Multicenter phase I/II study of intravenous gemcitabine + nab-paclitaxel combined with intraperitoneal paclitaxel for pancreatic ductal adenocarcinoma patients with peritoneal metastasis.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 702-702
Author(s):  
Suguru Yamada ◽  
Tsutomu Fujii ◽  
Tomohisa Yamamoto ◽  
Hideki Takami ◽  
Isaku Yoshioka ◽  
...  
Keyword(s):  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Peritoneal Metastasis ◽  
Symptom Relief ◽  
Ductal Adenocarcinoma ◽  
Peritoneal Cytology ◽  
Conversion Surgery ◽  
Grade 3

702 Background: Pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis, and an effective treatment strategy remains elusive. Methods: The aim of this study were to determine the recommended dose (RD) for a combination of intravenous (IV) gemcitabine, intravenous nab-paclitaxel, and intraperitoneal (IP) paclitaxel in chemotherapy-naive PDAC patients with peritoneal metastasis and to evaluate the clinical efficacy and safety. Gemcitabine and nab-paclitaxel was administered IV combined with paclitaxel IP on days 1, 8 and 15, followed by 1 week of rest. The frequency of dose-limiting toxicity was evaluated and the RD was determined. The primary endpoint of the phase II part was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect, symptom relief effect, safety and OS. Results: In the phase I part, RD for IV gemcitabine, IV nab-paclitaxel and IP paclitaxel were determined as 800 mg/m2, 75 mg/m2, and 20 mg/m2, respectively. A total of 46 patients were enrolled in the phase II part and drugs were delivered at the RD. All patients had positive intraperitoneal cytology and 29 patients (63.0%) had the peritoneal dissemination. The median treatment period was 6.0 (0-22.6) months. The response rate and disease control rate were 45.7% and 95.7%, respectively. Ascites disappeared in 40.0% and cytology turned negative in 67.4%. Median CA19-9 decrease ratio was 84.4 (16.9-99.1) %. The median survival time was 12.8 (3.1-32.7) months, and the 1-year survival rate was 52.2%. Finally, conversion surgery was performed in 8 (17.4%) patients and those who received conversion surgery survived significantly longer than those who did not (not reached vs. 11.7 months, P = 0.0070). Grade 3/4 hematologic toxicities occurred in 76.0% and nonhematologic adverse events in 15.0%, of which 6.5% were bowel obstructions. Conclusions: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis. Clinical trial information: 000018878.

Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2

2019 ◽  
Vol 37 (3) ◽  
pp. 230-238 ◽  
Author(s):  
Teresa Macarulla ◽  
Roberto Pazo-Cid ◽  
Carmen Guillén-Ponce ◽  
Rafael López ◽  
Ruth Vera ◽  
...  
Keyword(s):  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Ductal Adenocarcinoma ◽  
Tolerability Profile ◽  
Ecog Performance Status ◽  
Actuarial Survival ◽  
Number Of Patients

Purpose Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. Patients and Methods In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. Results Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). Conclusion NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.

Phase II study of intraperitoneal paclitaxel combined with S-1 plus cisplatin for gastric cancer with peritoneal metastasis: SP + IP PTX trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4529-4529
Author(s):  
Daisuke Kobayashi ◽  
Ryoji Fukushima ◽  
Mitsuhiko Ota ◽  
Sachio Fushida ◽  
Naoyuki Yamashita ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Response Rate ◽  
Phase Iii ◽  
Peritoneal Cytology ◽  
Response To Chemotherapy ◽  
Grade 3 ◽  
Gastric Cancer Patients

4529 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of IP paclitaxel (PTX) combined with S-1 and intravenous PTX over S-1/cisplatin (SP), the standard of care as a first-line treatment in Japan, the sensitivity analysis suggested clinical efficacy of the IP PTX. Thus, attempts to combine IP PTX with other systemic therapies with higher efficacy have been warranted. After a dose-finding study, we sought to explore efficacy of a new regimen that combined IP PTX with SP. Methods: Gastric cancer patients with peritoneal metastasis confirmed by diagnostic imaging, laparoscopy or laparotomy were enrolled in the phase II multi-institutional prospective trial. In addition to the established SP regimen (S-1 administered orally at a dose of 80 mg/m2 bid for 21 days followed by a 14-day rest and cisplatin administered intravenously at a dose of 60 mg/m2 on day 8), IP PTX was administered on days 1, 8 and 22 at a dose of 20 mg/m2. The primary endpoint is overall survival (OS) rate at one year after treatment initiation. Secondary endpoints are progression free survival (PFS), response rate and toxicity. Results: Fifty-three patients were enrolled and fully evaluated for OS and toxicity. The median number of courses was 7 (range 1-20). The 1-year OS rate was 74% (95% CI, 60-83%). The median survival time was 19.4 months (95% CI, 16.7 months-). The 1-year PFS rate was 57% (95% CI, 42-69%). The overall response rate was 20% (95% CI, 1-72%) in 5 patients with target lesions. Cancer cells ceased to be detected by peritoneal cytology in 23 (64%) of 36 patients. Fourteen (26%) patients underwent gastrectomy after response to chemotherapy. The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (23%), anemia (29%), diarrhea (13%) and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in 4 patients. There was 1 treatment-related death. Conclusions: IP PTX combined with SP is well tolerated and active in gastric cancer patients with peritoneal metastasis. Clinical trial information: UMIN000023000 .

Phase I study of weekly intraperitoneal paclitaxel combined with S-1 and oxaliplatin for gastric cancer with peritoneal metastasis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 146-146 ◽  
Author(s):  
Hironori Ishigami ◽  
Shoichi Kaisaki ◽  
Hironori Yamaguchi ◽  
Hiroharu Yamashita ◽  
Shigenobu Emoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Level 3 ◽  
Grade 3 ◽  
Dose Levels

146 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX in phase I and phase II studies. S-1 plus oxaliplatin (SOX) demonstrated efficacy in a phase II study, and is regarded as a candidate for the next-generation standard regimen for gastric cancer. We designed a new regimen combining weekly IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. A dose-escalation study of IP PTX in combination with fixed doses of SOX was carried out to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: PTX was administered intraperitoneally on days 1 and 8 with an initial dose of 20 mg/m2 (level 1), stepped up to 30 mg/m2 (level 2) or 40 mg/m2 (level 3) depending on observed toxicity. S-1 was administered orally at a dose of 80 mg/m2/day (b.i.d.) for 14 days followed by a 7-day rest. Oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. This treatment was repeated every 3 weeks. Toxicity was graded according to CTCAE v4.0. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 non-hematological toxicity. The MTD was defined as the dose level at which 2 or more of 3 or 6 patients developed DLTs during two courses of treatment. The RD was defined as one dose level under the MTD. Results: A total of 12 gastric cancer patients with peritoneal metastasis were enrolled. No DLTs were observed at all dose levels. Neutropenia in one patient at dose level 3 was the only grade 3 toxicity observed. Grade 2/3 leukopenia, neutropenia and thrombocytopenia were observed only in 2 patients at dose level 3. Regarding grade 2 non-hematological toxicities, anorexia, fatigue and nausea were observed in 6, 4 and 2 patients, respectively, independent of dose levels. Consequently, the MTD was not reached, and the RD of IP PTX was determined to be 40 mg/m2 (level 3). Conclusions: Combination chemotherapy of IP PTX with SOX was shown to be a safe regimen that should be further explored in clinical trials.

A phase I study of ASG-5ME, a novel antibody-drug conjugate, in pancreatic ductal adenocarcinoma.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 176-176 ◽  
Author(s):  
Andrew L. Coveler ◽  
Daniel D. Von Hoff ◽  
Andrew H. Ko ◽  
Nancy Cherry Whiting ◽  
Baiteng Zhao ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Antitumor Activity ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Human Antibody ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Grade 3 ◽  
Antibody Drug

176 Background: ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, an ion transporter expressed on >90% of pancreatic ductal adenocarcinoma (PDA). ASG-5ME comprises a fully human antibody covalently linked, with a protease-cleavable linker, to the microtubule-disrupting agent monomethylauristatin E (MMAE). Upon binding to SLC44A4 and internalization, MMAE is released by proteolytic cleavage, binds to tubulin, and subsequently induces cell cycle arrest and apoptosis. Selective targeting of tumor cells by an ADC represents a novel therapeutic approach for patients (pts) with PDA. Methods: This phase I, dose-escalation, multicenter study investigated the safety, PK, and antitumor activity of ASG-5ME in pts with metastatic PDA. Patients received ASG‑5ME IV in cohort-specific doses on Days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Results: Thirty-five pts (median age 63 yrs, range 32-73) were treated at doses of 0.3 to 1.5 mg/kg. All pts had metastatic PDA and ECOG status 0-1. Thirty-three pts (94%) had previously received chemotherapy for metastatic disease or in the perioperative setting; the median number of prior therapies for metastatic PDA was 3 (range 1-6; n=27). The maximum tolerated dose (MTD) was exceeded at the 1.5 mg/kg dose level, with 1 DLT of Grade 4 GI hemorrhage and 4 pts experiencing non-DLT Grade 3 or 4 neutropenia. Thus, 1.2 mg/kg was identified as the MTD and expanded (N=18). The most common AEs observed at the MTD were fatigue (50%), vomiting (44%), decreased appetite (39%), nausea (33%), and abdominal pain (33%); Grade 3 or 4 toxicities at the MTD included fatigue (28%), abdominal pain (22%), vomiting (17%), and neutropenia (17%). Antitumor activity was observed: 1 pt achieved an unconfirmed PR and 12 pts achieved SD. Five patients (14%) had reductions in CA19-9. Serum ASG-5ME exposures were approximately dose proportional. Of 23 pts with archived biopsies available for IHC analysis, 100% expressed SLC44A4 and 15 pts (65%) had high expression. Conclusions: ASG-5ME treatment was generally well tolerated in metastatic PDA pts, with preliminary evidence of antitumor activity. Further study of ASG-5ME in SLC44A4-expressing malignancies is warranted. Clinical trial information: NCT01166490.

Phase II study of intraperitoneal docetaxel plus capecitabine/cisplatin for gastric cancer with peritoneal metastasis: XP+IP DOC trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4039-4039 ◽  
Author(s):  
Ryoji Fukushima ◽  
Hironori Ishigami ◽  
Hiroto Miwa ◽  
Motohiro Imano ◽  
Daisuke Kobayashi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Phase Ii Study ◽  
Median Number ◽  
Peritoneal Cytology ◽  
Response To Chemotherapy ◽  
Grade 3 ◽  
Gastric Cancer Patients

4039 Background: Intraperitoneal (IP) chemotherapy with taxanes provides sustained high local concentrations, and the efficacy of IP paclitaxel (PTX) has been shown in ovarian cancer. We previously reported the safety and efficacy of IP PTX plus systemic chemotherapy in clinical trials. Capecitabine/cisplatin (XP) is one of the standard regimens for the first-line treatment of advanced gastric cancer worldwide. We designed a new regimen combining IP docetaxel (DOC) with XP, and the recommended dose of IP DOC was determined to be 10 mg/m2 in a phase I study. A phase II study of XP plus IP DOC was performed in gastric cancer patients with peritoneal metastasis. Methods: Gastric cancer patients with peritoneal metastasis confirmed by diagnostic imaging, laparoscopy or laparotomy were enrolled. DOC was administered intraperitoneally at 10 mg/m2 on days 1 and 8. Cisplatin was administered intravenously at 80 mg/m2 on day 1, and capecitabine was administered at 1000 mg/m2 bid for 14 consecutive days, repeated every 21 days. The primary endpoint was the 1-year overall survival (OS) rate. Secondary endpoints were response rate, negative conversion rate on peritoneal cytology and safety. Results: Out of 50 patients enrolled, 48 patients received protocol treatment, and were evaluated for OS and toxicity. The median number of courses was 6 (range 1-15). The 1-year OS rate was 75% (95% confidence interval, 60-85%). The best overall response was stable disease in all the three patients with target lesions. Cancer cells ceased to be detected by peritoneal cytology in 28 (76%) of 37 patients. Nineteen patients underwent gastrectomy after response to chemotherapy. The incidences of grade 3/4 hematological and non-hematological toxicities were 42% and 48%, respectively. The frequent grade 3/4 toxicities included neutropenia (21%), leukopenia (8%), anemia (29%), anorexia (25%) and nausea (17%). Infection of the intraperitoneal port was observed in one patient. There were no treatment-related deaths. Conclusions: Combination chemotherapy of XP plus IP DOC regimen is well tolerated and active in gastric cancer patients with peritoneal metastasis. Clinical trial information: UMIN000016469.

PhaseI/IIa Study evaluating the safety, efficacy of K-001 in advanced pancreatic ductal adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16770-e16770
Author(s):  
Jiujie Cui ◽  
Haiyan Yang ◽  
Donghui Chen ◽  
Jiong Hu ◽  
Haiyan Zhang ◽  
...  
Keyword(s):  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Clinical Activity ◽  
Marine Microorganisms ◽  
Open Label ◽  
Antitumor Effects ◽  
Durable Response ◽  
Grade 3

e16770 Background: K-001 is a potent, oral anticancer drug made from active ingredients of marine microorganisms. Its former phase I study did not observe the dose limited toxicity (DLT). Thus, further phase I/IIa trial was conducted to determine maximum tolerated dose (MTD), safety profile and antitumor effects of K-001 in advanced pancreatic ductal adenocarcinoma (PDAC). Methods: This open-label phase I/IIa study involved a dose-escalation to determine maximum tolerated dose (MTD), recommended dose (RD) of K001 in patients with pancreatic ductal adenocarcinoma, followed to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment. Results: Doses from 1350mg to 2160mg twice daily were evaluated. No dose-limiting toxic effects were observed. Totally, 47 adverse events (AE) were observed which included 27 (57.4%) grade 1 AEs, 17 (36.2%) grade 2 AEs and 3 (6.4%) grade 3 AEs. Only 2 AEs which were indigestion and gastrointestinal flatulence were affirmed to research drug and both grade 2. These two AEs were both symptoms of digestive system. For grade 3 AEs, The AEs were not dose dependent. Twelve patients were assessable for response. Clinical activity was observed at all doses tested with durable Response Evaluation Criteria in Solid Tumor (RECIST) . The objective RECIST response rate (ORR) was 0% (complete response + partial response) and the disease control rate (DCR) was 83.3% (10 of 12). Conclusions: K001 has promising efficacy and light side-effect profile. The activity observed demonstrates clinical benefit in pancreatic ductal adenocarcinoma, justifying the conduct of further studies. Clinical trial information: NCT02720666 .

Sa1451 Phase II Study of Intravenous and Intraperitoneal Paclitaxel With S-1 for Pancreatic Ductal Adenocarcinoma Patients With Peritoneal Metastasis

2016 ◽  
Vol 150 (4) ◽  
pp. S319
Author(s):  
Masamichi Mizuma ◽  
Sohei Satoi ◽  
Tsutomu Fujii ◽  
Hiroaki Yanagimoto ◽  
Masanao Kurata ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Phase Ii Study ◽  
Ductal Adenocarcinoma

scholarly journals Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (36) ◽  
pp. 4381-4389 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Recommended Dosage ◽  
Disease Response ◽  
Grade 3 ◽  
Minimal Residual

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

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