Overview
Primary Objectives Phase Ib To evaluate the safety and tolerability of Purinostat Mesylate in combination therapy for advanced solid tumors; and to explore the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of Purinostat Mesylate in combination therapy in patients with advanced solid tumors.
To determine the recommended Phase II dose (RP2D) of Purinostat Mesylate in combination therapy for advanced solid tumors.
Phase IIa To further evaluate the preliminary efficacy of Purinostat Mesylate in combination therapy in patients with advanced solid tumors.
Secondary Objectives Phase Ib To evaluate the safety and tolerability of Purinostat Mesylate Monotherapy for the treatment of advanced solid tumors; To evaluate the preliminary efficacy of Purinostat Mesylate in combination therapy in patients with advanced solid tumors; To evaluate the pharmacokinetic characteristics of Purinostat Mesylate in combination therapy for the treatment of advanced solid tumors.
Phase IIa To further evaluate the safety and tolerability of Purinostat Mesylate in combination therapy for advanced solid tumors.
To evaluate the pharmacokinetic characteristics of Purinostat Mesylate in combination therapy for advanced solid tumors.
Exploratory Objectives To assess the pharmacodynamic characteristics in Purinostat Mesylate combination therapy for advanced solid tumors.
Eligibility
Inclusion Criteria:
Participants must meet all of the following inclusion criteria:
1. Age: ≥18 years and ≤75 years, regardless of gender.
2. At least one measurable lesion as defined by RECIST 1.1 during the screening period (for the breast cancer cohort in the dose-escalation phase, measurable lesions are not required if the participant has only bone metastases).
3. Phase Ib:
Monotherapy Dose-Escalation Phase:
1. Monotherapy in Cohort A0 (Breast Cancer):
Histologically or cytologically confirmed locally advanced or metastatic breast cancer that has failed standard treatment, for which no standard treatment is available, or for which standard treatment is not suitable at the current stage.
2. Monotherapy in Cohort B0 (Solid Tumors):
Histologically or cytologically confirmed locally advanced or metastatic solid tumors that have failed standard treatment, for which no standard treatment is available, or for which standard treatment is not suitable at the current stage. This includes but is not limited to triple-negative breast cancer, colorectal cancer, and urothelial cancer.
Combination Therapy Dose-Escalation Phase:
1. Combination with Fulvestrant in Cohort A (Breast Cancer):
* Histologically or cytologically confirmed breast cancer in perimenopausal, premenopausal, or postmenopausal women with estrogen receptor (ER)-positive, progesterone receptor (PgR)-negative or positive, and non-HER2-positive (including HER2-negative and low-expression) disease.
* Participants must have progressed or recurred after at least one line of endocrine therapy (regardless of whether it was in the advanced, metastatic, or neoadjuvant chemotherapy setting), with up to two lines of prior chemotherapy allowed.
* Ineligible for surgical resection.
* Definition of menopause must meet one of the following criteria:
1. Previous bilateral oophorectomy;
2. Age 60 years or older;
3. Under 60 years old, with no chemotherapy, tamoxifen, toremifene, or ovarian suppression therapy within the past year, and naturally postmenopausal for more than 12 months with serum follicle-stimulating hormone and estradiol levels in the postmenopausal range;
4. Under 60 years old, currently receiving tamoxifen or toremifene therapy, with serum follicle-stimulating hormone and estradiol levels within the postmenopausal range on two consecutive tests;
5. If the above criteria are not met, the participant is considered premenopausal or perimenopausal. Female participants must meet the following criteria: Initiation of luteinizing hormone-releasing hormone (LHRH) agonists such as goserelin or leuprorelin at least 28±2 days before the first dose of study drug (participants who have already been using LHRH agonists for ≥21 days and \<26 days before the first dose must have hormone levels meeting the criteria), and continued use of such drugs throughout the study treatment period.
2. Combination with Tislelizumab in Cohort B (Solid Tumors):
* Histologically or cytologically confirmed locally advanced or metastatic solid tumors that have failed standard treatment, for which no standard treatment is available, or for which standard treatment is not suitable at the current stage.
* The definition of failure of standard treatment for each tumor type is as follows:
1. Non-small cell lung cancer: Metastatic patients without driver gene mutations: Progression or recurrence after at least second-line treatment (including platinum-based chemotherapy); Patients with tumors harboring EGFR, ROS1, ALK, or other driver gene mutations should have experienced failure of targeted therapy for these mutations and then progressed or recurred after at least second-line treatment (including platinum-based chemotherapy).
2. Small cell lung cancer: Progression or recurrence after at least second-line treatment.
3. Colorectal cancer: Progression or recurrence after at least second-line treatment (standard chemotherapy regimens previously received include fluorouracil or its derivatives, oxaliplatin, and irinotecan. Patients with BRAF V600E mutation should have received BRAF inhibitors. Patients with MSIH/dMMR should have received PD-1/PD-L1 therapy).
4. Head and neck squamous cell carcinoma: Progression or recurrence after at least second-line treatment (including platinum-based chemotherapy).
5. Urothelial cancer: Progression or recurrence after at least second-line treatment (recommended treatment regimens include PD-1/PD-L1 therapy, platinum-based chemotherapy, taxane chemotherapy, Disitamab Vedotin, and vinflunine. Patients with FGFR2/3 mutations should have received erdafitinib).
6. Esophageal cancer: Progression or recurrence after at least second-line treatment (including platinum-based chemotherapy).
7. Cervical cancer: Progression or recurrence after at least second-line treatment (including platinum-based chemotherapy. Patients with PD-L1 positivity, TMB-H, or MSI-H/dMMR should have received PD-1/PD-L1 therapy).
8. Hepatocellular carcinoma: Progression or recurrence after at least second-line treatment.
9. Renal cell carcinoma: Progression or recurrence after at least second-line treatment.
Phase IIa:
The tumor types and biomarker requirements for each expansion cohort in Phase IIa will be further determined based on data from Phase Ib and discussions with the Study Monitoring Committee (SMC).
4\. ECOG performance status ≤1. 5. Life expectancy of ≥12 weeks. 6. Organ function levels must meet the following criteria:
1. Absolute neutrophil count (ANC) ≥1.5×10\^9/L;
2. Hemoglobin (HGB) ≥90 g/L;
3. Platelet count (PLT) ≥100×10\^9/L;
4. Serum creatinine ≤1.5×ULN or estimated creatinine clearance ≥60 mL/min (according to the Cockcroft and Gault formula);
5. Serum total bilirubin (TBil) ≤1.5×ULN. For participants with liver metastases or Gilbert's syndrome, TBil \>1.5×ULN is allowed if direct bilirubin (DBil) is \
