Study of Anlotinib Combined With Pemetrexed in Patients With Advanced Nonsquamous NSCLC
Study of Anlotinib Combined With Pemetrexed in Patients With Advanced Nonsquamous NSCLC
In recent years, with the progress in the treatment field, NSCLC has become the most
 successful cancer species in precision medicine. Patients with positive driving genes such as
 EGFR, ALK, ROS1, BRAF and so on have clearly targeted drugs, which bring survival benefits to
 patients.However, about 50% of patients still lack a clear driving gene target, which has
 become the focus of current research.In the field of wild-type NSCLC with negative driver
 genes, the classic first-line treatment regimen is the two-drug regimen containing
 platinum.he phase II clinical study of pemetrexed in the second-line treatment of advanced
 non-small cell lung cancer patients with pemetrexed versus carboplatin pemetrexed showed that
 the median PFS time in the pemetrexed group was 3.5 months.

 Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and
 development.In the phase Ⅲ study, patients who failed at least two kinds of systemic
 chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib or
 placebo, the anlotinib group PFS and OS were 5.37 months and 9.63 months, the placebo group
 PFS and OS were 1.4 months and 6.3 months.

 The efficacy and safety of anrotinib combined with pemetrexed in the second-line treatment of
 advanced non-squamous and non-small cell patients deserve further exploration.
This is a multicentre single arm clinical trial conducted in China,the purpose of this study
 is to evaluate and observe Anlotinib (12mg QD PO d1-14, 21 days per cycle) Combined With
 Pemetrexed(500mg/m2,IV,d1,21 days per cycle) as the second-line Treatment in Patients With
 Advanced nonsquamous Non-Small-Cell Lung Cancer.As the report,The median PFS of advanced
 NSCLC treated by Pemetrexed as second-line was 3-3.5 months.We expect the median PFS of
 Anlotinib combined with Pemetrexed as the second-line Treatment in Patients With Advanced
 nonsquamous NSCLC was 6 months.Using PASS15, we calculated the sample size of this study was
 46(α=0.025、β=0.1), according to 10% censoring,the expected sample size is 51.
Inclusion Criteria:

 -  Signed the informed consent form prior to patient entry;

 -  Male or female patients aged 18-75 years old；

 -  Diagnosed with advanced NSCLC (phase IIIB/IV) through pathology, Neoadjuvant
 chemotherapy, or postoperative adjuvant chemotherapy or neoadjuvant chemotherapy
 combined with postoperative adjuvant chemotherapy or targeted chemoradiotherapy for
 local advanced disease recurrence within 6 months after completion;

 -  Patients with negative driver genes who had previously only received first-line
 platinum double-drug therapy progression or intolerance;

 -  In the past 3 months at least one target lesion that had not previously been
 irradiated,and at least one direction with the longest diameter at baseline greater
 than 10 mm (shorter diameter required not less than 15 mm if lymph nodes are
 involved)could be imaged by CT scan or MRI;

 -  Expected Survival Time: Over 6 months;

 -  had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1
 (on a 5-point scale, with higher scores indicating increasing disability);

 -  If there is central nervous system metastases,they must be asymptomatic central
 nervous system metastases;

 -  The main organs function are normally, the following criteria are met:(1)Blood routine
 examination criteria should be met (no blood transfusion and blood products within 14
 days, no correction by G-CSF and other hematopoietic stimuli): HB≥90 g/L; ANC ≥
 1.5×10^9/L; PLT ≥80×10^9/L;(2)Biochemical examinations must meet the following
 criteria: TBIL<1.5×ULN; ALT and AST < 2.5×ULN, and for patients with liver metastases
 < 5×ULN; Serum Cr ≤ 1.25×ULN or endogenous creatinine clearance > 60 ml/min
 (Cockcroft-Gault formula);

 -  Women of child-bearing age should take appropriate contraceptive measures and should
 not breastfeed from screening to 3 months after stopping the study and
 treatment.Before starting administration, the pregnancy test was negative, or one of
 the following criteria was met to prove that there was no risk of pregnancy:

 1. Postmenopause is defined as amenorrhea at least 12 months after age 50 and
 cessation of all exogenous hormone replacement therapy;

 2. Postmenopausal women under the age of 50 May also be considered postmenopausal if
 their amenorrhea is 12 months or more after the cessation of all exogenous
 hormone therapy and their luteinizing hormone (LH) and follicle-stimulating
 hormone (FSH) levels are within the reference value range of laboratory
 postmenopausal;

 3. has undergone irreversible sterilization surgery, including hysterectomy,
 bilateral ovectomy or bilateral salpingectomy, except for bilateral tubal
 ligation. For men, consent is required to use appropriate methods of
 contraception or to be surgically sterilized during the trial and 8 weeks after
 the last administration of the trial drug.

 Exclusion Criteria:

 -  Small cell lung cancer (including lung cancer mixed with small cell lung cancer and
 non-small cell lung cancer),Lung sarcomatoid carcinoma;

 -  Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma;

 -  EGFR、ALK mutation-positive by genetic testing technology (pathological examination
 results of other hospitals are acceptable) and who receive EGFR-TKI and ALK-TKI
 targeted drug therapy,except EGFR/ALK status cannot be determined for various reasons;

 -  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; or there is a significant pulmonary cavity or necrotizing tumor;

 -  have used Pemetrexed before and progressed;

 -  Patients with uncontrolled pleural effusion need to be treated with other chemotherapy
 drugs;

 -  Significant weight loss (more than 10% weight loss in the previous 6 weeks);

 -  Medical history and combined history：

 1. Had clinically symptomatic central nervous system metastasis(a patient with brain
 metastases who have completed treatment and stable symptoms in 28 days before
 enrollment may be enrolled, but should be confirmed by brain MRI, CT or
 venography evaluation as no cerebral hemorrhage symptoms or metastases in
 midbrain, pons, cerebellum, medulla oblongata, or spinal cord);

 2. The patient is participating in other clinical studies or completing the previous
 clinical study in less than 4 weeks;

 3. Had malignant tumors except NSCLC within 5 years before enrollment(except for
 patients with cervical carcinoma in situ , basal cell or squamous cell skin
 cancer who have undergone a curative treatment, local prostate cancer after
 radical resection, ductal carcinoma in situ or papillary thyroid cancer after
 radical resection);

 4. Patients with previous anti-tumor treatment-related adverse reactions (excluding
 hair loss) who have not recovered to NCI-CTCAE ≤1;

 5. 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;Note: Under the premise of prothrombin time international
 normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million
 to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for
 preventive purposes;

 6. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed
 24-hour urine protein ≥ 1.0g;

 7. The effects of surgery or trauma have been eliminated for less than 14 days
 before enrollment in subjects who have undergone major surgery or have severe
 trauma;

 8. Severe acute or chronic infections requiring systemic treatment;

 9. 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%;

 10. There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for
 trauma;

 11. Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including
 pleural effusion, ascites, pericardial effusion) requiring surgical treatment;

 12. Long-term unhealed wounds or fractures;

 13. Decompensated diabetes or other ailments treated with high doses of
 glucocorticoids;

 14. Factors that have a significant impact on oral drug absorption, such as inability
 to swallow, chronic diarrhea, and intestinal obstruction;

 15. Clinically significant hemoptysis (daily hemoptysis greater than 2.5ml) 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;

 16. Events of venous/venous 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;

 17. Participated in clinical trials of other antitumor drugs within 4 weeks before
 enrollment or planned systemic antitumor treatment within 4 weeks before grouping
 or prior to receiving the test drug including cytotoxic therapy, signal
 transduction inhibitors, immunotherapy( or use mitomycin C within 6 weeks prior
 to receiving the test drug).Radiation-rehabilitation radiotherapy (EF-RT) was
 performed within 4 weeks before grouping or limited-field radiotherapy to be
 evaluated for tumor lesions within 2 weeks before grouping.

 -  Physical examination and laboratory findings

 1. a known history of HIV testing positive or acquired immunodeficiency syndrome
 (AIDS);

 2. untreated active hepatitis (hepatitis b: HBsAg positive and HBV DNA more than 1 x
 103 copy /ml; Hepatitis c: HCV RNA is positive and liver function is abnormal);
 Combined with hepatitis b and hepatitis c infection;

 3. serious diseases that endanger patients' safety or affect patients' completion of
 research,according to the researchers' judgment.