A Phase 1b/2, Single-Arm, Open-Label, Dose-Escalation, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Chiauranib for the Treatment of Advanced Solid Tumors and Relapsed/Refractory SCLC
Overview
- Phase
- Phase 1
- Intervention
- Chiauranib
- Conditions
- Small Cell Lung Cancer
- Sponsor
- Chipscreen Biosciences, Ltd.
- Enrollment
- 36
- Locations
- 11
- Primary Endpoint
- Incidence of adverse events (AEs) and other safety parameters
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a Phase 1b/2, single-arm, open-label, dose-escalation study including 2 stages:
Phase 1b: Dose-Escalation Stage (Single-Dose and Consecutive-Dose Periods)
Phase 2: recommended Phase 2 dose (RP2D) of chiauranib will be given to all patients enrolled in this phase once daily for 28-day cycles continuously with no interruption between cycles.
Detailed Description
Phase 1b: Patients with advanced solid malignant tumor (including SCLC, NSCLC, colorectal carcinoma, pancreatic carcinoma, hepatocellular carcinoma, ovarian cancer, neuroendocrine tumors, non-Hodgkin's lymphoma and others) that has relapsed from or is refractory to standard therapy or for which no standard therapy exists will be enrolled to the 35 mg, 50 mg and 65 mg dose cohorts in this stage. The starting dose is 35 mg, and each higher dose cohort will not enroll until the lower dose is deemed safe. After screening, eligible patients will be enrolled sequentially in 3 dose-escalating cohorts. Based on an estimated average body weight of 60 kg, the initial dose of chiauranib will be 35 mg once daily, and the dose will be escalated to 50 mg and 65 mg once daily, depending on the occurrence and frequency of DLTs. The 3+3 design will be employed in dose escalation decisions. Each dose cohort will enroll at least 3 patients. Overenrolling dosing cohorts is allowed to allow for potential screen failures and/or subjects who end up being not evaluable by not completing the DLT evaluation period. Each subject will undergo both a single-dose period (6 days) and a consecutive-dose (1 cycle of 28 days) period, as described below. DLTs will be evaluated during this period (a total of 34 days). Phase 2: SCLC patients with progressive disease or recurrence after at least 2 previous regimens, including one platinum-based chemotherapy, will be enrolled in this stage. The RP2D will be given to all subjects enrolled in this stage. Subjects will take the RP2D chiauranib once daily for 28-day cycles continuously with no interruption between cycles.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient is at least 18 years of age, regardless of gender. Patient has a diagnosis of histologically or cytologically confirmed advanced solid malignant tumor (including SCLC, NSCLC, colorectal carcinoma, pancreatic carcinoma, hepatocellular carcinoma, ovarian cancer, neuroendocrine tumors, non-Hodgkin's lymphoma, and others) that has relapsed from or is refractory to standard therapy or for which no standard therapy exists.
- •Patient has at least one measurable target lesion as defined by RECIST1.1, i.e., a lesion that has radiologic evidence of disease progression, after treatment with radiotherapy or local-regional therapy.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at enrollment.
- •Major organ functions meet the following criteria (no corrective treatment, such as G CSF, erythropoietin, and blood transfusion, within 2 weeks before enrollment):
- •Hematology: absolute neutrophil count (ANC) ≥1.5×109/L, platelet ≥100×109/L, hemoglobin ≥100 g/L.
- •Biochemistry: total bilirubin ≤1.25×upper limit of normal (ULN), both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5×ULN (≤5×ULN for patients with hepatic metastasis), creatinine clearance \>60 mL/min (according to Cockcroft-Gault equation), fasting triglyceride ≤3.0 mmol/L, fasting total cholesterol ≤7.75 mmol/L.
- •Coagulation panel: international normalized ratio (INR) \<1.
- •Patient has a life expectancy ≥3 months.
- •Patient is able to provide voluntary informed consent.
- •Women of childbearing potential (WOCBP) must be willing and able to take highly effective contraceptive measures during the entire study treatment period and for 12 weeks after the last dose of study drug (see Appendix 11.7). Women of childbearing potential include premenopausal and not sterilized (by hysterectomy, bilateral ligation of fallopian tubes, or bilateral oophorectomy) females who have passed menarche.
Exclusion Criteria
- •Patient has received any systemic anticancer therapy (including chemotherapy, targeted therapy, biological immunotherapy, any investigational drug, or anti-cancer herbal medicine) within 21 days before enrollment, or any blood support therapy (including blood transfusion, blood products, or hematopoiesis stimulating agents such as granulocyte-colony stimulating factor \[G-CSF\]) within 2 weeks before enrollment.
- •a. Patients who are receiving corticosteroids at a dose of \> 10 mg prednisone or equivalent of other systemic steroids will be excluded.
- •Patient with prior or concurrent malignancy whose natural history or treatment has the potential to interfere with safety or efficacy assessment of investigational regimen.
- •Patient has uncontrolled or significant cardiovascular diseases, including:
- •New York Heart Association (NYHA) grade II or higher congestive cardiac failure, unstable angina pectoris, and/or myocardial infarction within the 6 months prior to the first dose of the investigational drug, clinically significant arrhythmia unable to be controlled with medical treatment or left ventricular ejection fraction (LVEF) \< 50% at screening.
- •Primary cardiomyopathies (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, indeterminate cardiomyopathy).
- •Clinically significant history of prolonged QTc interval, or QTcF interval \>470ms for females or \>450 ms for males during screening.
- •Coronary heart disease with symptoms requiring medication.
- •Patient has hypertension at screening (defined as systolic blood pressure \[SBP\] ≥140 mmHg, diastolic blood pressure \[DBP\] ≥90 mmHg). (Patients with a known history of hypertension if blood pressure is considered well controlled on a single anti-hypertensive medication (systolic blood pressure \<140 mmHg and diastolic blood pressure \<90 mmHg at screening) and in whom there has been no change in blood pressure medication for 3 months prior to screening due to poor control.)
- •Patient has active hemoptysis, has had active bleeding within 6 months prior to enrollment, or has definite predisposition to gastrointestinal bleeding as determined by the investigator (e.g., esophageal varix associated with bleeding risk, local active ulcer lesions).
Arms & Interventions
Study arm (35 mg)
Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally)
Intervention: Chiauranib
Study arm (50 mg)
Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally)
Intervention: Chiauranib
Study arm (65 mg)
Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally)
Intervention: Chiauranib
Outcomes
Primary Outcomes
Incidence of adverse events (AEs) and other safety parameters
Time Frame: Until 30 days after a patient takes the last dose of the study drug
Number of patients experienced AEs
Incidence and characteristics of DLTs
Time Frame: 34 days
Number of patients experienced any dose limited toxicity
MTD and recommended Phase 2 dose (RP2D)
Time Frame: 34 days
Determination of recommended phase II dose
Secondary Outcomes
- Time to maximum concentration (Tmax)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Maximum plasma concentration (Cmax)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Area under the plasma concentration-time curve from 0 to infinity (AUC 0-inf)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Half-life (t½)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Trough plasma concentration (Cmin)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Area under the plasma concentration-time curve (AUC0-t)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Oral clearance (CL/F)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- accumulation ratio(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Steady state plasma concentration (Css)(Phase 1b: days 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles. Phase 2: days 1, 14, 28 during Cycle 1; and day 28 in Cycle 2 and all subsequent cycles (all cycles in phase 1b and 2 are 28 days each))
- Objective response rate (ORR)(6 months)
- disease control rate (DCR)(6 months)
- duration of response (DoR)(6 months)
- progression-free survival (PFS)(6 months)
- overall survival (OS)(6 months)
- Correlation between ATRX gene mutation and efficacy(6 months)