Combination Therapy With NC-6004 and Gemcitabine Versus Gemcitabine Alone in Pancreatic Cancer

This clinical trial is designed to evaluate the impact of the addition of NC-6004 to gemcitabine in the treatment of patients with locally advanced or metastatic pancreatic cancer in Asian countries.

Pancreatic cancer is one of the most deadly cancers because of the predominately late diagnosis. Gemcitabine (GEM) is the standard treatment for advanced and metastatic pancreatic cancer. According to preclinical data and few early phase studies, a combined use of gemcitabine and cisplatin (CDDP) showed synergistic efficacy against pancreatic cancer. NC-6004, a novel micellar cisplatin formulation, retains the activity but avoids the renal toxicity and neurotoxicity caused by the high peak Cmax concentrations of cisplatin. This trial is designed to evaluate the impact of the addition of NC-6004 to gemcitabine in the treatment of patients with locally advanced or metastatic pancreatic cancer.

The main hypothesis of this study is that NC-6004 plus gemcitabine combination is superior to gemcitabine alone in terms of overall survival in locally advanced or metastatic pancreatic cancer patients

Eligibility Criteria:
Inclusion criteria:

1. Male or female aged between 20 to 80 years (inclusive)
2. Unresectable, histologically or cytologically confirmed, locally advanced or metastatic pancreatic cancer (adenocarcinoma, adenosquamous carcinoma or poorly differentiated carcinoma)
3. Presence of at least one measurable tumor lesion (longest diameter ≥ 10 mm)
4. No prior systemic anti-cancer therapy\* and radiotherapy\*\* for advanced pancreatic cancer

   \* Patients with post-operative adjuvant chemotherapy other than platinum products (e.g. cisplatin, carboplatin and oxaliplatin, etc.) or radiotherapy or chemo-radiotherapy completed more than 6 months before recurrence will be eligible.

   \*\* Patients with prior palliative radiotherapy of \< 20% bone marrow involvement prior to 6 months from screening will be eligible.
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
6. Adequate organ function defined as:

   * 3,000 cells/μL ≤ WBC ≤ 12,000 cells/μL
   * Absolute neutrophils count (ANC) ≥ 1,500 cells/μL
   * Platelets ≥ 100,000 cells/μL
   * Hemoglobin (Hb) ≥ 9.0 g/dL
   * Alanine amino transferase (ALT) and aspartate amino transferase (AST) ≤ 2.5 times the upper limit of normal (ULN) in patients with no demonstrable hepatic metastasis, or ≤ 5 x ULN in patients with hepatic metastasis
   * Serum bilirubin ≤ 1.5 x ULN in patients with no demonstrable hepatic metastasis and obstructive jaundice, or ≤ 2.5 x ULN in patients with hepatic metastasis or obstructive jaundice
   * Serum creatinine (SCr) ≤ 1.5 mg/dL and creatinine clearance (CrCl) ≥ 60 mL/min (from 24-hour urine test or Cockcroft-Gault formula)
   * Corrected serum calcium ≤ ULN
7. If fertile\*, willing to use barrier contraception till 6 months after the end of treatment

   \* With the following exceptions: 1) pre-menopausal females with bilateral tubal ligation, bilateral oophorectomy or hysterectomy; 2) post-menopausal women, defined as 12 months of spontaneous amenorrhea; 3) males with vasectomy.
8. Willing and able to comply with study procedures and provide written informed consent

Exclusion criteria:

1. Pregnancy or breastfeeding
2. Active concomitant malignancy or history of other cancer except carcinoma in situ of cervical squamous cell carcinoma, stage I colon cancer or other malignance that has remained disease-free for more than 3 years after curative intervention
3. Metastasis to the central nervous system or brain
4. Evidence of hearing impaired ≥ Grade 2 as assessed by pure tone audiometry or other neurotoxicity ≥ Grade 2

   \* Patients with age-associated hearing loss at the high frequencies that, in the judgment of the investigator, would not interfere significantly with patient's safety or study assessments will be eligible to enroll.
5. Patient with pulmonary fibrosis or interstitial pneumonia
6. Marked pleural effusion or ascites above Grade 2
7. Patient with known HIV infection
8. Patient with active hepatitis B, hepatitis C or any other ongoing severe infections
9. Patient with severe mental disorder
10. As judged by the investigator, any evidence of significant laboratory findings or severe/uncontrolled clinical disorders (e.g. dementia, myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) Class III or IV heart failure, unstable angina, active cardiomyopathy, unstable arrhythmia, and other unstable or uncompensated respiratory, cardiac, hepatic, renal and/or infectious disease)
11. Patient with known hypersensitivity to Pt compounds
12. Known severe drug hypersensitivity
13. Treatment with a non-approved or investigational product within 30 days before Day 1 of study treatment
14. Alcoholic liver disease\* or liver disease with obvious clinical symptom or sign

    \* the investigator should judge from medical examination by interview and laboratory test including γ-GTP, AST and ALT
15. Daily Alcohol consumption within 6 months before the screening as an average weekly intake of \>21 units (168 g of pure alcohol) or an average daily intake of \>3 units (24 g of pure alcohol) for males / an average weekly intake of \>14 units (112 g of pure alcohol) or an average daily intake of \>2 units (16 g of pure alcohol) for females.

    Kind of Alcohol Alcohol Percentage mL per 1 unit =8 g of pure alcohol

    Beer 5 % 200 mL

    Whiskey/Brandy 40 % 25 mL

    Wine 12 % approx. 83 mL

    Sake 15 % approx. 67 mL

    Distilled spirit 25 % 40 mL

    Kaoliang 50 % 20 mL
16. Patient with uncontrolled diabetes
17. Radiotherapy within 6 months before screening
18. Experienced Abdominal Radiotherapy
19. Experienced treatment of Gemtuzumab ozogamicin
20. Patient with autoimmune hepatitis or idiopathic thrombocytopenic purpura (ITP)
21. Observation of "attenuated or reversed hepatic venous portal blood flow\*" was confirmed by doppler ultrasonography or CT (recommend evaluation in arterial phase, portal-venous phase and equilibrium phase) of the liver \* On doppler ultrasonography of right and left branch of portal vein, blood flow is measured as about 0 mL/min or between plus and minus, which indicate obvious blood flow obstruction