Anlotinib Hydrochloride Combined With AP in Stage IIIB/IIIC/IV Non-squamous Non-small-cell Lung Cancer
Condition: Non-squamous Non-small-cell Lung Cancer; Anlotinib
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Anlotinib Hydrochloride
Intervention description: Patients receive pemetrexed with cisplatin/carboplatin once every 3 weeks, and anlotinib (dose escalation) once daily on days 1-14.
Intervention MeSH terms: Cisplatin; Carboplatin; Pemetrexed
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Sequential Assignment
Intervention model description: The initial dose of anlotinib was set as 12 mg/day with a 2-week on/1-week of schedule. The dose was reduced to 10 mg/day and 8 mg/day in sequence depending on observed DLTs in cycle 1.
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      Anlotinib is a novel oral multitarget tyrosine kinase inhibitor and primary targeted to
      VEGFR, FGFR, PDGFR and c-Kit. The ALTER-0303 trial showed that patients with advanced
      non-small cell lung cancer (NSCLC) who received anlotinib as third-line or further therapy
      had more survival benefit. Pemetrexed plus platinum-based chemotherapy (AP) was long
      considered as the first line treatment in non-squamous NSCLC patients with negative driver
      mutation. In this dose exploration study, the primary objective is to establish the safety
      profile of anlotinib combined with AP in non-squamous NSCLC patients by identifying dose
      limiting toxicity (DLT), maximum tolerance dose (MTD), the recommended phase II dose, and
      schedule. Secondary objective includes the assessment of preliminary antitumor effect.
    

Eligibility criteria:

        Inclusion Criteria:

          -  18 Years to 75 Years patients voluntarily participate in this study, signed and dated
             informed consent with good compliance and follow-up;

          -  Diagnosed as locally advanced and / or metastatic non-squamous non-small cell lung
             adenocarcinoma (NSCLC) by cytology or histology; Provide detectable specimens (tissue
             or blood) for genotyping before enrollment, and the patients should be with negative
             EGFR, ALK and ROS1 gene test results, and without prior systemic therapy;

          -  At least one target lesion that has not received radiotherapy, and has accurate
             measurement by magnetic resonance imaging (MRI) or computed tomography (CT)
             (conventional CT≥20 mm or spiral CT≥10 mm) in at least 1 direction;

          -  Life expectancy is at least 3 months;

          -  ECOG PS Scoring: 0~1 point;

          -  The main organs function are normally, the following criteria are met:

               -  Blood routine examination criteria (no blood transfusion and blood products
                  within 14 days, no correction by G-CSF and other hematopoietic stimuli):

                  i) hemoglobin (HB) ≥90g/L ii) neutrophil absolute (ANC) ≥1.5×109/L iii) platelet
                  (PLT) ≥80×109/L

               -  Biochemical tests meet the following criteria i) total bilirubin (TBIL) ≤1.5
                  times of upper limit of normal (ULN); ii) alanine aminotransferase (ALT) and
                  aspartate aminotransferase (AST)≤2.5 ULN, if liver metastasis occurred, ALT and
                  AST ≤5 ULN; iii) serum creatinine (Cr) ≤1.25 ULN or creatinine clearance
                  (CCr)≥45mL/min (Cockcroft-Gault formula).

          -  Female patients of childbearing age agree that contraceptive measures must be used
             within the study period and within 8 weeks after the end of the study drug treatment.
             The serum or urine test indicates unpregnancy within 7 days prior to the study. Male
             patients agree to have contraceptive use during the study period and within 8 weeks
             after the end of the study period or have had surgical sterilization.

        Exclusion Criteria:

          -  Patients with small cell lung cancer (including small cell carcinoma and non-small
             cell carcinoma mixed lung cancer) and lung adenosquamous carcinoma mixed with squamous
             carcinoma;

          -  Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT
             or MRI screening for brain or pia mater disease (a patient with brain metastases who
             have completed treatment and stable symptoms in 21 days before enrollment may be
             enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no
             cerebral hemorrhage symptoms);

          -  Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood
             vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood
             vessel and the distance between tumor and bronchial tree is ≤ 2 cm; or there is a
             significant pulmonary cavity or necrotizing tumor;

          -  Uncontrollable hypertension (systolic blood pressure ≥140 mmHg or diastolic blood
             pressure ≥90 mmHg after optimal medical treatment);

          -  Suffering from severe cardiovascular disease: myocardial ischemia or myocardial
             infarction above grade II, poorly controlled arrhythmias (including men with QTc
             interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV
             Insufficient function, or cardiac color Doppler ultrasound examination indicates left
             ventricular ejection fraction (LVEF) <50%;

          -  Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or
             APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant
             therapy;

          -  Urine routine test protein ≥++, and confirmed 24 hours urine protein> 1.0 g;

          -  There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for trauma;

          -  Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including pleural
             effusion, ascites, pericardial effusion) requiring surgical treatment;

          -  Long-term unhealed wounds or fractures;

          -  Serious infection (≥CTC AE Level 2 infection) requiring systemic antibiotics;
             decompensated diabetes or other ailments treated with high doses of glucocorticoids;

          -  Active or chronic hepatitis C or/and hepatitis B infection;

          -  Factors that have a significant impact on oral drug absorption, such as inability to
             swallow, chronic diarrhea, and intestinal obstruction;

          -  Patients have undergone major surgery within 4 weeks before enrollment or have severe
             trauma, fracture and ulcer;

          -  Severe weight loss (greater than 10%) within 6 weeks prior to enrollment;

          -  Clinically significant hemoptysis (daily hemoptysis greater than 50ml) within 3 months
             prior to enrollment; or significant clinically significant bleeding symptoms or
             defined bleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric
             ulcer, baseline fecal occult blood ++ and above, or suffering from vasculitis;

          -  Events of venous/ arterious thrombosis occurring within the first 12 months prior to
             enrollment, such as cerebrovascular accidents (including transient ischemic attacks,
             cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary
             embolism;

          -  Patients have contraindication to platinum drugs (cisplatin/carboplatin) and cytotoxic
             drug (Pemetrexed);

          -  Patients have anaphylactic reaction due to anlotinib Hydrochloride or the excipient in
             investigational drug.

          -  Patients have anaphylactic reaction due to contrast agent;

          -  Planned for systemic anti-tumor therapy during the study period or within 4 weeks
             prior to enrollment, including cytotoxic therapy, signal transduction inhibitors,
             immunotherapy (or use mitomycin C within 6 weeks prior to receiving investigational
             drug). Radiation-rehabilitation radiotherapy (EF-RT) was performed within 4 weeks
             before enrollment or limited-field radiotherapy was performed for planned tumor
             lesions within 2 weeks before enrollment.

          -  Patients were diagnosed with disease which will severely endanger the security of
             patients or influence the completion of this research, or patients with other
             situations are not suitable for the study according to the researchers.