Background
Methods/design
Study design
Eligibility criteria
Inclusion criteria | Subjects who must meet all of the following inclusion criteria can be enrolled in this study |
1 | Be voluntarily enrolled in the study with signed informed consent, good compliance. |
2 | Age ≥ 18 years, age ≤ 75 years, regardless of gender. |
3 | Histologically and radiologically proved ES-SCLC according to the Veterans Adminstration Lung Study Group staging. |
4 | According to RECIST1.1 [13], at least one measurable lesion, and can be accurately measured at the baseline, the longest diameter of the baseline period ≥ 10 mm (in the case of lymph nodes, a short diameter ≥ 15 mm is required) without local treatment previously such as irradiation or tissue biopsy during the screening period. The selected measurement method is suitable for repeated measurement accurately, which can be computed tomography (CT) or magnetic resonance scan (MRI). If there is only one measurable suitable lesion, a baseline assessment of the tumor lesion should be performed at least 14 days after the diagnostic biopsy after acceptance as a target lesion. |
5 | Have received standard platinum-based (two of cisplatin, carboplatin or lobaplatin) chemotherapy, and been considered to have disease progression assessed by imaging during the treatment period or within 6 months after the end of the last treatment according to RECIST1.1. |
6 | The Eastern Cooperative Oncology Group (ECOG) physical status score of 0–2 with a minimum expected survival of 12 weeks. |
7 | Peripheral hemogram and liver and kidney function should achieve the following permissible limits (tested within 7 days prior to treatment initiation): White blood cells (WBC) ≥ 3.0 × 109/L or neutrophils (ANC) ≥ 1.5 × 109/L; (a) Hemoglobin (HGB) ≥ 80 g/L; (b) Platelets (PLT) ≥ 80 × 109/L; (c) Hepatic transaminases (AST, ALT) < 2.5 times the high limit of the normal range.; (d) Total bilirubin (TBIL) < 2 times the high limit of the normal range; (e) Creatinine (CREAT) < 1.5 times the high limit of the normal range. |
8 | Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ low limit of normal (50%). |
9 | Women of childbearing age should take appropriate contraceptive measures from the beginning of screening to 3 months after stopping the treatment and should not breastfeed. No risk of pregnancy should be proved by a negative pregnancy test (urine or serum) within 7 days before the start of administration, or one of the following criteria a. Postmenopausal, defined as age ≥ 50, and amenorrhea for at least 12 months after cessation of all exogenous hormone replacement therapy. b. Postmenopausal age ≤ 50, and amenorrheic for 12 months or more after discontinuation of all exogenous hormone therapy, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are within reference values for postmenopause. c. Previous irreversible sterilization, including hysterectomy, bilateral oophorectomy or bilateral salpingo-oophorectomy, not including bilateral tubal ligation. |
10 | Male patients should use barrier contraception (i.e., condoms) from beginning of screening to 3 months after stopping treatment. |
11 | Patients with asymptomatic brain metastases, or controlled brain metastases (clinical symptoms are stable for at least 2 weeks after symptomatic treatment for brain metastases). In addition, patients with prophylactic irradiation of the brain are allowed. |
Exclusion criteria | Subjects are not eligible for enrollment in this study if they met any of the following criteria. |
1 | 1. Have received any of the following treatments: a. Prior treatment with any PARP inhibitor or anti-angiogenic drug including anlotinib, avastin, sorafenib and thalidomide, etc. b. Have undergone major surgery within 4 weeks prior to the first dose. c. Have received more than 30% bone marrow irradiation or has received extensive radiotherapy within 4 weeks prior to the first dose. |
2 | Patients with uncontroled brainmets, or other malignant tumors, except basal cell carcinoma of the skin and carcinoma in situ. |
3 | The presence of significant cavitary lung tumors on imaging (CT or MRI). |
4 | Being treated in another clinical research study or having been treated in another clinical research study within 4 weeks prior to the start of the study. |
5 | Known hypersensitivity to the components of the study drug involved in the study. |
6 | Have received chemotherapy, radiotherapy or other experimental anticancer therapy (other than bisphosphonates) within 4 weeks prior to the first dose: those who have received prior local radiotherapy may be enrolled if the following conditions are met: the radiotherapy ended more than 4 weeks (more than 2 weeks for brain radiotherapy) from the start of study treatment; and the target lesion selected for this study is not in the radiotherapy area; or the target lesion is in the radiotherapy area but has been confirmed progression. |
7 | Patients who have not recovered from antineoplastic therapy-related adverse effects (except alopecia) to NCI-CTCAE ≤ grade 1 after prior systemic antineoplastic therapy. |
8 | Abnormal coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 s or APTT > 1.5 ULN), with prone to bleeding or on thrombolytic or anticoagulant therapy; Note: The use of low-dose heparin for prophylactic purposes (adult daily dose of 0.6 to 1.2 10,000 U) or low-dose aspirin (dosage ≤ 100 mg daily) is accepted for prophylactic purposes. |
9 | Clinically significant hemoptysis (hemoptysis > ½ tablespoon per day) within 3 months prior to enrollment; or clinically significant hemorrhage symptom or prone to bleeding within 4 weeks prior to cohort, such as alimentary tract hemorrhage, hemorrhagic gastric ulcer (including gastrointestinal perforation and/or fistula, but the gastrointestinal perforation or fistula that has been surgically removed may be allowed), fecal occult blood (≥ + +) at baseline, unhealed wounds, ulcers, or fractures. |
10 | Renal insufficiency: urine protein ≥ + + , or 24-h urine protein amount > 1.0 g. |
11 | Patients with poor blood pressure control (systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥ 100 mmHg) after drug therapy. |
12 | Patients with severe cardiovascular disease: grade II or higher myocardial ischemia or myocardial infarction, poorly controlled arrhythmias; grade III-IV cardiac insufficiency by NYHA criteria, or cardiac ultrasound suggestive of left ventricular ejection fraction (LVEF) < 50%. |
13 | The current presence of peripheral neuropathy ≥ CTCAE degree 2, except the cause of trauma. |
14 | Moderate or large uncontrolled plasma cavity effusions (including pleural, ascites, and pericardial effusions) via fluid aspiration, exacerbated chronic obstructive pulmonary disease, and respiratory disease in the active phase of pulmonary infection and/or acute bacterial or fungal infection that should accept intravenous antibiotic therapy. |
15 | There are factors that significantly affect absorption of oral drugs, such as inability to swallow, chronic diarrhea and intestinal obstruction. |
16 | Arterial/venous thrombotic events such as cerebrovascular accidents (including cerebral hemorrhage and cerebral infarction), deep vein thrombosis and pulmonary embolism that occurred within the 6 months prior to cohort. |
17 | Known history of psychotropic substance abuse, alcohol or drug abuse. |
18 | Active hepatitis (hepatitis B: HBsAg positive and HBV DNA ≥ 1 × 104 copies/ml; hepatitis C: HCV RNA positive and abnormal liver function) that cannot be controlled, or the combined infection of hepatitis B and C. |
19 | The positive blood or urine pregnancy result of women within 3 days prior to the first dose. |
20 | Poor compliance in the procedures and requirements of the study. |
21 | Any condition that will endanger patient's life or interference assessment results. |
Withdrawal from the study criteria | |
1 | Withdrawal of informed consent form at any time by the subjects |
2 | Disease progressed assessed by medical imaging or clinical feature. |
3 | A pregnancy event occurs in the subject during the study |
4 | Other reasons that the trial treatment cannot be continued by the investigator The subject have to discontinue drug upon the occurrence of any of the following (including but not limited to) |
Criteria for termination of the study | |
1 | An unintended, significant or unacceptable risk to the subject is identified |
2 | A significant failure of the protocol is discovered during trial execution |
3 | The investigational drug/trial treatment is ineffective, or it is not meaningful to continue the trial |
4 | Extreme difficulty in completing the trial due to serious delays in subject enrollment or frequent protocol deviations |
Intervention
NCI CTCAE 5.0 | Management (after active treatment and observation) | Dose adjustment after the study drug is continued | |
---|---|---|---|
Anlotinib | |||
Abnormal liver function | Grade 1 | Conduct follow-up as planned | 8 mg, qd |
Grade 2 (normal baseline) | Delay dose, strengthen guarantees the liver treatment and close monitoring of liver function once a week till < grade 2 within 2 weeks, and then continue anlotinib at a lower dose level | 8 mg, qod | |
Grade 2 (abnormal baseline) | Strengthen guarantees the liver treatment and close monitoring of liver function once a week, continue anlotinib at an o initial dose | 8 mg, qd | |
Grade 3 | Delay dose, strengthen guarantees the liver treatment and close monitoring of liver function twice a week till < grade 2 within 2 weeks, till < grade 2 within 2 weeks, and then continue anlotinib at a lower dose level | 8 mg, qod | |
Grade 4 | Strengthen guarantees the liver treatment and close monitoring of liver function once/twice a week till < grade 2. Or have reasons for this issue | Discontinue anlotinib | |
Hypertension | SBP 120–139 mmHg or DBP 80–89 mmHg | Closely monitor, continue anlotinib at an initial dose | 8 mg, qd |
Asymptomatic grade 2 hypertension | Continue anlotinib at an initial dose. Start taking antihypertension medication or adjust its dose till blood pressure is effectively controlled (SBP < 140 mmHg or DBP < 90 mmHg) within two weeks, otherwise dose can be reduced as per investigator’s discretion | 8 mg, qd, or dose can be reduced as per investigator’s discretion | |
Symptomatic grade 2 hypertension, or grade 3 hypertension | Discontinue anlotinib, and then start taking antihypertension medication or adjust its dose till blood pressure is effectively controlled within two weeks, continued anlotinib at an initial dose or a lower dose level | 8 mg, qd, or 8 mg, qod as per investigator’s discretion | |
Abnormalities of bleeding and coagulation | Grade 1 | Closely monitor, continue anlotinib at an initial dose | 8 mg, qd |
Grade 2 | Discontinue anlotinib, till AE ≤ 1, and then continue anlotinib at a lower dose | 8 mg, qod | |
≥ Grade 3, or ≥ Grade 2 occurred twice (after discontinue or dose adjustment) | Withdraw from the pilot study | ||
Fluozopalib | |||
Grade 3 hematological toxicity | Grade 3 leukopenia not accompanied by fever | Discontinue fluozopalib till Grade ≤ 2 hematological toxicity, then fluozopalib was continued at an initial dose level | 150 mg twice daily |
While grade 3 hematologic toxicity occurred again, discontinue fluozopalib till grade ≤ 2 hematological toxicity, then fluozopalib was continued at a lower dose level | 100 mg twice daily | ||
While grade 3 hematologic toxicity occurred third time, discontinue fluozopalib till grade ≤ 2 hematological toxicity, then fluozopalib was continued at a much lower dose level | 50 mg twice daily | ||
Grade 3 neutropenia not accompanied by fever | Discontinue fluozopalib till Grade ≤ 2 hematological toxicity, then fluozopalib was continued at an initial dose level | 150 mg twice daily | |
While grade 3 hematologic toxicity occurred again, discontinue fluozopalib till grade ≤ 2 hematological toxicity, then fluozopalib was continued at a lower dose level | 100 mg twice daily | ||
While grade 3 hematologic toxicity occurred third time, discontinue fluozopalib till grade ≤ 2 hematological toxicity, then fluozopalib was continued at a much lower dose level | 50 mg twice daily | ||
Grade 3 neutropenia accompanied by fever | Discontinue fluozopalib till Grade ≤ 2 hematological toxicity, then fluozopalib was continued at a lower dose level | 100 mg twice daily | |
While occurred again, discontinue fluozopalib till grade ≤ 2 hematological toxicity, then fluozopalib was continued at a much lower dose level | 50 mg twice daily | ||
Grade 3 leukopenia or neutropenia accompanied by grade 2 thrombocytopenia/grade 2 anemia | Discontinue fluozopalib till Grade ≤ 2 hematological toxicity, then fluozopalib was continued at a lower dose level | 100 mg twice daily | |
While occurred again, discontinue fluozopalib till grade ≤ 2 hematological toxicity, then fluozopalib was continued at a much lower dose level | 50 mg twice daily | ||
Grade 4 hematological toxicity | Discontinue fluozopalib till Grade ≤ 2 hematological toxicity, then fluozopalib was continued at a lower dose level | 100 mg twice daily | |
While occurred again, discontinue fluozopalib till grade ≤ 2 hematological toxicity, then fluozopalib was continued at a much lower dose level | 50 mg twice daily | ||
Grade 3 non-hematologic toxicity | Discontinue fluozopalib till Grade ≤ 1 hematological toxicity, then fluozopalib was continued at an initial dose level or a lower dose level | 150 mg twice daily or 100 mg twice daily | |
While occurred again, discontinue fluozopalib till grade ≤ 1 hematological toxicity, then fluozopalib was continued at a lower dose level | 100 mg twice daily or 50 mg twice daily | ||
Grade 4 non-hematologic toxicity | Discontinue fluozopalib till Grade ≤ 1 hematological toxicity, then fluozopalib was continued at a lower dose level | 100 mg twice daily | |
While occurred again, discontinue fluozopalib till grade ≤ 1 hematological toxicity, then fluozopalib was continued at a much lower dose level or discontinue | 50 mg twice daily or discontinue |