A Study of Fluzoparib Combined With Apatinib as Second-Line Treatment of Patients With Extensive Stage Small Cell Lung Cancer（FA-ES-SCLC）

A Single-Arm,Single-Center, Phase Ib/II Clinical Study of Fluzoparib (SHR-3162) Combined With Apatinib as Second-Line Treatment of Patients With Extensive Stage Small Cell Lung Cancer（SCLC）

This open-label, dose finding phase Ib trial studies the tolerability and the best dose of fluzoparib in combination with apatinib and to see how well these two drugs work together as second-line treatment of patients with extensive stage small cell lung cancer. The safety and efficacy of fluzoparib in combination with apatinib will be explored. Both dose escalation and dose expansion parts are included in this study.

Study Overview

• Status: Unknown
• Conditions: Small Cell Lung Cancer Extensive Stage
• Intervention / Treatment: Drug: Fluzoparib; Drug: Apatinib

Detailed Description

The degree of malignancy of small cell lung cancer is extremely high. About 60% to 70% of patients are diagnosed as extensive. The median survival time of the disease is only 9 to 10 months, and the 2-year survival rate is less than 10%. Fluzoparib is an oral potent, selective poly-ADP ribose polymerase-1 (PARP-1) and PARP-2 inhibitor. Apatinib is an oral selective vascular endothelial growth factor receptor (VEGFR) inhibitor.This open-label, dose finding phase Ib trial studies the tolerability and the best dose of fluzoparib in combination with apatinib as second-line treatment of patients with extensive stage small cell lung cancer. The safety and efficacy of fluzoparib in combination with apatinib will be explored.

• Study Type: Interventional
• Enrollment (Anticipated): 53
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Tianjin
    • Tianjin, Tianjin, China, 300211
      • Recruiting
      • Tianjin Medical University Second Hospital
      • Contact: Haitao Wang; Phone Number: +86-022-88326791; Email: peterrock2000@126.com
      • Contact: Li Zang; Phone Number: +86-15202259910; Email: 15202259910@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:

1. Patients with Extensive Stage Small Cell Lung Cancer diagnosed by pathology (histology or cytology) (according to WHO classification in 2015);
2. Failure of first-line treatment；
3. Age 18-70 years old;
4. ≤21 days before the first study drug, CT or MRI scan, at least one target lesion without previous radiotherapy as defined by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1);
5. PS score: 0-2; the expected survival time ≥ 12 weeks;
6. No anti-angiogenesis drugs or PARP inhibitors have been used in previous treatments;
7. All acute toxic reactions caused by previous anti-tumor treatments or surgical operations were relieved before the screening period 0-1 grade (according to NCI CTCAE 5.0 judgment) or to the level specified by the inclusion/exclusion criteria (hair loss and other researchers believe that the subjects are not Except for toxicity that poses a safety risk);

8. No blood transfusion or blood products, no correction with G-CSF and other hematopoietic stimulating factors within 14 days before the first administration. First research before investigating drugs, laboratory test values meet the following conditions:

   1. Blood routine: white blood cell count (WBC) ≥3.0 × 109/L; absolute neutrophil count (ANC) ≥1.5 × 109/L; Platelet (PLT) ≥100 × 109/L; Hemoglobin content (HGB) ≥9.0 g/dL;
   2. Liver function: Aspartate aminotransferase (AST) ≤2.5 x ULN in subjects without liver metastasis, alanine liver aminotransferase (ALT) ≤2.5 x ULN; ALT and AST in subjects with liver metastases <5 x ULN; Serum total bilirubin (TBIL) ≤1.5 x ULN (except Gilbert syndrome total bilirubin <3.0 mg/dL); Albumin (ALB) ≥3 g/dL;
   3. Renal function: serum creatinine ≤1.5 x ULN or creatinine clearance CrCl≥40 mL/minute;
   4. Coagulation function: International normalized ratio (INR) ≤ 1.5, activated partial thromboplastin time (APTT) ≤ 1.5 x ULN;
   5. Others: Lipase ≤ 1.5 x ULN, if lipase> 1.5 x ULN but no clinical or imaging confirmed pancreatitis can be included; amylase ≤ 1.5 x ULN, if amylase> 1.5 x ULN but no clinical or imaging confirmed pancreatitis can be included in the group. Alkaline phosphatase (ALP)≤2.5ULN, subjects with bone metastases, ALP≤5ULN;
9. Non-surgically sterilized female subjects of childbearing age must have a negative serum HCG test within 3 days before the first medication, and non-lactating period. Male subjects and females of childbearing age must start the first study drug to after the last study drug 6 contraception within months;
10. Subjects voluntarily join the study, with good compliance, with safety and survival follow-up.

Exclusion Criteria:

1. Active brain metastases or meningeal metastases with clinical symptoms. Subjects with treated brain metastases need to meet the following conditions to be tested considered into the group:

   1. It is confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) that the lesion is stable since the end of treatment≥4 weeks;
   2. No need to receive systemic corticosteroids (>10mg/day prednisone or equivalent dose) treatment;
2. The third space effusion with clinical symptoms, such as pericardial effusion, pleural effusion and effusion that cannot be controlled by pumping or other treatments ascites;
3. People with symptoms of cough, hemoptysis, bloody sputum within 1 month before the first medication;
4. Minor surgery (including catheterization) was performed within 48 hours before the first study drug;
5. Other anti-tumor drugs are currently being used within 4 weeks after the last systemic cytotoxic drug treatment or radiotherapy drug treatment;
6. Currently or recently (within 30 days before enrollment) using another investigational drug or participating in another clinical study;
7. Other malignant tumors (fully treated cervical carcinoma in situ or skin squamous cell carcinoma, or controlled skin except for basal cell carcinoma);
8. Have previously received PARP inhibitors or small molecule inhibitors targeting vascular endothelial cell growth factor receptor (VEGFR) agent treatment;
9. Patients with hypertension who cannot be reduced to the normal range after treatment with antihypertensive drugs (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg);
10. There are clinical symptoms or diseases of the heart that are not well controlled, such as: I. Heart failure above NYHA 2; II. Instability Stereotyped angina; III. Myocardial infarction occurred within 1 year; IV. clinically significant supraventricular or ventricular arrhythmia needs treatment or intervention; V QTc>470ms;
11. Abnormal coagulation function (INR>1.5 or prothrombin time (PT)>ULN+4 seconds or APTT>1.5 ULN), with have a bleeding tendency or are receiving thrombolysis or anticoagulation therapy;
12. Have significant clinically significant bleeding symptoms or have a clear bleeding tendency within 3 months before signing the ICF (Information Consent Form), such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood++ and above, or suffering from vasculitis;
13. Arterial/venous thrombotic events, such as cerebrovascular accidents (including temporary ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism, etc;
14. Have the following medical history within 24 weeks before signing the ICF: peptic ulcer, gastrointestinal perforation, corrosive esophagitis or gastritis, inflammation enteropathy or diverticulitis, abdominal fistula, tracheo-esophageal fistula, or intra-abdominal abscess;
15. Major surgery or severe traumatic injury, fracture or ulcer occurred within 4 weeks before treatment;
16. There are factors that significantly affect the absorption of oral drugs, such as inability to swallow, chronic diarrhea, and intestinal obstruction;
17. Urine routine test indicates urine protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0 g;
18. The investigator judges other situations that may affect the conduct of clinical research and the judgment of research results;
19. Patients with a clear history of allergies may be potentially allergic or intolerant to Apatinib and Fluzoparib;
20. Human immunodeficiency virus (HIV) infection, active hepatitis B (hepatitis B surface antigen positive and HBV DNA ≥ 500 IU/ml), hepatitis C (hepatitis C antibody is positive and HCV-RNA is higher than the detection limit of the analytical method);
21. According to the judgment of the investigator, there is an accompanying disease (such as poorly controlled hypertension, severe diabetes, neurological or mental illness, etc.) that seriously endangers the safety of the subject, may confuse the research results, or affects the subject to complete the study Any other situation.

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: Fluzoparib + Apatinib; Fluzoparib and apatinib will be administered continuously and orally in combination, 28 days per cycle, until disease progression or unacceptable toxicity.	Drug: Fluzoparib; Take Fluzoparib orally（either at 50,100mg bid）until disease progression or appearance of unbearable toxicity; Other Names: SHR3162; HS10160; Drug: Apatinib; Take apatinib orally (either at 375mg、500mg、750mg qd）until disease progression or appearance of unbearable toxicity; Other Names: Apatinib mesylate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase Ⅰb: Determination of Recommended Phase II dose (RP2D) of Escalating Dose of Fluzoparib with Apatinib	The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for the dose expansion arms, based on safety, tolerability and efficacy data collected during the dose escalation portion of the study	Up to 28 days after the first dose of Fluzoparib and Apatinib combination therapy
PhaseⅠb: Incidence of Adverse Events [safety and tolerability]	Adverse events defined according to Common Terminology for Adverse Events (CTCAE) v5.0	From screening up to 28 days after end of treatment
Phase Ⅱ: Objective Response Rate(ORR) as Assessed by the Investigator according to RECIST v1.1	Objective Response Rate(Complete response + Partial response (CR+PR)), determined using RECIST v1.1 criteria, defined as best overall response (complete or partial response) across all assessment time points.	up to approximately 2 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival（PFS）	Progression Free Survival, defined as first assessment of disease progression or death, whichever is earlier.	Up to approximately 2 Years
Overall survival（OS）	Overall survival is the time from intervention to death due to any reason or lost of follow-up	Up to approximately 2 Years
Duration of Response（DoR）	Duration of Response, determined using RECIST v1.1 criteria.	Up to approximately 2 Years
Adverse Event Rate（AER）	Adverse events defined according to Common Terminology for Adverse Events (CTCAE) v5.0	Up to approximately 2 Years
Biomarker Detection	Evaluation of TP53 gene status through next-generation sequencing technology	Up to approximately 2 Years

Collaborators and Investigators

• Sponsor: Tianjin Medical University Second Hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2020
• Primary Completion (Anticipated): July 31, 2021
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: December 2, 2020
• First Submitted That Met QC Criteria: December 2, 2020
• First Posted (Actual): December 9, 2020

Study Record Updates

• Last Update Posted (Actual): December 9, 2020
• Last Update Submitted That Met QC Criteria: December 2, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Apatinib; Small Cell Lung Cancer; Fluzoparib
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Apatinib
• Other Study ID Numbers: ES-SCLC-2nd-IIT-SHR3162-APA

Drug and device information, study documents

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