A Phase III Clinical Study of Kanglaite Injection Combined with Chemotherapy (PVM Scheme) in the Treatment of Non-Small Cell Lung Cancer (NSCLC)

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1 hase III Clinical Study of Kanglaite Injection Combined with Chemotherapy (VM Scheme) in the Treatment of Non-Small Cell Lung Cancer (NSCLC) Chu Datong, Wang Jinwan, Liu Shuxian, Yang Shiyong, Ye Daqian, Li Jide, Cui Chengxu, Qu Fenglian The Tumor Hospital ffiliated to Chinese cademy of Medical Sciences bstract phase III clinical trial for Kanglaite Injection (KLT) manufactured by Zhejiang Kanglaite harmaceutical Co., Ltd. was carried out by the Tumor Hospital ffiliated to Chinese cademy of Medical Sciences from Feb.1996 to May The purpose of the study was to evaluate the efficacy of KLT combined with chemotherapy to define whether an additive effect or synergistic action was existed and whether the toxic reaction of chemotherapy could be reduced by KLT. Methods: 80 patients suffering from NSCLC confirmed by pathological or cytological examination were enrolled in this multicenter, randomized, controlled study and divided into the trial group of KLT + chemotherapy (VM scheme) and the control group of chemotherapy alone (VM scheme). Results: (1) The total response rate was 34.7% and that in the trial group as 45% (18/40) vs % (7/3) in the control group with significant difference (<0.05) between the two groups. () In these two groups, change in physical condition (KS) before and after the chemotherapy had marked difference (<0.05) and body weight changes before and after treatment were not significant (>0.05). (3) few of patients had nausea, low fever or skin rash after KLT intravenous infusion and phlebitis was occasionally noted. The peripheral phlebitis could be prevented by subclavian vein cannulated infusion. Conclusion: KLT could significantly raise the chemotherapy efficacy in NSCLC patients, improve the physical condition of the patients (KS) and protect and raising the platelets. KLT had no obvious side effects. Key words: Kanglaite Injection, NSCLC, VM scheme ulmonary carcinoma has become the leading factor of death caused by cancer among which NSCLC accounts for 70-80% of lung cancers. lthough surgical removal remains the first choice in the treatment of NSCLC, 70-80% of patients have lost their opportunity of operation due to delayed diagnosis. So the curative rate is only about 10%. For this reason, how to improve the therapeutic efficacy in treating NSCLC is a research subject at present. VM regime (DD, VDS, MMC) is widely applied in the treatment of advanced NSCLC, but the total response rate generally looks unfavorable. KLT injection is a new anticancer drug extracted from a Chinese herbal plant semen coicis with advanced scientific technology. It could be applied in the treatment of different kinds of cancers. Reported below is a review of clinical observation conducted between Feb May 1997 on KLT combined with chemotherapy (VM scheme) in the treatment of mid and late stage of NSCLC. 1. Materials and methods 1.1 Criteria for enrollment of patients

2 iv iv (1) NSCLC confirmed by pathological or cytological examination () Size of lesion available for evaluation (3) erformance status score (KS) 60 and above (4) Normal Function of major organs (5) revious treatment was already stopped (e.g. chemotherapy withdrawn for more than 1 month ) and the scheme had not been used before. (6) ge>15 years, non pregnant (7) Expectant survival >3 months 1. Criteria for exclusion of patients (1) Treatment cycle was less than two weeks due to various reasons. () Treatment and observation were not carried out according to the scheme. 1.3 Origin of drugs Drugs for trial were supplied by Zhejiang Kailaite harmaceutical Co., Ltd. 1.4 Trial design Multicenter, randomized and controlled methods were adopted and 80 patients were divided into a trial group (45 cases) and a control group (35 cases). (1) Trial group DD, 80mg/m, iv drip, day 1 or day 1, and 3( with same total dosage), VDS, mg/m injection, day 1 and day 8, MMC, 8mg/m injection, day 1 KLT, 00ml, iv drip, day 9 to day 8 Each cycle lasted for 8 days and -4 cycles as a treatment course. () Control group The treatment was the same as above except KLT injection. 1.5 Data for observation (1) Image examination: to evaluate tumor size before, during and after treatment () Examination of blood picture (WBC, platelets Hgb): 1- times a week (3) Quality of life and body weight: variations in KS and body weight before and after treatment (4) Liver and renal function: once a week 1.6 Criteria of therapeutic efficacy (1) Change in tumor size: Standard for evaluating therapeutic efficacy on solid tumors made by WHO" was adopted with effective rate = CR+R () Blood picture: Grading standard of acute and sub-acute toxicity reaction of anticancer drugs made by WHO was applied.. (3) State of life quality: grading according to KS standard before and after each treatment Excellent: KS increased by 0 points Improved: KS increased by 10 points Steady: KS without any change before and after treatment

3 X X X Decreased: KS decreased by 10 points (4) Body weight: Increase or decrease more than 1kg was termed as increased or decreased and that less than 1kg as steady.. Result mong the 80 patients enrolled 7 cases were evaluated and 8 cases were excluded due to various reasons..1 Sex Table 1. Sex Group Male Female Total Trial group Control group Total =0.604, >0.05, no significant difference between two groups. ge distribution Table. ge distribution Group atient Mean age S Min. age Max. age Trial group Control group T=1.64, >0.05, no significant difference between two groups.3 athological type Table 3. athological type Group Squamous deno careinoma Total Trial group Control group 10 3 Total 50 7 =0.013, >0.05, no significant difference between two groups Table 4. Clinical staging Group Stage III Stage IV Total Trial group Control group 30 3 Total =0.4, >0.05, no significant difference between two groups.4 Therapeutic efficacy: This study group had no CR case. Table 5. Comparison of therapeutic efficacy between two groups Group R MR SD D Total Response rate (%) Trial group Control group Total

4 X X X and cycles cycle =4.19, <0.05, Therapeutic efficacy had significant difference between two groups. Based on the above data, the age, sex, pathological type and clinical staging in two groups had no remarkable difference. Therefore comparison between groups was established..5 Effect on quality of life (KS) and body weight Table 6. Changes of KS before and after treatment Group Improved and stable Decreased Total Trial group Control group Total =5.67, <0.05, Changes of KS had significant difference in two groups. Table 7. Changes of body weight before and after treatment Group Increased Stable Decreased Total Trial group Control group Total =.18, >0.05, no significant difference in two groups.6 Effect on peripheral blood picture.6.1 Effect on WBC Table 8. Comparison on incidence of blood toxicity (grade II and above) during treatment cycle Group Before treatment First cycle Second cycle Third cycle Trial group 0/40 1/40 10/40 4/40 Control group 0/3 14/3 1/3 7/3 value >0.05 >0.05 >0.05 No significant difference between two groups.6. Effect on platelet Table 9. Comparison on incidence of blood toxicity (grade II and above) during treatment cycle Group Before treatment First cycle Second cycle Third cycle Trial group 0/40 3/40 1/40 1/40 Control group 0/3 6/3 5/3 5/3 value >0.05 <0.05 <0.05 st No significant difference between two groups before and during the 1 of treatment, but different nd rd markedly in the 3 of treatment..6.3 Effect on HB

5 opaque rib Table 10. Comparison on incidence of blood toxicity (grade II and above) during treatment cycle Group Before treatment First cycle Second cycle Third cycle Trial group /40 5/40 9/40 4/40 Control group 1/3 6/3 7/3 5/3 value >0.05 >0.05 >0.05 No significant difference between two groups..7 Toxicity and side effect few patients had nausea, low fever after KLT iv infusion with occasional skin rash and phlebitis. The peripheral phlebitis could be avoided by intravenous drip through subclavian vein puncture and catheterization. No obvious heart, liver and kidney toxicity was noted. 3. Typital cases Case 1 Guo xx, Case No. 17, a 78-year-old man, worker He complained of paroxysmal cough, expectoration, chest distress and short breathe for 3 months. Chest CT confirmed a left lung cancer (central type). He was admitted on July 9,1996. Examination: T 36.5, 86/min, R 19/min, B135/80mmHg without enlargement of lymph nodes and no th xanthochromia in skin or sclera. Dullness on the 8 in left subscapular region was noted on percussion. The breathe sound was decreased and rale heard on left chest. The left lower border of heart was enlarged and heart rate 86 min with regular rhythm. No cardiac murmur was heard. Soft and flat abdomen and liver and spleen were impalpable with informal intestinal sound. Chest CT showed a 6.3x4.cm shadow in left upper lung, narrowing of the tongue segment of left upper lobe and bronchial lumen, a streaky opaque of high density shadow was shown in the left tongue segment. No air within trachea and an arc shadow of fluid in the thoracic cavity was noted. Thoracic fluid cytology revealed large amount of adeno-carcinoma cells. Diagnosis: pulmonary carcinoma (central type) with atelectasis of left tongue lobe, left lower obstructive pneumonia and left side hydrothorax. VM regime (DD 80mg/m, VDS 4mg, MMC 8mg/m ) and KLT 00ml/day x 1d as one cycle. Re-examination was done after two cycles and chest CT showed the tumor size decreased more than 50% and cough, chest distress and choke were relieved evidently. No WBC or platelets reduction occurred during treatment. Case Yu xx, Case No , a 58-year-old man He complained of hemoptysis for more than a year. Chest CT confirmed left lung cancer. Bronchoscopy revealed a diagnosis of NSCLC. CB/V16 were given for 4 cycles of chemotherapy and additional 30 times of radiotherapy (once per day). The symptoms were relieved and tumor size reduced after treatment and then increased two months after leaving hospital. nd two times of interventional chemotherapy were given with poor results. The patient was re-admitted to hospital under DD/V-16 chemotherapy for cycles followed by CB for cycles. The patient condition became exacerbated after 10 days of radiotherapy with blood in sputum. nd CT showed prominent

6 in enlargement of the tumor. Then he was again admitted on Oct. 5, Examination: T 36.5, Bp165/100mmHg. He was normally developed and moderately nourished with consciousness and cooperative. No xanthochromia in skin or sclera. No hemorrhagic spots and rash on skin. No enlargement of lymph nodes. Trachea was on mid-position. Breathe sound was slightly decreased in left lung. No rale heard. No enlargement of heart. Heart rate 80/min with regular rhythm and no heart murmur heard. Soft and flat abdomen, liver and spleen impalpable. The intestinal sound was present. Chest CT: adjacent to the dorsal segment of left lower lobe and descending aorta, an opaque shadow of soft tissue about 3.8 x 4cm size was noted and lymph nodes shadow (max.1.6cm ) appeared below the protuberance. ulmonary window showed a mass in the left lower lung with peripheral spotted shadows. The bronchus of dorsal segment in left lower lobe was not clearly appeared. Diagnosis: pulmonary carcinoma (central type) in left lower lobe with inflammation due to left lower dorsal segment obstruction and atelectasis with mediastinal lymphatic metastasis. VM intravenous chemotherapy + KLT 00ml daily x 0d as a cycle of treatment. Re-examination with CT after two cycles of treatment showed that reduction of tumor size was more than 50% with partial response. Cough and chest distress got improved and hemoptysis disappeared. No prominent reduction in WBC or platelets was found during treatment. Biochemical examination was normal and NK cell activity without remarkable variation. 4.Discussion The efficacy of combined chemotherapy for NSCLC has been improved along with the invention and application of alkylate, adriamycin and DD in recent 30 years, but therapeutic result remains unsatisfactory. KLT can be applied for the treatment of various malignant tumors. The outcome from phase II clinical trial of KLT held by Shanghai University of Traditional Chinese Medicine (clinical pharmacology base under Ministry of ublic Health) showed that KLT's efficacy rate for NSCLC was 0.61%. nd the efficacy rate of M (control group) was 5.3% suggesting no significant difference between the two groups. In our study total efficacy rate for NSCLC was 34.7% of which the efficacy rate was 45% in combined chemotherapy group KLT + VM (trial group) vs % in VM mono-therapy( control group). There was a significant difference between the two groups. This showed that KLT injection presented an additive and synergistic action in the combination of chemotherapy and could markedly improve efficacy of chemotherapy for NSCLC. The above phase II clinical trail also revealed that KLT could protect blood picture, improve KS and increase patient weight. nd this study also demonstrated that long term administration of KLT could help improve general condition of patients (KS) without a significant action on increasing body weight and that KLT had certain action on protecting and increasing platelets but had no obvious effect on WBC and Hgb. In addition our study also indicated that KLT's protection and improvement of platelets presented a slow process and would become obvious after one cycle treatment. Our trial did not show that KLT had effect on weight increase. However It needs further study to find out the causes. KLT had no apparent toxic and side effect. Some patients might have nausea, low fever and occasional skin rash or phlebitis that could be prevented by drip infusion through subclavian vein puncture and cannulation. 5. Conclusion (1) KLT injection combined with chemotherapy (VM) to treat NSCLC could notably raise therapeutic efficacy. () KLT injection combined with chemotherapy could evidently improve general condition of patient and also protect and increase platelets to certain extent. (3) KLT injection has no apparent toxic and side effect