Safety, Tolerability and Pharmacokinetics of Simmiparib in Patients With Malignant Advanced Solid Tumor

Study Overview
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Brief Summary
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Phase I dose escalating trial. Primary objectives of this study are to assess the safety and tolerability of Simmiparib following single and multiple oral doses in patients with advanced solid malignancies, to determine the maximum tolerance dose (MTD) and dose limiting toxicity (DLT), and pharmacokinetic profile. The Secondary objective is to observe the preliminary antitumor effect of Simmiparib.

Detailed Description
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This single-center, nonrandomized, open-label, dose-escalating study. The trial was divided into dose escalation and expansion stages.

Official Title
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A Safety, Tolerability and Pharmacokinetic Study of Single and Repeat Oral Escalating Doses of Simmiparib in Patients With Advanced Malignant Tumors

Conditions
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Malignant Advanced Solid Tumor

Intervention / Treatment
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* Drug: Simmiparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients confirmed with advanced solid tumor based on pathology and/or cytology, considered unresponsive or poorly responsive to standard therapies, no curative therapies or can't tolerate standard therapies; Patients must have measurable disease in accordance with RECIST criteria v. 1.1, at least one lesion that can be accurately measured in CT and MRI at least one dimension ( longest diameter≥10mm; if lymph node, short diameter≥15mm ); Age≥18 and ≤75 years, both men and women, no history of drug abuse and alcohol; Life expectancy≥ 3 months and can be followed for safety and efficiency Received no prior anti-tumor therapies at least within past 4 weeks and no other adjuvant anti-tumor regimen(including steroids mediations ) Have recovered to≤ common terminology criteria of adverse events (CTC-AE) 1 from toxicities of prior therapy Not participated in any clinical trials within 28 days; Not have received treatment of poly-ADP ribose polymerase (PARP) inhibitor; No serious abnormal hematopoiesis function, has adequate cardiac, pulmonic, hepatic and renal function. Blood routine and blood biochemical examination within 2 weeks before enrollment : White blood cell (WBC) ≥4000/mm3, Absolute neutrophil count (ANC) ≥1,500/mm3, Platelets ≥100,000/mm3, Coagulation function ≤ 1.5 times upper limit of normal (ULN), serum creatinine ≤ 1.5 times ULN, Total bilirubin ≤ 1.5 times ULN, Patients without liver metastasis, Aspartate aminotransferase (AST)/alanine aminotransferase (ALT)≤ 2.5 times ULN; Patients with liver metastasis, Aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/≤ 2.5 times ULN, NYHAclass≤Ⅱand Left ventricular ejection fraction ( LVEF)>50%; Virology test: negative HbsAg, HCV, HIV and syphilis Eastern Cooperative Oncology Group(ECOG) performance status ≤2; No history of other malignant tumors, except cervical carcinoma in situ, basal skin cancer or squamous-cell carcinoma that have been cured; No other serious illnesses that are in conflict with this study and significant heart disease and psychosis; Ability to understand and a willingness to sign a written informed consent; Obtaining consent before any operation Exclusion Criteria: Patients with serious medical disease, including, severe cardiopathy, vascular disease, uncontrolled diabetes, uncontrolled hypertension, severe infection , or psychosis, etc.; Patients with primary brain lesion or metastases lesion; Female patient who is pregnant, breast feeding or unwilling to contraception; Patient who received or is receiving any other investigational agents within 4 weeks prior to treatment; Patients, with poor compliance, or based on the opinion of the investigator, should not be enrolled into this study; has not recovered to grade 1 or better from any adverse events related to previous therapy. Neurotoxicity observed in previous antineoplastic therapy has not recovered to grade 1 or below.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simmiparib tablet monotherapy<br>Drug: Simmiparib tablet oral Qd or Bid | Drug: Simmiparib<br>* Simmiparib Tablets, oral administration<br>* Other names: SMOCL-9112;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | The Dose level at which more than 1/6 patients develop a Dose Limiting Toxicity (DLT) | Per doselevel of 3 to 6 patients (When 3-6 patients have completed DLT periods of 4 weeks) | 
| Pharmacokinetic Cmax (maximum concentration) | PK blood collection Before 0:00h and after 0.25h、0.50h、1:00h、1.50h、2:00h、3:00h、4:00h、6:00h、8:00h、10:00h、24:00h、48:00h、72:00h at single dose period. PK blood collection before 0:00h and after 0.25h、0.50、1:00h、1.50h、2:00h、3:00h、4:00h、6:00h、8:00h、10:00h and 12:00h at multiple dose period | At day 1 single dose period, day 8 and 28 multiple dose period day | 
| Pharmacokinetic Tmax (Time of maximum concentration) |  | At day 1 single dose period, day 8 and 28 multiple dose period day | 
| Pharmacokinetics AUC (Area Under the Curve) |  | At day 1 single dose period, day 8 and 28 multiple dose period day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Poly ADP-ribose polymerase (PARP) inhibition measured by PAR assay |  | Up to 4 months | 
| Overall Response Rate (ORR) | ORR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) | Up to 4 months |