Clinical trial NCT05728541: Dose Escalation and Expansion Study of SYH2043 in Patients With Advanced Malignant Tumors
Official title: A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile and Preliminary Efficacy of SYH2043 in Patients With Advanced Malignant Tumors
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Advanced Malignant Tumors
Lead sponsor: CSPC Ouyi Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2023-02-15
Enrollment: 367
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of this study is designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of SYH2043 in patients with advanced malignant tumors.

Detailed description: This study is an open-label, single-arm, multi-center Phase I clinical study, which includes four stages:

A: Dose-escalation Stage: The dose escalation stage is divided into 5 dose levels, and a Bayesian Optimal Interval Design (BOIN) including accelerated titration will be used for dose escalation.

B: PK Expansion Stage: Two or three dose groups will be selected for PK expansion; After PK extension the cohort extension study will be conducted as required, and will include 4 cohorts according to the tumor types.

C: Combination dose Escalation: This study will use a 3+3 design with up to 2 dose escalation cohorts at increasing levels.

D: According to the results of stage C, 1-2 combination doses will be selected for combination dose expansion, and Simon 2 stage was adopted for the expansion stage.

Eligibility criteria: Inclusion Criteria:

* 1. Patients aged 18-75 years (inclusive);
* 2. Histological or cytological confirmation of advanced malignant tumors;
* 3. Patients who failed or were intolerant to standard treatment or had no standard treatment, and meet the criteria as below of the corresponding stages:

  * Part A and PK Expansion Stage of part B: advanced malignant tumors;
  * Cohort extension of part B: solid tumors such as locally advanced/metastatic breast cancer, relapsed/refractory ovarian cancer, locally advanced/metastatic liver cancer, etc;
  * Part C and D: locally advanced/metastatic breast cancer with histological confirmation of ER+, HER2-;
* 4. With at least one measurable lesion according to RECIST v1.1;
* 5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1;
* 6. Life expectancy greater than 3 months;
* 7. Main organs meet the following criteria within 7 days before treatment:

  * Hematology: no component blood transfusion, human granulocyte colony-stimulating factor (G-CSF), and erythropoietin (EPO) within 2 weeks prior to the investigational drug administration
  * Absolute neutrophil count (ANC) ≥1.5×10\^9/L;
  * Platelet count (PLT) ≥90×10\^9/L;
  * Hemoglobin (HGB) ≥90 g/L or ≥5.6 mmol/L;
  * Renal Function: Serum creatinine ≤ 1.5×ULN or creatinine clearance rate ≥ 50 mL/min;
  * Liver function: Total bilirubin (TBIL) ≤ 1.5×ULN, or ≤ 3×ULN for patients with Gilbert syndrome; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤ 2.5×ULN, or ≤ 5×ULN in case of liver metastases;
  * Coagulation Function: Activated partial thromboplastin time (APTT)≤ 2×ULN; International normalized ratio (INR)≤ 2×ULN;
* 8. The serum pregnancy test for women of childbearing potential (WOCBP) is negative within 7 days prior to the first dose of the investigational drug. Patient and his/her spouse must agree to take adequate contraception from signing of ICF to 6 months after the last dose, during which women should be non-lactating and men should refrain from donating sperms;
* 9. Patients voluntarily participate in this clinical study, understand the study procedures and sign the ICF.

Exclusion Criteria:

* 1. Have received anti-tumor treatments such as chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, etc. within 4 weeks before the first dose of the investigational drug;
* 2. Have received other unmarketed clinical investigational drugs or treatments within 4 weeks before the first dose of the investigational drug;
* 3. Have received major surgery (excluding needle biopsy), or severe unhealed wounds, trauma, etc. within 4 weeks before the first dose of the investigational drug in the study;
* 4. Have received glucocorticoids for systemic therapy over 7 days (Prednisone\>10 mg/day or equivalent doses) or other immunosuppressant within 2 weeks before the first dose of investigational drug, and patients who need long-term use these therapies;
* 5. Have received potent inhibitors or inducers of CYP3A4 and inhibitors of P-gp within 1 weeks before the first dose of the investigational drug;
* 6. The adverse events due to previous anti-tumor treatments without recovering to Grade 1 (except for alopecia; some toxicities may be excluded as judged by the investigator) according to NCI-CTCAE v5.0;
* 7. Breast cancer patients with visceral crisis or symptomatic visceral metastasis;
* 8. With active central nervous system (CNS) metastasis and/or cancerous meningitis;
* 9. Active HBV or HCV infection (HbsAg positive and/or HBcAb positive with HBV DNA ≥ 2000 IU/mL, and HCVAb positive with HCV RNA positive), or HIV positive;
* 10. Participants with a history of severe cardiovascular disease;
* 11. Inability to swallow medications orally, or conditions that, in the judgment of the investigator, significantly affect gastrointestinal absorption;
* 12. Patients who have received a live attenuated vaccine within 2 weeks before the first use of the investigational drug or plan to receive during the study;
* 13. Other situations that the investigator considers not suitable for participating in the clinical study.

Primary outcomes:
measure: AE
timeFrame: Up to approximately 3 years
measure: SAE
timeFrame: Up to approximately 3 years
measure: DLT
timeFrame: At the end of Cycle 1 (each cycle is 28 days)
measure: MTD
timeFrame: At the end of Cycle 1 (each cycle is 28 days)
measure: RP2D
timeFrame: At the end of Stage A (approximately 1 year)
Secondary outcomes:
measure: AUC
timeFrame: Up to approximately 3 years
measure: Cmax
timeFrame: Up to approximately 3 years
measure: t1/2
timeFrame: Up to approximately 3 years
measure: Tmax
timeFrame: Up to approximately 3 years
measure: Vz/F
timeFrame: Up to approximately 3 years
measure: CL/F
timeFrame: Up to approximately 3 years
measure: pRb
timeFrame: Up to approximately 3 years
measure: ORR
timeFrame: Up to approximately 3 years
measure: PFS
timeFrame: Up to approximately 3 years
measure: OS
timeFrame: Up to approximately 3 years
measure: DoR
timeFrame: Up to approximately 3 years
measure: DCR
timeFrame: Up to approximately 3 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: Cancer Hospital Chinese Academy of Medical Sciences
state: Beijing
Study officials:
References: