A Study of Mitoxantrone Hydrochloride Liposome Injection Combination Therapy in Chinese Patients With Advanced Solid Tumors

The purpose of this study is to evaluate the tolerability, safety, pharmacokinetics (PK) and efficacy of mitoxantrone hydrochloride liposome injection combination therapy in Chinese patients with advanced solid tumors.

This is a multicenter, open-label, phase I dose-escalation and dose-expansion study aimed to evaluate the tolerability, safety, pharmacokinetics and efficacy of mitoxantrone hydrochloride liposome injection combination therapy. This study consists of two phases: dose-escalation phase and dose expansion phase.

The dose-escalation phase will be conducted to determine the maximum tolerated dose (MTD) of mitoxantrone hydrochloride liposome injection combination therapy in patients with advanced solid tumors based on a Rolling-6 design. Patients enrolled in this phase will be allocated to two arms A and B. The patients of A arm will receive mitoxantrone hydrochloride liposome injection and capecitabine followed by a 3-week DLT observation period. The patients of B arm will receive mitoxantrone hydrochloride liposome injection and albumin-paclitaxel followed by a 3-week DLT observation period.

After DLT observation, one dose cohort will be selected for dose-expansion to further explore the safety and efficacy of study drug according to the dose-escalation results. In the dose-expansion phase, patients will receive mitoxantrone hydrochloride liposome injection combination therapy every 3 weeks (q3w, a cycle) until disease progression, intolerable toxicity, death, or withdrawal by investigator or patient decision (a maximum of 6 cycles).

Eligibility Criteria:
Inclusion Criteria:

* Patients fully understand and voluntarily participate in this study and sign informed consent;
* Aged 18-65 years, male or female;
* Patients with advanced solid tumors confirmed by histopathology or cytologically and who have failed standard therapy;
* At least one measurable lesion according to RECIST v1.1 at baseline;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1;
* Adverse events（AEs） from the previous treatment have resolved to ≤ Grade 1 based on CTCAE (except for alopecia, hyperpigmentation and the toxicity without safety risk judged by the investigator);
* Adequate organ function defined as:

  * Absolute neutrophil count (ANC) ≥1.5\*10\^9/L (No Granulocyte Colony Stimulating Factor treatment within 2 weeks prior to the laboratory test);
  * Hemoglobin ≥ 90 g/L (No red blood cell transfusion within 2 weeks prior to the laboratory test);
  * Platelet count ≥ 100\*10\^9/L (No platelet transfusion within 2 weeks prior to the laboratory test);
  * Creatinine ≤1.5 upper limit of normal (ULN);
  * Total bilirubin ≤1.5 ULN;
  * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3ULN, ≤ 5ULN for patients with liver metastases;
  * Coagulation: prothrombin time (PT) and International Normalization Ratio (INR) ≤1.5ULN；
* Female patients must have a urine or blood human chorionic gonadotropin（HCG） negative test before enrolment (except for menopause and hysterectomy); Patients and their partners must agree to use effective contraceptives measures during the study until 6 months after the end of the last dose.

Exclusion Criteria:

* History of severe allergy to mitoxantrone hydrochloride or liposomal drugs; allergy to capecitabine or any excipients of its components; previous serious and unexpected reaction to fluoropyrimidine or known allergy to fluorouracil; known complete deficiency of dihydropyrimidine dehydrogenase (DPD) activity; allergy to paclitaxel or human albumin;
* Cerebral or meningeal metastases;
* Life expectancy \< 3 months;
* Patients with chronic hepatitis B (HBsAg or HBcAb positive with HBV DNA ≥ 2000 IU/mL), chronic hepatitis C (HCV antibody positive with HCV RNA above the lower limit of detection of the study center), or human immunodeficiency virus (HIV) antibody positive;
* Active bacterial, fungal or viral infections that require intravenous infusion treatment within 1 week prior to the first dose;
* Any anticancer treatment within 4 weeks prior to the first dose (e.g., radiotherapy, targeted therapy, immunotherapy, endocrine therapy, etc.); Traditional Chinese medicine or proprietary Chinese medicine with an approved oncology indication within 2 weeks prior to the first dose;
* Enrolled in any other clinical trials within 4 weeks prior to the first dose;
* Patients have undergone major surgery within 3 months prior to the first dose, or have a surgical schedule during the study period;
* Serious thrombosis or thromboembolism as judged by the investigator within 6 months prior to screening;
* History of additional malignant tumor within 3 years, except for locally curable cancer that has been cured, such as basal or squamous cell skin cancer or in situ prostate, cervical or breast cancer;
* Patients with the following cardiac function defects:

  * Long QTc syndrome or QTc interval \> 480 ms;
  * Complete left bundle branch block, II-III degree atrioventricular block (except after pacemaker implantation);
  * Severe, uncontrolled arrhythmias requiring pharmacological treatment;
  * History of chronic congestive heart failure, NYHA grade III\~IV;
  * Cardiac ejection fraction \< 50% within 6 months prior to screening;
  * Severe heart valve disease (regurgitation or stenosis) requiring medical treatment
  * Uncontrollable hypertension (defined as a measured systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg under pharmacological control);
  * ECG evidence of myocardial infarction, unstable angina, history of severe pericardial disease, and acute ischemic or severe conduction system abnormalities within 6 months prior to screening;
* Lactating female;
* Significant gastrointestinal disease during screening, which may affect the intake, transportation or absorption of drugs (such as inability to swallow, chronic diarrhoea, intestinal obstruction, etc.);
* Patients who diagnosed with peripheral nerve dysfunction affect their daily life；
* Serious and/or uncontrolled medical condition that, in the judgment of the investigator, may affect the patient's participation in this study (including, but not limited to: diabetes not effectively controlled, kidney disease requiring dialysis, severe liver disease, life-threatening autoimmune and bleeding disorders, substance abuse, neurological disorders, etc.);
* Not suitable for this study as decided by the investigator due to other reasons.