Liposomal Irinotecan in Combination With Temozolomide and Bevacizumab in Patients With Advanced STS

A Study of Liposomal Irinotecan in Combination With Temozolomide and Bevacizumab in Patients With Relapsed or Refractory Soft Tissue Sarcoma

The study is expected to include 24 patients with metastatic or surgically unresectable relapsed/refractory soft tissue sarcoma confirmed by histological evidence, who have received at least one line of systemic treatment previously. The efficacy and safety of liposome irinotecan combined with temozolomide and bevacizumab in the treatment of relapsed/refractory soft tissue sarcoma will be evaluated.

Inclusion Criteria:

1. Age ≥14 years old, gender not limited;
2. For metastatic or surgically unresectable recurrent and refractory soft tissue sarcomas confirmed by histological evidence, this combination therapy regimen can be used as determined by the researcher.
3. Disease progression or intolerable toxicity has occurred after at least one line of systemic therapy (with or without targeted therapy) in the past.
4. At least one measurable lesion (RECIST v1.1);
5. ECOG: 0-2;
6. Expected survival period ≥3 months;
7. Good function of major organs, that is, meeting the following criteria (without receiving any blood components or cell growth factors within 14 days prior to randomization) :

Neutrophils ≥1.5*109/L; Platelet count ≥80*109/L; Hemoglobin ≥9g/dl; Serum albumin ≥3g/dl; (2) Total bilirubin ≤ 1.5 times the upper limit of the normal value (biliary drainage is allowed for biliary obstruction); ALT and AST≤ 3 times the upper limit of the normal value (for patients with liver metastasis, it can be relaxed to ≤ 5 times the upper limit of the normal value).

(3) Serum creatinine ≤ 1.5 times the upper limit of the normal value, creatinine clearance rate ≥60ml/min; (4) INR≤ 1.5 times the upper limit of the normal value and APTT≤ 1.5 times the upper limit of the normal value (screening can be conducted for anticoagulant therapy with stable doses such as low-molecular-weight heparin or warfarin and INR within the expected therapeutic range of the anticoagulant); (5) Electrocardiogram: QTcF≤450ms(for males), ≤470ms(for females); (6) Cardiac color Doppler ultrasound: LVEF (left ventricular ejection fraction) ≥50%; Women of childbearing age must undergo a blood pregnancy test within 3 days before randomization, and the result must be negative. They must also be willing to take appropriate contraceptive measures during the trial and for 6 months after the end of treatment. For men, it should be agreed to use appropriate methods of contraception during the study period and within 3 months after the end of treatment; 9. The subjects voluntarily joined this study and signed the informed consent form.

Exclusion Criteria:

1. Patients with known central nervous system metastases;

2. Severe gastrointestinal dysfunction (with bleeding, obstruction; inflammation above grade 2; diarrhea above grade 1);

3. Patients who have a history of treatment with irinotecan, temozolomide, bevacizumab or similar drugs;

4. Within the two weeks prior to randomization, there was third space effusion (such as a large amount of pleural effusion) that could not reach a stable state except for ascites (no intervention treatment is required after the drainage tube is removed);

5. Patients with ascites with clinical symptoms who require puncture or drainage, or those who have received ascites drainage within the past 3 months (except for those with only a small amount of ascites shown on imaging and controllable, but without clinical symptoms);

6. Currently accompanied by interstitial pneumonia or interstitial lung disease, or those with a history of interstitial pneumonia or interstitial lung disease requiring hormone therapy in the past, or other conditions that may interfere with the judgment and management of immune-related lung toxicity such as pulmonary fibrosis or organizing pneumonia (for example, Subjects with obliterative bronchiolitis, pneumoconiosis, drug-related pneumonia, idiopathic pneumonia, or those with active pneumonia or severely impaired lung function as shown by chest CT during the screening period; Active tuberculosis

7. Subjects with active autoimmune diseases or a history of autoimmune diseases that may relapse [including but not limited to autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, and hypothyroidism (subjects that can be controlled only through hormone replacement therapy can be enrolled)]; Those with skin diseases that do not require systemic treatment, such as vitiligo, psoriasis, alopecia, controlled type 1 diabetes treated with insulin, or childhood asthma that has been completely relieved and does not require any intervention in adulthood can be enrolled.

8. Known peripheral neuropathy (CTCAE≥ grade 3);

9. Known dihydropyrimidine dehydrogenase (low activity) or deficiency;

10. Severe infections (CTCAE > grade 2) occurred within 4 weeks prior to randomization, such as severe pneumonia requiring hospitalization, bacteremia, infectious complications, etc. There were symptoms and signs of infection within 2 weeks prior to randomization, requiring intravenous antibiotic treatment (except for prophylactic antibiotic use).

11. Have received any of the following treatments:

    The concomitant medication contained CYP3A4, CYP2C8 strong suppressor/strong inducer or UGT1A1 strong suppressor within 2 weeks prior to randomization; Use immunosuppressants or systemic hormones for immunosuppressive purposes within 2 weeks before randomization (dose >10mg/ day, prednisone or other equivalent therapeutic hormones); <s:1> Received radiotherapy within 2 weeks prior to randomization; Undergo major surgeries (such as thoracotomy, laparotomy, etc.) within 4 weeks before randomization; The patient has received any other clinical study drug treatment within 4 weeks prior to randomization, unless it is an observational (non-interventional) clinical study or follow-up of an interventional clinical study.

12. Abnormal coagulation function, with a bleeding tendency, or currently undergoing thrombolytic or anticoagulant therapy. Prophylactic use of low-dose aspirin (≤100mg/ day) and low-molecular-weight heparin (enoxaparin 40mg/ day and other low-molecular-weight heparin at equivalent doses) is permitted.

13. There are poorly controlled clinical symptoms or diseases of the heart, such as: (1) NYHA grade 2 or above heart failure; (2) Unstable angina pectoris; (3) Has suffered a myocardial infarction within six months; (4) Patients with clinically significant supraventricular or ventricular arrhythmias who require treatment or intervention;

14. Within the 3 years prior to randomization, the patient had a malignant tumor other than relapsed or refractory soft tissue sarcoma, excluding well-treated carcinoma in situ, cutaneous basal cell or squamous cell carcinoma, etc., which showed no signs of recurrence.

15. Individuals who are known to be allergic to irinotecan liposomes, other liposome products, temozolomide, bevacizumab, or any of the components in the above products;

16. Those who are known to have acquired immune deficiency syndrome (AIDS) or test positive for HIV, or are active syphilis carriers;

17. There is a clear history of neurological or mental disorders in the past, including epilepsy or dementia;

18. As determined by the researchers, the subjects have other factors that may force them to terminate the study halfway, such as non-compliance with the protocol, suffering from other serious diseases (including mental disorders) that require concurrent treatment, having severely abnormal laboratory test values of clinical significance, family or social factors that may affect the safety of the subjects or the collection of trial data, etc.