A phase II study of liposomal irinotecan with 5-fluorouracil, leucovorin and oxaliplatin in patients with resectable pancreatic cancer: the nITRO trial

Background: Up-front surgery followed by postoperative chemotherapy remains the standard paradigm for the treatment of patients with resectable pancreatic cancer. However, the risk for positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the common metastatic relapse limit the overall clinical outcomes achieved with this strategy. Polychemotherapeutic combinations are valid options for postoperative treatment in patients with good performance status. liposomal irinotecan (Nal-IRI) is a novel nanoliposome formulation of irinotecan that accumulates in tumor-associated macrophages improving the therapeutic index of irinotecan and has been approved for the treatment of patients with metastatic pancreatic cancer after progression under gemcitabine-based therapy. Thus, it remains of the outmost urgency to investigate introduction of the most novel agents, such as nal-IRI, in perioperative approaches aimed at increasing the long-term effectiveness of surgery. Methods: The nITRO trial is a phase II, single-arm, open-label study to assess the safety and the activity of nal-IRI with fluorouracil/leucovorin (5-FU/LV) and oxaliplatin in the perioperative treatment of patients with resectable pancreatic cancer. The primary tumor must be resectable with no involvement of the major arteries and no involvement or <180° interface between tumor and vessel wall of the major veins. A total of 72 patients will be enrolled to receive a perioperative treatment of three cycles before and three cycles after surgical resection with nal-IRI 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 200 mg/m2, and 5-fluorouracil 2400 mg/m2, days 1 and 15 of a 28-day cycle. The primary objective is to improve from 40% to 55% the proportion of patients achieving R0 resection after preoperative treatment. Discussion: The nITRO trial will contribute to strengthen the clinical evidence supporting perioperative strategies in resectable pancreatic cancer patients. Moreover, this study represents a unique opportunity for translational analyses aimed to identify novel immune-related prognostic and predictive factors in this setting. Trial registration Clinicaltrial.gov : NCT03528785. Trial registration data: 1 January 2018 Protocol number: CRC 2017_01 EudraCT Number: 2017-000345-46

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Phase II trial of neoadjuvant S-1 and concurrent radiotherapy for borderline resectable pancreatic cancer: Interim results of JASPAC05.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4107 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4107-4107 ◽

Cited By ~ 1

Author(s):

Shinichiro Takahashi ◽

Izumi Ohno ◽

Masafumi Ikeda ◽

Masaru Konishi ◽

Tatsushi Kobayashi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Adverse Events ◽

Phase Ii ◽

Primary Endpoint ◽

R0 Resection ◽

Resection Rate ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Borderline Resectable Pancreatic Cancer ◽

Concurrent Radiotherapy

4107 Background: Borderline resectable pancreatic cancer (BRPC) has a high probability of a positive surgical margin and poor prognosis because the tumor interacts with surrounding arteries or veins. Chemoradiotherapy (CRT) with S-1 has shown favorable activity in locally advanced pancreatic cancer. This study was designed to assess S-1 and concurrent radiotherapy in a neoadjuvant setting to determine whether it increases R0 resection rate for BRPC. Methods: This was a multicenter, single-arm phase II study. Patients with BRPC received S-1 (40 mg/m2 BID) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery if they fulfilled any of the following: (1) bilateral impingement of superior mesenteric vein or portal vein; (2) tumor contact with superior mesenteric artery ≤180°; or (3) tumor contact with common hepatic artery or celiac axis ≤180°. Primary endpoint was R0 resection rate in BRPC confirmed by central review. At least 40 patients were required, with one-sided α = 0.05 and β = 0.05, with an expected and a threshold values for primary endpoint of 30% and 10%. Results: Fifty-two patients were eligible between December 2012 and May 2016. CRT was completed in 50 patients (96%) and was safe, with mostly grade 1 or 2 adverse events. Protocol treatment was withdrawn before surgery in 12 patients because of progressive disease diagnosed by computed tomography, and in one because of treatment refusal. Ten patients received exploratory laparotomy, or palliative/noncurative resection. In the rest of 29, R0 resection was conducted in 27, and R1 and RX in 1 patient each. This gave an R0 resection rate of 52% in all 52 eligible patients. In the 41 cases of BRPC confirmed by central review, R0 was confirmed in 26 (63%). Destruction of > 50% of tumor cells was confirmed pathologically in 10 (32%). Postoperative grade III/IV adverse events according to Clavien–Dindo classification were observed in 6 (15%). Conclusions: S-1 and concurrent radiotherapy were well tolerated and found to be effective in BRPC. A randomized controlled trial comparing neoadjuvant CRT and chemotherapy, including gemcitabine+nab-paclitaxel, for BRPC is under planning. Clinical trial information: NCT02459652.

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NEONAX trial: Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer, a phase II study of the AIO pancreatic cancer group (AIO-PAK-0313)—Safety interim analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4128 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4128-4128 ◽

Cited By ~ 2

Author(s):

Waldemar Uhl ◽

Thomas Jens Ettrich ◽

Anke C. Reinacher-Schick ◽

Hana Algül ◽

Helmut Friess ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Interim Analysis ◽

Phase Ii Study ◽

Neoadjuvant Treatment ◽

Postoperative Mortality ◽

Preoperative Imaging ◽

Resectable Pancreatic Cancer ◽

Perioperative Treatment ◽

Grade 3

4128 Background: Survival in pancreatic cancer (PDAC) is still poor even after curatively intended resection. Perioperative treatment approaches improve outcome in various tumor entities. Data on perioperative treatment in resectable PDAC are limited and there is a debate whether neoadjuvant treatment might impair subsequent surgery by adding perioperative morbidity or mortality. Methods: NEONAX is a randomized phase II study (planned 166 patients) of perioperative gemcitabine/nab-paclitaxel (Arm A: 2 pre- and 4 post-operative cycles, Arm B: 6 cycles adjuvant) for patients with primarily resectable PDAC. Primary objective is DFS at 18 months after randomization. Secondary objectives are 3-year OS-rate and DFS-rate, progression during neoadjuvant therapy, R0/R1 resection rate and QoL. Results: NEONAX was initiated in March 2015 in 26 centers for PDAC surgery in Germany. The data represent the safety interim analysis (IA) of the first 48 patients. 25 patients were randomized to Arm A and 23 to Arm B. Patients’ median age was 65.3 years (56.3% males, 43.8% females, 85.4% ECOG 0). Out of 25 patients in Arm A 20 patients (80%) underwent surgery, compared to 21 of 23 patients (91.3%) in Arm B with upfront surgery. Reasons for no resection were intraoperatively determined small liver metastases (2 cases, Arm A), withdrawal of informed consent (2 cases in each arm) and 1 patient with uncontrolled cholestasis (arm A). Postoperative complications occurred in 45% of arm A and 42.8% of arm B. (pancreatic fistula: 15% in arm A and 9.5% in arm B, infections: 10% in arm A and 9.5% in arm B) All resected patients were alive 60 days after surgery. At least 1 adverse event (AE) NCI-CTCAE ≥ grade 3 occurred in 60% of the perioperative and 39.1% of adjuvant treatment arm. Most common AEs were neutropenia (16.7%), fatigue (10.4%) and infections (10.4%). Conclusions: There was an increase in NCI-CTCAE ≥ grade 3 events in the perioperative arm, but this was manageable and did not result in increased peri- or postoperative mortality. 8% of patients in the perioperative arm did not get resected due metastases detectable during surgery, but not on preoperative imaging immediately prior to surgery. Therefore, it cannot be determined whether these metastases were preexistent or developed during neoadjuvant treatment. In conclusion, the first interim analysis of the NEONAX trial shows that this protocol can be safely applied to patients with resectable PDAC in a perioperative setting. Clinical trial information: NCT02047513.

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Final results of JASPAC05: Phase II trial of neoadjuvant S-1 and concurrent radiotherapy followed by surgery in borderline resectable pancreatic cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4127 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4127-4127 ◽

Cited By ~ 2

Author(s):

Shinichiro Takahashi ◽

Izumi Ohno ◽

Masafumi Ikeda ◽

Masaru Konishi ◽

Tatsushi Kobayashi ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Primary Endpoint ◽

Response Rate ◽

R0 Resection ◽

Resection Rate ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Borderline Resectable Pancreatic Cancer ◽

Concurrent Radiotherapy

4127 Background: Borderline resectable pancreatic cancer (BRPC) is frequently associated with positive surgical margins and a poor prognosis when treated with upfront surgery. This study was designed to assess whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate. Methods: This was a multicenter, single-arm, phase II study. Patients with BRPC received S-1 (40 mg/m2 bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery if they fulfilled any of the following: (1) bilateral impingement of the superior mesenteric vein or portal vein; and (2) tumor contact ≤180° with the superior mesenteric artery, common hepatic artery, or celiac axis. The primary endpoint was the R0 resection rate in BRPC confirmed by central review. Secondary endpoints were overall survival (OS), progression-free survival (PFS), response rate (RECISTv1.1), pathological response rate, surgical morbidity (Clavien–Dindo classification), and toxicity (CTCAEv4.0). At least 40 patients were required, with one-sided α = 0.05 and β = 0.05, with an expected and threshold value for the primary endpoint of 30% and 10%. Results: Fifty-two patients were eligible, of whom 41 had BRPC by central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade 3/4 toxicity with CRT was 43%. The R0 resection rate was 52% (95% CI, 37.6%–66.0%) in 52 eligible patients and 63% (95% CI, 46.9%–77.9%) in 41 patients with BRPC. The radiological response rate was 5.8%, while destruction of > 50% of tumor cells was shown microscopically in 32% of patients. Postoperative grade III/IV adverse events were observed in 7.5% of operated patients. Among the 52 eligible patients, the 2-year OS rate, median OS, and median PFS were 51%, 25.8 mo, and 6.7 mo. Of the 41 patients with BRPC, the 2-year OS rate, median OS, and median PFS were 58%, 30.8 mo, and 10.4 mo. Conclusions: S-1 and concurrent radiotherapy appear to be feasible and effective at increasing the R0 resection rate with encouraging survival rates in BRPC. A phase II/III trial evaluating this treatment is ongoing. Clinical trial information: NCT02459652.

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A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps446 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS446-TPS446

Author(s):

Brian Hemendra Ramnaraign ◽

Steven J. Hughes ◽

Kathryn Hitchcock ◽

Ji-Hyun Lee ◽

Sherise C. Rogers ◽

...

Keyword(s):

Phase Ii ◽

Care Delivery ◽

Performance Status ◽

Neoadjuvant Treatment ◽

Tumor Board ◽

R0 Resection ◽

Preoperative Treatment ◽

Open Label ◽

Patient Reported ◽

Liposomal Irinotecan

TPS446 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Liposomal irinotecan injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase II, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table below every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038. [Table: see text]

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FOLFIRINOX (F-NOX) followed by individualized radiation for borderline-resectable pancreatic cancer: Preliminary toxicity and R0 resection rates from a prospective phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.368 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 368-368 ◽

Cited By ~ 1

Author(s):

Janet E. Murphy ◽

Jennifer Yon-Li Wo ◽

David P. Ryan ◽

Wenqing Jiang ◽

Beow Y. Yeap ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Phase Ii Study ◽

Lung Metastases ◽

R0 Resection ◽

Resection Rate ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Borderline Resectable Pancreatic Cancer ◽

Short Course

368 Background: F-NOX has been increasingly utilized in borderline resectable pancreatic cancer (BRPC) due to the improved response rate compared to gemcitabine. However, prospective data remains limited, with the largest series being a 22 patient (pt) cooperative group trial (Alliance A021101), in which 14 pts had R0 resection. In this study, we evaluate neoadjuvant F-NOX followed by individualized chemoradiation (CRT) for BRPC. Methods: Pts ECOG PS 0-1 with biopsy-proven BRPC as defined by NCCN criteria (SMV/PV involvement with suitable flow, abutment of SMA < 180 degrees or of hepatic artery) were enrolled in a single institution, NCI-sponsored phase II study (NCT01591733). Pts received F-NOX for 8 cycles. If after chemotherapy, the tumor was radiographically resectable, pts received short course CRT in 5 (protons 25 GyE) or 10 fractions (photons 30 Gy) with capecitabine 825 mg/m2 bid. If the tumor was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. The primary endpoint of the study was R0 resection rate. Results: 50 pts were enrolled from 8/2012 to 8/2016. One pt was ineligible (lung metastases) and 1 pt is still on treatment, thus 48 patients were evaluable for this analysis. Median age was 62y (46-74). Median tumor size was 37 mm (21-56). Tumor location was in the head of pancreas for 36 (75%) pts. Of the evaluable pts, 40 (83%) completed therapy. Reasons for not completing therapy included pt withdrawal (3), physician decision (3), unacceptable toxicity (1) and progression (1). Grade 3 or greater toxicity occurred in 21 (44%) pts, including diarrhea (6, 12%), febrile neutropenia (4, 8.5%), neutropenia (4, 8.5%), elevated AST/ALT (3, 6.2%), thrombocytopenia (2, 4.2%), anemia (2, 4.2%), elevated alkaline phosphatase (2, 4.2%). 27 (56%) had short course CRT, while 13 (27%) had long course CRT. In evaluable pts, R0 resection rate was 28/40 (58%). Conclusions: Preoperative F-NOX followed by individualized chemoradiation results in a high R0 resection rate. Final results including PFS outcomes on the entire cohort will be presented at the meeting. Clinical trial information: NCT01591733.

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Randomized multicenter phase II/III study with adjuvant gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX in resectable pancreatic cancer: The NEPAFOX trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.406 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 406-406

Author(s):

Salah-Eddin Al-Batran ◽

Alexander Reichart ◽

Ulli Simone Bankstahl ◽

Claudia Pauligk ◽

Thomas Werner Kraus ◽

...

Keyword(s):

Pancreatic Cancer ◽

Phase Ii ◽

Tumor Staging ◽

R0 Resection ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Perioperative Morbidity ◽

Safety Issues ◽

Post Surgery ◽

Secondary Endpoints

406 Background: The outcome of pancreatic cancer remains poor. Few patients (pts) can be assigned to surgery and 80% of resected pts experience a relapse. Currently, adjuvant ctx is standard, but prognosis remains poor. FOLFIRINOX (FFX) is a SOC in metastatic and meanwhile in the adjuvant setting and may represent a valuable neoadjuvant option in resectable and borderline resectable stages. We initiated the NEPAFOX– trial in Germany to explore the efficacy of perioperative FFX. Methods: This is a multicenter randomized phase II/III trial. Recruitment of the trial was stopped after 40 patients (pts) due to poor accrual. Pts with resectable or borderline resectable adenocarcinoma of the pancreas without metastases were eligible. Eligible pts were randomized to (arm A) upfront surgery followed by adjuvant gemcitabine (1000 mg/m2) for 6 months or (arm B) perioperative FFX (irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, 5-FU 400mg/m² bolus, 5-FU 2400 mg/m², sodium folinate 400 mg/m2) 4-6 cycles (8-12 weeks) pre and further 4-6 cycles post surgery. The primary endpoint is OS. Secondary endpoints include PFS, perioperative morbidity, mortality, and others. Results: 40 pts (42.5% female) were randomized over 3 years (05.03.2015 FPI - 23.03.2018 LPI), 21 in arm A, 19 in arm B. Age range was 46-84y, median age 64y.Before randomization, 76.2% of the pts in Arm A and 78.9% in Arm B were classified as primarily resectable the remaining pts as borderline resectable. Patients received in median 3 cycles in Arm A (range: 0-6) and 6 in Arm B (range: 1-12). Surgery was performed in 18 pts (85.7%) in Arm A and 11 (57.9%) in Arm B. Reasons for not conducting surgery were for Arm A patient´s wish (1 pt) and inoperability (2 pts), for Arm B early progressive disease (4 pts), death (1 pt), pneumonia (1 pt), and toxicities (1 pt). 13 (Arm A) and 5 (Arm B) pts had a R0-Resection. Perioperative morbidity occurred in 72.2% of operated pts in Arm A and 45.5% in Arm B. Median OS was 25.68 months in Arm A (6 events of death) and 10.03 months in Arm B (14 events) with HR 0.366 and p = 0.0337. Median PFS was 9.8 months in Arm A (12 events) and 6.64 months in Arm B (16 events) with HR 0.722 and p = 0.4099. Conclusions: Due to low pt numbers, the analyses for primary and secondary endpoints are not robust and only descriptive. Median OS for Gemcitabine- arm was in the line with literature data and better than for FFX, but pt/event numbers are too for conclusion. Only 11 out of 19 FFX pts underwent surgery, only 9 pts had pancreatic resection, indicating that pts should be extremely good selected before starting a neoadjuvant approach. According to CT or MRI pts of arm B were not more advanced regarding tumor staging. Nevertheless, there were no safety issues in the FFX arm regarding surgical complications, so neoadjuvant/ perioperative treatment approach seems to be feasible, subjected to the small number of pts in the study. Clinical trial information: NCT02172976.

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Added Value of Radiotherapy Following Neoadjuvant FOLFIRINOX for Resectable and Borderline Resectable Pancreatic Cancer: A Systematic Review and Meta-Analysis

Annals of Surgical Oncology ◽

10.1245/s10434-021-10276-8 ◽

2021 ◽

Author(s):

Quisette P. Janssen ◽

Jacob L. van Dam ◽

Isabelle G. Kivits ◽

Marc G. Besselink ◽

Casper H. J. van Eijck ◽

...

Keyword(s):

Pancreatic Cancer ◽

Meta Analysis ◽

Pathologic Complete Response ◽

Complete Response ◽

Added Value ◽

R0 Resection ◽

Resection Rate ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Borderline Resectable Pancreatic Cancer

Abstract Background The added value of radiotherapy following neoadjuvant FOLFIRINOX chemotherapy in patients with resectable or borderline resectable pancreatic cancer ((B)RPC) is unclear. The objective of this meta-analysis was to compare outcomes of patients who received neoadjuvant FOLFIRINOX alone or combined with radiotherapy. Methods A systematic literature search was performed in Embase, Medline (ovidSP), Web of Science, Scopus, Cochrane, and Google Scholar. The primary endpoint was pooled median overall survival (OS). Secondary endpoints included resection rate, R0 resection rate, and other pathologic outcomes. Results We included 512 patients with (B)RPC from 15 studies, of which 7 were prospective nonrandomized studies. In total, 351 patients (68.6%) were treated with FOLFIRINOX alone (8 studies) and 161 patients (31.4%) were treated with FOLFIRINOX and radiotherapy (7 studies). The pooled estimated median OS was 21.6 months (range 18.4–34.0 months) for FOLFIRINOX alone and 22.4 months (range 11.0–37.7 months) for FOLFIRINOX with radiotherapy. The pooled resection rate was similar (71.9% vs. 63.1%, p = 0.43) and the pooled R0 resection rate was higher for FOLFIRINOX with radiotherapy (88.0% vs. 97.6%, p = 0.045). Other pathological outcomes (ypN0, pathologic complete response, perineural invasion) were comparable. Conclusions In this meta-analysis, radiotherapy following neoadjuvant FOLFIRINOX was associated with an improved R0 resection rate as compared with neoadjuvant FOLFIRINOX alone, but a difference in survival could not be demonstrated. Randomized trials are needed to determine the added value of radiotherapy following neoadjuvant FOLFIRINOX in patients with (B)PRC.

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