Anlotinib Hydrochloride Combined With Epirubicin and Ifosfamide for Soft Tissue Sarcoma Patients (ALTER-S005)

Anlotinib Hydrochloride Combined With Epirubicin and Ifosfamide for Locally Recurrent or Metastatic Soft Tissue Sarcoma Patients: a One-arm, Multi-center, Prospective Clinical Trial

Anlotinib is a multi-target receptor tyrosine kinase inhibitor. It can inhibit the angiogenesis related kinase, such as Vascular Endothelial Growth Factor Receptor (VEGFR), Fibroblast Growth Factor Receptor(FGFR), Platelet-Derived Growth Factor Receptor(PDGFR), and tumor cell proliferation related kinase c-Kit kinase. Anlotinib is an efficient second line therapeutic agent in treatment for metastatic soft tissue sarcoma which has been approved in clinical trials (ALTER-0203).Therefore , this study evaluates the safety and efficacy of anlotinib plus epirubicin and ifosfamide treat the metastatic or advanced soft tissue sarcoma .

Study Overview

• Status: Unknown
• Conditions: Sarcoma, Soft Tissue
• Intervention / Treatment: Drug: anlotinib

Detailed Description

This study is planned to be carried out in Liaoning, Jilin and Harbin provinces regional multi-center. 47 cases are preliminarily expected to be included. The study started in January 2019 and ended in December 2019. It is expected that the trial will end in December 2020. This study is a phase 2 study evaluating the safety and efficacy anlotinib and plus epirubicin and ifosfamide treat the metastatic or advanced soft tissue sarcoma .

All those participants need to sign informed consent forms for data collection and use for research purpose before inclusion .Those participants who were not treated with anthracyclines or other tyrosinase inhibitors or angiostatins within the first 6 months should be enrolled.

47 subjects with metastatic or advanced soft tissue sarcoma will receive epirubicin at 30mg/m2/day（day1-2 IV）, ifosfamide at 1.8g/m2/day (day1-5 IV) anlotinib at a dose of 12 mg once daily (day8-21 PO). After 6 treatment cycles,those participants will receive anlotinib at a dose of 12 mg once daily (day8-21 PO) in 21-day cycles until disease progression (defined by RECIST version 1.1) ot unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Anticipated): 47
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Li Shenglong, master; Phone Number: 18900918348; Email: lishenglong@cancerhosp-ln-cmu.com

Study Locations

• China
  • Liaoning
    • Shenyang, Liaoning, China, 110042
      • Recruiting
      • Liaoning Province Tumor Hospital
      • Contact: Li Shenglong, master

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed the informed consent form prior to patient entry;
• ≥ 18 years of age , regardless of gender；ECOG :0-1;Expected Survival Time: Over 3 months;
• Histologically confirmed diagnosis of un-resectable or recurrent metastatic soft tissue sarcoma, such as: leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, liposarcoma , angiosarcoma and other sarcomas. The following histologies are excluded: alveolar Soft tissue sarcoma, rhabdomyosarcoma, chondrosarcoma, osteosarcoma, gastrointestinal stromal tumor, humeral cutaneous fibrosarcoma, Ewing sarcoma/primary neuroectodermal tumor, inflammatory myofibroblastic sarcoma and malignant mesothelioma.
• Patients who were not treated with anthracyclines or other tyrosinase inhibitors or angiostatins within the first 6 months should be enrolled.
• Evaluable disease by imaging or physical exam or measurable disease defined as at least one lesion that can be accurately measured according to RECIST version 1.1.
• normal main organs function as defined below: Hemoglobin (Hb) ≥ 80g / L, Neutrophils (ANC) ≥ 1.5 × 109 / L, Platelet count (PLT) ≥ 80 × 109 / L, Serum creatinine (Cr) ≤ 1.5 × normal upper limit (ULN) or creatinine clearance (CCr) ≥ 60ml / min, Blood urea nitrogen (BUN) ≤ 2.5 × normal upper limit (ULN); Total bilirubin (TB) ≤ 1.5 × ULN; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; If accompanied by liver metastases, ALT and AST ≤ 5 × ULN Albumin (ALB) ≥ 25 g/L. Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ normal low limit (50%)
• Women of childbearing potential should agree to use and utilize an adequate method of contraception (such as intrauterine device，contraceptive and condom) throughout treatment and for at least 6 months after study is stopped；the result of serum or urine pregnancy test should be negative within 7 days prior to study enrollment，and the patients required to be non-lactating；Man participants should agree to use and utilize an adequate method of contraception throughout treatment and for at least 6 months after study is stopped.

Exclusion Criteria:

• Prior treatment with any VEGFR tyrosine kinase inhibitor(such as sunitinib, sorafenib, bevacizumab, imatinib, famitinib, apatinib, regorafenib and other drugs).
• Systemic anti-tumor therapy, including cytotoxic therapy, signal transduction inhibitors, and immunotherapy, is planned for the first 4 weeks prior to enrollment or during the study. Radiation radiotherapy (EF-RT) was performed within 4 weeks prior to enrollment.
• A history of other malignancy ≤ 3 years previous
• Known brain metastases.
• The investigator judged that during the follow-up study, the tumor is very likely to invade the important blood vessels and cause fatal hemorrhage, or the formation of tumor thrombosis with large veins (iliac vessels, inferior vena cava, pulmonary veins, superior vena cava);
• The investigator judged that the presence of distinct pulmonary cavitary or necrotic tumors;
• Serosal effusion with clinical symptoms requiring surgical management (including hydrothorax and ascites pericardial effusion)
• with any severe and/or uncontrolled disease, including:1)Uncontrollable hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, despite optimal drug treatment).2)Arrhythmias with grade II and above myocardial ischemia or myocardial infarction, poor control (including corrected QT interval(QTc) men ≥ 450 ms, women ≥ 470 ms) and ≥ 2 congestive heart failure (New York Heart Association ( NYHA) rating).3)Poor control of diabetes (fasting blood glucose > 10mmol / L).4)Active or uncontrolled serious infection (≥ Common Terminology Criteria for Adverse Event(CTC AE) grade 2 infection);5)Patients with active hepatitis B or hepatitis C (hepatitis B: HBsAg-positive and hepatitis B virus(HBV) DNA ≥ 500 IU/mL; hepatitis C: hepatitis C virus(HCV) RNA-positive and abnormal liver function), or active infection requiring antimicrobial treatment (eg Treated with antibacterial drugs, antiviral drugs, antifungal drugs);6)renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0 g;7)Patients with seizures and need treatment
• Abnormal coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or activated partial thromboplastin time(APTT) > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy.
• Patients treated with anticoagulants or vitamin K antagonists such as warfarin, heparin.
• significant coughing blood in the 2 months before enrollment, or daily hemoptysis of 2.5ml or more.
• history of psychotropic substance abuse who are unable to quit or have a mental disorder.
• Tendencies of hereditary or acquired hemorrhagic and thrombotic (such as hemophilia patients, coagulopathy, thrombocytopenia, hypersplenism, etc.)
• Any major unhealed wound, ulcer, or fracture occurred in a patient who had undergone major surgery or trauma within 4 weeks and/or had any bleeding or bleeding episodes which the degree is bigger than CTCAE 3 grade within 4 weeks prior to enrollment.
• Active period digestive ulcers.
• Cavity sinus or perforation occurred within 6 months.
• Participated in other anti-tumor clinical trials within 4 weeks.
• Received a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole, erythromycin, and clarithromycin) within 7 days, or received a potent CYP3A4 inducer within 12 days prior to the study (eg. catarrh Treatment with imipramine, rifampicin and phenobarbital).
• Allergic reactions, hypersensitivity reactions or intolerance to anlotinib hydrochloride or its excipients.
• Pregnancy or lactation.
• The investigator believes that there are any conditions that may damage the subject or result in the subject not being able to meet or perform the research request.

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: anlotinib & epirubicin& ifosfamide; interventions:Anlotinib 12 mg once daily for 14 days tablet by mouth ; epirubicin 30mg/m2 intravenous injection from 1 day to 2 , ifosfamide 1.8g/m2 intravenous injection from 1day to 5day with 6 cycles. Anlotinib 12 mg once daily for 14 days tablet by mouth to progressive disease	Drug: anlotinib; Anlotinib 12 mg once daily for 14 days tablet by mouth ; epirubicin 30mg/m2 intravenous injection from 1 day to 2 , ifosfamide 1.8g/m2 intravenous injection from 1day to 5day with 6 cycles. Anlotinib 12 mg once daily for 14 days tablet by mouth to progressive disease; Other Names: epirubicin ifosfamide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progress free survival	Progress free survival (PFS) defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.	Until Progressive Disease(PD) or death(up to 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall Survival (OS) is defined as the time until death due to any cause.	From randomization until death (up to 24 months)
Objective Response Rate	Objective Response Rate (ORR) is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.	Each 42 days up to intolerance the toxicity or PD (up to 24 months)
Disease Control Rate	Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.	Each 42 days up to intolerance the toxicity or PD (up to 24 months)
Safety(Number of Participants with Adverse Events and Clinical laboratory numerical evaluation as a Measure of Safety)	Number of Participants with Adverse Events and Clinical laboratory numerical evaluation as a Measure of Safety.	Each 42 days up to intolerance the toxicity or PD (up to 24 months)

Collaborators and Investigators

• Sponsor: Liaoning Tumor Hospital & Institute
• Collaborators: China-Japan Friendship Hospital; First Hospital of China Medical University; Second Hospital of Jilin University; The Second Affiliated Hospital of Dalian Medical University; The Third Affiliated Hospital of Harbin Medical University; Dalian Municipal Central Hospital; Daqing Oil Field Hospital
• Investigators: Principal Investigator: Li Shenglong, master, Project sponsor of Liaoning Province Tumor Hospital

Publications and helpful links

General Publications

• Chawla SP, Papai Z, Mukhametshina G, Sankhala K, Vasylyev L, Fedenko A, Khamly K, Ganjoo K, Nagarkar R, Wieland S, Levitt DJ. First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial. JAMA Oncol. 2015 Dec;1(9):1272-80. doi: 10.1001/jamaoncol.2015.3101.
• Spannuth WA, Sood AK, Coleman RL. Angiogenesis as a strategic target for ovarian cancer therapy. Nat Clin Pract Oncol. 2008 Apr;5(4):194-204. doi: 10.1038/ncponc1051. Epub 2008 Feb 12.

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2019
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: January 22, 2019
• First Submitted That Met QC Criteria: January 22, 2019
• First Posted (Actual): January 24, 2019

Study Record Updates

• Last Update Posted (Actual): July 9, 2019
• Last Update Submitted That Met QC Criteria: July 7, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Epirubicin; Ifosfamide
• Other Study ID Numbers: KY2018012

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