Patient case: 49-year-old male with colorectal cancer; genetic feature: NRAS

Clinical trial: Study to Evaluate the Safety, Tolerability, Preliminary Efficacy and Pharmacokinetics of Simmitecan and Simmitecan, 5-fluorouracil and Leucovorin Calcium, in Patients With Advanced Solid Tumors

Summary: This study evaluates the safety, tolerability, preliminary efficacy and pharmacokinetics of Simmitecan in patients with advanced solid tumors and Simmitecan, 5-fluorouracil and Leucovorin Calcium in patients with advanced solid tumor or advanced/metastatic colorectal cancer.


Eligibility: Inclusion Criteria:
  1. To be enrolled in the study, all patients shall meet all the following criteria: Patients who have fully understood the study, and are willing to sign the informed consent form(ICF);
  2. To be enrolled in part 1, 2 and 3 of the study, patients should be diagnosed as advanced solid tumor by pathological histology and/or cytology; and patients should be diagnosed as advanced or metastatic CRC by pathological histology prior to enrollment in part 4 of the study; Note: the patients enrolled in the part 2 of the study shall be patients with advanced solid tumor who is suitable for the regimen of Simmitecan combined with 5-FU-LV as judged by the investigator;
  3. Patients who had failed standard treatments for advanced cancer, or are intolerant to the current standard treatments, or have no suitable standard treatments for advanced cancer;
  4. Patients who have at least one measurable lesion (according to RECIST, version 1.1); note: the lesions previously treated with radiotherapy cannot be regarded as the target lesion, unless the lesion showed definite progression after radiotherapy;
  5. Patients with Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
  6. Patients aged ≥ 18 years and ≤ 70 years, male or female is allowed;
  7. Patients with life expectancy of 12 weeks or more;
  8. Patients with appropriate organ function as documented by:
  1. Absolute neutrophil count ≥ 1.5×109/L;
  2. Hemoglobin ≥ 9 g/dL (without erythrocyte transfusions within 14 days);
  3. Platelet count ≥ 100×109/L.
  4. Total serum bilirubin ≤ 1.5 times of upper limit of normal (ULN) (for the patients with Gilbert syndrome, total bilirubin is allowed to be ≤ 3×ULN and direct bilirubin is allowed to be 1.5×ULN);
  5. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5×ULN, or AST and ALT ≤ 5×ULN for patients with liver metastasis;
  6. Creatinine clearance ≥ 50 mL/min ;
  7. International normalized ratio (INR) ≤ 1.5 × ULN, or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (INR only for patients who have not received anticoagulant therapy).
  9. Patients with negative hepatitis b surface antigen; for patients with positive hepatitis b surface antigen, quantitative result of hepatitis b virus (HBV) DNA should be < 1000 cps/mL;
  10. Toxicity caused by any previous treatment, surgery or radiotherapy have recovered to CTCAE grade 0 or 1 (except for alopecia );
  11. Female patients are eligible for the study if the following conditions are met:
  1. Patients have no fertility (i.e., physiological infertility), including postmenopausal period (complete menolipsis for more than 1 year) or documented irreversible sterilization operation including hysterectomy, bilateral ovariectomy, or bilateral salpingectomy (instead of tubal ligation);
  2. For patients of childbearing potential, the results of serum pregnancy test screening should be negative (within 7 days before the first dose of investigational drug), and breastfeeding is not allowed before the start of the study and throughout the study. Moreover, the patients should agree to take effective contraception measures during the study and within 90 days after the last dose, and should always conduct strict birth control in accordance with the label of drug/appliance and the investigator's instructions. Effective contraception measure is defined as:
  -  The sexual partner with removed deferens is the only sexual partner of female patient;
  -  Use of any intrauterine device with documented failure rate less than 1% per year;
  -  Double contraception, such as spermicide plus male condom, female condom, diaphragm, cervical cap or intrauterine contraceptive device.
  12. Male patients should have undergone vasectomy, or agree to take effective contraception measures during the study and within 90 days after the last dose;
  13. Patients are able to follow the study procedures, restrictions and requirements at the investigator's discretion.
  Exclusion Criteria:
  -  1. Patients are still within 5 half-life of previous anticancer chemotherapy, biological agents or other investigational drugs (if 5 half-life exceeds 28 days calculated as 28 days) at the time of screening;
  2. Patients received systemic radiotherapy (including whole brain radiotherapy) within 28 days before enrollment, or received small area radiotherapy (stereotactic radiotherapy of central nervous system (CNS)) within 7 days before enrollment, or have not yet recovered from the previous radiotherapy;
  3. Patients have not yet recovered from the toxic reaction (except alopecia ) caused by previous anti-tumor treatments (> CTCAE grade 2);
  4. Patients underwent major surgery or have not yet fully recovered from pervious surgery (major surgery is defined as grade 3 or 4 surgery specified in "Management Measures for Clinical Application of Medical Technology" implemented on May 1st, 2009).
  5. Patients had CNS metastasis or cancer-related epilepsy requiring clinical intervention; however, patients with CNS metastasis who received treatments, or the asymptomatic patient can be enrolled;
  6. Patients with a history of allergy to 5-FU or LV;
  7. Patients with active HBV or hepatitis C virus (HCV) infection;
  8. Patients diagnosed with human immunodeficiency virus (HIV) infection, or are not willing to have HIV test;
  9. Patients with clinically significant active infection;
  10. Patients with previous or concurrent other malignant tumors (except effectively controlled non-melanoma skin basal cell carcinoma, breast/cervical carcinoma in situ, or other effectively controlled tumors in the past 5 years even without treatments);
  11. Patients with impaired cardiac function or clinically significant heart diseases, including grade 2 or higher congestive heart failure per New York Heart Association (NYHA) classification, arrhythmia, conduction abnormalities requiring treatment, cardiomyopathy, or uncontrolled hypertension;
  12. Patients with serious kidney damage requiring kidney dialysis;
  13. Patients with serious liver damage, grade B or C end-stage liver diseases per Child-Pugh classification (see appendix 8);
  14. Any other diseases or conditions with clinical significance that may affect the protocol compliance or patient's signature of ICF at the investigator's discretion (such as uncontrolled diabetes, etc.);
  15. Patients with disease of digestive tract such as duodenal ulcer, ulcerative colitis, intestinal obstruction or other conditions that may cause alimentary tract hemorrhage or gastrointestinal perforation as judged by the investigator, or have past medical history of gastric-intestinal perforation or intestinal fistula;
  16. Patients with physical condition that will cause the risk of investigational drug use, or render the toxicity or adverse effect difficult to explain at the investigator's discretion.

Relevance to patient case: not relevant