Soft Tissue Sarcoma Update, Issue 1, 2017 (Video Program)Mechanism of action and tolerability of trabectedin for liposarcoma and leiomyosarcoma
3:26 minutes.
TRANSCRIPTION:
DR LOVE: Maybe you can talk a little bit about what trabectedin is? And where it fits in in the whole spectrum of treatment. DR VAN TINE: So trabectedin was isolated in the 1960s at NIH. And it’s been a drug that went through some complications with the FDA after its original trial and got worldwide approval. And it’s been used for about a decade everywhere but here. And so there’s extensive data. And so because of what happened with the original trial and the FDA, the bar was set pretty high for this Phase III clinical trial for what needed to happen, which is an overall survival benefit. And what was done at the time was they chose the 2 most sensitive histologies, which were high-grade liposarcomas and leiomyosarcomas for this minor DNA groove binder. And doxorubicin binds to the major groove. This binds to the minor groove. What it actually does beyond that, I think, it does a lot of things. We don’t understand the drug as well as we should. But given as a 24-hour infusion, it’s actually well tolerated other than — DR LOVE: Could I just clarify? In terms of the mechanism, could you draw the analogy again of where doxorubicin works and where trabectedin works? DR VAN TINE: So in the DNA, as it twists you’ve got both the major groove, which doxorubicin likes to bind into and the minor groove, where this drug binds. And we’ve done trials looking to see if using them together is better, and it doesn’t seem to be. But it’s a well-tolerated drug given as a slow infusion. And this is going to get more complicated because there’s an ovarian trial coming out of trabectedin soon, and the timing for sarcoma patients and the timing for ovarian patients is very different. Sarcoma patients, they’re going to have to get this drug over 24 hours. We’ve done a trial of 3 hours versus 24. And 24 was superior. Whereas ovarian patients are just going to get this over 3 hours. But this is something where you can send patients home on a pump, and they come back the day, get detached, get the on-body pegfilgrastim and go home. And so this is a drug that you do have to know how to use. DR LOVE: What specific tolerability and toxicity issues have been observed with the drug? DR VAN TINE: So I think the first thing that you have to worry about with trabectedin are liver function issues. And so you can get a lot of AST/ALT elevations, which I think have to be carefully monitored for and carefully adjusted dose wise. I think, just like any cytotoxic agent, you expect neutropenia, thrombocytopenia, anemia. These all have to be treated appropriately. There’s a couple of other side effects of this, which I think are important and that don’t always come out. I think the first is, this drug can cause rhabdomyolysis. And so checking CKs is incredibly important in these patients because you don’t want to miss that. And then there’s a very complicated issue of heart failure. And whether or not it’s actually caused by the trabectedin or if it’s caused by prior exposure in this trial to the doxorubicin, there becomes this question of, does this actually add to it? And I think the prudent thing, as recommended, is that you continue getting echoes just to make sure that you’re not inducing heart failure. And at any signs, you would stop. |