Apatinib Combine With EGFR-TKI for Advanced EGFR-TKI-resistant Non-Small Cell Lung Cancer

A Study of Apatinib Combine With EGFR-TKI for Advanced EGFR-TKI-resistant Non-Small Cell Lung Cancer

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib demonstrate excellent effect on the treatment of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, patients who are initially sensitive to the drugs eventually become resistance. Apatinib is a highly selective VEGFR2 inhibitor and reduces the angiogenesis of tumor efficiently. In this study, the investigators aim to explore the efficacy and reasonable dosage of apatinib combining with EGFR-TKI in advanced non-squamous non-small cell lung cancer with EGFR-TKI resistance.

Study Overview

• Status: Unknown
• Conditions: Nonsmall Cell Lung Cancer
• Intervention / Treatment: Drug: Apatinib Mesylate Tablets; Drug: EGFR-TKIs (Erlotinib, Gefitinib and Osimertinib)

Detailed Description

Primary Outcome Measure: efficacy and reasonable dosage of the combination of apatinib and EGFR-TKI in advanced non-squamous non-small cell lung cancer with EGFR-TKI resistance.

Secondary Outcome Measures: Progression free survival, overall survival, Side effects.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Recruiting
      • Peking University Third Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Obtain of informed consent.
2. Histologically or cytologically confirmed, inoperable, recurrence or metastasis advanced non-small cell lung cancer (TNM Stage ⅢB or stage Ⅳ), took EGFR-TKI longer than 6 months and appeared disease progression.
3. At least one measurable lesion (helical CT scan long diameter ≥10mm, meet the requirements of the standard Response Evaluation Criteria In Solid Tumors（RESCIST） version 1.1).
4. Eastern Cooperative Oncology Group（ECOG）Performance Status（PS） :0-2.
5. Aged from 18 to 75 years (18 and 75 years are included).
6. Life expectancy ≥12 weeks.

7. Adequate bone marrow reserve and organ function as follows:

   • Absolute neutrophils count (ANC) ≥1.5 x 10 to the 9th power/L (band neutrophil and segmented neutrophil), platelets > 100 x 10 to the 9th power/L and Hb≥90g/L.
   • Hepatic: total bilirubin less than or equal to 1.5 times upper limit of normal (ULN).
   • Alkaline phosphatase (AP), alanine transaminase (ALT) and aspartate transaminase (AST) less than or equal to 3.0 times ULN (or less than or equal to 5 times ULN in case of known liver involvement.
   • Renal: Serum Creatinine less than or equal to 1.25 times upper limit of normal (ULN).
8. Have history of hypertension (less than 135/85mmHg).
9. Females of child-bearing potential must have negative serum pregnancy test. Sexually active males and females (of childbearing potential) willing to practice contraception during the study.

Exclusion Criteria:

1. Do not meet the above criteria.
2. Prior treatment with VEGFR tyrosine kinase inhibitors or VEGFR targeting agent.
3. Unhealed toxicity of prior anti-cancer treatment (CTCAE Level 1) or surgery.
4. Symptomatic Central Nervous System (CNS) metastases.
5. Uncontrolled hypertension (systolic ≥140mmHg and/or diastolic ≥90mmHg after medication treatment).
6. Clinical uncontrolled active infection, such as acute pneumonia, active hepatitis B or C (prior hepatitis B history, despite medication treatment control or not, HBV DNA≥500copies or ≥100IU/ml), etc.
7. Arterial thrombosis or venous thrombosis in 6 months, or disposition evidence of thrombosis/bleeding in 2 month (despite severity), hemoptysis in 2 weeks (bright red blood, 1/2 teaspoon).
8. Stroke or transient ischemic attack (TIA) in 12 month.
9. Unhealed skin lesions, surgical site, injuries, severe mucous membrane ulcer or bone fracture.
10. Cardiac function evaluation: LVEF <50%, a recent history of MI in 6 months, severe/unstable angina or coronary bypass surgery, or cardiac insufficiency ≥ NYHA 2.
11. Prior other malignant disease in 5 years (except carcinoma in situ of cervix, or non melanoma skin cancers, or localized prostate cancer with Gleason ≤6).
12. Documented history of neurological or psychiatric disorders, include epilepsy and dementia.
13. Recent active digestive disease such as duodenal ulcers, ulcerative colitis, ileus, ect., intestinal perforation, intestine fistula, or other conditions may lead to gastrointestinal bleeding or perforation which regimented at investigators' discretion.
14. Difficulty swallowing or known malabsorption.
15. A history of organ transplantation and long-term immunosuppressive medication.
16. Take part in new drug clinical trials within one month or taking part in a trial now.
17. Pregnant or lactating woman.
18. A history of anaphylaxis of apatinib analogue and/or excipient of drugs in this study.
19. Other conditions regimented at investigators' discretion.

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: Apatinib; Apatinib in combination with EGFR-TKIs	Drug: Apatinib Mesylate Tablets; 250mg, 500mg, 750mg, q.d., p.o.; Drug: EGFR-TKIs (Erlotinib, Gefitinib and Osimertinib); EGFR-TKIs include but are not limited erlotinib, gefitinib and osimertinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Optimal Dosage	Optimal dosage of Apatinib which combine with EGFR-TKIs	9 months
Progression free survival	PFS is evaluated in 24 months since the treatment begin	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival is evaluated in the 24th month since the treatment began	24 months
Side effects	Side effects evaluated in the 24th month since the treatment began according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0	24 months

Collaborators and Investigators

• Sponsor: Peking University Third Hospital
• Investigators: Study Chair: Li Liang, Prof. M.D., Peking University Third Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2016
• Primary Completion (Anticipated): June 1, 2019
• Study Completion (Anticipated): October 1, 2019

Study Registration Dates

• First Submitted: January 9, 2017
• First Submitted That Met QC Criteria: February 9, 2017
• First Posted (Actual): February 10, 2017

Study Record Updates

• Last Update Posted (Actual): February 10, 2017
• Last Update Submitted That Met QC Criteria: February 9, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Non Small Cell Lung Cancer; Apatinib; EGFR-TKI resistance; anti-angiogenesis drugs
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Gefitinib; Osimertinib; Apatinib
• Other Study ID Numbers: IRB00006761-2016162