Combination of antiangiogenic therapy using the mTOR inhibitor RAD001 (everolimus) and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer: Dose-finding study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 360-360
Author(s):  
Mareile Joka ◽  
Stefan Hubert Boeck ◽  
Christian Hosius ◽  
Laetitia Decroix ◽  
Christoph May ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Low Dose ◽  
Mtor Inhibitor ◽  
Antiangiogenic Therapy ◽  
Locally Advanced ◽  
Study Drug ◽  
Dose Finding ◽  
Metastatic Pancreatic Cancer ◽  
Low Dose Chemotherapy

360 Background: This was an open-label, multicenter two-arm combined phase I (dose finding, cohort 1-5)/II (dose expansion) study of continuous doses of RAD001 every 2nd day or every day in combination with escalating low dose gemcitabine in patients (pts) with locally advanced and/or metastatic pancreatic cancer. The primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). The secondary objectives were to characterize safety and tolerability and to evaluate preliminary efficacy (ORR). Methods: A total of 27 pts were enrolled in phase I. All of these were analyzed in the safety population and 23 pts in the MTD-determining population. In total, 21 pts completed the study. Results: The MTD was determined to be 500mg/m2/week gemcitabine and 5mg/d RAD001 (cohort 4, 7 pts treated). In total, 3 DLTs occured: hepatic toxicity and unknown DLT as worsed case assumption in cohort 5 and hepatic toxicity in cohort 4. Overall, 25 of 27 pts (92.59%) reported at least one AE. Thrombocytopenia was most frequent AE, followed by leukopenia and nausea. In the individual dose groups, thrombocytopenia was most common in cohorts 1, 2 and 5, leukopenia in cohort 3 and nausea in cohort 4. The majority of pts experienced AEs with suspected relation to study drug (81.48%), AEs leading to dose adjustments or temporary interruption (77.78%) or required concomitant medication (66.67%). A total of 11 pts (40.74%) experienced SAEs. Two pts died during the study (not related to study drug). 4 pts were dicontinued permanently due to 2 AEs and 2 SAEs. ORR was 13%. None of the pts reported complete response (CR), the progressive disease rate was 13%. The clinical benefit rate was 78.3%. Conclusions: The present study was prematurely terminated due to slow recruitment and the dose expansion phase (phase II) was not started. In phase I, the MTD was determined to be 500mg/m2/week Gemcitabine and 5mg/d RAD001. No new safety concerns were identified for combination of antiangiogenic therapy using the mTOR- inhibitor RAD001 (Everolimus) and low dose chemotherapy for locally advanced and/or metastatic pancreatic cancer.

scholarly journals Combination of antiangiogenic therapy using the mTOR-inhibitor everolimus and low-dose chemotherapy for locally advanced and/or metastatic pancreatic cancer

2014 ◽  
Vol 25 (9) ◽  
pp. 1095-1101 ◽  
Author(s):  
Mareile Joka ◽  
Stefan Boeck ◽  
Christoph J. Zech ◽  
Thomas Seufferlein ◽  
Goetz von Wichert ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Low Dose ◽  
Mtor Inhibitor ◽  
Antiangiogenic Therapy ◽  
Locally Advanced ◽  
Metastatic Pancreatic Cancer ◽  
Low Dose Chemotherapy

Gemcitabine Combined with the mTOR Inhibitor Temsirolimus in Patients with Locally Advanced or Metastatic Pancreatic Cancer. A Hellenic Cooperative Oncology Group Phase I/II Study

2018 ◽  
Vol 13 (6) ◽  
pp. 715-724 ◽  
Author(s):  
Vasilios Karavasilis ◽  
Epaminontas Samantas ◽  
Georgia-Angeliki Koliou ◽  
Anna Kalogera-Fountzila ◽  
George Pentheroudakis ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Locally Advanced ◽  
Metastatic Pancreatic Cancer ◽  
Oncology Group

NANT cancer vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS463-TPS463 ◽  
Author(s):  
Tara Elisabeth Seery ◽  
John H. Lee ◽  
Leonard S. Sender ◽  
Frank R. Jones ◽  
Arvind Manohar Shinde ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Vaccine ◽  
Low Dose ◽  
Metastatic Pancreatic Cancer ◽  
Immune Recognition ◽  
Tumor Cell Death ◽  
Low Dose Chemotherapy

TPS463 Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that effective and sustained response against tumors requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we developed the NANT Cancer Vaccine (NCV), which combines metronomic low-dose chemotherapy, radiotherapy and multifaceted immunotherapy. In proof-of-concept trials, the NCV was tested in 10 patients with 3rd-line or greater pancreatic cancer. These trials showed that the NCV could be safely administered in an outpatient setting, with AEs that were manageable by dose-reduction, and preliminary survival results that exceed the standard of care in this heavily-treated population. We believe these results warrant further research, and this abstract describes our newly-designed trial. Methods: A phase 1b, single-arm, open-label trial of the NANT Cancer Vaccine in patients with recurrent metastatic pancreatic cancer has been initiated. Treatment will occur in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic high affinity CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA vaccine (Ad-CEA), yeast vector-based RAS vaccine (Ye-RAS), and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events. Secondary endpoints include ORR, DCR, PFS, and OS. A maximum of 24 patients will be enrolled. Clinical trial information: NCT03586869.

GA CPI 613: A single arm, open-label phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel for patients with locally advanced or metastatic pancreatic cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS459-TPS459
Author(s):  
Angela Tatiana Alistar ◽  
Bonny Morris ◽  
Lawrence Harrison ◽  
Kai Bickenbach ◽  
Nancy Ginder ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Locally Advanced ◽  
Glutamine Metabolism ◽  
Metastatic Pancreatic Cancer ◽  
Clinical Activity ◽  
First Line ◽  
Open Label ◽  
Effective Treatments

TPS459 Background: Pancreatic cancer is the third leading cause of cancer death in the USA. The most effective treatments for first-line metastatic pancreatic cancer are FOLFIRINOX and gemcitabine plus nab-paclitaxel, which provide a median overall survival of 11·1 months and 8·5 months with moderate toxicity. Safer and more effective treatments are needed. The glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as Nab-Paclitaxel. CPI- 613 is a novel antimitocondrial developed by Rafael Pharmaceuticals that showed preclinical activity in pancreatic cancer cell lines as well as promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggests possible synergy of CPI- 613 with nab-paclitaxel. Methods: This is a single arm, open-label, nonblinded phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer. Key eligibility criteria include: histologically or cytologically documented and measurable locally advanced or metastatic pancreatic adenocarcinoma, ECOG performance status 0-2, first line treatment for both locally advanced or metastatic. CPI-613 will be infused intravenously with a starting dose of 500 mg/m2 followed by 125 mg/m2 nab-paclitaxel and 1,000 mg/m2 gemcitabine on day 1, 8, 15 of a 28-day cycle. The study is comprised of a two-stage dose-escalation schema to evaluate the MTD of CPI-613. At least six months of treatment is planned for patients who have a response. Primary endpoint of the study is MTD of CPI 613 when combined with gemcitabine and nab-paclitaxel and secondary endpoints of the study are treatment related adverse events, CR and PR. This study was initiated in February 2018 at Atlantic Health System and within first seven months of the study, 11 out of 24 planned patients have been enrolled. Clinical trial information: NCT03435289.

Clinical and immune responses using anti-CD3 x anti-EGFR bispecific antibody armed T cells (BATs) for locally advanced or metastatic pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4135-4135 ◽  
Author(s):  
Lawrence G. Lum ◽  
Tri Minh Le ◽  
Minsig Choi ◽  
Archana Thakur ◽  
Matthew Reilley ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Phase I ◽  
Phase Ii ◽  
Bispecific Antibody ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Metastatic Pancreatic Cancer ◽  
Cytotoxic T Cell ◽  
Ifn Γ

4135 Background: Conventional chemotherapy (chemo) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC) has dismal responses and poor survival rates. Arming activated T cells (ATC) with anti-CD3 x anti-EGFR bispecific antibody (BATs) makes every ATC into an EGFR-specific cytotoxic T cell that secretes cytokines, proliferates, and kills tumor. Methods: We report on 5 phase I (P1) and 15 phase II (P2) patients. In our phase I study, BATs were used to treat LAPC or MPC patients at Karmanos Cancer Institute (NCT0140874) in a dose escalation involving 3 weekly infusions of 1, 2, and 4 x 1010 BATs/infusion, followed by a booster infusion at 3 months (mos) for a total of up to 8 x 1010 BATs. No dose limiting toxicities were observed in the outpatient infusions. Fifteen patients treated on a phase II (NCT02620865) at KCI and (NCT03269526) at University of Virginia received biweekly infusions of 1010 BATs/infusion over 4 weeks for a total of 8 x 1010 EGFR BATs. Results: Four patients had stable disease (SD) for 6.1, 6.5, 5.3, and 36 mos. Two patients had complete responses (CR) when chemo was restarted after BATs. The median overall survival (OS) for 17 evaluable patients (3 of 4 infusions in the P1 and all 8 infusions in the P2) was 31 mos, and the median OS for all 20 patients (3 in the P2 who did not complete 8 infusions) is 14.5 mos (95% CI, 7.5-45.2 mos). Patient IT20104 had an apparent “pseudoprogression” after 3 BATs infusions, but achieved a CR after restarting capcitabine and is alive off therapy at 54 mos (24 mos after stopping capecitabine). Immune evaluations on the P1 patients show specific cytotoxicity to MiaPaCa-2 by peripheral blood mononuclear cells (PBMC) increased from 21% to 31% 2 weeks after the 3rd infusion, and IFN-γ EliSpots increased from < 20 to 1000 IFN-γ EliSpots/106 PBMC (p < 0.03). Patient IT 20121 (SD for 36 mos) increased IFN-γ EliSpots from 250 to 3200/106 PBMC after 8 infusions. Innate cytotoxicity responses in the P1 patients increased significantly after infusions (p < 0.04). Levels of IP-10 increased significantly (p < 0.04), and levels of IL-8 decreased but not significantly (p < 0.07). Conclusions: Infusions of BATs are safe and induce endogenous adaptive anti-tumor responses. Targeting PC with BATs may stabilize disease, leading to improved OS, as well as evidence that BATs infusions can induce anti-tumor activity and immunosensitize tumors to subsequent chemo. Clinical trial information: NCT014084,NCT03269526,NCT02620865.

Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15787-e15787
Author(s):  
Tara Elisabeth Seery ◽  
Mira Kistler ◽  
Leonard S. Sender ◽  
John H. Lee ◽  
Arvind Manohar Shinde ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Low Dose ◽  
Outpatient Setting ◽  
Metastatic Pancreatic Cancer ◽  
Immune Recognition ◽  
Tumor Cell Death ◽  
Low Dose Chemotherapy

e15787 Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that sustained response against pancreatic cancer requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low-dose chemotherapy, SBRT, cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with recurrent metastatic pancreatic cancer was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral CEA vaccine, yeast Ras vaccine, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 12 subjects with 3rd-line or greater metastatic pancreatic cancer were treated. All treatment was administered in an outpatient setting. AEs were primarily hematologic and managed by planned chemo dose reduction. Grade ≥3 TRAEs were observed in 9 out of 12 subjects, predominately chemotherapy-related neutropenia. 9 out of 12 subjects (75%) had a best response of stable disease (≥ 8 weeks). Median PFS is 7.1 months (4.4 – 8.8) and median OS is 8.2 months (5.7 – 9.7) with 1 subject continuing treatment. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting. Preliminary OS of 8.2 months is encouraging for this heavily-pretreated population. Clinical trial information: NCT03586869.

Sign in / Sign up

Export Citation Format

Share Document