A Trial of Y101D in Combination With Gemcitabine and Albumin Paclitaxel in Patients With Advanced Pancreatic Cancer

The Phase Ib/II study is an open-label, single-arm, multicenter trial designed to assess the efficacy and safety of Y101D in combination with Gemcitabine and Albumin Paclitaxel as first-line systemic treatment for advanced pancreatic cancer patients. The Phase Ib portion of the study aims to evaluate the safety of escalating doses of Y101D in combination with the standard regimen of Gemcitabine and Albumin Paclitaxel and determine the recommended phase 2 dose (RP2D). The Phase II portion of the study aims to evaluate the effectiveness of this combination treatment in a small population of patients.

A total of 57-81 systemic treatment-naïve patients with advanced pancreatic cancer will be enrolled in the study. Phase Ib will enroll 12-36 patients to assess the safety of Y101D combined with Gemcitabine and Albumin Paclitaxel at doses of 20mg/kg or 30mg/kg. The recommended phase 2 dose (RP2D) for Y101D in combination with the other drugs will be determined based on the safety profile and preliminary efficacy data.

Following determination of the RP2D, Phase II will enroll a total of 40-45 patients to evaluate the effectiveness of the combination treatment using the RP2D of Y101D. The primary endpoint of the Phase II study will be the objective response rate. Secondary endpoints will include progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety profiles. Pharmacodynamic parameters such as serum tumor biomarkers and TGF-β concentration will also be evaluated.

Overall, the study aims to assess the safety, efficacy, and pharmacodynamics of Y101D in combination with Gemcitabine and Albumin Paclitaxel as a first-line systemic treatment for advanced pancreatic cancer patients.

Eligibility Criteria:
Inclusion Criteria:

* Patients diagnosed with pancreatic cancer (including ductal adenocarcinoma and acinar cell carcinoma) confirmed by histology or cytology; and evidence of unresectable or distant metastasis.
* No prior systemic treatment for advanced/metastatic pancreatic cancer.
* Previous use of anti-tumor Chinese herbal medicine or traditional Chinese medicine preparations, but discontinued use at least 28 days before the first administration of the investigational drug.
* According to RECIST 1.1 criteria, the subject must have at least one measurable target lesion confirmed by CT or MRI examination that has not been locally treated (unless the target lesion has clearly progressed).
* Expected survival time ≥ 12 weeks.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
* According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, any toxicity from previous anti-tumor treatment or surgery must have recovered to grade 0-1 or to the level specified by the inclusion/exclusion criteria. Note: Exclusions include alopecia, pigmentation changes, ≤ grade 2 neuropathy, hypothyroidism due to hormone replacement, or other adverse events confirmed to have become chronic.
* Organ function levels must meet the following requirements:

Hematology: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelets (PLT) ≥ 100 × 109/L, hemoglobin (HGB) ≥ 90g/L (within 14 days before screening without blood transfusion, use of blood products, or correction with granulocyte colony-stimulating factor \[G-CSF\] or other hematopoietic growth factors).

Liver function: Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal, aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times the upper limit of normal (if there is liver metastasis, AST and ALT up to 5 times the upper limit of normal are allowed).

Renal function: Serum creatinine (Cr) ≤ 1.5 times the upper limit of normal or creatinine clearance rate ≥ 50 mL/min (Cockcroft-Gault formula).

Coagulation function: International normalized ratio (INR) ≤ 1.5, prothrombin time (PT), and activated partial thromboplastin time (APTT) ≤ 1.5 times the upper limit of normal.

Exclusion Criteria:

* Patients diagnosed with central nervous system (CNS) metastasis confirmed by imaging.
* Patients with diseases associated with a high risk of clinically significant gastrointestinal bleeding (such as tumor invasion of the gastrointestinal tract or bile ducts) or any other condition or history related to severe bleeding.
* Presence of clinically uncontrollable third-space fluid accumulation before the first administration of the investigational drug, such as pleural effusion, ascites, or pericardial effusion that cannot be controlled by drainage or other methods, as determined by the investigator.
* Underwent major surgery within 4 weeks prior to the first administration of the investigational drug (excluding needle biopsies and tooth extractions).
* Use of immunosuppressive drugs within 7 days prior to the first administration of the investigational drug, excluding nasal and inhaled corticosteroids or physiological doses of systemic corticosteroid hormones
* Significant clinical pancreatitis.
* History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
* Presence of active clinical infection of grade 2 or higher (according to CTCAE v5.0 criteria) at screening, requiring systemic (oral or intravenous) antimicrobial treatment.
* Patients requiring long-term use of steroids or immunosuppressive agents for conditions such as active autoimmune diseases or post-organ transplant maintenance therapy. Exceptions include type 1 diabetes, hypothyroidism that can be controlled by replacement therapy alone, and skin diseases (such as vitiligo, psoriasis, or alopecia) that do not require systemic treatment.
* Severe respiratory system diseases or patients judged by the investigator to be unsuitable for inclusion, or patients with concomitant interstitial pneumonia.
* Average corrected QT interval (QTcF) \>450 msec (males) or \>470 msec (females) based on three electrocardiogram (ECG) examinations during screening (repeat testing and averaging of three measurements are required only if the first ECG indicates QTcF \>450 msec \[males\] or \>470 msec \[females\]). History of long or short QT syndrome in the family or individual, or significant cardiovascular diseases within 6 months before screening.
* History of non-study malignancy (excluding non-invasive lesions with extremely low risk of recurrence, such as squamous cell carcinoma and basal cell carcinoma of the skin, cervical carcinoma in situ, or breast carcinoma in situ) within 5 years prior to the first administration of the investigational drug.
* Active hepatitis B (positive hepatitis B surface antigen \[HBsAg\] or hepatitis B core antibody \[HBcAb\], peripheral blood HBV DNA titers \<500 IU/mL allow inclusion), active hepatitis C, active syphilis, HIV-positive patients.
* Pregnant or lactating women, or individuals with reproductive potential within 6 months after the end of this clinical study, regardless of gender.
* Known history of substance abuse or drug addiction.
* History of clear neurological or psychiatric disorders, as determined by the investigator, that would hinder compliance with treatment or adherence to instructions.