A Phase I Study of Liposomal Irinotecan (Nal-IRI, ONIVYDE®) Plus Cisplatin in Patients With Advanced or Metastatic Solid Malignancies.

Phase I Trial to Evaluate Safety and Efficacy of Combination of Liposomal Irinotecan (Nal-IRI; ONIVYDE®) and Cisplatin in Patients With Advanced or Metastatic Solid Malignancies (ICONIC Study)

Phase I trial, Multiple centers, open-label, non-randomized single-arm study

To assess the safety and anti-tumor activity of liposomal irinotecan (nal-IRI; ONIVYDE®) and cisplatin in patients with advanced solid malignancies Primary endpoint To find the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of liposomal irinotecan (nal-IRI; ONIVYDE®) and cisplatin

Inclusion Criteria:

• 1. Patients with age 20-85 years old.

• 2. Cytologically or histologically confirmed solid malignancies which are locally advanced, recurrent or metastatic diseases. The disease cannot be cured by surgical intervention or local therapies.

• 3. The malignancies are refractory to standard systemic therapy or there is no available systemic therapy.

• 4. Followings are the diseases entities which are limited in each part:

  • a. Dose escalation phase (cohort 1): non-small cell lung cancer, small cell lung cancer, gastric cancer, neuroendocrine carcinoma, biliary tract cancer (including intrahepatic cholangiocarcinoma [CCA], extrahepatic CCA, gallbladder cancer, ampullary cancer), ovarian cancer, esophageal cancer, thymoma or thymic carcinoma.
  • b. Dose expansion phase (cohort 2): only thymic carcinoma.

• 5. Radiologically measurable disease as defined by RECIST v1.1.

• 6. Baseline ECOG performance status score 0-1.

• 7. Life expectancy of at least 12 weeks.

• 8. Adequate hematologic parameters, and hepatic and renal functions defined as

  • a. Absolute neutrophil count ≥ 1500 /μL (without growth factor support [filgrastim or lenograstim] for at least 7 days).
  • b. Platelets ≥ 90000 /μL (evaluated at least 7 days after last platelet transfusion).
  • c. Hemoglobin ≥ 9 g/dL (evaluated at least 14 days after last RBC transfusion).
  • d. Total bilirubin ≤ 1.5X ULN.
  • e. AST/ALT ≤ 2.5X ULN (≤ 5X ULN if attributable to liver metastases).
  • f. serum creatinine ≤ 1.5 x ULN or creatinine clearance rate (CCr) ≥ 50 mL/min (calculated by Cockcroft-Gault formula [CCr={((140-age) x weight [kg])/(72x serum creatinine [mg/dL])}x 0.85 (if female)] or 24-hour urine collection).

• 9. Normal ECG or ECG without any clinical significant findings.

• 10. Able to understand and sign an informed consent (or have a legal representative who is able to do so).

• 11. Women or men of reproductive potential should agree to use an effective contraceptive method.

Exclusion Criteria:

• 1. Patients who have major surgery, radiotherapy or other systemic chemotherapy or immunotherapy within 3 weeks are not eligible. Patients who have palliative radiotherapy will be eligible if the irradiated area does not involve the only lesion of measurable / evaluable disease.
• 2. Patient with history of severe allergy to liposomal irinotecan (nal-IRI; ONIVYDE®) or cisplatin.
• 3. Significant cardiovascular impairment: (1) history of congestive heart failure greater than New York Heart Association (NYHA) Class II, left ventricular ejection fraction< 50%; or (2) unstable angina, myocardial infarction or stroke within 6 months; or (3) uncontrolled cardiac arrhythmia.
• 4. Patients with electrolyte abnormalities that have not been corrected.
• 5. Patients with active metastatic lesions in central nervous system, or need prednisolone ≥ 10 mg/day to control related symptoms
• 6. Patients with active bacterial, fungal, tuberculosis or human immunodeficiency virus infection
• 7. Patients with positive hepatitis B surface antigen (HBsAg) but not receiving anti-hepatitis B drug. Patients who have positive HBsAg, positive anti-HBc, or positive anti-HCV are eligible if the corresponding HBV-DNA or HCV-RNA are undetectable.
• 8. Subjects who have not recovered adequately from any toxicity from other anti-cancer treatment regimens and/or complications from major surgery prior to starting therapy.
• 9. Patients who have peripheral neuropathy > grade I of any etiology.
• 10. Patients who have serious concomitant systemic disorders incompatible with the study, i.e. poorly controlled diabetes mellitus, auto-immune disorders, or other condition that in the opinion of the investigator would preclude the subject's participation in the study.
• 11. Patients who have other prior or concurrent malignancy except for adequately treated in situ carcinoma or basal cell carcinoma of skin, or any malignancy which remains disease-free for 3 or more years after curative treatment.
• 12. Females who are breastfeeding or pregnant at screening or baseline.
• 13. Patients with psychiatric illness which would preclude study compliance.