Phase I Dose Escalation and Pharmacokinetics Clinical Trial of Mitoxantrone Hydrochloride Liposome in Children With Relapsed and Refractory Lymphoma and Solid Tumors

Study Overview
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Brief Summary
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Phase I dose escalation clinical trial: to explore the dose limiting toxicity (DLT) of mitoxantrone hydrochloride liposome injection in the treatment of children with relapsed and refractory lymphoma and solid tumors. Pharmacokinetics clinical trial: to observe the pharmacokinetics of mitoxantrone hydrochloride liposomes in children with relapsed and refractory lymphoma and solid tumors. To evaluate the safety and efficacy of mitoxantrone hydrochloride liposomes in children with lymphoma and solid tumors.

Detailed Description
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This is a phase I dose escalation and pharmacokinetics clinical trial to evaluate the safety and efficacy of mitoxantrone hydrochloride liposomes in children with lymphoma and solid tumors. In the phase Ia dose escalation study, patients with relapsed and refractory lymphoma and solid tumors will be treated with mitoxantrone hydrochloride liposome alone or combined treatment at the dose of 16 mg/m2, 20 mg/m2 and 24 mg/m2, each cohort wil enroll 9 18 children. Simultaneously 6 15 cases were added for pharmacokinetic study to ensure 8 cases are included in each dose group with the same mitoxantrone hydrochloride liposome dose. In phase Ib, patients received the combination therapy of mitoxantrone hydrochloride liposome at the MTD dose (24mg/m2) .

Official Title
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Phase I Dose Escalation and Pharmacokinetics Clinical Trial of Mitoxantrone Hydrochloride Liposome in Children With Relapsed and Refractory Lymphoma and Solid Tumors

Conditions
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Pediatric Solid Tumor

Intervention / Treatment
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* Drug: Mitoxantrone Hydrochloride Liposome
* Drug: Irinotecan
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Subjects fully understand and voluntarily participate in this study and sign the informed consent form (ICF); 2. 2-21 years old; 3. Expected survival ≥ 3 months; 4. Subjects with histologically confirmed diagnosis of relapsed and refractory lymphoma and solid tumors, which is one of the following subtypes: Lymphoblastic lymphoma Anaplastic large T cell lymphoma Burkitt's lymphoma Diffuse large B-cell lymphoma Peripheral T, NK/T cell lymphoma Soft tissue sarcoma Neuroblastoma Other subtypes of lymphoma or solid tumors that the investigators believe can be included 5. Relapsed lymphoma is defined as the lymphoma that relapse after obtaining complete response (CR) after initial chemotherapy; Refractory lymphoma subjects meet one of the following conditions: 1) The tumor shrinks <50% or disease progression after 4 cycles of standard chemotherapy,; 2) CR after standard chemotherapy, but relapse within half a year; 3) 2 or more relapses after CR; 4) relapse after hematopoietic stem cell transplantation; 6. Lymphoma subjects must have at least one evaluable or measurable lesion per lugano2014 criteria: for lymph node lesions, the length should be > 1.5cm; For non-lymph node lesions, the length should be > 1.0cm; 7. Solid tumors must have tumor lesions measurable by CT or MRI; 8. ECOG Performance Status: 0-2; 9. Bone marrow function: Absolute neutrophil count ≥1.5×109/L, Platelet count ≥75×109/L, Hemoglobin ≥ 80g/L (Absolute neutrophil can be relaxed to ≥ 1.0×109/L, Platelet count can be relaxed to ≥50×109/L, Hemoglobin can be relaxed to ≥75 g/L in subjects with poor bone-marrow reserve); 10. Liver and kidney function: serum creatinine ≤ 1.5×ULN (upper limit of normal); AST and ALT ≤ 2.5×ULN (≤ 5×ULN for subjects with liver metastases); total bilirubin ≤ 1.5×ULN (≤ 3×ULN for subjects with liver metastases). Exclusion Criteria: 1. The subject had previously received any of the following anti-tumor treatments: Subjects who have been treated with mitoxantrone or mitoxantrone liposomes; Previously received doxorubicin or other anthracycline treatment, and the total cumulative dose of doxorubicin was more than 360 mg/m2 (1 mg doxorubicin equivalent to 2 mg epirubicin); Subjects who received anti-tumor treatment (including chemotherapy, targeted therapy, glucocorticoid, traditional Chinese medicine with anti-tumor activity, etc.) or participated in other clinical trials and received trial drugs; Subjects who received autologous hematopoietic stem cell transplantation within 100 days after the first medication or allogeneic hematopoietic stem cell transplantation. 2. Hypersensitivity to any study drug or its components; 3. Uncontrolled systemic diseases (such as active infection, uncontrolled hypertension, diabetes, etc.); 4. Heart function and disease meet one of the following conditions: Long QTc syndrome or QTc interval > 480 ms; Complete left bundle branch block, grade II or III atrioventricular block; Serious and uncontrolled arrhythmias requiring drug treatment; New York Heart Association grade ≥ III; Cardiac ejection fraction (LVEF)< 50%; A history of myocardial infarction, unstable angina pectoris, severe unstable ventricular arrhythmia or any other arrhythmia requiring treatment, a history of clinically serious pericardial disease, or ECG evidence of acute ischemia or active conduction system abnormalities within 6 months before recruitment. 5. Hepatitis B and hepatitis C active infection (plus HBV DNA if one positive for hepatitis B surface antigen or core antibody and HBV DNA more than 1×103 copy/mL excluded; plus HCV RNA if hepatitis C antibody positive and HCV RNA more than 1×103 copy/mL exclude); 6. Human immunodeficiency virus (HIV) infection (HIV antibody positive); 7. Subjects with other malignant tumors past or present (except for non-melanoma skin basal cell carcinoma, breast/cervical carcinoma in control, and other malignant tumors that have been effectively controlled without treatment within the past five years); 8. Subjects suffering from primary or secondary central nervous system (CNS) lymphoma or a history of CNS lymphoma at the time of recruitment; 9. Pregnant and lactating women and childbearing age patients unwilling to take contraceptive measures; 10. Unsuitable subjects for this study determined by the investigator.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 21 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mitoxantrone hydrochloride liposome alone or combined with Irinotecan+Vincristine<br>In phase Ia, patients with relapsed and refractory lymphoma and solid tumors will receive mitoxantrone hydrochloride liposome alone (at three doses of 16 mg/m2, 20 mg/m2 and 24 mg/m2, ) or combination of Irinotecan 50mg/ m2，d1-5, Vincristine 1.5mg/ m2，d1 for up to 6 cycles (21 days per cycle). In phase Ib, patients will recive mitoxantrone hydrochloride liposome 24 mg/m2, combination of Irinotecan 50mg/ m2，d1-5, Vincristine 1.5mg/ m2 | Drug: Mitoxantrone Hydrochloride Liposome<br>* In phase Ia, mitoxantrone hydrochloride liposome will be administered by an intravenous infusion at three doses of 16 mg/m2, 20 mg/m2 and 24 mg/m2 . In phase Ib, mitoxantrone hydrochloride liposome will be administered by an intravenous infusion of 24mg/m2. Up to 6 cycles (21 days per cycle)<br>Drug: Irinotecan<br>* 50mg/ m2，d1-5, 21 days per cycle<br>Drug: Vincristine<br>* Vincristine 1.5mg/ m2，d1 , 21 days per cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose | To investigate the safety and preliminary antitumor efficacy | Up to 21 days | 
| peak time (Tmax) | To evaluate the pharmacokinetics of mitoxantrone hydrochloride liposome at different doses in subjects | Up to 18 weeks | 
| Maximum Plasma Concentration (Cmax) | To evaluate the pharmacokinetics of mitoxantrone hydrochloride liposome at different doses in subjects | Up to 18 weeks | 
| Area under the plasma concentration versus time curve (AUC) | To evaluate the pharmacokinetics of mitoxantrone hydrochloride liposome at different doses in subjects | Up to 18 weeks | 
| Elimination half life (t1/2) | To evaluate the pharmacokinetics of mitoxantrone hydrochloride liposome at different doses in subjects | Up to 18 weeks | 
| Incidence and severity of hematological adverse events | To evaluate the incidence and severity of hematological adverse events in patients enrolled in phase Ib | From date of randomization until 4 weeks after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities | To investigate the safety | Up to 21 days | 
| Objective response rate | To investigate the preliminary antitumor efficacy of phase I dose escalation and pharmacokinetics study | Up to 18 weeks | 
| Complete response rate | To investigate the preliminary antitumor efficacy of phase I dose escalation and pharmacokinetics study | Up to 18 weeks | 
| Progression free survival | To investigate the preliminary antitumor efficacy of phase I dose escalation and pharmacokinetics study | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 70 weeks | 
| The incidence and severity of AE and SAE | To identify the incidence and severity of AE and SAE (NCI CTCAE v5.0) | up to 42 weeks unless related serious adverse events need to be recorded indefinitely | 
| Incidence and severity of non-hematological adverse events | The incidence and severity of non-hematological adverse events were evaluated in patients enrolled in Phase Ib | From date of randomization until 4 weeks after the last dose |