Anlotinib Combined With Docetaxel Versus Docetaxel for Previous Treated Advanced NSCLC (ACWDVDFPTAN)

Anlotinib Combined With Docetaxel Versus Docetaxel for Platinum-based Therapy Treated Advanced NSCLC: a Multicentre, Randomised Explorative Trial

Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and development. It can inhibit the angiogenesis related kinase, such as VEGFR, FGFR, PDGFR, and tumor cell proliferation related kinase -c-Kit kinase. In the phase Ⅲ study, patients who failed at least two kinds of systemic chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib（12mg，po. qd. on day 1to14 of a 21-day cycle） or placebo, the anlotinib group PFS and OS were 5.37 months and 9.63 months, the placebo group PFS and OS were 1.4 months and 6.3 months. Therefore,we envisage using anlotinib plus docetaxel treat the EGFR wild-type advanced Non-small cell lung cancer patients who were failure in the treatment of chemotherapy with platinum containing drugs, to further improve the patient's PFS or OS.

Study Overview

• Status: Unknown
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Anlotinib combined Docetaxel; Drug: Docetaxel

Detailed Description

This multicentre randomised controlled clinical trial conducted in China include phase I study and phase II study.

Phase I study: to get the maximum tolerated dose of anlotinib when combined with Docetaxel.

Phase II study: to compare the effectiveness and safety of Anlotinib Plus Docetaxel in patients of EGFR wild-type Advanced Non-squamous Non-small Cell Lung Cancer.

• Study Type: Interventional
• Enrollment (Anticipated): 97
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • Sir Run Run Shaw Hospital
      • Contact: Hongming Pan, MD; Phone Number: （86）571 86006926; Email: panhm@srrsh.com
      • Sub-Investigator: Yong Fang, MD

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. Subjects voluntarily joined the study and signed informed consent, with good compliance and follow-up;
• 2. Diagnosed as locally advanced and / or metastatic non-small cell lung adenocarcinoma (NSCLC) by cytology or histology; diagnosed as stage IIIB, IIIC or IV according to the 2017 new version of the UICC lung cancer staging criteria (8th edition);
• 3. At least one target lesion that has not received local treatment in the past 3 months, and accurate measurement by magnetic resonance imaging (MRI) or computed tomography (CT) in at least 1 direction
• 4. first line chemotherapy used platinum-based doublet chemotherapy and failed.
• 5. Provide detectable specimens (tissue or cancerous pleural effusion) for genotyping before enrollment, and the patients should be with negative EGFR, ALK, and ROS1 gene test results;
• 6. 18~75 years old, ECOG PS 0-1 points. Life expectancy is at least 3 months.
• 7. The damage subjects received from other treatments has recovered(NCI-CTCAE version 4.0 grade ≤ 1), the interval of subjects receiving nitrosourea or mitomycin should be at least 6 weeks; the interval subjects receiving other cytotoxic drugs, bevacate Avastin (Avastin), surgery should be at least 4 weeks; the interval subjects receiving radiotherapy (except for local palliative radiotherapy) should be at least 2 weeks;

• 8. The main organs function are normally, the following criteria are met:

  1. Blood routine examination criteria should be met (no blood transfusion and blood products within 14 days, no correction by G-CSF and other hematopoietic stimuli): HB≥90 g/L; ANC ≥ 1.5×10^9/L; PLT ≥80×10^9/L;
  2. Biochemical examinations must meet the following criteria: TBIL<1.5×ULN; ALT and AST < 2.5×ULN, and for patients with liver metastases < 5×ULN; Serum Cr ≤ 1.25×ULN or endogenous creatinine clearance > 60 ml/min (Cockcroft-Gault formula).
• 9. Avoid pregnancy during treatment and 6 month after treatment.

Exclusion Criteria:

• 1. Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer);
• 2. Have used anlotinib / docetaxel before, or have used other VEGFR-TKI drugs.
• 3. Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor;

• 4. History and comorbidities

  1. Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms);
  2. The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks;
  3. Other active malignancies that require simultaneous treatment;
  4. Patients with a history of malignant tumors except for patients with cutaneous basal cell carcinoma, superficial bladder cancer, cutaneous squamous cell carcinoma or orthotopic cervical cancer who have undergone a curative treatment and have no disease recurrence within 5 years from the start of treatment
  5. Patients with previous anti-tumor treatment-related adverse reactions (excluding hair loss) who have not recovered to NCI-CTCAE ≤1;
  6. Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy;
  7. Note: Under the premise of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes;
  8. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g;
  9. Uncontrollable hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, despite optimal medical treatment);
  10. The effects of surgery or trauma have been eliminated for less than 14 days before enrollment in subjects who have undergone major surgery or have severe trauma;
  11. Severe acute or chronic infections requiring systemic treatment;
  12. Suffering from severe cardiovascular disease: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including men with QTc interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV Insufficient function, or cardiac color Doppler ultrasound examination indicates left ventricular ejection fraction (LVEF) <50%;
  13. There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for trauma;
  14. Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including pleural effusion, ascites, pericardial effusion) requiring surgical treatment;
  15. Long-term unhealed wounds or fractures;
  16. Severe weight loss (greater than 10%) within 6 weeks prior to randomization;
  17. Decompensated diabetes or other ailments treated with high doses of glucocorticoids;
  18. Factors that have a significant impact on oral drug absorption, such as inability to swallow, chronic diarrhea, and intestinal obstruction;
  19. Clinically significant hemoptysis (daily hemoptysis greater than 50ml) within 3 months prior to enrollment; or significant clinically significant bleeding symptoms or defined bleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood ++ and above, or suffering from vasculitis;
  20. Events of venous/venous thrombosis occurring within the first 12 months prior to enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
  21. Planned for systemic anti-tumor therapy, including cytotoxic therapy, signal transduction inhibitors, immunotherapy (4 weeks prior to enrollment in other anti-cancer drug clinical trials or within 4 weeks prior to grouping or during the study period Or use mitomycin C) within 6 weeks prior to receiving the test drug. Radiation-rehabilitation radiotherapy (EF-RT) was performed within 4 weeks before grouping or limited-field radiotherapy to be evaluated for tumor lesions within 2 weeks before grouping.

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: Anlotinib combined Docetaxel; patients treated with anlotinib and Docetaxel (21 days for 1 cycle) until PD (progressive disease)	Drug: Anlotinib combined Docetaxel; Anlotinib ( dose base on phase I study, QD PO d1-14, 21 days per cycle) and Docetaxel (60mg/m2 IV, d1, 21 days per cycle)
Active Comparator: Docetaxel; patients treated with Docetaxel (21 days for 1 cycle) until PD (progressive disease)	Drug: Docetaxel; Docetaxel (60mg/m2 IV, d1, 21 days per cycle)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	Progress free survival	each 42 days up to PD or death(up to 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Overall Survival	From randomization until death (up to 24 months)
ORR	Objective Response Rate	each 42 days up to intolerance the toxicity or PD (up to 24 months)
DCR	Disease Control Rate	each 42 days up to intolerance the toxicity or PD (up to 24 months)
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	Record Adverse Events (AEs) according to CTCAE (V4.03). To find Potential adverse reaction, measure blood pressure at least 2 times a week and test blood routine, Blood biochemical, Urine routine, stool routine, coagulation function, electrocardiogram for each follow-up, record and analyze the number of abnormal data.	Until 21 day safety follow-up visit
quality of life	use EORTC QLQ-C30(version 3) questionnaire to evaluate the quality of life	each 42 days up to intolerance the toxicity or PD (up to 24 months)

Collaborators and Investigators

• Sponsor: Yong Fang
• Collaborators: Zhejiang Cancer Hospital; Zhejiang Provincial People's Hospital; Ningbo No. 1 Hospital; Huizhou Municipal Central Hospital; Ningbo No.2 Hospital; Affiliated Hospital of Jiaxing University

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2018
• Primary Completion (Anticipated): November 1, 2019
• Study Completion (Anticipated): November 1, 2020

Study Registration Dates

• First Submitted: October 23, 2018
• First Submitted That Met QC Criteria: October 30, 2018
• First Posted (Actual): October 31, 2018

Study Record Updates

• Last Update Posted (Actual): June 7, 2019
• Last Update Submitted That Met QC Criteria: June 6, 2019
• Last Verified: November 1, 2018

More Information

Terms related to this study

• 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; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel
• Other Study ID Numbers: ALTER-L016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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