Retrospective registration

An open, multicenter Phase Ib/IIa study to evaluate the safety, tolerability, pharmacokinetics, and initial efficacy of combination purinostat mesylate for injection in advanced solid tumors

An open, multicenter Phase Ib/IIa study to evaluate the safety, tolerability, pharmacokinetics, and initial efficacy of combination purinostat mesylate for injection in advanced solid tumors

Liangkun Sun 

Herui Yao 

9th Floor, Building E3, Frontier Medical Center,High-tech Zone,Chengdu,Sichuan

33 Yingfeng Road, Haizhu District, Guangzhou City, Guangdong Province

Chengdu Zenitar Biomedical Technology Co., Ltd.

Sun Yat-sen Memorial Hospital,Sun Yat-sen University

Yes

Medical Ethics Committee, Sun Yat-sen Memorial Hospital, Sun Yat-sen University

Liushan Qu

107 Yanjiang Xi Road, Guangzhou City, Guangdong Province

Sun Yat-sen Memorial Hospital,Sun Yat-sen University/West China Hospital of Sichuan University

33 Yingfeng Road, Haizhu District, Guangzhou City, Guangdong Province/No.37, Guoxue Lane, Wuhou District, Chengdu City, Sichuan Province

Self-raised

Advanced solid cancer

Interventional study

N/A

Single arm 

Main objective: Ib phase: 1. To evaluate the safety and tolerability of purinostat mesylate in combination therapy for advanced solid cancer; and to explore the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of purinostat mesylate in combination therapy in patients with advanced solid cancer; 2. To determine the recommended phase II dose (RP2D) of purinostat mesylate in combination therapy for advanced solid cancer. IIa phase: To further evaluate the preliminary efficacy of purinostat mesylate in combination therapy in patients with advanced solid cancer. Secondary Objectives: Ib phase: 1. To evaluate the safety and tolerability of purinostat mesylate monotherapy in treating advanced solid cancer; 2. To evaluate the preliminary efficacy of purinostat mesylate combination therapy in patients with advanced solid cancer; 3. To evaluate the pharmacokinetic characteristics of purinostat mesylate combination therapy in treating advanced solid cancer. IIa phase: 1. To further evaluate the safety and tolerability of purinostat mesylate combination therapy in treating advanced solid cancer; 2. To evaluate the pharmacokinetic characteristics of purinostat mesylate combination therapy in treating advanced solid cancer. Exploratory objective: To evaluate the pharmacodynamic significance of the combination therapy of purinostat mesylate in treating advanced cancer tumors with respect to biomarkers.

1. Age: > =18 years old, and < =75 years old, regardless of gender; 2. At least one measurable lesion defined by RECIST 1.1 in the screening phase (for the breast cancer cohort, non-measurable lesions with bone-only metastases could be accepted in the dose-escalation phase); 3. Phase Ib single-agent dose-escalation phase: (1) Monotherapy A0 cohort (breast cancer): Patients with histologically or cytologically confirmed locally advanced or metastatic breast cancer who have failed standard treatment, have no standard treatment options, or are not suitable for standard treatment at this stage. (2) Monotherapy B0 cohort (solid tumors): Locally advanced or metastatic solid tumors confirmed by histopathology or cytology, and standard treatment fails, or there is no standard treatment plan, or is not suitable for standard treatment at this stage, including but not limited to triple negative breast cancer, colorectal cancer, urothelial cancer, etc. Phase Ib combination dose-escalation phase: (1)Combined fulvestrant therapy cohort A (breast cancer) : 1) perimenopausal, premenopausal, and postmenopausal women with breast cancer confirmed by histopathology or cytology as estrogen receptor (ER) positive, progesterone receptor (PgR) negative or positive, non-HER2-positive (including those with HER2-negative and HER2-low expression); 2) progression or recurrence after receiving at least one previous line of endocrine therapy (whether at advanced stage, metastasis, or neoadjuvant chemotherapy), with no more than two previous lines of chemotherapy; 3) not suitable for surgical resection; 4) Menopause is defined by one of the following: a. Prior bilateral oophorectomy; b. 60 years of age or older; c. Less than 60 years old, had not received chemotherapy, tamoxifen, toremifene, or ovarian suppression therapy within one year before enrollment, had been naturally menopausal for more than 12 months, and the serum follicle stimulating hormone and estradiol were at postmenopausal levels; d. Younger than 60 years of age, being treated with tamoxifen or toremifene, and having serum follicle-stimulating hormone and estradiol levels within the postmenopausal range for two consecutive times; e.. Not meeting the above criteria is considered to be premenopausal or perimenopausal, and female subjects are required to meet the following criteria: Luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin and leuprolide, were started at least 28±2 days before the first dose of the study drug (if the duration of LHRH agonist use was > 21 days and < 26 days before the first dose of the study drug, the hormone level was required to be eligible), and the subjects were required to continue using such drugs during the study treatment; (2) tislelizumab plus cohort B (solid tumors) : Patients with cytologically or histologically confirmed, locally advanced or metastatic solid tumors who have failed standard treatment, who have no standard treatment options, or who are not currently suitable for standard treatment, are defined as follows for each tumor type: 1) Non-small cell lung cancer: a. Metastatic patients without driver mutations: disease progression or relapse after at least second-line therapy, including platinum-based chemotherapy; b. Patients whose tumors have driver mutations such as EGFR, ROS1, or ALK should have disease progression or relapse after failure of targeted therapies targeting these mutations after at least a second line of therapy, including platinum-based chemotherapy; 2) small cell lung cancer: disease progression or relapse after at least second-line therapy; 3) Colorectal cancer: Disease progression or recurrence after at least two previous lines of therapy (standard chemotherapy including fluorouracil or its derivative, oxaliplatin, and irinotecan, BRAF inhibitor for patients with BRAF V600E mutation, or PD-1/PD-L1 for patients with MSI-H/dMMR); 4) head and neck squamous cell carcinoma: disease progression or recurrence after at least previous second-line therapy (including platinum-based chemotherapy); 5) urothelial carcinoma: disease progression or recurrence after at least two previous lines of therapy (guideline-recommended regimens include PD-1/PD-L1 therapy, platinum-based chemotherapy, taxane chemotherapy, vedecitumumab, vflunine, or erlotinib for patients with FGFR2/3 mutations); 6) esophageal cancer: disease progression or recurrence after at least previous second-line therapy (including platinum-based chemotherapy); 7) cervical cancer: disease progression or recurrence after at least two previous lines of therapy (including platinum-based chemotherapy or PD-1/PD-L1 therapy in patients with PD-L1-positive or TMB-H or MSI-H/dMMR) 8) hepatocellular carcinoma: disease progression or recurrence after at least previous second-line therapy; 9) renal cell carcinoma: disease progression or recurrence after at least second-line therapy; Phase IIa dose expansion phase: The inclusion of tumor species and tumor tissue biomarkers in each phase IIa expansion cohort requires that further decisions be made based on phase Ib data and SMC discussion. 4. ECOG <=1; 5, the expected survival time > =12 weeks; 6. Organ function level must meet the following requirements: (1) Absolute neutrophil count (ANC) > =1.5×109/L; (2) hemoglobin (HGB) > =90 g/L; (3) Platelet count (PLT) > =100×109/L; (4) serum creatinine <=1.5×ULN or estimated creatinine clearance > =60 mL/min (according to Cockcroft and Gault formula); (5) Serum total bilirubin (TBil) <=1.5×ULN, subjects with liver metastasis or GILBERT's syndrome were allowed TBil > 1.5×ULN, but direct bilirubin (DBil) < ULN; AST and ALT<=2.5×ULN, AST/ALT<=5×ULN was allowed for subjects with liver metastasis or GILBERT's syndrome; 7. Those who agreed to participate in the study and signed the informed consent form; 8. All acute toxic effects from previous anticancer therapy or surgery resolved to baseline severity or NCI-CTCAE version 5.0<= grade 1 (except for alopecia or other toxicity that was deemed by the investigator to be not a safety risk to the patient).

1. Known severe allergy to the investigational drug, concomitant drugs or any excipient (hydroxypropyl beta-cyclodextrin, arginine, methylamine, mannitol); 2. Currently or previously suffering from other malignancies (except for skin basal cell carcinoma or squamous cell carcinoma that have been fully treated and cervical intraepithelial carcinoma), unless radical treatment has been undergone and there is no evidence of recurrence or metastasis within the past 5 years; 3. Subjects with symptomatic central nervous system (CNS) metastasis or those requiring steroid treatment within 2 weeks before the first administration of the investigational drug, and without symptomatic CNS metastasis. Subjects with carcinomatous meningitis or periventricular leptomeningeal dissemination. 4. Patients whose previous anti-tumor treatment history meets the following conditions should be excluded: (1) Those who received mitomycin C or nitrosourea-based chemotherapy within 6 weeks before the first administration; (2) Those who received systemic anti-tumor treatment within 4 weeks before the first administration, such as chemotherapy, endocrine therapy, immunotherapy, biological therapy, etc.; (3) Those who received clinical trial drug treatment within 4 weeks before the first administration, or are currently participating in other clinical trials; (4) Those who received oral fluorouracil-based drugs or small molecule targeted drugs within 2 weeks before the first administration, or within the 5 half-life periods of the known drugs (whichever is longer); (5) Those who received local palliative radiotherapy within 2 weeks before the first administration; (6) Those who received Chinese herbal medicine or Chinese patent medicine with anti-tumor indications within 2 weeks before the first administration. Note: If the subject received different release periods of drug treatment simultaneously, the actual release period shall be executed according to the longer one. 5. Patients who have received HDAC inhibitors in the past; 6. Patients who have received any estrogen receptor degrading agents, including but not limited to fulvestrant, in the past, cannot be included in the cohort receiving combined treatment with fulvestrant; 7. Patients who have received anti-PD-1/PD-L1 antibody treatment cannot be included in the cohort receiving combined treatment with tislelizumab, unless they have benefited from the treatment in the advanced/metastatic stage* and are thus allowed to be included. *The definition of benefit after anti-PD-1/PD-L1 antibody treatment is as follows: (1) After receiving anti-PD-1/PD-L1 antibody monotherapy or combination therapy with targeted drugs or other immunotherapeutic agents, the best response as assessed by imaging is CR or PR; (2) After receiving anti-PD-1/PD-L1 antibody combined with chemotherapy, there is no imaging evidence suggesting disease progression within ≤ 6 months after treatment. 8. For patients who had severe infections within 4 weeks before the first administration of the investigational product, or who required oral or intravenous antibiotics for active infections within the previous 2 weeks; 9. For patients who received blood transfusion, recombinant human thrombopoietin, recombinant human interleukin-11, erythropoietin, granulocyte colony-stimulating factor, etc. within 2 weeks before the first use of the study drug; 10. For breast cancer patients: those with symptomatic, metastatic, and at risk of developing life-threatening complications within a short period of time in the advanced stage (patients with visceral crises), and patients with inflammatory breast cancer; 11. Patients who had >= 3 grade immune-related adverse events during previous immunotherapy cannot be included in the combination treatment cohort with tislelizumab; 12. Patients with active or previously had and may relapse autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.) cannot be included in the combination treatment cohort with tislelizumab; Patients with the following conditions are allowed to be enrolled: patients with type 1 diabetes and those with autoimmune thyroiditis that can accept alternative treatment; 13. Patients who received systemic corticosteroids (prednisone > 10 mg/day or equivalent doses of similar drugs) or other immunosuppressants within 14 days before the first dose of PM cannot be included in the cohort treated with tislelizumab in combination; except for the following situations: treatment with topical, ocular, intra-articular, nasal and inhalation corticosteroids, short-term use of corticosteroids for prophylaxis, such as use of contrast agents. 14. There are uncontrollable or significant cardiovascular and cerebrovascular diseases, including: (1) Congestive heart failure of NYHA grade II or above, unstable angina pectoris, myocardial infarction within 6 months before the first administration of PM, or arrhythmias requiring treatment at the screening stage, or left ventricular ejection fraction (LVEF) < 50% at the screening stage; (2) Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, undetermined cardiomyopathy); (3) Symptomatic coronary artery disease requiring drug treatment during the screening stage; (4) A history of clinically significant QTcF interval prolongation, or the average corrected QT interval (QTc) > 450 msec (for males) or > 470 msec (for females) obtained from 3 electrocardiogram (ECG) examinations during the screening stage (repeated measurement and taking the average corrected value are required if the QTc > 450 msec (for males) or > 470 msec (for females) is indicated by the first ECG); history of long QT syndrome or confirmed family history of long QT syndrome; a history of clinically significant ventricular arrhythmia, or currently using anti-arrhythmic drugs or having an implanted defibrillator for treating ventricular arrhythmia; (5) A cerebrovascular accident (including cerebral hemorrhage, cerebral infarction, transient ischemic attack, etc.) occurred within 6 months before the first administration of PM; (6) Inadequate blood pressure control during the screening stage (regardless of whether antihypertensive drugs are being taken): Systolic blood pressure >=140 mmHg or diastolic blood pressure >= 90 mmHg; (7) Other cardiovascular and cerebrovascular diseases judged by the investigator to be unsuitable for inclusion. 15. Uncontrollable electrolyte imbalance may affect the prolongation of the QTc effect of the drug (such as hypocalcemia < 1.0 mmol/L, hypokalemia < lower limit of normal value, hypomagnesemia < 0.5 mmol/L), but retesting can be conducted after intervention treatment; 16. Currently suffering from or having a history of any interstitial lung disease with severe severity and/or severely impaired pulmonary function; 17. There is third-space effusion that cannot be controlled by drainage or other methods (such as pleural effusion and ascites); 18. PM was administered within 4 weeks before the first administration and the patient had undergone major surgery requiring general anesthesia or had not withdrawn from other clinical trials; within 2 weeks before enrollment, the patient had undergone surgery requiring local anesthesia/electroanesthesia and had not recovered (excluding tissue biopsy); 19. There are clinically significant active infections, including hepatitis B (HBV) and hepatitis C (HCV). Active hepatitis B is defined as: subjects with positive HBsAg or HBcAb and HBV-DNA above the detection limit (i.e., the upper limit of normal value of the laboratory department of each research center), if HBV-DNA becomes negative after antiviral treatment and they have received at least 2 weeks of antiviral drug treatment before the first administration, and are willing to continue antiviral treatment during the study period, they are allowed to enroll; active hepatitis C is defined as HCV antibody positive and HCV-RNA above the detection limit (upper limit of normal value). Positive Treponema pallidum antibody (TP-Ab) and positive non-specific antibody titer of syphilis; 20. History of immunodeficiency disease, including positive human immunodeficiency virus (HIV) antibody test, or having other acquired or congenital immune deficiency diseases, or having a history of organ transplantation; 21. Participated in other interventional clinical trials within 4 weeks before enrollment; 22. Pregnant or lactating female patients or those who cannot ensure the use of contraception measures during the study period and at least 6 months after the last treatment with puristisib within the study period; 23. Other severe acute or chronic medical or mental disorders or laboratory test abnormalities that may increase the risk of participating in the study or increase the risk of drug administration related to the study drug, or interfere with the study results, and other situations that the investigator considers that the patient is not suitable to participate in this study.

None

https://edc08.emedyun.com/ ,January 2027.

CRF and EDC