DCV in the Treatment of Recurrence and Refractory Childhood Solid Tumors

Phase 1

• Conditions: Unrecognized Condition
• Interventions: Drug: pegylated liposomal doxorubicin, cyclophosphamide, vincristine,

• Registration Number: NCT04213612
• Lead Sponsor: Sun Yat-sen University

Brief Summary

Doxorubicin is an anthracycline antibiotic that is part of the standard treatment for many pediatric malignancies, but its long-term cardiotoxicity cannot be ignored. Without affecting overall survival, in order to improve the quality of life of childhood tumor survivors and reduce cardiotoxicity, drugs with less cardiotoxicity should be selected; compared with ordinary doxorubicin, PEGylated doxorubicin (PLD ) The biggest advantage is the low cardiotoxicity.

PEGylated doxorubicin (Caelyx®) has undergone a Phase I dose climbing clinical trial in children with solid tumors. The drug is safe by testing PK. The results of Phase II clinical studies of Caelyx® in children with progressive soft tissue sarcoma show that the drug is safe. Domestically produced PEGylated doxorubicin has no data on childhood tumors in China. Therefore, we plan to conduct a phase I study in pediatric solid tumors of pegylated doxorubicin combined with cyclophosphamide, vincristine, relapsed, and refractory childhood solid tumors. Maximum tolerated dose and effectiveness of stellate in children with solid tumors, thus laying the foundation for future phase II / III clinical studies

Detailed Description

Purpose of Phase I:

the main purpose: To evaluate the safety of PLD in combination with cyclophosphamide, vincristine, regenerative, and refractory solid tumors in children, including dose absorption toxicity (DLT)

Secondary purpose:

* determine the appropriate maximum tolerated dose (MTD) and /or PLD for further clinical studies in this patient population;

* Describe the antitumor activity of PLD combined with cyclophosphamide and vincristine in children with advanced solid tumors or primary CNS tumors;

Exploratory purpose:

Effectiveness of PLD combined with cyclophosphamide and vincristine in treatment progress, relapse, and refractory solid tumors in children.

Study Timeline

• Status Verified: 2019-12
• Study First Submitted: 2019-12-24
• Study First Submitted QC: 2019-12-25
• Last Update Submitted: 2019-12-25
• Study Start: 2019-12-30
• Study First Posted: 2019-12-30
• Last Update Posted: 2019-12-30
• Primary Completion: 2020-08-30
• Study Completion: 2020-11-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

• 1. Age: 1-18 years;
• 2. ECOG PS score: 0-1 points;
• 3. Patients with solid tumors confirmed by histopathology in children;
• 4. Patients who have progressed, relapsed, or are refractory after first-line treatment (there is no complete or partial response after recent treatment);
• 5. Must have at least one measurable lesion as defined by the RECIST standard;
• 6. Expected survival time ≥ 6 months;
• 7. Heart function:
  1. Cardiac ultrasound detection LVEF ≥ 50%;
  2. EKG indicates no myocardial ischemia;
  3. no history of arrhythmia requiring drug intervention before enrollment;
• 8. Patients must fully recover from the acute toxic effects of all previous anti-cancer chemotherapy:
  1. Myelosuppressive chemotherapy: at least 21 days after the last myelosuppressive chemotherapy (42 days if nitrosourea was used earlier);
  2. Experimental drugs or anti-cancer therapies other than chemotherapy: Do not use within the first 28 days of the planned start of doxycycline. Full recovery from the clinically significant toxicity of the therapy must be clearly identified;
  3. Hematopoietic growth factor: at least 14 days after the last dose of long-acting growth factor or 3 days after the last dose of short-acting growth factor;
  4. immunotherapy: at least 42 days after completing any type of immunotherapy (except steroids), such as immune checkpoint inhibitors and tumor vaccines;
  5. X-ray therapy (XRT): at least 14 days after local palliative XRT ( small range of mouth); if other solid bone marrow (BM) irradiation, including prior radioactive iodized meta-iodobenzidine (131I-MIBG) treatment, You must end at least 42 days;
  6. Stem cell infusion without total body irradiation (TBI): There is no evidence of active graft-versus-host disease, and transplantation or stem cell infusion must end at least 56 days;
• 9. For patients who are not known to have BM:
  1. Absolute neutrophil count (ANC) ≥ 1.0 × 109 / L;
  2. Platelet count ≥100.0 × 109 / L;
  3. hemoglobin ≥90 g / L;
• 10. Liver and kidney function should meet the following standards:
  1. Bilirubin (combined + unbound total) ≤ 2.5 × upper limit of normal value (ULN) (corresponding to age), patients with Gilbert's syndrome can be enrolled according to the researchers' judgment
  2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN;
  3. Estimated glomerular filtration rate ≥ 30 mL / min / 1.73 m2 or serum creatinine (Cr) ≤ 1.5ULN;
• 11. During the participation in the study, be able to comply with outpatient treatment, laboratory monitoring and necessary clinical visits;
• 12. The parent/ guardian of the child or adolescent subject has the ability to understand, agree, and sign the research informed consent (ICF) and applicable child consent form before initiating any protocol-related procedures; subject to parent/ guardian consent Candidates have the ability to express consent (if applicable).

Exclusion Criteria

• 1. Previous or concurrent active clinical cardiovascular disease including congenital heart disease or pericardial disease, history of heart failure, myocardial infarction, coronary heart disease, heart valve disease, cardiomyopathy, arrhythmia (including persistent atrial fibrillation, Complete left bundle branch block, frequent ventricular early); or the QT interval (QTc) after the current corrected heart rate is extended> 480 milliseconds;
• 2. previous severe skin diseases;
• 3. previous allergic asthma or severe allergic disease;
• 4. Poorly controlled hypertension and diabetes;
• 5. Have a history of other tumors, except for cured cervical cancer or skin basal cell carcinoma;
• 6. Patients with hepatitis B surface antigen-positive;
• 7. Patients infected with HIV or syphilis;
• 8. Patients who have received organ transplants in the past;
• 9. Uncontrolled active systemic bacterial, viral or fungal infections;
• 10. Contraindications to high-dose hormone use, such as uncontrollable high blood sugar, gastric ulcer or mental illness;
• 11. Patients who have used a total cumulative dose of doxorubicin ≥ 450 mg / m2, or a total cumulative dose of epirubicin ≥ 550 mg / m2, or previously used anthracyclines to cause heart disease;
• 12. Have a serious neurological or psychiatric history, including epilepsy or autism.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
PLD+CTX+VCR	pegylated liposomal doxorubicin, cyclophosphamide, vincristine,	CTX 1g/m2/d，D1-2 VCR 1.5mg/m2，D1

Primary Outcome Measures

Name	Time	Method
Maximum tolerated dose	At the end of Cycle 1 (each cycle is 21 days)	Maximum tolerated dose

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate	At the end of Cycle 2 (each cycle is 21 days)	Complete remission + partial remission
Adverse event	through study completion, an average of 1 year	Hematological and non-hematological toxicity (NCI CTCAE v5.0)