Liposomal Irinotecan Plus Cisplatin in Patients With Advanced or Metastatic Solid Malignancies

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

• Liposomal Irinotecan Plus Cisplatin (Drug): Liposomal irinotecan and cisplatin are administered intravenously on Days 1 and 15 of each 28-day cycle.

Primary outcomes

• Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) [During cycle one, approximately 28 days]: To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of liposomal irinotecan (nal-IRI) in combination with cisplatin in patients with advanced or metastatic solid malignancies.

Secondary outcomes

• Objective Response Rate (ORR) by RECIST Version 1.1 [up to approximately 5 years]: Objective response rate (ORR) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Every 8 weeks from first dose until documented disease progression or death from any cause, whichever occurs first.
• Progression-Free Survival (PFS) [up to approximately 5 years]: Progression-free survival (PFS), defined as the time from the first dose to documented disease progression or death from any cause, whichever occurs first.
• Safety Profile [From initiation of study treatment through 30 days after the end of study treatment.]: Safety profile assessed by the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE Version 5.0.
• Overall survival (OS) [up to approximately 5 years]: OS will be measured from the start date of study treatment to the date of death.
• Objective Response Rate (ORR) [Every 8 weeks from treatment initiation until documented disease progression, withdrawal, death, or end of study participation, up to approximately 5 years.]: ORR is defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST version 1.1. Tumor assessments will be performed by CT scan within 28 days prior to registration and every 8 weeks after treatment initiation, or as clinically indicated. Objective responses must be confirmed by a subsequent tumor assessment performed at least 4 weeks after the initial response.

Sex: All, ages: 20 Years to 85 Years

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 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.
* 13\. Patients with psychiatric illness which would preclude study compliance.
* 14\. Patients who have received any prior treatment with ONIVYDE® (liposomal irinotecan) or irinotecan-containing regimens

• Hui-Jen Tsai, MD, PhD, Study director, National Health Research Institutes, Taiwan
• Li-Yaun Bai, MD, PhD, Study chair, China Medical University Hospital