A Study of Sulfatinib on Relapsed or Refractory Drug Resistant Osteosarcoma

Study Overview
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Brief Summary
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This is a phase 1/2 study evaluating safety, tolerability, and efficacy of Sulfatinib in combination with chemotherapy (ifosfamide and etoposide) in children and adolescents with refractory or relapsed osteosarcoma ( combination Sulfatinib).

Detailed Description
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The study consists of 2 cohorts: Cohort 1 (Traditional chemotherapy) will evaluate the efficacy of ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. Cohort 2 (Combination Expansion) will evaluate the efficacy of Sulfatinib in combination with ifosfamide and etoposide in children, adolescents, and young adults with relapsed or refractory osteosarcoma. Sulfatinib will be provided as hard capsules containing 300 mg Sulfatinib. Sulfatinib capsules should be dissolved in water or apple juice for those who are unable to swallow capsules.

Official Title
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A Study of Etoposide and Ifosfamide Combined With or Without Sulfatinib on Relapsed or Refractory Drug Resistant Osteosarcoma

Conditions
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Osteosarcoma

Intervention / Treatment
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* Drug: Sulfatinib
* Drug: Etoposide
* Drug: Isophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Osteosarcoma subjects Male or female participants aged 2 to 25 years at the time of informed consent(Histologically or cytologically confirmed diagnosis of high grade osteosarcoma) Recurrent or refractory solid tumor malignancies that have treated with standard anticancer therapy but have no available treatment options. Evaluable or measurable disease that met the following criteria: 1. Participants must have an evaluable or measurable disease based on RECIST 1.1, using computed tomography (CT)/ magnetic resonance imaging (MRI). 2. Lesions that have been treated locally, such as external beam radiation therapy (EBRT) or radiofrequency (RF) ablation, must subsequently grow clearly to be considered target lesions. Life expectancy is 3 months or more. Adequate bone marrow function : ①. Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L. ②. Hemoglobin ≥ 8.0 g/ deciliter (hemoglobin ≤ 8.0 g/ deciliter is acceptable if corrected by growth factors or transfusion before starting sovanitinib). ③. Platelet count ≥ 75 x 10^9/L. Adequate liver function: 1. Bilirubin ≤ 1.5 times the upper limit of normal (ULN). 2. Alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times of ULN. Adequate renal function, such as creatinine clearance (or radioisotope glomerular filtration rate [GFR]), must be greater than 70 mL/min/ 1.73 square meters. (8)A baseline left ventricular ejection fraction (LVEF) of 50% or greater, as determined by echocardiography, indicates adequate cardiac function. (9) Good control of blood pressure (BP) with or without antihypertensive medication was defined as : blood pressure below 95% for sex, age, and height/length at screening (according to National Heart, Lung, and Blood Institute guidelines) and no change in antihypertensive medication during the cycle 1 of project. participants with osteosarcoma had blood pressure ≤150/90 mm Hg at screening and had no change in antihypertensive therapy during the cycle 1 of project. (10)Parents or legal representative (guardian) shall sign the written informed consent and obtain the consent of minor participants. Written informed consent from subjects ≥18 years of age. Willing and able to abide by the researchers determine solutions, plans, and toxicity of follow-up management. Exclusion Criteria: Any active infection or infectious disease. Any medical condition or other condition that the investigator believes will prevent the participant from participating in the clinical study. Other organ toxicity (except hair loss) caused by previous anti-cancer treatment (research drug, chemotherapy or radiotherapy) Known hypersensitivity to any component of the product (soventinib or ingredient). Any other anti-tumor treatment is given at the same time. He has been treated with sovantinib before. Two or more previous VEGF/VEGFR targeted therapies. Currently receiving any study drug or device in another clinical trial or within 30 days before informed consent. Clinically significant ECG abnormalities, including significant baseline QT or QTc interval prolongation (e.g., QTc interval duplication is demonstrated to be greater than 480 milliseconds). Gastrointestinal malabsorption or any other condition that the investigator believes may affect the absorption of sovantinib. Gastrointestinal bleeding or active hemoptysis (at least half a teaspoon of bright red blood) occurred within 3 weeks before the first administration of the study drug. Active second malignant tumor (excluding superficial melanoma, in situ, basal or squamous cell skin cancer with definite treatment) within 2 years before enrollment. Previously treated with ifosfamide with nephrotoxicity or encephalopathy grade greater than or equal to grade 3. Women who were breastfeeding or pregnant at the time of screening or baseline. If a negative screening pregnancy test is obtained more than 72 hours before the first administration of the study drug, a separate baseline assessment is required. -

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Etoposide plus Ifosfamide group<br>Children and adolescents with relapsed or refractory drug resistant osteosarcoma | Drug: Etoposide<br>* (1) Etoposide: 100 mg/m2/day (initial dose) will be administered on the first to third days of each 21 day cycle, a total of 5 cycles. The dose of etoposide can be reduced to 80 mg/m2/day and 60 mg/m2/day.;<br>Drug: Isophosphamide<br>* (1) Isophosphamide: 3000 mg/m2/day (initial dose) will be administered on the first to third days of each 21 day cycle for 5 cycles. The dose of ifosfamide can be reduced to 2400 mg/m2/day and 1800 mg/m2/day.<br>|
| Experimental: Etoposide plus Ifosfamide Combined With Sulfatinib<br>Children and adolescents with relapsed or refractory drug resistant osteosarcoma | Drug: Sulfatinib<br>* (1) Sulfatinib: 300 mg, oral once a day (QD), 21 days as a cycle<br>Drug: Etoposide<br>* (1) Etoposide: 100 mg/m2/day (initial dose) will be administered on the first to third days of each 21 day cycle, a total of 5 cycles. The dose of etoposide can be reduced to 80 mg/m2/day and 60 mg/m2/day.;<br>Drug: Isophosphamide<br>* (1) Isophosphamide: 3000 mg/m2/day (initial dose) will be administered on the first to third days of each 21 day cycle for 5 cycles. The dose of ifosfamide can be reduced to 2400 mg/m2/day and 1800 mg/m2/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 4 months progression-free survival | The proportion of patients who had no objective tumor progression or death from the start of treatment to 4 months of follow-up. | 4 months | 
| Efficacy evaluation in solid tumors | Complete response (CR), all target and non-target lesions (non-lymph nodes) disappear, and the diameter of all pathologic lymph nodes (both target and non-target) must be reduced to <10 mm; Partial response (PR), using baseline total diameter as reference, reduced the total diameter of target lesions by at least 30%. | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best of response,BOR | From the date of the first administration of the study drug to disease progression or death, whichever occurs first. | 4 months | 
| Duration of Remission (DOR) | Complete response (CR)/ partial response (PR) was first recorded until disease progression was first recorded until the data cutoff date. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory or Relapsed osteosarcoma, Sulfatinib, Tyrosine kinase inhibitors, Etoposide, Ifosfamide