Abstract PO-018: Inflaming advanced solid tumors including pancreatic cancer using LOAd703, a TMZ-CD40L/4-1BBL-armed oncolytic virus

2021 ◽  
Author(s):  
Jessica Wenthe ◽  
Emma Eriksson ◽  
Linda Sandin ◽  
Tanja Lövgren ◽  
Justyna Leja Jarblad ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Solid Tumors ◽  
Oncolytic Virus ◽  
Advanced Solid Tumors

A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3013-3013 ◽  
Author(s):  
Michael Friedlander ◽  
Tarek Meniawy ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
Paul R. Harnett ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Multiple Tumor ◽  
Study Results

3013 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4; enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts; 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for > 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.

scholarly journals Phase I Trial of Sorafenib and Gemcitabine in Advanced Solid Tumors with an Expanded Cohort in Advanced Pancreatic Cancer

2006 ◽  
Vol 12 (1) ◽  
pp. 144-151 ◽  
Author(s):  
Lillian L. Siu ◽  
Ahmad Awada ◽  
Chris H. Takimoto ◽  
Martine Piccart ◽  
Brian Schwartz ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Advanced Pancreatic Cancer ◽  
Advanced Solid Tumors

Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009 for the treatment of advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14012-14012
Author(s):  
H. Oettle ◽  
T. Seufferlein ◽  
R. Schmid ◽  
T. Luger ◽  
S. Ludwig ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Malignant Glioma ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Cell Cultures ◽  
Melanoma Cell ◽  
Dose Escalation ◽  
Tumor Therapy ◽  
Advanced Solid Tumors

14012 Background: TGF-β overexpression in advanced tumors is correlated with tumor-induced immunosuppression, proliferation and angiogenesis. Furthermore, it is a key factor for induction of epithelial to mesenchymal transition (EMT), thus promoting invasion and metastasis. Targeted tumor therapy by an antisense oligonucleotide has already been proven to be successful in tumor therapy: AP 12009, a TGF-β2-mRNA-specific antisense oligodeoxynucleotide, has shown strong clinical indication of efficacy including complete and lasting remissions in malignant glioma. Methods: Spurred by the highly encouraging clinical data in malignant glioma and strong anti-tumor activity in a wide variety of preclinical assays, clinical studies in further indications were initiated. A multi-center dose-escalation phase I/II trial with AP 12009 in patients suffering from advanced solid tumors was started in 2005. Primary endpoint is to assess the maximum tolerated dose (MTD) as well as the dose-limiting toxicity (DLT). AP 12009 is administered i.v. in 14-day cycles. Results: Preclinically, in human pancreatic cancer and melanoma cell cultures AP 12009 significantly reduced the TGF-β2 secretion of cancer cells, inhibited tumor cell proliferation, and blocked migration of cancer cells. Additionally, AP 12009 reversed TGF-β2 mediated immunosuppression induced by pancreatic carcinoma cells. In the ongoing clinical phase I/II dose-escalation study, two cohorts of tumor patients have already been treated intravenously with AP 12009 as of Dec 2005. Further dose escalations are ongoing. So far, no DLT, no possibly related SAEs and only seven possibly related AEs were observed. MTD is not yet reached. The majority of patients received more than the minimum number of two cycles, one of them received ten full cycles. First signs of efficacy could also be observed. Conclusions: In conclusion, the preclinical results with pancreatic cancer and malignant melanoma cell cultures as well as the successful clinical application of AP 12009 in the lead indication malignant glioma form a rational basis for the use of the antisense compound AP 12009 as targeted therapy of advanced, TGF-β2 overexpressing tumors. [Table: see text]

Abstract CT244: A phase 1 study of IV MEDI5395, an oncolytic virus, in combination with durvalumab in patients with advanced solid tumors

2020 ◽  
Author(s):  
Grace K. Dy ◽  
Diwakar Davar ◽  
Evanthia Galanis ◽  
Danielle Townsley ◽  
Djuro Karanovic ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Oncolytic Virus ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Phase 1 Study

A phase I/I b study of GSK1120212 (trametinib) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20004-e20004
Author(s):  
Takayasu Kurata ◽  
Junji Furuse ◽  
Isamu Okamoto ◽  
Akiyoshi Kasuga ◽  
Yasuhito Fujisaka ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Solid Tumors ◽  
Japanese Patients ◽  
Maximum Tolerated Dose ◽  
Salivary Gland Cancer ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Western Countries ◽  
Observation Period

e20004 Background: Trametinib is a potent and selective allosteric MEK1/2 inhibitor. In Western countries, trametinib was investigated as monotherapy and in combination with various agents including gemcitabine in the studies with pancreatic cancer, melanoma and other types of cancer. According to these studies, the recommended dose (RD) and maximum tolerated dose (MTD) were determined as 2.0 mg QD and 3.0 mg QD respectively as monotherapy, and as 2.0 mg QD for both in combination with gemcitabine. The objectives of this study are to assess its tolerability and safety, and to evaluate the RD and the MTD in Japanese patients (pts). Methods: This open-label, dose-escalation study evaluated the tolerability/safety, pharmacokinetics (PK), and preliminary efficacy (RECIST) of trametinib alone (part 1) and in combination with gemcitabine (1000 mg/m2on Days 1, 8, and 15 of each 28-day cycle) (part 2) in Japanese pts with advanced solid tumors (NCT01324258). After confirming the tolerability and safety in part 1, part 2 was investigated. Results: (Part 1) Thirteen pts received trametinib at doses of 1.0 mg (n=4), 2.0 mg (n=6), and 3.0 mg (n=3). Various cancer types including melanoma were enrolled. One DLT (Grade 3 infectious pneumonia) was observed in part 1 in a subject at the 2.0 mg dose. The most common AE was Grade 1/2 rash (n=12). One PR (salivary gland cancer) and 3 long SDs (appendix cancer (n=1) and melanoma (n=2)) were observed. Preliminary PK results showed no obvious ethnic difference. (Part 2) Five pts with pancreatic cancer received trametinib (2.0 mg QD) in combination with gemcitabine. Although there was no DLT in the first 28 days (DLT observation period), interstitial lung disease (ILD) was observed in 3 pts after DLT observation period. Best responses were 3 PRs and 2 SDs. Conclusions: The RD (2.0 mg QD) and the MTD (3 mg QD) of trametinib that were determined in Western countries were tolerated in Japanese patients as monotherapy. In combination with gemcitabine, although trametinib was tolerated in the short term and showed promising antitumor efficacy, it is required to closely monitor patients for ILD while the combination is administered to patients. Clinical trial information: NCT01324258.

A phase Ib trial of ERK inhibition with ulixertinib combined with palbociclib in patients (Pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3103-3103
Author(s):  
Alison L. Raybould ◽  
Brian Burgess ◽  
Clarissa Urban ◽  
Rashid Naim ◽  
Michael Sangmin Lee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Lymphocyte Count ◽  
Rational Approach ◽  
Advanced Solid Tumors ◽  
Phase Ib ◽  
Starting Dose ◽  
Grade 3 ◽  
Wbc Count

3103 Background: Activating KRAS mutations are the most frequently detected aberrant oncogenes in pancreatic adenocarcinoma. Combination strategies to target the downstream RAF-MEK-ERK effector pathway are a rational approach. Preclinical data with ERK and CDK4/6 inhibition in both pancreatic cancer cell lines and xenografts demonstrates synergistic cell death and tumor growth suppression. Ulixertinib (BVD-523) is an oral small molecule inhibitor of ERK1/2. This phase 1b study evaluated the safety, pharmacokinetics, and early clinical efficacy of ulixertinib when combined with the oral CDK4/6 inhibitor palbociclib in pts with advanced solid tumors. Methods: Using a 3+3 design, pts received ulixertinib at a starting dose of 300mg (range 300-600mg) twice daily continuously with palbociclib at a starting dose of 75mg (range 75-125mg) on D1-21 out of a 28 day cycle. The primary objective was to establish the maximum tolerated dose (MTD) of the combination. Secondary objectives included characterizing safety and estimating progression free survival (PFS). Dose limiting toxicities (DLTs) were evaluated during the first cycle of treatment. Adverse events were graded by CTCAE v4.03. Response was evaluated after 2 cycles (8 weeks) by RECIST 1.1 criteria. Results: 26 pts were enrolled (13 colorectal, 9 pancreas, 2 melanoma, 1 cholangiocarcinoma, 1 GIST); 16 were evaluable for response. The MTD of the combination was ulixertinib 450mg BID and palbociclib 125mg daily. DLTs included grade 3 fatigue, grade 3 acute kidney injury and grade 3 hyponatremia (Table). Due to toxicity in cohort 3, the protocol was amended to include two additional cohorts (2A and 2B) with a reduced dose of ulixertinib and increasing doses of palbociclib. The most common treatment-related adverse events (TRAEs) (all grades) were fatigue (70%), rash (62%) and nausea (54%). The most common laboratory TRAEs were decreased lymphocyte count (77%), decreased WBC count (73%) and anemia (65%). Grade 3 TRAEs were decreased WBC count, decreased lymphocyte count, anemia and fatigue. No grade 4/5 TRAEs were reported. Three pts demonstrated stable disease (SD). For this heavily pre-treated pt population, PFS was 2.05 months (95% CI 1.87, not determined). PK analysis for ulixertinib and palbociclib was linear and consistent with previously reported data; no drug-drug interactions were observed. Conclusions: The MTD of this phase Ib study of advanced solid tumor pts was ulixertinib 450mg BID combined with palbociclib 125 mg daily. At this dosing, 2 pts demonstrated SD, one with pancreatic cancer and one with cholangiocarcinoma. An expansion cohort of metastatic pancreatic cancer pts is ongoing. Clinical trial information: NCT03454035. [Table: see text]

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