Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial.

Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m2, nab-paclitaxel 150 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 and oral capecitabine 1250 mg/m2 on days 1-28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. Celgene.

Reni M ，Zanon S ，Peretti U ，Chiaravalli M ，Barone D ，Pircher C ，Balzano G ，Macchini M ，Romi S ，Gritti E ，Mazza E ，Nicoletti R ，Doglioni C ，Falconi M ，Gianni L ... -  《The Lancet Gastroenterology & Hepatology》

Alternating gemcitabine plus nab-paclitaxel and gemcitabine alone versus continuous gemcitabine plus nab-paclitaxel after induction treatment of metastatic pancreatic cancer (ALPACA): a multicentre, randomised, open-label, phase 2 trial.

A standardised dose-reduction strategy has not been established for the widely used gemcitabine plus nab-paclitaxel regimen in patients with metastatic pancreatic ductal adenocarcinoma. We aimed to investigate the efficacy and tolerability of alternating treatment cycles of nab-paclitaxel-gemcitabine combination therapy and gemcitabine alone versus continuous treatment with the nab-paclitaxel-gemcitabine combination. ALPACA was a randomised, open-label, phase 2 trial conducted at 29 study centres across Germany. Patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma who had not been previously treated for advanced disease were enrolled. After an induction phase with three cycles of nab-paclitaxel-gemcitabine combination therapy (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients were randomly assigned (1:1) by stratified permuted block randomisation either to continue treatment with standard nab-paclitaxel-gemcitabine or to receive alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone. Patients and investigators were not masked to treatment allocation. Randomisation was done centrally by the study statistician using a computer-generated randomisation list, and was stratified by Karnofsky Performance Status and presence of liver metastases. The primary endpoint was the derivation of an unbiased point estimate and an associated confidence interval with a confidence coefficient of 80% for the hazard ratio (HR) for overall survival after randomisation, without testing a specific hypothesis, analysed by intention to treat in all patients who started randomised treatment. Safety was analysed according to treatment received. This trial is registered with ClinicalTrials.gov, NCT02564146, and is completed. Between May 27, 2016, and May 27, 2021, 325 patients were enrolled. Following three cycles of induction treatment, 174 patients were randomly assigned: 85 to continue receiving standard nab-paclitaxel-gemcitabine, of whom 79 started treatment, and 89 to the alternating treatment schedule, of whom 88 started treatment. Of the 167 patients who started randomised treatment, 88 (53%) were female and 79 (47%) were male. Median overall survival after randomisation was 10·4 months (80% CI 9·2-12·0) in the group that received standard treatment and 10·5 months (10·2-11·1) in the group that received alternating treatment (HR 0·90, 80% CI 0·72-1·13; p=0·56). The most common adverse events of any grade were peripheral neuropathy (59 [74%] of 80 patients in the continuous treatment group vs 53 [62%] of 85 patients in the alternating treatment group) and fatigue (43 [54%] vs 44 [52%]). Treatment-emergent serious adverse events after randomisation occurred in 40 (50%) patients in the continuous treatment group and in 28 (33%) in the alternating treatment group. Fewer treatment-emergent adverse events of grade 3 or higher occurred in patients treated with alternating cycles compared with those receiving standard therapy, especially for peripheral neuropathy (17 [21%] patients in the continuous treatment group vs 12 [14%] in the alternating treatment group) and infections (16 [20%] vs nine [11%]). There were two treatment-related deaths after randomisation, both in the continuous treatment group (one multiple organ dysfunction syndrome, not treated after randomisation, and one interstitial lung disease). Our findings suggest that a dose-reduced regimen with alternating cycles of nab-paclitaxel-gemcitabine and gemcitabine alone after three induction cycles is associated with similar overall survival to that for standard treatment with nab-paclitaxel-gemcitabine, but with improved tolerability. We therefore propose that a switch to the alternating schedule could be considered in a clinical setting for patients with metastatic pancreatic cancer who have at least stable disease after three cycles of nab-paclitaxel-gemcitabine treatment. Celgene/Bristol Myers Squibb.

Dorman K ，Boeck S ，Caca K ，Reichert M ，Ettrich TJ ，Oettle H ，Waidmann O ，Modest DP ，Müller L ，Michl P ，Kanzler S ，Pink D ，Reinacher-Schick A ，Geißler M ，Pelz H ，Kunzmann V ，Held S ，Schichtl T ，Heinemann V ，Kullmann F ... -  《The Lancet Gastroenterology & Hepatology》

A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma.

The current trial assessed whether the addition of cisplatin and capecitabine to the nab-paclitaxel-gemcitabine backbone is feasible and active against borderline and locally advanced pancreatic adenocarcinoma (PDAC). Fifty-four chemo-naive patients, aged between 18 and 75 years, with a pathological diagnosis of locally advanced or borderline resectable PDAC were randomised to receive either nab-paclitaxel, gemcitabine, cisplatin and oral capecitabine (PAXG; arm A; N = 26) or nab-paclitaxel followed by gemcitabine (AG; arm B; N = 28). The primary end-point was the tumour resection rate. If at least four such resections were performed, the treatment was considered as active. The secondary end-points were progression-free survival (PFS), overall survival (OS), Response Evaluation Criteria in Solid Tumours response rate, Hartman's pathologic response, carbohydrate antigen 19.9 response rate and toxicity. Eight patients (31%) in the PAXG arm and nine (32%) in the AG arm underwent resection. PFS at 1-year was 58% in arm A and 39% in arm B. OS at 18-month was 69% in arm A and 54% in arm B. In this phase II study, the addition of cisplatin and capecitabine to the AG backbone was feasible and yielded promising results in terms of disease control without detrimental impact on tolerability. The approach warrants further investigation in a phase III study. NCT01730222.

Reni M ，Zanon S ，Balzano G ，Passoni P ，Pircher C ，Chiaravalli M ，Fugazza C ，Ceraulo D ，Nicoletti R ，Arcidiacono PG ，Macchini M ，Peretti U ，Castoldi R ，Doglioni C ，Falconi M ，Partelli S ，Gianni L ... -  《-》

Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial.

Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil. We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m2) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m2) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m2 on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the modified intention-to-treat (ITT) population, defined as all randomly assigned and assessable patients regardless of their eligibility and received treatments. This trial is registered at ClinicalTrials.gov, number NCT01964534. The trial has ended and we report the final analysis here. Between Dec 12, 2013, and Oct 31, 2014, we randomly assigned 114 patients to treatment: 75 patients to the leucovorin and fluorouracil group and 39 to the gemcitabine group. One patient in the leucovorin and fluorouracil group did not have a 4-month assessment, and was thus excluded from the modified ITT analysis. Median follow-up was 13·1 months (95% CI 12·5-14·1). At 4 months, 40 (56%, 90% CI 45-66) of 72 patients in the leucovorin and fluorouracil group were alive and free from disease progression (21 [54%, 40-68] of 39 patients in the gemcitabine group were also alive and progression-free at 4 months). Grade 3-4 adverse events occurred in 33 (87%) of 38 patients in the gemcitabine group and in 56 (77%) of 73 patients in the leucovorin and fluorouracil group, with different toxicity profiles. The most common grade 3-4 adverse events in the leucovorin and fluorouracil group were neutropenia without fever (17 [23%]), fatigue (16 [22%]), paraesthesia (14 [19%]), diarrhoea (nine [12%]), and mucositis (seven [10%]); in the gemcitabine group they were neutropenia without fever (12 [32%]), thrombocytopenia (seven [18%]), fatigue (eight [21%]), anaemia (five [13%]), increased alanine aminotransferase and aspartate aminotransferase concentrations (five [13%] for both), and paraesthesia (four [11%]). Two participants died; one in the leucovorin and fluorouracil group from septic shock, and one in the gemcitabine group from diabetes compensation with acidosis; these deaths were deemed to be not related to treatment. Treatment-related serious adverse events occurred in 28 (38%) of 73 patients in the leucovorin and fluorouracil group and in 14 (37%) of 38 in the gemcitabine group. Nab-paclitaxel plus simplified leucovorin and fluorouracil fulfilled the primary endpoint in that more than the required 50% of our study population were progression-free at 4 months, with a tolerable toxicity profile. This regimen thus deserves further assessment in a phase 3 trial. GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and Celgene through grants to GERCOR.

Bachet JB ，Hammel P ，Desramé J ，Meurisse A ，Chibaudel B ，André T ，Debourdeau P ，Dauba J ，Lecomte T ，Seitz JF ，Tournigand C ，Aparicio T ，Meyer VG ，Taieb J ，Volet J ，Monier A ，Bonnetain F ，Louvet C ... -  《The Lancet Gastroenterology & Hepatology》

Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study.

Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23 and is complete. Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3-10·1); median progression-free survival was 10·9 months (90% CI 9·3-11·6), and median overall survival was 18·8 months (90% CI 15·0-24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3-83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6-41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients. The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings. Celgene.

Philip PA ，Lacy J ，Portales F ，Sobrero A ，Pazo-Cid R ，Manzano Mozo JL ，Kim EJ ，Dowden S ，Zakari A ，Borg C ，Terrebonne E ，Rivera F ，Sastre J ，Bathini V ，López-Trabada D ，Asselah J ，Saif MW ，Shiansong Li J ，Ong TJ ，Nydam T ，Hammel P ... -  《The Lancet Gastroenterology & Hepatology》