Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen.

Abstract

4034 Background: TGF-β2 overexpression in solid tumors triggers key cancer pathomechanisms, i.e. suppression of antitumor immune responses system and metastasis. Trabedersen specifically inhibits TGF-β2 expression. In the clinical Phase I/II study we evaluate MTD, safety, pharmakokinetics (PK), and efficacy of i.v. trabedersen in patients with advanced tumors. Methods: A total of 61 patients with pancreatic cancer (PancCa, n=37), malignant melanoma (MM, n=19), or colorectal carcinoma (n=5) were treated with i.v. trabedersen as 2nd to 4th-line therapy with escalating doses in 2 treatment schedules. (1st schedule: 7d on, 7d off; 2nd schedule: 4d on, 10d off; up to 10 cycles). Within the 1st schedule, the MTD was established at 160 mg/m2/d. In the 2nd schedule dose-escalation was stopped before reaching MTD. In the Phase II-part of the study further PancCa and MM patients were treated with 140 mg/m2/d. For assessment of PK parameters, plasma time profiles were analyzed for trabedersen and its n-1 to n-5 metabolites by non-compartimental analysis. Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. Only 2 SAEs (gastrointestinal hemorrhage und pyrexia) were considered as possibly related to study medication. Further clinical development will focus on PancCa patients receiving 140 mg/m2/d trabedersen as 2nd-line treatment. Survival analysis of these patients revealed a mOS of 13.4 months (n=9; 95% CI: 2.2, 39.7). One PanCa patient had a complete response of liver metastases and is still alive after 75 months. Promising efficacy data were also seen in MM patients enrolled into the last cohort (140 mg/m2/day) with a current mOS of 9.3 months (n=14; 95% CI: 6.5, 12.2). PK analyses showed for both treatment schedules that exposure to trabedersen was in the expected range for all doses and half-life of trabedersen (1.12 to 2.08 hrs) as well as clearance (2.22-4.37 L/h*m2) were independent of dose. Conclusions: Trabedersen showed excellent safety and encouraging survival results in the Phase I/II clinical study. A randomized, active-controlled study in 2nd line stage IV PanCa patients is in preparation.

TGFβ2-induced formation of lipid droplets supports acidosis-driven EMT and the metastatic spreading of cancer cells

“…A role for TGF-β2 in supporting the invasive potential of 6.5/ cancer cells was next evaluated using Trabedersen, a specific TGF-β2-targeting antisense oligonucleotide currently evaluated in clinical trials [38][39][40] , and SB431542, a selective TGF-βRI inhibitor. We first documented that Trabedersen reduced TGF-β2 mRNA and protein expression ( Supplementary Fig.…”

“…Importantly, we documented the druggability of this intrinsic alteration of the cancer cell phenotype with SB431542, a potent and specific inhibitor of TGF-β superfamily type 1 receptor, and AP12009/Trabedersen, a FDA-and EMEA-approved orphan anticancer drug, active as a TGF-β2-specific antisense oligodeoxynucleotide. While TGF-β2 was identified as an attractive target to block oncogenesis resulting from stem cell renewal 62 and encouraging survival results have been reported with Trabedersen in gliomas 38 and pancreatic cancers 39,40 , inhibitors of TGF-β2 signaling may actually represent a therapeutic strategy with a broader potential of reducing metastatic burden. Potential therapeutic targets may also be derived from the observation that LD represent a nondispensable source of fuels to support anoikis resistance.…”

TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives

“…It was also successfully tested in an open label Phase I/II study in patients with stage III/IV pancreatic cancer, malignant melanoma, and colorectal cancer (CRC). 156 Results showed that the drug was safe and well tolerated even if some patients developed thrombocytopenia. Furthermore, in one pancreatic cancer patient there was a complete response of liver metastases to the treatment and, at that time, he was still alive after 75 months.…”

Analytical Characterization of an Enzyme-Linked Immunosorbent Assay for the Measurement of Transforming Growth Factor β1 in Human Plasma

“…In cancer, inhibition of TGF-βsignaling targets the tumor microenvironment to prevent progression via multiple mechanisms including inhibiting metastasis and reducing immunosuppression. Hepatocellular carcinoma (HCC), renal cell carcinoma, melanoma, glioblastoma, pancreatic carcinoma, and breast cancer are tumor types that are currently being evaluated for treatment with TGF-β-signaling inhibitors (9)(10)(11)(12)(13)(14). Fibrosis of tissues such as lungs, heart, and kidneys is also associated with increased TGF-β-signaling, likely due to excess ligand availability (15).…”