SCLC: Chiauranib for Relapsed/Refractory Small Cell Lung Cancer
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
Phase 1b:
Patients with SCLC that has relapsed from or is refractory to standard treatment or for which no treatment is available will be enrolled to the 35 mg and 50 mg dose cohorts in this stage. The starting dose is 35 mg and that the 50 mg dose cohort will not enroll until the 35 mg is deemed safe. Patients with progressive SCLC or recurrence after at least 2 previous regimens, including one platinum-based chemotherapy, can be enrolled in any cohort.
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. 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Study arm (35 mg) Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally) |
Drug: Chiauranib
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
Other Names:
|
| Experimental: Study arm (50 mg) Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally |
Drug: Chiauranib
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
Other Names:
|
| Experimental: Study arm (65 mg) Phase 1b: Patients will be enrolled sequentially in 3 dose-escalating cohorts (Chiauranib capsules 35, 50, and 65 mg, orally) |
Drug: Chiauranib
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
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of adverse events (AEs) and other safety parameters [Until 30 days after a patient takes the last dose of the study drug]
Number of patients experienced AEs
- Incidence and characteristics of DLTs [34 days]
Number of patients experienced any dose limited toxicity
- MTD and recommended Phase 2 dose (RP2D) [34 days]
Determination of recommended phase II dose
Secondary Outcome Measures
- 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)]
PK Profile
- 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)]
PK Profile
- 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)]
PK Profile
- 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)]
PK Profile
- 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)]
PK Profile
- 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)]
PK Profile
- 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)]
PK Profile
- 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)]
PK Profile
- 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)]
PK Profile
- Objective response rate (ORR) [6 months]
preliminary efficacy of chiauranib
- disease control rate (DCR) [6 months]
preliminary efficacy of chiauranib
- duration of response (DoR) [6 months]
preliminary efficacy of chiauranib
- progression-free survival (PFS) [6 months]
preliminary efficacy of chiauranib
- overall survival (OS) [6 months]
preliminary efficacy of chiauranib
- Correlation between ATRX gene mutation and efficacy [6 months]
Efficacy outcomes in patients with ATRX gene mutation and wild-type respectively.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patient is 18 to 75 years of age, inclusive, 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 for both Phase 1b and Phase 2 stages. Patients have previously received local standard of care treatment such as including platinum-based chemotherapy and anti-PD-(L)1 therapy.
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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.
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Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 at screening.
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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.
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Coagulation panel: prothrombin time (PT) and international normalized ratio (INR) <1.5.
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Patient has a life expectancy ≥3 months.
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Patient is able to provide voluntary informed consent.
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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.
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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.
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Patient has uncontrolled or significant cardiovascular diseases, including:
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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.
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Primary cardiomyopathies (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, indeterminate cardiomyopathy).
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Clinically significant history of prolonged QTc interval, or QTcF interval >470ms for females or >450 ms for males during screening.
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Coronary heart disease with symptoms requiring medication.
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Patient has hypertension (defined as systolic blood pressure [SBP] ≥140 mmHg, diastolic blood pressure [DBP] ≥80 mmHg). During the dose-expansion stage, a patient can be enrolled if his or her blood pressure is reduced to SBP <140 mmHg and DBP <80 mmHg after treatment with a single antihypertensive agent, but the patient must be monitored and treated for hypertension during entire study.
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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).
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Patient has uncontrolled pleural effusion, hydropericardium, or ascites.
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Patient has active or symptomatic central nervous system (CNS) metastases that require treatment.
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Patient has a history of deep vein thrombosis or pulmonary embolism within 6 months prior to screening.
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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).
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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.
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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.
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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.
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Patient has urine protein ≥2+ by urine routine examination and urine protein ≥1 g/24 h by 24-hour urine protein quantification.
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Patient has active infections or hepatitis B or hepatitis C infection in active stage, HIV/AIDS, or other serious infectious diseases.
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Patient has any mental or cognitive impairment that may limit their understanding and implementation of written informed consent and compliance in this study.
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Patient has previously received treatment with Aurora kinase inhibitors or VEGF/VEGFR inhibitors, such as sorafenib, sunitinib, pazopanib, bevacizumab, regorafenib, axitinib, vandetanib, or dasatinib.
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Patient has current drug or alcohol abuse disorders that may affect study evaluation, according to the investigator's judgment.
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Women who are pregnant, planning to become pregnant, lactating, or who have positive pregnancy test results at screening or before the first dose.
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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.
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Any other conditions that make the patient inappropriate for participation in this study, at the investigator's discretion
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Gabrail Cancer Center Research | Canton | Ohio | United States | 44718 |
Sponsors and Collaborators
- Chipscreen Biosciences, Ltd.
Investigators
- Principal Investigator: Nashat Gabrail, MD, Gabrail Cancer Center Research
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CAR107