A Study of Anlotinib Combined With or Without PD-1 Antibody on Unresectable High-grade Chondrosarcoma

Brief Title

A Study of Anlotinib Combined With or Without PD-1 Antibody on Unresectable High-grade Chondrosarcoma

Official Title

A Multicenter Clinical Controlled Study of Anlotinib Combined With PD-1 Antibody on Unresectable High-grade Chondrosarcoma With Different IDH Genotypes

Brief Summary

      There is no standard treatment for chondrosarcoma. Some small sample of studies has shown
      that anti-angiogenic TKIs show certain activity in the treatment of chondrosarcoma. PD-1
      inhibitors, in recent years, have also been used in clinical practice and showed good
      efficacy. We intend to explore the response of chondrosarcoma to PD-1 monoclonal antibody and
      the influence of different IDH genotypes on PD-1 monoclonal antibody response.
    

Detailed Description

      We intend to explore the response of chondrosarcoma to PD-1 monoclonal antibody and the
      influence of different IDH genotypes on PD-1 monoclonal antibody response. Patients with
      unresectable locally advanced or metastatic chondrosarcomas(CS), including high-grade
      (II-III) ordinary CS and dedifferentiated CS, are qualified. The experimental group was PD-1
      monoclonal antibody combined with Anlotinib for treatment of unresectable locally advanced or
      metastatic CS, and the control group was anlotinib monotherapy. The treatment is continuous
      until the disease progression or intolerable toxicity. CS with disease progression in the
      control group was allowed to enter the experimental group to continue treatment. The primary
      endpoint was 6-month PFSR.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

6month-PFSR

Secondary Outcome

 ORR

Condition

Chondrosarcoma

Intervention

Anlotinib hydrochloride

Study Arms / Comparison Groups

 Anlotinib combined with PD-1 monoclonal antibody
Description:  Anlotinib, a multi-target tyrosine kinase inhibitor,oral,12mg/10mg/8mg,2 weeks on and 1 week off; PD-1 monoclonal antibody,PD-1 inhibitor,Intravenous injection,once 3 week.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

70

Start Date

March 31, 2022

Completion Date

March 31, 2026

Primary Completion Date

March 31, 2025

Eligibility Criteria

        Inclusion Criteria:

          -  1. Age ≥18 years old, no gender limit; 2. ECOG PS score 0-2 points; 3. unresectable
             locally advanced or metastatic chondrosarcoma confirmed by histopathology, including
             high-grade (grade II-III) conventional CS and dedifferentiated CS; 4. Allow previous
             surgery, radiotherapy, or chemotherapy therapies; 5. Have at least 1 measurable lesion
             in accordance with the RECIST1.1; 6. The main organs are functioning normally and meet
             the following criteria within 7 days before treatment:

               -  The standard of routine blood examination must be met (no blood transfusion and
                  blood products within 14 days, no correction with G-CSF and other hematopoietic
                  stimulating factors):

                    1. Hemoglobin (HB) ≥90g/L;

                    2. The absolute value of neutrophils (ANC) ≥ 1.5×109/L;

                    3. Platelets (PLT) ≥100×109/L ② The biochemical inspection shall meet the
                       following standards:

                    1. Total bilirubin (TBIL)≤1.5×upper limit of normal (ULN);

                    2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤
                       2.5×ULN, if there is liver metastasis, ALT and AST ≤ 5×ULN;

                    3. Serum creatinine (Cr)≤1.5×ULN or creatinine clearance (CCr)≥60ml/min;

                       ③ Urine protein <2+, and 24h urine protein quantitatively shows that the
                       protein must be ≤ 1g;

                       ④ Coagulation function: INR <2.0 and APTT≤1.5×ULN

                       ⑤ Doppler ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥
                       lower limit of normal value (60%)

                       ⑥ Thyroid function: TSH ≤ upper limit of normal (ULN); if abnormal, T3 and
                       T4 levels should be considered, and T3 and T4 levels are normal and can be
                       included in the group; 9. The fertile male or female agrees to use reliable
                       contraceptive methods during treatment and at least 12 months after the last
                       study drug is taken; 10. Sign the informed consent form with my consent,
                       have good compliance and cooperate with follow-up.

                       Exclusion Criteria:

          -  1. Received anti-CTLA-4/PD-1/PD-L1 antibody treatment previously ; 2. Received
             anti-angiogenic TKI drugs (such as Anlotinib, Apatinib, Regofenib, etc.) or
             anti-angiogenic antibody drugs (such as Bevacizumab) previously; 3. Received other
             anti-tumor treatments within 4 weeks before enrollment, including systemic therapy,
             radiotherapy, major surgery, open biopsy, or participated in other clinical trials; 4.
             Patients who have not recovered from adverse events caused by any previous treatment
             to NCI-CTCAE (5.0) ≤1, excluding hair loss; 5. The investigator determines that there
             is a significant risk of bleeding, including but not limited to:

               1. Imaging shows that the tumor has invaded important blood vessels or it is judged
                  by the investigator that the tumor is likely to invade important blood vessels
                  and cause fatal hemorrhage during the follow-up study, or accompanied by large
                  veins (iliac blood vessels, inferior vena cava, pulmonary vein, superior vena
                  cava) tumor thrombus formation, or a history of aneurysm and the possibility of
                  rupture;

               2. Received major surgical operations or had obvious traumatic injuries within 4
                  weeks before enrollment, or had any bleeding or bleeding event ≥ NCI-CTCAE Grade
                  3, or had any unhealed wounds, ulcers or fractures;

               3. There is a tendency for hereditary or acquired bleeding and thrombosis, such as
                  hemophilia patients, blood coagulation dysfunction, thrombocytopenia,
                  hypersplenism, etc.;

               4. Abnormal coagulation function (INR>1.5 or prothrombin time (PT)>ULN+4 seconds or
                  APTT>1.5 ULN), have bleeding tendency, or are receiving thrombolytic or
                  anticoagulant therapy;

               5. Patients treated with anticoagulants or vitamin K antagonists such as warfarin,
                  heparin or similar drugs; Note: Under the premise that the international
                  normalized ratio of prothrombin time (INR) ≤ 1.5, the use of low-dose heparin
                  (daily dosage for adults is 6,000 to 12,000 U) or low-dose aspirin (daily dosage
                  ≤100 mg); 6. The following symptoms or comorbidities exist:

               1. A history of hypertension, and can not be well controlled after treatment with
                  1-2 kinds of antihypertensive drugs (systolic blood pressure ≥150mmHg or
                  diastolic blood pressure ≥100mmHg);

               2. Poorly controlled diabetes (fasting blood glucose> 10mmol/L);

               3. Significant cardiovascular damage includes, but is not limited to: unstable
                  angina, myocardial ischemia or myocardial infarction, grade ≥2 congestive heart
                  failure (New York Heart Association (NYHA) classification); occurred within 6
                  months Arterial/venous thrombotic events, such as cerebrovascular accidents
                  (including temporary ischemic attacks), deep vein thrombosis and pulmonary
                  embolism;

               4. Sinus bradycardia of grade I or higher; or atrioventricular block of second
                  degree or higher, or sinus arrest (except for pacemaker); arrhythmia (including
                  QTc ≥480ms); need to take it at the same time to prolong the QTc interval Period
                  drug

               5. Liver cirrhosis, decompensated liver disease, active hepatitis or chronic
                  hepatitis require antiviral treatment;

               6. Urine routine test shows urine protein ≥ ++, and the 24-hour urine protein
                  quantitative is confirmed to be> 1.0 g;

               7. Renal failure requires hemodialysis or peritoneal dialysis;

               8. A history of immunodeficiency, including HIV positive or other acquired or
                  congenital immunodeficiency diseases, or a history of organ transplantation,
                  hematopoietic stem cell transplantation, or receiving systemic corticosteroids
                  within 2 weeks before enrollment Or any other form of immunosuppressive therapy;
                  Note: In the absence of active autoimmune diseases, inhaled or topical steroids
                  and adrenal corticosteroids with a dose of> 10 mg/day prednisone equivalent dose
                  are allowed, and the use of no more than 10 mg/day prednisone curative dose is
                  allowed Adrenal corticosteroid replacement therapy, allowing glucocorticoids to
                  be used as a preventive drug for hypersensitivity reactions (such as
                  pre-docetaxel prophylaxis);

               9. Active or uncontrolled serious infection (≥CTC AE grade 2 infection) occurred
                  within 4 weeks before enrollment;

              10. Judging by imaging studies, there is a central nervous system metastasis;

              11. Suffered from other malignant tumors in the past 5 years, excluding cured
                  cervical carcinoma in situ, skin basal cell carcinoma, skin squamous cell
                  carcinoma, and superficial bladder tumors;

              12. Those who have a history of psychotropic drug abuse and cannot be quit or have
                  mental disorders;

              13. Those who have received ascites or pleural effusion drainage within 2 months of
                  enrollment, or those who have uncontrollable pericardial effusion, pleural
                  effusion and ascites;

              14. Complications of pulmonary fibrosis or interstitial pneumonia, or severe chronic
                  obstructive pulmonary disease;

              15. Severe gastrointestinal diseases, such as gastric perforation, active peptic
                  ulcer, etc.; 8. Combined medication

               1. During the study period, strong CYP3A inhibitors (such as itraconazole,
                  telithromycin, clarithromycin, ritonavir, etc.) or moderate CYP3A inhibitors
                  (such as ciprofloxacin) should be used;

               2. During the study period, strong CYP3A inducers (such as phenobarbital, phenytoin,
                  rifampicin, carbamazepine) or moderate CYP3A inducers should be used;

               3. During the study period, it is necessary to take traditional Chinese medicines,
                  especially those with anti-tumor activity; 9. Other

               1. It is expected that any form of systemic or local anti-tumor therapy will be
                  taken during the study period;

               2. As judged by the investigator, there is a serious hazard to patient safety,
                  concomitant diseases that may confuse the results of the study, or affect the
                  patient to complete the study or any other conditions, such as a history of
                  gastrointestinal disease that may affect the absorption of oral drugs.

               3. Those who have multiple factors that affect oral medications (such as inability
                  to swallow, chronic diarrhea, intestinal obstruction, etc.);

               4. Allergic to the drugs in this study;

               5. Live vaccines have been vaccinated within 30 days before enrollment. Live
                  vaccines include but are not limited to the following vaccines: measles, mumps,
                  rubella, varicella/shingles (chickenpox), yellow fever, rabies, Bacillus
                  Calmette-Guerin (BCG), typhoid vaccine.
      

Gender

All

Ages

18 Years - 100 Years

Accepts Healthy Volunteers

No

Contacts

Binghao Li, Medical PhD, 86-0571-87783777, [email protected]



Administrative Informations


NCT ID

NCT05193188

Organization ID

LS2021-387


Responsible Party

Sponsor

Study Sponsor

Second Affiliated Hospital, School of Medicine, Zhejiang University


Study Sponsor

Binghao Li, Medical PhD, Principal Investigator, Second Affiliated Hospital of Zhejiang University School of Medicine


Verification Date

December 2021