Submitted That Met QC Criteria: January 17, 2021
• First Posted (Actual): January 22, 2021

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 10, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Recurrence; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Hypoglycemic Agents; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Fibrin Modulating Agents; Purinergic Antagonists; Purinergic Agents; Antineoplastic Agents; Gastrointestinal Agents; Micronutrients; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Poly(ADP-ribose) Polymerase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Vitamins; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Anti-Ulcer Agents; Proton Pump Inhibitors; Dopamine Uptake Inhibitors; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Midazolam; Vitamin K; Bupropion; Warfarin; Caffeine; Omeprazole; Repaglinide; Fluzoparib
• Other Study ID Numbers: FZPL-Ⅰ-120

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