Paclitaxel (Albumin-bound) and Oxaliplatin for Advanced Hepatobiliary and Malignant Tumors
Paclitaxel (Albumin-bound) and Oxaliplatin for Advanced Hepatobiliary and Malignant Tumors
1. Advantages of albumin-bound paclitaxel Paclitaxel for injection (albumin-binding type)
 uses human serum albumin (HAS) as a carrier, and paclitaxel and HSA are made into
 paclitaxel-bound albumin nanoparticles by a high-pressure homogenization technique. After
 injection of paclitaxel (albumin-binding) into the blood, it rapidly disintegrates and
 disperses into a smaller albumin-paclitaxel complex, which binds and activates the gp60
 albumin receptor on vascular endothelial cells, interacts with Caveolin on the cell membrane,
 and then is transported to the tumor intercellular substance by transcytosis. Tumor cells can
 secrete a SPARC protein with a specific affinity for albumin, which actively captures the
 albumin-paclitaxel complex in the tumor stroma and accumulates around the tumor cells. Since
 tumor neovascular endothelial cells highly express gp60 receptor and the SPARC protein is
 also highly expressed in the tumor region, the special transport mechanism of "gp60- Caveolin
 / caveola -SPARC protein" makes the paclitaxel for injection (albumin binding) have unique
 targeting and penetrating properties toward tumor tissues, hence the drug is highly
 concentrated in the tumor tissue, which can better increase the therapeutic effect and reduce
 the damage to normal tissues.

 Paclitaxel for injection (albumin-binding type) has the following advantages: (1) it is
 unnecessary to pre-administer anti-allergic drugs, the infusion time is within 30 min, and
 patients have good compliance; (2) due to its higher safety, the dosage can be given as high
 as 260-300 mg/m2; (3) it makes full use of gp60 / cysteine acid secretory protein (SPARC
 protein) channel to make the drug enrich toward the tumor area, and the effect is good; (4)
 as the dosage is within 80 ~ 300 mg/m2, the AUC increase proportionally with the administered
 dose, ]the body is linearly metabolized., the half-life period does not prolong with the
 dose, and the clinical medication is safe and controllable. Currently, the drug has been
 approved for breast cancer treatment in China; approved by the US Food and Drug
 Administration (FDA) for breast cancer, lung cancer, and pancreatic cancer treatment;
 approved for gastric cancer treatment in Japan; and NCCN guidelines recommend it for the
 treatment of intrahepatic cholangiocarcinoma, melanoma, ovarian cancer, and cervical cancer.

 In summary, based on the biological advantages of albumin-binding paclitaxel such as
 high-distribution, high-dose, high-efficiency, and low-toxicity, the reported good clinical
 benefit and safety for hepatobiliary and malignant tumors, and the limited data about
 albumin-bound paclitaxel + oxaliplatin as the first-line treatment for advanced hepatobiliary
 and pancreatic malignancies, especially in Chinese patients, our center believes that is
 feasible and necessary to explore the effectiveness and safety of paclitaxel for injection
 (albumin-binding) combined with oxaliplatin as the first-line drugs for treatment of advanced
 oxaliplatin-based malignant tumors.

 2 Purposes To evaluate the efficacy and safety of paclitaxel (albumin-bound) combined with
 oxaliplatin as the first-line drugs for treatment of advanced hepatobiliary and malignant
 tumors.

 Primary endpoint: progression-free survival (PFS) Secondary study endpoints: disease control
 rate (DCR), overall survival (OS), and incidence and severity of adverse events (AE).

 3 Research plan 3.1 Research Design This study was a single-center, one-arm, phase II/III
 clinical trial, which plans to recruit 57 patients.
Inclusion Criteria:

 -  1) Patients are ≥ 18 years old; 2) Pathological diagnosis confirmed advanced
 hepatocellular carcinoma, intrahepatic cholangiocellular carcinoma, extrahepatic
 cholangiocellular carcinoma, gallbladder carcinoma and pancreatic cancer by
 histopathological examination; 3) Having at least one measurable lesion according to
 the RECIST 1.1 tumor evaluation criteria; 4) Estimated survival time > 3 months; 5)
 There are no other concurrent anti-cancer treatments (including local radiotherapy and
 molecular targeted therapy, etc.) or previous treatment history; 6) ECOG PS score ≤ 2
 points; 7) Cardiac color Doppler examination indicates a left ventricular ejection
 fraction (LVEF) ≥ 50%; 8) Having no obvious signs of hematological disease,
 ANC≥1.5×109/L, platelet count≥100×109/L, Hb≥90g/L, WBC≥3.0×109/L, and no bleeding
 tendency before enrollment; 9) Liver function test: total bilirubin (TBIL) is ≤ 1.5
 times the upper limit of normal value, alanine aminotransferase (ALT), aspartate
 aminotransferase (AST) are ≤ 2.5 times the upper limit of normal value; renal function
 test: serum creatinine (Cr) ≤ 1.5mg/dl, or calculated creatinine clearance ≥50ml/min;
 10) Patients can understand and sign the informed consent form.

 Exclusion Criteria:

 -  1) Pregnant or lactating female patients (women of childbearing age must be confirmed
 to have negative pregnancy test results within 7 days prior to the first dose, if they
 are positive, ultrasound examination is required to be performed to exclude
 pregnancy); women of childbearing age refuse to receive contraception.

 2) Having other malignant tumors, except cured basal cell carcinoma of the skin or
 squamous cell carcinoma of the skin or in situ carcinoma in any other regions; 3)
 Having abnormal bone marrow hyperplasia and other hematopoietic disorders; 4) Having
 active infections, HIV infection, and viral hepatitis that require systemic treatment;
 5) Child-Pugh score > 7 points; 6) Being combined with medium-large ascites or hepatic
 encephalopathy; 7) Subjects with ≥1 peripheral neuropathy according to the National
 Cancer Institute Common Toxicity Response Standard (NCI-CTC) version 5.0; 8)Patients
 with severe cardiovascular diseases such as cerebrovascular accidents occurring within
 6 months, myocardial infarction, hypertension that cannot be controlled after drug
 intervention, unstable angina pectoris, heart failure (NYHA 2-4), and arrhythmia
 requiring drugs intervention; 9) Being allergic to the drug or drug ingredients used
 in this test or having hypersensitivity history; 10) Having received any other drug
 treatment or participated in another interventional clinical trial within 30 days of
 the screening period; 11) Having dementia, mental state changes or any mental illness
 that may interfere with understanding or making informed consent or completing a
 questionnaire; 12) Being considered to be unsuitable for enrollment by investigators.