Among the 13 compounds investigated in combination with regorafenib (Stivarga), irinotecan seemed to produce the most favorable response in subcutaneous xenograft models of pediatric rhabdomyosarcomas (RMS), according to findings presented at the 2018 ESMO Congress.
In the study, researchers included established and emerging agents for the treatment of pediatric patients with RMS. These drugs were tested in combination with regorafenib; the multikinase inhibitor is currently being explored in an ongoing phase I trial of pediatric cancers.
Subcutaneous xenografts were crafted from pediatric alveolar (RH30) and embryonal (RD) RMS tumor cell lines in vivo. Mice were treated with 13 compounds, including with irinotecan and vincristine. One mouse was examined in each group in a stepwise dose escalation, monitoring for tolerability and tumor growth.
After 4 weeks of treatment, time to regression was assessed. Results revealed that single-agent regorafenib at a dose of 10 mg/kg/d slowed the growth of both RMS xenografts. Complete responses (CRs) near the maximum-tolerated dose (MTD) were seen in combination with irinotecan in both models, paclitaxel in the RH30 model, and vincristine in the RD model. No drug-related deaths were reported.
Because irinotecan and vincristine demonstrate potent activity as single agents, further studies are needed to attribute the benefit in the study to the combination with regorafenib.
In an interview with OncLive®
during the 2018 ESMO Congress, Dieter Zopf, principal scientist, director, Innovation Sourcing Oncology Bayer Pharmaceuticals, Germany, discussed the identification of effective drug combinations with regorafenib for the treatment of patients with pediatric rhabdomyosarcomas.
OncLive: Please provide an overview of the study you presented on regorafenib combinations in pediatric rhabdomyosarcomas.
: In Europe, there is a requirement by the regulatory authorities that you have to do a pediatric investigation plan (PIP). Since regorafenib has an approved indication in gastrointestinal stromal tumors (GISTs), which also occur in children, Bayer was requested to submit a PIP. Regorafenib is approved in GISTs, but GISTs don’t often occur in pediatric patients. A trial was already running in patients with GISTs, but they could not recruit their official number of patients in time to achieve the PIP.
We needed to negotiate with the European Medicines Agency (EMA) on how to come to an agreement or do this differently. The idea was to test regorafenib in solid malignant tumors in children. This would be a phase I, all-comer study that would investigate all sorts of tumors. Of course, all of the tolerability aspects, which are done in a phase I setting, would be included as well. This PIP constituted 2 different kinds of approaches; one was clinical and one was preclinical.
We were requested to test regorafenib in all sorts of models in these indications and see whether we could obtain antitumor activity in preclinical and clinical settings. We observed some activity in rhabdomyosarcoma. That's why we went back to the EMA and discussed how to proceed. We agreed that we would look into rhabdomyosarcoma. The next issue was connecting with experts and pediatric oncologists on how that can be done.
There was some reluctance to use regorafenib as monotherapy, based on the fact that our results were not dramatic. We didn't see complete remissions or partial remissions (PRs) in preclinical models. We did see some PRs, though not confirmed, in 1 patient in the clinical trial. That, with the knowledge about other receptor tyrosine kinase inhibitors—which mainly have an effect on antiangiogenesis—was not convincing enough for them to agree to a monotherapy trial.
Then, the question was how to get the next step together. We decided along with the Innovative Therapies for Children with Cancer (ITCC) Consortium. They have a large network of clinical institutions to recruit the necessary number of patients in order to do such a study.
After talking to these experts, they provided us with a collection of drugs, which were either standard drugs or were previously used in these kinds of pediatric tumors. We then designed a preclinical study in which we tested the combination of these drugs with regorafenib. This was a bit of a challenge because we had a lot of groups, so [we were tasked with] doing this in a reasonable manner. We decided to use only 1 mouse per group, which is challenging because you have to make sure the mouse survives the study before the study ends. In order to achieve that, we decided to do dose escalate with the combination.