Colorectal cancer

Primary Objective: To evaluate the safety and tolerability, including maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of Lipotecan® in combination with capecitabine-based CCRT as neoadjuvant chemoradiotherapy in patients with surgically resectable locally advanced rectal cancer Secondary Objective: To explore efficacy and potential clinical benefits of Lipotecan® in combination with capecitabine-based CCRT as neoadjuvant chemoradiotherapy in patients with surgically resectable locally advanced rectal cancer

Lipotecan® (TLC388 HCl for injection)

TLC388 HCl

Injection

40 mg

Primary Endpoints:
 To determine the MTD of Lipotecan® in combination with
capecitabine-based CCRT as neoadjuvant chemoradiotherapy
in patients with surgically resectable locally advanced rectal cancer
 To determine the rate of pathological complete response (pCR) at surgery

Secondary Endpoints:
 To determine best overall response before surgery
 To determine the rates of Tumor Regression Grade (TRG) 1, 2 and 3 at surgery
 To determine the rate of histopathological tumor and nodal downstaging at surgery
 To determine the rates of R0 and R1 resection at surgery

1. Females or males ≥ 20 years of age
2. Patients with histologically confirmed diagnosis of rectal cancer (adenocarcinoma)
3. Clinical TNM stage of T3, T4; or any T and N1-2
4. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-2
5. Females of child-bearing potential and male participants are willing to follow birth control procedure when receiving study treatment and continue the contraceptive procedure until the end of study
6. Patients are willing and able to comply with the study procedure and to provide a written informed consen

1. Patients with evidence of any distant metastasis
2. Patients with evidence of any synchronous or metachronous primary colorectal cancer
3. Patients with history of polyposis syndromes, inflammatory bowel disease or other primary malignancy within 5 years prior to the screening visit; except effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix; or carcinoma in situ of the colon or rectum
4. Patients with evidence of primary tumor with an inferior margin below anorectal junction defined by MRI study
5. Patients with evidence of primary rectal cancer with an inferior margin located above 12 cm from the anal verge on rigid endoscopy or MRI study
6. Patients with evidence of complete obstruction, severe ileus, bowel perforation or fistula formation around disease site
7. Patients with history of chemotherapy for rectal cancer
8. Patients with history of internal radiation therapy, radiotherapy to bone marrow rich area or patients who have received radiotherapy to the abdominal area or pelvis prior to the initiation of study treatment
9. Patients with inadequate bone marrow function defined as follows:
。Platelet count <100,000 /mm3
。WBC count <4000 /mm3 and ANC <1500/mm3
。Hemoglobin <8.0 g/dL (accept correction by transfusion)
10. Patients with inadequate liver and renal function defined as follows:
。AST and ALT >3-fold of upper limit of normal (ULN)
。Total bilirubin >2-fold of ULN
。Serum creatinine >2.0 mg/dL
11. Patients with history of hyponatremia <120 mmol/L or symptomatic hyponatremia within 6 months prior to the screening visit or blood sodium level <130 mmol/L at the screening visit (corrected sodium concentration is used for the confirmation of eligibility for patients with possible pseudohyponatremia at the screening visit)
12. Patients with intolerance to immobilization methods for radiotherapy
13. Patients receiving major surgery at PI’s discretion within 28 days of study screening, excluding colostomy
14. Patients fail to follow radiation dose constraints in any critical organ at risk
15. Patients with ill-defined tumor margin for radiotherapy planning that may have an impact on patient treatment or safety based on investigation's judgment
16. Patients with severe comorbidities are defined as follows:
。Unstable angina, history of myocardial infarction requiring hospitalization within 6 months or congestive heart failure with NYHA functional classification III or IV
。Acute bacterial or fungal infection requiring systemic antibiotics treatment
。Unstable COPD or other respiratory distress which resulted in admission within 30 days
。Active bleeding without definite treatment within 30 days, excluding tumor bleeding
。Evidence of liver cirrhosis of Child-Pugh B or above
。Receiving hemodialysis or peritoneal dialysis
。History of organ transplantation
。Uncontrolled seizure/epilepsy disorders
。Uncontrolled or poorly controlled hypertension or diabetes with HbA1c greater than 10%
。Evidence of HIV infection
。History of alcohol dependence/abuse or substance abuse within 3 months
。Other unstable psychiatric/neurological disorders, laboratory abnormality, or other co-morbidity, which the Investigator judges to be unsafe for the patient participating the trial or may interfere with the study compliance or trial results interpretation
17. Patients with other systemic diseases requiring long-term usage of systemic glucocorticosteroid or immunosuppressant within 4 weeks prior to the initiation of study treatment for more than two weeks
18. Patients who have participated in previous Lipotecan® clinical trials
19. Patients who have received other investigational products within 4 weeks prior to the initiation of study treatment
20. Patients who have experienced significant allergy or hypersensitivity to radiocontrast agents
21. Females who are pregnant or planning to become pregnant or who intend to maintain lactation during study period, or females of childbearing potential who do not use medically recognized contraception methods