Dieter Zopf, Principal Scientist at Bayer AG, Research and Development, Pharmaceuticals, Oncology, discusses the clinical development of regorafenib (Stivarga) combinations in pediatric rhabdomyosarcoma.

Physician experience and phase III data have shown that vincristine plus irinotecan is more effective than monotherapy approaches. In an ongoing trial investigating the optimal combination with regorafenib in pediatric rhabdomyosarcoma, researchers are using mode of action analysis in order to better understand whether there is a molecular basis for the combination of regorafenib plus irinotecan. Moreover, investigators are testing different schedules. The combination was tolerated in a mouse model, but toxicity has also been noted in the clinic.

The trial consists of 2 arms; one arm is giving the irinotecan plus vincristine together with regorafenib, and the other arm is giving chemotherapy followed by regorafenib one week later. The latter seems to be better tolerated, says Zopf. Researchers are hoping to see antitumor effects that will support subsequent clinical development of the combination.

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Clinical Development of Regorafenib Combinations in Pediatric Rhabdomyosarcoma

Dieter Zopf, Principal Scientist at Bayer AG, Research and Development, Pharmaceuticals, Oncology, discusses the rationale for a study of regorafenib (Stivarga) combinations in pediatric patients with rhabdomyosarcomas (RMS).

In a study of 13 compounds in combination with regorafenib, investigators sought to find the most favorable response in subcutaneous xenograft models of pediatric RMS. Zopf explains that in Europe, there is a requirement by the regulatory agencies that a pediatric investigation plan (PIP) must be done. Regorafenib is currently approved for gastrointestinal stromal tumors (GIST), which do occur in pediatric patients, but not frequently. Investigators failed to get a PIP for GIST due to low enrollment, so a different approach had to be formulated.

Zopf says that in order to get approval to run a trial of regorafenib without a PIP, investigators were requested to test regorafenib in multiple tumors to see whether antitumor activity in preclinical and clinical settings could be achieved. There was some activity observed in RMS, so the investigators went back to the European Medicines Agency and agreed to look into regorafenib in pediatric RMS.

Dieter Zopf, Principal Scientist at Bayer AG, Research and Development, Pharmaceuticals, Oncology, discusses the rationale for a study of regorafenib (Stivarga) combinations in pediatric patients with rhabdomyosarcomas (RMS).
 

Rationale for Regorafenib Combination Study in Pediatric Rhabdomyosarcoma

Dieter Zopf, Principal Scientist at Bayer AG, Research and Development, Pharmaceuticals, Oncology, discusses the optimal partner for regorafenib (Stivarga) in pediatric rhabdomyosarcomas.

In the study analyzing effective combinations with regorafenib for the treatment of pediatric rhabdomyosarcomas, irinotecan (Onivyde) was identified as the best drug to use in combination with regorafenib based on its anti-tumor activity. As these are both potent single agents, researchers had to determine that there was a synergistic benefit with the combination, explains Zopf.

The growth curve following treatment with bone irinotecan alone and irinotecan plus regorafenib showed tumor shrinkage until it was gone. Researchers gave treatment for 4 weeks and then looked at the time to progression. The tumor stayed low or absent for 2 or 3 weeks, notes Zopf. Researchers saw that the tumor regrew in the irinotecan arm as opposed to the combination arm—which saw no regrowth after approximately 80 days. This confirmed that irinotecan is most likely the best combination partner with regorafenib, says Zopf.

Optimal Regorafenib Combinations in Pediatric Rhabdomyosarcomas

Dieter Zopf, Principal Scientist at Bayer AG, Research and Development, Pharmaceuticals, Oncology, discusses a study analyzing effective combinations with regorafenib (Stivarga) for the treatment of pediatric rhabdomyosarcomas.

Regorafenib was tested with drugs that were recommended by a consortium of European experts, Zopf says. Results of the preclinical study suggest that more work should be done with regorafenib in combination with irinotecan and vincristine, according to findings presented at the 2018 ESMO Congress. There was a heterogenous pattern of response in the preclinical models ranging from complete remission (CR) to insensitivity, notes Zopf. CRs were observed in monotherapy with irinotecan, vincristine, and paclitaxel.

Zopf adds that although treatment interruptions were required due to toxicity issues, no treatment-related deaths occurred. This was significant because only 1 mouse was used for each drug. A stepwise dosing strategy was utilized, starting with half the standard dose, then three-quarters the dose, then the standard.

Dieter Zopf, Principal Scientist at Bayer AG, Research and Development, Pharmaceuticals, Oncology, discusses a study analyzing effective combinations with regorafenib for the treatment of pediatric rhabdomyosarcomas.

Dieter Zopf

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Clinical Development of Regorafenib Combinations in Pediatric Rhabdomyosarcoma

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