Chiauranib for Advanced Solid Malignant Tumors and Relapsed/Refractory SCLC.

Study Overview
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Brief Summary
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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
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Phase 1b: Patients with advanced solid malignant tumor (including SCLC, NSCLC, colorectal carcinoma, hepatocellular carcinoma, ovarian cancer, neuroendocrine tumors, non-Hodgkin's lymphoma, or etc.) that has relapsed from or is refractory to standard therapy or for which no standard therapy exists will be enrolled in three cohorts (35 mg, 50 mg, and 65 mg). 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. The 50 mg dose cohort will not enroll until the 35 mg is deemed safe. The same for the 65 mg dose cohort, it will not enroll until the 50 mg is deemed safe. Each dose cohort will enroll at least 3 patients. Each patient 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 patients enrolled in this stage. Patients will take the RP2D chiauranib once daily for 28-day cycles continuously with no interruption between cycles.

Official Title
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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

Conditions
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Small-cell Lung Cancer, Advanced Solid Malignant Tumor

Intervention / Treatment
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* Drug: Chiauranib


Participation Criteria
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Eligibility Criteria
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Phase 1b 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, hepatocellular carcinoma, ovarian cancer, neuroendocrine tumors, non-Hodgkin's lymphoma, or etc.) 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 screening. Major organ functions meet the following criteria (no corrective treatment, such as G CSF, erythropoietin, and blood transfusion, within 2 weeks before screening): 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) <1.5. 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. Male patients must be willing and able to use male condoms and their female partners who are WOCBP during the entire study treatment and for the 12 weeks after the last dose of the study drug. 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 screening 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 screening. Patient has current or a history of other malignant tumors. This criterion does not apply to patients who have had basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ of cervix that was adequately treated or patients who received radical therapy and have no evidence of recurrence and metastasis within the past 5 years. 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, or arrhythmia requiring 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 (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 screening, is currently on anticoagulant treatment (patients on prophylactic anticoagulants may be enrolled), or has definite predisposition to gastrointestinal bleeding as determined by the investigator (e.g., esophageal varix associated with bleeding risk, local active ulcer lesions). Patient has uncontrolled pleural effusion, hydropericardium, or ascites. Patient has active or symptomatic central nervous system (CNS) metastases that require treatment. Patient has a history of deep vein thrombosis or pulmonary embolism within 6 months prior to screening. Patient has an interstitial lung disease (ILD) that requires treatment, such as idiopathic interstitial pneumonia, pulmonary fibrosis, or evidence of ILD in baseline chest computed tomography (CT) or magnetic resonance imaging (MRI). Patient has any current toxicity (except alopecia) of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, Grade 2 or higher caused by previous therapy. Patient has clinically significant gastrointestinal abnormalities that may affect the intake, transport, or absorption of the study drug (e.g., inability to swallow, chronic diarrhea, intestinal obstruction), or has had total gastrectomy, according to the investigator's judgment. Patients has undergone a major surgical operation within 6 weeks prior to screening or a minor surgical operation within 2 weeks prior to screening. A major surgical operation refers to an operation involving general anesthesia but excludes endoscopies for diagnostic purpose or an implantation of vascular access devices. Patient has urine protein ≥2+ by urine routine examination and urine protein ≥1 g/24 h by 24-hour urine protein quantification. Patient has active infections or hepatitis B or hepatitis C infection in active stage, HIV/AIDS, or other serious infectious diseases. Patient has any mental or cognitive impairment that may limit their understanding and implementation of written informed consent and compliance in this study. Patient has previously received treatment with Aurora kinase inhibitors or VEGF/VEGFR inhibitors, such as sorafenib, sunitinib, pazopanib, bevacizumab, regorafenib, axitinib, vandetanib, or dasatinib. Patient has current drug or alcohol abuse disorders that may affect study evaluation, according to the investigator's judgment. Women who are pregnant, planning to become pregnant, lactating, or who have positive pregnancy test results at screening or before the first dose. Patients who are currently taking and have to continue taking strong CYP3A4 inhibitor drugs, such as ketoconazole, itraconazole, clarithromycin, telithromycin, nefazodone, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, as well as strong CYP3A4 inducers, such as rifampin, dexamethasone, carbamazepine, during Phase 1b (dose escalation stage) of the study. Any other conditions that make the patient inappropriate for participation in this study, at the investigator's discretion Phase 2 Inclusion Criteria: Patient is at least 18 years of age, regardless of gender. Patient has a diagnosis of histologically or cytologically confirmed small cell lung cancer (SCLC) and has previously received at least 2 systemic chemotherapy regimens. Patients have previously received local standard of care treatment such as including platinum-based chemotherapy and anti-PD-(L)1 therapy. 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 screening. Major organ functions meet the following criteria (no corrective treatment, such as G CSF, erythropoietin, and blood transfusion, within 2 weeks before screening): Hematology: absolute neutrophil count (ANC) ≥1.5×109/L, platelets ≥100×109/L, hemoglobin ≥90 g/L (9 g/dL). . 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) <1.5. 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. Male patients must be willing and able to use male condoms and their female partners who are WOCBP during the entire study treatment and for the 12 weeks after the last dose of the study drug. 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 screening 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 screening. Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessments of the 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, or 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. Patients with hypertension that cannot be medically controlled to a systolic blood pressure <140 mmHg and a diastolic blood pressure <90 mmHg. . Patient has active hemoptysis, has had active bleeding within 6 months prior to screening, is currently on anticoagulant treatment (patients on prophylactic anticoagulants may be enrolled), or has definite predisposition to gastrointestinal bleeding as determined by the investigator (e.g., esophageal varix associated with bleeding risk, local active ulcer lesions). Patient has uncontrolled pleural effusion, hydropericardium, or ascites. Patient has active or symptomatic central nervous system (CNS) metastases that require treatment. Patient has a history of deep vein thrombosis or pulmonary embolism other serious thrombotic event within 6 months prior to screening. Patient has an interstitial lung disease (ILD) that requires treatment, such as idiopathic interstitial pneumonia, pulmonary fibrosis, or evidence of ILD in baseline chest computed tomography (CT) or magnetic resonance imaging (MRI). Patient has current Gastrointestinal or pulmonary hemorrhage, pneumonia, QTc interval prolongation or Hand-foot syndrome/ Palmoplantar erythrodysesthesia syndrome caused by previous therapy of Grade 2 or higher; or has any other current toxicity caused by previous therapy of Grade 3 or higher of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Patient has clinically significant gastrointestinal abnormalities that may affect the intake, transport, or absorption of the study drug (e.g., inability to swallow, chronic diarrhea, intestinal obstruction), or has had total gastrectomy, according to the investigator's judgment. Patients has undergone a major surgical operation within 6 weeks prior to screening or a minor surgical operation within 2 weeks prior to screening. A major surgical operation refers to an operation involving general anesthesia but excludes endoscopies for diagnostic purpose or an implantation of vascular access devices. Patient has urine protein ≥2+ by urine routine examination and urine protein ≥1 g/24 h by 24-hour urine protein quantification. Patient has active hepatitis B or hepatitis C infection, HIV, or any other serious infectious diseases. Patient has any mental or cognitive impairment that may limit their understanding and implementation of written informed consent and compliance in this study. Patient has previously received treatment with Aurora kinase inhibitors or VEGF/VEGFR inhibitors, such as sorafenib, sunitinib, pazopanib, bevacizumab, regorafenib, axitinib, vandetanib, or dasatinib. Patient has current drug or alcohol abuse disorders that may affect study evaluation, according to the investigator's judgment. Women who are pregnant, planning to become pregnant, lactating, or who have positive pregnancy test results at screening or before the first dose. Patients who are currently taking and have to continue taking strong CYP3A4 inhibitor drugs, such as ketoconazole, itraconazole, clarithromycin, telithromycin, nefazodone, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir, as well as strong CYP3A4 inducers, such as rifampin, dexamethasone, carbamazepine, during Phase 1b (dose escalation stage) of the study. Any other conditions that make the patient inappropriate for participation in this study, at the investigator's discretion.

Ages Eligible for Study
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Minimum Age: 18 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

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35mg, 50 mg and 65 mg once daily)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study arm (35 mg)<br>Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally) | Drug: Chiauranib<br>* Phase 1b: Each patient will undergo both a single-dose period (6 days) and a consecutive-dose (1 cycle of 28 days) period Phase 2: Patients will take the RP2D once daily for 28-day cycles continuously with no interruption between cycles<br>* Other names: CS2164;|
| Experimental: Study arm (50 mg)<br>Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally) | Drug: Chiauranib<br>* Phase 1b: Each patient will undergo both a single-dose period (6 days) and a consecutive-dose (1 cycle of 28 days) period Phase 2: Patients will take the RP2D once daily for 28-day cycles continuously with no interruption between cycles<br>* Other names: CS2164;|
| Experimental: Study arm (65 mg)<br>Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally) | Drug: Chiauranib<br>* Phase 1b: Each patient will undergo both a single-dose period (6 days) and a consecutive-dose (1 cycle of 28 days) period Phase 2: Patients will take the RP2D once daily for 28-day cycles continuously with no interruption between cycles<br>* Other names: CS2164;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) and other safety parameters | Number of patients experienced AEs | Until 30 days after a patient takes the last dose of the study drug | 
| Incidence and characteristics of DLTs | Number of patients experienced any dose limited toxicity | 34 days | 
| MTD and recommended Phase 2 dose (RP2D) | Determination of recommended phase II dose | 34 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to maximum concentration (Tmax) | PK Profile | 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) | PK Profile | 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) | PK Profile | 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) | PK Profile | 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) | PK Profile | 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) | PK Profile | 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) | PK Profile | 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 | PK Profile | 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) | PK Profile | 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) | preliminary efficacy of chiauranib | 6 months | 
| disease control rate (DCR) | preliminary efficacy of chiauranib | 6 months | 
| duration of response (DoR) | preliminary efficacy of chiauranib | 6 months | 
| progression-free survival (PFS) | preliminary efficacy of chiauranib | 6 months | 
| overall survival (OS) | preliminary efficacy of chiauranib | 6 months | 
| Correlation between ATRX gene mutation and efficacy | Efficacy outcomes in patients with ATRX gene mutation and wild-type respectively. | 6 months |