2nd-line Therapy With Nal-IRI After Gem/Nab-pac in Advanced Pancreatic Cancer - Predictive Role of 1st-line Therapy

Study Overview
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Brief Summary
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Second-line therapy with Nal-IRI after failure gemcitabine/nab-paclitaxel in advanced pancreatic cancer - predictive role of 1st-line therapy

Detailed Description
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Research hypothesis: Patients profit from 2nd-line therapy with Nal-IRI if they also had a benefit from 1st-line treatment. Benefit from treatment (either 1st or 2nd-line) will be defined as a patient specific Time-To-Treatment Failure (TTF) which is in the upper third of the distribution of TTF values of the studied population.

Official Title
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Second-line Therapy With Nal-IRI After Failure Gemcitabine/Nab-paclitaxel in Advanced Pancreatic Cancer - Predictive Role of 1st-line Therapy

Conditions
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Locally Advanced Pancreatic Cancer, Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: Irinotecan Liposomal Injection [Onivyde]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent including participation in translational research and any locally-required authorization (EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations Clinical indication for a 2nd-line systemic therapy according to current standard-of-care. Age ≥ 18 years at time of study entry Patients with histologically or cytologically confirmed pancreatic ductal adenocarcinoma Imaging of evaluable lesions within 2 weeks of inclusion (either sonography, X-ray, CT scans, MRI) ECOG performance status 0-2 One line of systemic gemcitabine/Nab-paclitaxel -based therapy for advanced disease (irrespective of prior adjuvant therapy) OR Previous adjuvant gemcitabine/Nab-paclitaxel-based chemotherapy with documented progression less than 6 months after termination Detailed documentation of prior therapy (duration, dose-intensity, maximum toxicity, reason for discontinuation) Adequate blood count, liver-enzymes, and renal function: neutrophil count > 1.5 x 10^6/mL Platelet count ≥ 100 x 10^9/L (≥100,000 per mm^3) AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal bilirubin ≤1.5 ULN (<3 x ULN in patients with confirmed mechanical cholestasis) Creatinine Clearance CLcr ≥ 30 mL/min Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Exclusion Criteria: Medical criteria: Any condition or comorbidity that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results, including but not limited to: Active uncontrolled infection, chronic infectious diseases, immune deficiency syndromes Premalignant hematologic disorders, e.g. myelodysplastic syndrome Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) 6 months before enrollment Prior (<3 years) or concurrent malignancy (other than biliary-tract cancer) which either progresses or requires active treatment. Exceptions are: basal cell cancer of the skin, pre-invasive cancer of the cervix, T1a or T1b prostate carcinoma, or superficial urinary bladder tumor [Ta, Tis and T1]. Pre-existing lung disease of clinical significance or with impact on performance status History or clinical evidence of CNS metastases Exceptions are: Subjects who have completed local therapy and who meet both of the following criteria: I. are asymptomatic and II. have no requirement for steroids 6 weeks prior to start of study treament. Screening with CNS imaging (CT or MRI) is required only if clinically indicated or if the subject has a history of CNS metastases Allogeneic transplantation requiring immunosuppressive therapy or other major immunosuppressive therapy Severe non-healing wounds, ulcers or bone fractions Evidence of bleeding diathesis or coagulopathy Major surgical procedures, except open biopsy, or significant traumatic injury within 28 days prior to star of study treatment, or anticipation of the need for major surgical procedure during the course of the study except for surgery of central intravenous line placement for chemotherapy administration. Known Gilbert-Meulengracht syndrome Known chronic hypoacusis, tinnitus or vertigo Bone marrow depression (e.g., after radiation therapy) Pernicious anemia and other megaloblastic anemias secondary to vitamin B12 deficiency Severe impairment of hepatic function Diarrhea Drug related criteria: Medication that is known to interfere with any of the agents applied in the trial. Known dihydropyrimidine dehydrogenase (DPD) deficiency History of hypersensitivity to any of the study drugs or any of the constituents of the products. Any other efficacious cancer treatment except protocol specified treatment at study start. Safety criteria: Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are: implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner]. Women of childbearing potential must have a negative pregnancy test (urine or serum β-HCG acc. to SOC) at Screening. Methodological criteria: Any experimental pretreatment for advanced disease Participation in another clinical study with an investigational product during the last 30 days before inclusion or 7 half-lifes of previously used trial medication, whichever is longer. Previous enrollment in the present study (does not include screening failure). Regulatory and ethical criteria: Patient who might be dependent on the sponsor, site or the investigator Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open label, single arm, multicenter phase IIIb trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single Arm<br>Cancer treatment for PDAC: Nal-IRI (4.3 mg/ml) 70 mg/m2 as 1.5 hour infusion 5-FU 2400 mg/m2 as 46 hour infusion Folinic acid 400 mg/m2 as 0.5 hour infusion all on D1 of each cycle; Cycle q2w ± 5 days Treatment until progressive disease or intolerable toxicity or withdrawal of consent. | Drug: Irinotecan Liposomal Injection [Onivyde]<br>* Cancer treatment for PDAC: Nal-IRI (4.3 mg/ml) 70 mg/m2 as 1.5 hour infusion 5-FU 2400 mg/m2 as 46 hour infusion Folinic acid 400 mg/m2 as 0.5 hour infusion all on D1 of each cycle; Cycle q2w ± 5 days Treatment until progressive disease or intolerable toxicity or withdrawal of consent.<br>* Other names: Nal-IRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Treatment Failure of second-line treatment (TTF2) | Time-To-Treatment-Failure - (TTF2) is defined as date of signed ICF until permanent treatment discontinuation (or day of initially planned next cycle) due to progressive disease or unacceptable toxicity. Expected increase of the TTF2 by 50% in the cohort of patients with favorable TTF1 (TTF1 high: upper third of the patient population) as compared to patients with short TTF1 (TTF low: lowest third of the patient population) | up to 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Survival will be calculated from the date ICF signature until the date of death from any cause. If no event is observed (e.g. lost to follow-up) OS is censored at the day of last subject contact. | up to 12 month | 
| Progression Free Survival (PFS) | PFS is defined as the number of months from the date of first dose of 2nd-line treatment to the date of death or investigator assessed progression (by any imaging techique), whichever occurred earlier. If neither death nor progression is observed during the study, PFS data will be censored at the last valid tumor assessment. | up to 12 month | 
| AEs / SAEs | The Safety Population is the primary population for the evaluation of treatment administration/compliance and all safety data and will comprise all patients enrolled who received at least one dose of study medication. Patients will be analyzed according to the treatment actually received. | up to 12 month | 
| Quality of Life (QoL) EORTC QLQ-C30 | Helath related Quality of Life will be evaluated with: - EORTC QLQ-C30 | up to 6 month | 
| Quality of Life (QoL) EORTC QLQ-PAN26 | Helath related Quality of Life will be evaluated with: - EORTC QLQ-PAN26 | up to 6 month | 
| Quality of Life (QoL) EORTC EQ-5D-5L | Helath related Quality of Life will be evaluated with: - EORTC EQ-5D-5L | up to 6 month | 
| Evaluation of time to definitive deterioration of QoL (TDD) | Time to QoL deterioration is defined as a loss of ≥ 10 points in the EORTC QLQ-C30 compared to base-line. | from date of baseline Scrore until date QoL Score deterioration, assessed up to 12 month | 
| Growth modulation index (GMI) | The ratio of time to progression with the nth-line (TTP(n)) of therapy to the TTP(n-1) with the n-1th-line. GMI >1.33 is considered as a sign of activity in phase II trials. | up to 6 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Second-line therapy, Nal-IRI, failure gemcitabine/nab-paclitaxel, predictive role of 1st-line therapy