Background: Overexpression of transforming growth factor-beta 2 (TGF-β2) is associated with poor prognosis and plays a key role in malignant progression of various tumors by inducing proliferation, metastasis, angiogenesis and immunosuppression. Previously reported P-001 trial of Trabedersen - Safety and Tolerability of AP 12009, Administered I.V. in Patients With Advanced Tumors Known to Overproduce TGF-beta 2 was evaluated to determine if treatment with Trabedersen primed the tumors to subsequent chemotherapy.

Methods: A total of 37 patients with advanced pancreatic cancer were treated with Trabedersen by intravenous infusion in escalating doses of 2 treatment schedules (initial schedule: 7-days on, 7-days off; modified schedule: 4-days on, 10-days off; two cycles as core study and up to 10 cycles for expanded study). Blood samples from 18 patients were taken at the screening/baseline (BSL) visit, after completion of the first 2 treatment cycles at Day 29 (D29) and during follow-up (FU) visits, which were conducted every 8 weeks after start of the 1st Trabedersen cycle for the tumor markers of cancer antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA).

Results: Maximum tolerated dose (MTD) for 7/7 regimen (N = 11) was 160 mg/m2/d; whereas MTD was not reached on 4/10 regimen (N = 27) even at highest dose of 330 mg/m2/d. There were16 2nd line patients and 11 3rd line and beyond on 4/10 regimen. The progression free survival/overall survival (PFS/OS) of these 2nd line patients in months (mos) were: 1.87/5.60 (N = 6), 1.87/9.93 (N = 11) and 2.72/11.80 (N = 5) at increasing mean dose of 140, 167, and 196 mg/m2/d, respectively. The OS of 9.93 and 11.80 mos are higher than the highest reported OS in the 65 trials reported in the literature during 1997-2015 (range = 2.50-9.20/median = 5.50 mos). The corresponding PFS values were in line with reported literature (range = 0.00-7.65/median = 2.43 mos). The OS of this 4/10 cohort treated with subsequent chemotherapies was 14.7 and 2.93 mos with and without subsequent chemotherapies, p = 0.0023. Chemotherapy on 2nd line followed with subsequent Trabedersen 4/10 regimen as third line was ineffective with OS of 2.80 mos (N = 9) versus 9.93 mos (N = 11), p = 0.046. CA19.9 and CEA biomarker data were consistent with OS data.

Conclusion: Trabedersen treatment was characterized by outstanding OS which was not supported by PFS. The effect was seen primarily when chemotherapies were used as third line after Trabedersen treatment; OS benefit was not observed for the converse- chemotherapies used first followed by Trabedersen. The data supports the enhancement of subsequent chemotherapies following Trabedersen treatment, suggesting a combination trial of Trabedersen and chemotherapies with sequencing.

Citation Format: Larn Hwang, Kevin Ng, Wen Wang, Vuong Trieu. Treatment with trabedersen, an anti-TGF-beta 2 antisense, primed tumors to subsequent chemotherapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3742.