Clinical trial NCT05105464: A Study to Investigate the Safety of SYHA1815 in Subjects With Unresectable Locally Advanced or Metastatic Solid Tumors
Official title: A Multi-center, Open-label, Dose Escalation and Expansion, Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) Characteristic of SYHA1815 in Subjects With Unresectable Locally Advanced or Metastatic Solid Tumors
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Locally Advanced Unresectable Carcinoma
Keywords: Locally advanced unresectable or metastatic solid tumors
Lead sponsor: Shanghai Runshi Pharmaceutical Technology Co., Ltd
Sponsor class: INDUSTRY
Collaborators: name: Jilin Provincial Tumor Hospital
First posted: 2021-11-03
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a multi-center, open-label, dose escalation and expansion, phase I study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) characteristics, preliminary efficacy of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors. Once the expected effective dose is identified, the dose expansion study will be started to further evaluate the safety, clinical activity and PK profile of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors.

Detailed description: This is a multi-center, open-label, dose escalation and expansion, phase I study to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) characteristics, preliminary efficacy of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors. The dose escalation study will include six dose cohorts starting at 2 mg/day. Once the expected effective dose is identified, the dose expansion study will be started to further evaluate the safety, clinical activity and PK profile of SYHA1815 in subjects with unresectable locally advanced or metastatic solid tumors.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects aged 18 to 75 years (inclusive)；
* Histologically or cytologically confirmed diagnosis of unresectable locally advanced or metastatic solid tumors (thyroid cancer, non-small cell lung cancer, gastric cancer \[including gastroesophageal junction cancer\], colorectal cancer, pancreatic cancer, soft tissue sarcoma, etc.), failure of standard treatment (disease progression or intolerance), or no alternative standard treatment or refusal of standard treatment;
* The subjects included in the dose expansion study should provide written biomarker test reports or tumor tissue samples to the central laboratory;
* The time interval between the last dose of anti-tumor drug and the first administration of SHYA1815 must meet the following conditions: ≥ 4 weeks for cytotoxic drugs, PD-1 / PD-L1, cellular immunotherapy; ≥2 weeks for oral molecular targeted drug therapy; ≥4 weeks for radiotherapy (≥ 2 weeks for palliative local radiotherapy for pain relief), and had recovered from the toxicities of radiotherapy; ≥2 weeks for anticancer Traditional Chinese medicine or Chinese patent medicine;
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
* Life expectancy ≥ 12 weeks;
* At least one measurable lesion according to RECIST 1.1 at the screening phase;
* The organ function level and related laboratory values of the subjects must meet the following requirements within 7 days before the first dose of study drug (not receiving blood transfusion within 14 days before the first administration):

  1. Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; Platelet count ≥ 75 × 10\^9/L /L; Hemoglobin ≥ 90 g / L; the values of blood phosphorus and calcium are in normal range;
  2. Blood biochemistry: serum total bilirubin ≤ 1.5× upper limit of normal value (ULN); AST / ALT ≤ 3 ×ULN (≤ 5 ×ULN for liver metastasis); Serum creatinine ≤ 1.5 × ULN;
  3. Coagulation: Internationally standardized ratio (INR) or prothrombin time (PT) ≤ 1.5×ULN, activated partial thrombin time (APTT) ≤ 1.5×ULN;
* For women of childbearing potential: the serum pregnancy test within 7 days before the first administration must be negative, and female subjects are willing to take adequate contraceptive measures during the treatment period and for at least 3 months after the last dose of the study drug. Male subjects must agree to take contraceptive measures (non-drug or instrumental contraception) from the beginning of the study to at least 3 months after the last dose of study drug;
* Voluntarily participate in the study and sign the informed consent form.

Exclusion Criteria:

* The previous anti-tumor or surgical treatment history with any of the following conditions:

  1. Received the treatment of other intervention clinical studies with 4 weeks before the first dose of study drug;
  2. Had undergone major surgery within 4 weeks before the first dose of study drug or had not fully recovered from any previous invasive operation;
  3. Prior treatment of RET/FGFR inhibitors or small molecular kinase inhibitors with RET/FGFR as the main targets;
* Any unresolved toxicities from prior anti-tumor therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1, except for alopecia, pigmentation, previous chemotherapy-related neurotoxicity (≤ grade 2) and other adverse reactions judged no safety risk by the investigators;
* Subjects with symptomatic brain metastasis or meningeal metastasis, spinal cord compression or mental disorder, and asymptomatic brain metastasis can be enrolled (there is no disease progress within at least 4 weeks after radiotherapy and/or no neurological symptoms after surgical resection, and glucocorticoids, anticonvulsant drugs and mannitol are not required);
* Impaired cardiac function or clinically significant cardiovascular and cerebrovascular diseases, including any of the following:

  1. History of myocardial infarction, congestive heart failure (NYHA grade ≥ grade III), and unstable angina pectoris within 6 months prior to screening;
  2. Cerebrovascular disease occurred within 6 months before screening (except for transient ischemic attack (TIA), lacunar infarction with no clinical significance);
  3. Severe uncontrollable arrhythmia requiring medical treatment;
  4. Electrocardiogram (ECG) examination, female QTc interval\>470 milliseconds (ms), male QTc interval\>450 milliseconds (ms) according to Fridericia formula;
  5. The left ventricular ejection fraction is less than 50% according to cardiac ultrasound examination;
* History of active bleeding within 6 months before screening;
* Any serious or uncontrollable disease, and not suitable for this study as determined by the investigator;
* Any uncontrollable active infection that will prevent the subjects from receiving the study drug within 2 weeks prior to the first dose of study drug;
* HIV positive, HCV positive with HCV RNA quantity higher than the upper limit of normal value in the research center;
* Active hepatitis B infection, with the HBV DNA quantity higher than the upper limit of normal value of the research center;
* A history of any other malignant tumors within 5 years (except for effectively controlled non-melanoma skin basal cell carcinoma, cervical carcinoma in situ, and other malignant tumors that have been effectively controlled without treatment in the past 5 years;
* Subjects who have taken potent inhibitors and inducers of CYP3A4 liver metabolic enzymes within 2 weeks before the first administration and still need to continue to use such drugs;
* Women who are breastfeeding;
* Concomitant disease or condition that may interfere with the conduct of the trial, or that would pose an unacceptable risk to the subject in this trial in the opinion of the investigator.

Primary outcomes:
measure: Number of participants with Dose-limiting Toxicities
timeFrame: Baseline through 28 days after the first dose of study drug
measure: Incidence of adverse events and SAEs
timeFrame: Up to 3 years
measure: Clinically significant changes from baseline in routine blood test
timeFrame: Up to 3 years
measure: Clinically significant changes from baseline in blood biochemistry test
timeFrame: Up to 3 years
measure: Clinically significant changes from baseline in routine urine test
timeFrame: Up to 3 years
measure: Clinically significant changes from baseline in coagulation function test
timeFrame: Up to 3 years
measure: Clinically significant changes from baseline in 12-lead electrocardiogram (ECG)
timeFrame: Up to 3 years
measure: Clinically significant changes from baseline in vital signs examination
timeFrame: Up to 3 years
measure: Clinically significant changes from baseline in physical examination
timeFrame: Up to 3 years
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to 3 years
measure: Disease control rate (DCR)
timeFrame: Up to 3 years
measure: Duration of response (DOR)
timeFrame: Up to 3 years
measure: Progression free survival (PFS)
timeFrame: Up to 3 years
measure: Time to maximum plasma concentration (Tmax)
timeFrame: Up to 3 years
measure: Maximum Plasma Concentration (Cmax)
timeFrame: Up to 3 years
measure: Plasma half-life (T1/2)
timeFrame: Up to 3 years
measure: Area under the plasma concentration-time curve from time 0 to time t (AUC0-t)
timeFrame: Up to 3 years
measure: Area under the plasma concentration-time curve from time 0 to infinity (AUCinf)
timeFrame: Up to 3 years
measure: Terminal disposition rate constant (λz)
timeFrame: Up to 3 years
measure: Apparent total clearance of the drug from plasma after oral administration (CL/F)
timeFrame: Up to 3 years
measure: Apparent volume of distribution during terminal phase after non-intravenous administration (Vz/F)
timeFrame: Up to 3 years
measure: Change from baseline in serum phosphate
timeFrame: Up to 3 years
measure: Serum carcinoembryonic antigen (CEA)
timeFrame: Up to 3 years
measure: Calcitonin (thyroid cancer detection only)
timeFrame: Up to 3 years
measure: Fibroblast growth factor 23 (FGF23)
timeFrame: Up to 3 years
measure: Vascular endothelial growth factor receptor 2 (sVEGFR2)
timeFrame: Up to 3 years
measure: Potential population who benefit from the study drug
timeFrame: Up to 3 years
measure: Correlation between the changes of RET/FGFR gene and efficacy
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
Study officials:
affiliation: CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd
name: Huang Yanli, PD
role: STUDY_DIRECTOR
References: