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Toxicity of Olaratumab and Doxorubicin

Insights From: Mark Agulnik, MD, Northwestern University Feinberg School of Medicine; Brian Van Tine, MD, PhD, Washington University; Richard F. Riedel, MD, Duke University Health System; Victor Villalobos, MD, PhD, University of Colorado Denver
Published: Tuesday, Jan 17, 2017


Transcript:

Richard F. Riedel, MD:
Olaratumab in combination with doxorubicin did have some toxicities compared to doxorubicin alone. The most common side effects that were seen for the combination included nausea, vomiting, diarrhea, neutropenia, and mucositis. Although it’s important to note that while grade 3 or higher neutropenia was seen for the combination, the rates of febrile neutropenia were not significantly different between the combination compared to doxorubicin alone. It’s also important to note that there was no significant cardiac signal suggesting cardiac toxicity for the combination when compared to doxorubicin alone. Despite the increase in some of those side effects, namely nausea, vomiting, diarrhea, mucositis, and neutropenia, it’s important to note that those are side effects that are commonly seen in the community for a wide range of chemotherapeutic agents, and I wouldn’t expect the ability to manage those toxicities to pose a significant challenge to either academic- or community-based providers.

Brian Van Tine, MD, PhD: There was a phase I trial done after the phase I/II trial looking specifically at interactions between doxorubicin and olaratumab, looking at PKs (pharmacokinetics), and looking at cardiac indications. There doesn’t look like there is increased cardiotoxicity in the presence of olaratumab. And so there doesn’t seem to be an increased drug-drug interaction. What I think is important to remind users of doxorubicin is, if you’re going to go above 300 mg/m2, the judicious use of dexrazoxane as a cardioprotectant was also written into these trials.

I think one of the things that has come out of the sarcoma field is, a number of us actually push the amount of lifetime anthracyclines that patients see. A lot of us have gotten very comfortable going well beyond the 300-mg/m2 lifetime max that the breast cancer doctors have capped the breast cancer patients at. I think the first thing you have to have is a little bit of perspective. So, if you’re not curing someone and your best drug is an anthracycline, you may need to use more. And so, I think knowing how to use more is also important. I think knowing when to use dexrazoxane, when to get a cardiologist involved, all of this is something that will test the comfort level of a lot of the private practice doctors and our community colleagues that we have to partner with. We have a really nice cardio-oncology unit at Washington University that actually pairs with us as we go above these thresholds. And, remember, you’re going to be giving on this protocol, 8 x 75, which is 600 mg/m2 of doxorubicin. That is going to push you toward patients that would get heart failure. So, knowing how to give your anthracycline, whether as a continuous infusion to try to prevent cardiotoxicity or to add dexrazoxane, is something where I think this partnership between the academics that do this all the time and the local doctors who should be giving this is really important to really build trust with.

Transcript Edited for Clarity
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Transcript:

Richard F. Riedel, MD:
Olaratumab in combination with doxorubicin did have some toxicities compared to doxorubicin alone. The most common side effects that were seen for the combination included nausea, vomiting, diarrhea, neutropenia, and mucositis. Although it’s important to note that while grade 3 or higher neutropenia was seen for the combination, the rates of febrile neutropenia were not significantly different between the combination compared to doxorubicin alone. It’s also important to note that there was no significant cardiac signal suggesting cardiac toxicity for the combination when compared to doxorubicin alone. Despite the increase in some of those side effects, namely nausea, vomiting, diarrhea, mucositis, and neutropenia, it’s important to note that those are side effects that are commonly seen in the community for a wide range of chemotherapeutic agents, and I wouldn’t expect the ability to manage those toxicities to pose a significant challenge to either academic- or community-based providers.

Brian Van Tine, MD, PhD: There was a phase I trial done after the phase I/II trial looking specifically at interactions between doxorubicin and olaratumab, looking at PKs (pharmacokinetics), and looking at cardiac indications. There doesn’t look like there is increased cardiotoxicity in the presence of olaratumab. And so there doesn’t seem to be an increased drug-drug interaction. What I think is important to remind users of doxorubicin is, if you’re going to go above 300 mg/m2, the judicious use of dexrazoxane as a cardioprotectant was also written into these trials.

I think one of the things that has come out of the sarcoma field is, a number of us actually push the amount of lifetime anthracyclines that patients see. A lot of us have gotten very comfortable going well beyond the 300-mg/m2 lifetime max that the breast cancer doctors have capped the breast cancer patients at. I think the first thing you have to have is a little bit of perspective. So, if you’re not curing someone and your best drug is an anthracycline, you may need to use more. And so, I think knowing how to use more is also important. I think knowing when to use dexrazoxane, when to get a cardiologist involved, all of this is something that will test the comfort level of a lot of the private practice doctors and our community colleagues that we have to partner with. We have a really nice cardio-oncology unit at Washington University that actually pairs with us as we go above these thresholds. And, remember, you’re going to be giving on this protocol, 8 x 75, which is 600 mg/m2 of doxorubicin. That is going to push you toward patients that would get heart failure. So, knowing how to give your anthracycline, whether as a continuous infusion to try to prevent cardiotoxicity or to add dexrazoxane, is something where I think this partnership between the academics that do this all the time and the local doctors who should be giving this is really important to really build trust with.

Transcript Edited for Clarity
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