Novel Compound Offers Hope in Soft Tissue Sarcoma

For patients with metastatic nonresectable soft tissue sarcoma (STS), the investigational compound 5-imino-13-deoxydoxorubicin (GPX-150) was active and well-tolerated, according to data from a phase 2 study that was presented at the 2016 Connective Tissue Oncology Society Annual Meeting.

Among 21 evaluable patients with locally advanced and/or metastatic intermediate or high-grade STS, GPX-150 induced a clinical benefit rate (CBR) of 43 percent. The CBR included one partial response and eight patients with stable disease.

GPX-150 was well tolerated, detecting no irreversible cardiotoxicity and no grade 3 or 4 toxicities besides hematological toxicity. The toxicities included two patients (10 percent) with grade 3/4 neutropenia, one patient (5 percent) with grade 3 febrile neutropenia and three patients (14 percent) with grade 3 anemia. The toxicities that were less than grade 3 included mucositis, nausea, vomiting, alopecia and fatigue.

Can you give an overview of the phase 2 trial of GPX-150 in metastatic nonresectable soft-tissue sarcoma?

Can you discuss the design of the study?

What were the most significant findings?

What are the next steps with this research?

What impact do you expect the FDA approval of Lartuvo to have on the treatment landscape?

Are there any related trials that you are excited to see the results of?

What do you hope to see in the next five to 10 years for the treatment landscape?

In an interview with CURE at CTOS, Brian Van Tine, M.D., Ph.D., assistant professor of Medicine, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine, Siteman Cancer Center, discussed the potential of GPX-150 in metastatic and nonresectable STS.The compound that we presented at CTOS — and with more preliminary data earlier this year at ASCO — was called GPX-150. This is a novel anthracycline compound that doesn’t seem to cause the cardiotoxicity of the compound doxorubicin. This was a small phase 2 study run by a company called Gem Pharmaceuticals, where we took patients with soft tissue sarcoma in the frontline metastatic setting. Instead of giving them doxorubicin, which was standard of care at the time, we gave them a compound called GPX-150 and instead of capping doxorubicin, patients were allowed to continue this treatment for up to a year. There were a number of patients on the trial that made the full year with no signs of cardiotoxicity. Now the standard of care is doxorubicin with Lartruvo (olaratumab) but since this study was done over a year ago the standard was just doxorubicin.The most significant finding was that we don't seem to see the cardiotoxicity that we were worried about. In addition, it looks like there's efficacy of the compound that is comparable to doxorubicin in the first place. We may be able to develop a compound that can not only can replace doxorubicin, but get rid of the biggest problem. I believe the next step is dealing with the transitional shift that we just had with the approval of Lartruvo. Also, building a more formalized randomized phase II trial or even going back to a phase I trial with Lartruvo and then building forward to see if we can design a study where we can show that this should be the compound to replace doxorubicin.Until we get the final results of the phase 3 study on a new standard of care for most metastatic patients, the patient should be receiving Lartruvo b upfront. I am still looking forward to seeing the final reanalysis of the aldoxorubicin compound because that also affects the landscape long-term. If in the reanalysis it becomes more of a positive trial, I will be excited because there may be a third anthracycline trying to get rid of the cardiotoxicity of doxorubicin, which will allow us to use it more. What I would hope to see in the next five years is two-fold. I think that our understanding in the rare tumor space of what immunotherapies to use and who to use them with is going to develop. I also think the more exciting thing is for the tumors where immunotherapy isn't going to be the treatment. We recently published a paper in Cell Death and Disease, where we found that argininosuccinate synthetase 1 is not expressed in over 90 percent of any sarcomas that we have ever looked at. That is going to be the basis for metabolic therapies that are trying to get developed in the next wave after immunotherapy.

When do you think metabolic therapies will be ready for the prime-time?

The metabolic therapies are acting in conjunction with other compounds that are coming. As everybody is focused on immunotherapy, a lot of us are already moving on to the next wave of developments, so when the metabolic therapies are truly ready for prime time they won't be forgotten in the rare tumor space.We're working on opening the arginine deiminase trial of sarcoma in the next year or so. But these things take the time to report out and the right combinations still have to be found. Just like with immunotherapy where we're playing around with A versus B versus C, the same thing has to be done with these treatments. Unfortunately, all the sarcomas are deficient in ASS1 until you have a more unified metabolic approach that you can build off of as a base.