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Paclitaxel

Albumin-Bound Paclitaxel

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Antimitotic Agents

In the phase I study, all pts enrolled in this arm will receive Nab-FOLFIRI: Irinotecan, 180 mg per square meter of body surface area (m2 ) + Leucovorin, 400 mg/m2 and 5-Fluorouracil, 400 mg/m2 given as a bolus followed by 2400 mg/m2 given as a 46-hour continuous infusion, plus Nab-p per cohort escalation assignment starting with 90 mg/m2 every 2 weeks. Pts continued treatment until a total of 12 administrations, disease progression or unacceptable toxicity.

Pts enrolled in arm A for phase II will receive the dose of Nab-FOLFIRI as determined in the Phase I and in the same sequence.

In the phase I study, all pts enrolled in this arm will receive Nab-FOLFOX: Oxaliplatin 85 mg/m2 +Leucovorin, 400 mg/m2 and 5-Fluorouracil, 400 mg/m2 given as a bolus followed by 2400 mg/m2 given as a 46-hour continuous infusion, plus Nab-p per cohort escalation assignment starting with 90 mg/m2, every 2 weeks.

Pts continued treatment until a total of 12 administrations, disease progression or unacceptable toxicity.

Pts enrolled in arm B for phase II will receive the dose of Nab-FOLFOX as determined in the Phase I and in the same sequence

Paclitaxel bound albumine

Francesco Di Costanzo, MD

Elisa Giommoni, MD

At this moment, FOLFIRINOX is the best treatment for selected patients (pts) with metastatic pancreatic cancer (mPC). Investigator would like to evaluate the substitution of CPT11 or Oxaliplatin in FOLFIRINOX schedule with Nab-paclitaxel (Nab-p) \[Nab-FOLFIRI and Nab-FOLFOX\].

Doses for Nab-FOLFIRI and Nab-FOLFOX will be determined by the phase I trial. One or both schedules will be evaluated in successive phase II part.

The primary objective for phase I of the study is to determine the MTD of Nab-p when used in substitution of OXA or CPT11 in FOLFIRINOX schedule, as first-line treatment in pts with mPC. The dose finding strategy will be based on the classical 3+3 dose escalation design.

-Analysis sets: Modified intention-to-treat population: it consists of all pts who are allocated and receive at least one dose of any component of study treatment. Pts will be grouped according to the randomized treatment assignment. Pts treated during the phase I step will be not included in this population.

Safety population: it consists of all pts who are allocated and receive at least one dose of any component of study treatment. Groups are defined by the study treatment actually received. Pts treated at the MTD during the phase I step will be not included in this population.

Statistical methods Best ORR will be summarized and 95% confidence limits will be calculated according to the exact method for each of the treatment arms included in the phase II step.

All the analyses of primary and secondary efficacy variables will be performed on the modified intention-to-treat population.

The overall incidences of AEs will be summarized. Pts who experienced the same event on more than one occasion are counted only once in the calculation of the event frequency, at the highest intensity ever observed.

Serious adverse events will be summarized. All the safety analyses will be performed on the safety population.

-Sample size: The experimental treatment, to be considered clinically worthwhile, should determine an overall best RR equal to or greater than 40%. According to the Fleming single stage design, for a 90% power towards an alternative hypothesis of an ORR equal to or greater than 40% and a one-sided type I error rate of 5%, respect to the null hypothesis of an ORR equal to or less than 20%, 42 pts must be included in the final evaluation, in each arm of the phase II step. According to the exact binomial test, the experimental treatment will be considered sufficiently promising and candidate to further studies in the case of a major objective response is seen in at least 14 pts.

Phase I/II Study to Evaluate Nab-paclitaxel in Substitution of CPT11 or Oxaliplatin in FOLFIRINOX Schedule as First Line Treatment in Metastatic Pancreatic Cancer

To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination Nab-paclitaxel+ Irinotecan+ Leucovorin+ 5-Fluorouracil (Nab-FOLFIRI) and of the combination Nab-paclitaxel+ Oxaliplatin+ Leucovorin+ 5-Fluorouracil (Nab- FOLFOX) in pts with mPC in first-line chemotherapy (CT).

To assess efficacy of Nab-FOLFIRI and Nab-FOLFOX in pts with mPC in first-line CT , in term of ORR \[Complete response (CR) + partial responses (PR)\].

- Clinical benefit rate \[CR+PR+ stable diseases (SD)\]: this is defined as the occurrence of either a confirmed CR or PR objective response or a SD over the entire course of treatment, as determined by the RECIST 1.1 criteria based on investigator assessment. Pts for whom no records of post-baseline tumor assessments are reported will be counted as non-responders

- Duration of PFS: this is defined as the time between the date of randomization and the date of first evidence of progressive disease or date of death, whichever occurs first. Documentation of disease progression will be defined as per RECIST 1.1 criteria based on investigator assessment. The censoring date for a patient who is known to be progression-free would be the date of the last tumor assessment.

- Duration of OS: is the time from the date of randomization to the date of death from any cause. For pts who are still alive on the date of clinical data cut-off for the OS analysis, the last date when the patient is known to be alive on or prior to the clinical cut-off date will be used to determine the censoring date. For pts who do not have any post-baseline information, data will be censored at the date of randomization plus one day.

- QoL : assessment of quality of life with the use of the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life core questionnaire (QLQ-C30, version 3.0). The primary QoL endpoint will be the time to a definitive 5% deterioration in the global health status/QoL scale of the QLQ-C30 questionnaire.

- Safety profile: Safety of the treatment will be evaluated by serious and non serious adverse events (AEs). AEs will be graded according to the CTCAE v4.03

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I/II Study to Evaluate Nab-paclitaxel in Substitution of CPT11 or Oxaliplatin in FOLFIRINOX Schedule as First Line Treatment in Metastatic Pancreatic Cancer	NCT02109341	Metastatic Panc...	Paclitaxel boun...	18 Years - 75 Years	Gruppo Oncologico Italiano di Ricerca Clinica
Phase I/II Study to Evaluate Nab-paclitaxel in Substitution of CPT11 or Oxaliplatin in FOLFIRINOX Schedule as First Line Treatment in Metastatic Pancreatic Cancer	NCT02109341	Metastatic Panc...	Paclitaxel boun...	18 Years - 75 Years	Gruppo Oncologico Italiano di Ricerca Clinica

Spots Global Cancer Trial Database for paclitaxel bound albumine