A Study to Evaluate the Safety and Efficacy of Docetaxel for Injection (Albumin-bound)in Different Dose Regimens in Patients With Advanced Solid Tumors

Safety, Tolerability, Pharmacokinetics and Preliminary Antitumor Activity of Docetaxel for Injection (Albumin-bound) in Different Dose Regimens in Patients With Advanced Solid Tumors: An Open-label, Multicenter, Phase 1b Study

The aim of this study is designed to evaluate the safety, tolerability, pharmacokinetics and preliminary antitumor activity of docetaxel for injection (albumin-bound) in different dose regimens in patients with advanced solid tumors.

This study will be conducted in two stages. The first stage (Stage I) is a dose-escalation study. A classic 3+3 design will be used to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Patients will receive the docetaxel for injection (albumin-bound) until disease progression, or intolerable toxicity, or other reasons for termination of the study. All dose-escalation decisions will be based on the safety data generated from the current highest dose group.

In the cohort-expansion study (Stage Ⅱ), patients with a potential to have better response to the study drug will be recruited. Patients will receive the docetaxel for injection (albumin-bound) at the recommended phase 2 dose (RP2D) and follow the treatment regimen established in Stage I.

Inclusion Criteria:

1. Patients aged ≥18, ≤75 years (subject to the date when the informed consent form is signed) and voluntarily signed the informed consent form.

2. Histologically or cytologically confirmed diagnosis of advanced or metastatic solid tumors, for which standard therapy either does not exist or has proven to be ineffective, intolerable or unacceptable for the patient.

3. At least one measurable lesion according to RECISTv1.1.

4. Patients with Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.

5. Patients with estimated survival time of ≥ 3 months.

6. Main organ function meets the following criteria within 7 days before treatment (no medical supportive treatments such as blood component transfusion, human granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), interleukin-11, and erythropoietin (EPO) within 2 weeks before baseline examination):

   Absolute neutrophil count ≥1.5×10^9/L; Platelets ≥100×10^9/L; Hemoglobin ≥90 g/L or ≥5.6 mmol/L; Serum creatinine ≤ 1.5×ULN or creatinine clearance rate ≥ 50 mL/min; Liver function: total bilirubin≤ 1.0 × ULN, ≤ 1.5 × ULN for patients with liver metastasis or liver cancer; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN, ≤ 2.5 × ULN for patients with liver metastasis or liver cancer.

7. Fertile patients must use contraceptive measures (such as intrauterine device [IUD], contraceptive pill or condom) during the study period and within 6 months after the end of the study, and men should avoid sperm donation; Women of childbearing age must have negative serum pregnancy test within 7 days before study enrollment, and must be non-lactating women.

Exclusion Criteria:

1. Patients with central nervous system metastasis or meningeal metastasis, accompanied by the following conditions:

1. Patients with clinical symptoms related to central nervous system metastasis or meningeal metastasis;
2. New lesions in the brain or progression of the original lesions on imaging from the end of brain radiotherapy or surgery to the first administration;
3. Central nervous system metastasis with cortical alcohols, radiotherapy, dehydration drugs and other drugs for symptoms control within the last two weeks;
4. Patients has brain stem (midbrain, pons, medulla oblongata) metastasis;
5. Other evidence shows that the patient's central nervous system metastasis or meningeal metastasis has not been controlled, which is not suitable for inclusion according to the judgment of the researcher.

2. Known human immunodeficiency virus (HIV) test positive or known history of acquired immunodeficiency syndrome (AIDS), history of organ transplantation, history of serious autoimmune diseases judged by the researchers to be unsuitable for inclusion.

3. HCV antibody (+) or active hepatitis B (HBsAg positive and HBV DNA > 500 IU/mL) and uncontrolled active infection (those who must receive systematic anti infection treatment, or those with unexplained body temperature > 38 ℃ (axillary temperature) before administration).

4. Patients have a history of serious cardiovascular diseases, including but not limited to:

1. Severe heart rhythm or conduction abnormalities, such as ventricular arrhythmia requiring clinical intervention and third-degree atrioventricular block;
2. History of myocardial infarction, angina pectoris, angioplasty, coronary artery bypass surgery;
3. Patients with prolonged QT/QTc interval (QTcF > 480 ms, Fridericia's formula: QTcF = QT/RR^0.33, RR = 60/heart rate) by ECG during the screening period;
4. left ventricular ejection fraction (LVEF) ≤ 50% by echocardiography (ECHO) or multi-gated acquisition (MUGA) during the screening period;
5. Heart failure with New York Heart Association (NYHA) Classification of Class Ш and above;
6. Poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 95 mmHg despite optimal treatment);
7. Previous or current cardiomyopathy;
8. Patients with severe pulmonary hypertension or a history of pulmonary embolism within 6 months.

5. Patients with a third space effusion (e.g., pleural effusion, ascites, or pericardial effusion) that is difficult to control, who, in the judgment of the investigator, are not suitable for the study.

6. Allergic history to taxane or any excipients of the study drug (CTCAE 5.0 grade ≥ 3 grade).

7. Adverse reactions from the previous anti-tumor treatment have not yet recovered to ≤ level 1 based on CTCAE 5.0 (except for the toxicity without safety risk judged by the investigator, such as alopecia).

8. Patients who have previously received docetaxel containing regimen and progressed during treatment or within 6 months after treatment.

9. Patients who have undergone major organ surgery (excluding puncture biopsy) or significant trauma within 4 weeks before the first dose of the investigational drug, or who need to undergo elective surgery during the study period.

10. The time between the last anti-tumor treatment and the first medication meet the following time interval: anti-tumor treatment such as chemotherapy, radiotherapy (except local radiotherapy for pain relief), targeted therapy, immunotherapy and other clinical research drugs within 4 weeks before the first administration; oral fluorouracils, small molecule targeted drugs and traditional Chinese medicine with anti-tumor indications within 2 weeks before the first administration.

11. Patients who have received corticosteroid (prednisone > 10 mg/day or equivalent) or other immunosuppressive therapies within 2 weeks before the first dose of the investigational drug, except for the following: a. use of topical, ocular, intra-articular, nasal and inhaled glucocorticoids; b. short-term use of glucocorticoids for prophylaxis (such as prevention of contrast agent allergy).

12. Patients who have used potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of the investigational drug.

13. Patients with alcohol or drug dependence. 14. Patients have clear history of neurological or psychiatric disorders, including epilepsy and dementia.

15. The researcher believes that the patient has other reasons that affect the safety or compliance, or is not in the best interests of the subject and is not suitable to participate in this clinical study (for example, eye diseases, venous thrombosis, etc., which affect the safety according to the judgment of the researcher).