Prospective phase II trial in patients with first relapse of high-grade astrocytoma using TVB-2640 in combination with bevacizumab versus bevacizumab alone.

Abstract

2064 Background: Recurrent glioblastoma (rGBM) following chemoradiation is associated with a poor prognosis. While bevacizumab is the most common salvage therapy, responses remain brief and without an associated survival benefit. Resistance may involve overexpression of Fatty Acid Synthase (FASN). Our institution is conducting a phase 2 study of bevacizumab with FASN inhibitor TVB-2640 in patients with GBM in first relapse. Methods: This is a prospective, phase 2 study of bevacizumab with TVB-2640 in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Inclusion criteria are: age ≥ 18, ECOG 0 to 2, GBM progression following standard combined modality treatment. Randomization into two arms for the first 28 days is included for exploratory biochemical analysis: patients in arm 1 receive bevacizumab every 2 weeks in combination with TVB-2640; those in arm 2 receive bevacizumab alone every 2 weeks. MR-Spectroscopy (MRS) and serum sampling for exosome analysis are obtained on patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients converge to a single arm and continue to receive bevacizumab in combination with TVB-2640. Results: We have enrolled 24 patients to date; 23 have started treatment. Of those 23 patients, 10 have died, 4 have progressed but are still alive, 2 withdrew, and 7 are still active on trial. The PFS6 is and OS9 are both currently 50%, which compares favorably with historical controls. There have been no reports of grade 4 or 5 treatment-related AEs (of note, 2 deaths were thought definitely unrelated to treatment, including 1 case of intracerebral hemorrhage, and 1 case of sepsis). There have been two cases of grade 3 hand-foot syndrome thought definitely related to treatment. Updated results will include PFS, response, and biomarker analysis (exosome, MRS). Conclusions: The combination of TVB2640 with bevacizumab appears be well tolerated. PFS6 and OS9 are both currently 50%. The study has completed accrual with final data expected later in 2019. Clinical trial information: NCT03032484.

Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat

“…FASN TVB-2640 clinical phase 2 (monotherapy and/or co-treatment) [25,26] Orlistat FDA-approved (as an anti-obesity drug) [27,28] C75 preclinical [29,30] GSK2194069 preclinical [31,32] Fasnall preclinical [33] SCD A939572 preclinical [34,35] MF-438 preclinical [36,37] CAY10566 preclinical [38,39] BZ36 preclinical [40] SREBP1 Fatostatin preclinical [41] FGH10019 preclinical [42] NAFLD, nonalcoholic fatty liver disease; SREBP1, sterol regulatory element-binding protein 1.…”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…Moreover, partial results of the phase 2 trial of TVB-2640 in combination with Bevacizumab in patients with the first relapse of high-grade astrocytoma showed that co-treatment is well-tolerated in humans. 118 In 2016, Alwarawrah et al discovered a potent thiophenopyrimidine-based FAS inhibitor with broad antitumor activity against various non-tumorigenic and aggressive tumor-forming breast cancer cell lines. Fasnall (25, Figure 4) with an IC 50 of 3.71 μM for hFAS, can produce a significant change in the global cellular lipid profile.…”

“…Now, phase 2 of clinical trials of TVB‐2640 (monotherapy and/or co‐treatment) is underway, and includes the treatment of lung, colon, breast, and astrocytoma cancer (NCT03808558, NCT02980029, NCT03179904, and NCT03032484). Moreover, partial results of the phase 2 trial of TVB‐2640 in combination with Bevacizumab in patients with the first relapse of high‐grade astrocytoma showed that co‐treatment is well‐tolerated in humans 118 …”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…Nowadays, the phase 2 of clinical trials of TVB-2640 (monotherapy and/or cotreatment) is underway, including the treatment of lung, colon, breast, and astrocytoma cancer (NCT03808558, NCT02980029, NCT03179904, and NCT03032484). Moreover, partial results of the phase 2 trial of TVB-2640 in combination with Bevacizumab in patients with the first relapse of high-grade astrocytoma, showed that the co-treatment is well tolerated in humans (117).…”