Based on preclinical studies of screening drugs to treat peripheral nerve tumors, researchers at the Children ‘s Hospital of Philadelphia (CHOP) as part of the Neurofibromatosis Clinical Trials Consortium have shown that the drug, cabozantinib, reduces tumor size and pain in patients with the genetic disorder neurofibromatosis type 1 (NF1).
The results of a Phase 2 clinical trial, co-chaired by Michael J. Fisher, MD at CHOP, were recently published in Nature’s cure.
“This is the second class of drugs to demonstrate a promising response rate for NF1 patients with these tumors,” said first author Fisher, Head of the Department of Neuro-Oncology and Director of the Neurofibromatosis Program at CHOP, and Group Chair for the NF Clinical Trials Consortium, which includes 25 sites developing innovative biologically based clinical trials for NF complications.
“Together, the data presented in this study reflect a true bed-to-bed approach, coordinating translational and clinical efforts to advance targeted treatments for a rare disease such as NF1.”
NF1 is a rare tumor predisposition syndrome, affecting approximately 1 in 3000 people worldwide. The condition involves the proliferation of tumors throughout the central and peripheral nervous system.
One of the most common tumor types in NF1 is plexiform neurofibromas (PN), multicellular tumors composed of tumorigenic Schwann cells, fibroblasts, perineural cells, macrophages, mast cells, and secretory collagen.
The tumors arise inside nerves, affecting up to half of patients with NF1, grow rapidly during infancy, and can lead to motor and sensory dysfunction, pain, and deformity.
When the tumors affect vital structures such as the airway or the spine, they can be life-threatening, and while the tumors are not malignant, they can be so time.
Because chemotherapy and radiation are ineffective in treating these tumors, surgery is the current level of care. However, because the tumors can be interconnected by nerves and other vital structures, surgery is often not possible.
Recent studies have shown that an MEK inhibitor called selumetinib may be an effective treatment in some children with NF1-related PNs, but not all patients respond to this treatment, and therefore more treatment options are needed.
Based on preclinical studies of cabozantinib, a tyrosine kinase inhibitor that targets both tumorigenic Schwann cells in PNs as well as complex tumor microenvironments, the researchers enrolled patients in a single-arm Phase 2 clinical trial , multi-center.
Twenty-three patients between 16 and 34 were enrolled in the trial; twenty-one were valuable for drug poisoning and 19 were valuable for their response to treatment. Of the 19 patients examined for response, eight (42%) had a partial response, described as less than 20% in tumor volume, and 11 had persistent disease after 12 cycles of treatment .
No patient had any disease progression while participating in the trial. The eight patients who received a complementary response to treatment also reported a significant reduction in tumor pain intensity and pain inhibition in daily life.
Patients enrolled in the trial reported several adverse events, including diarrhea, nausea, asymptomatic hypothyroidism, muscle weakness, and palmar-plantar erythrodysesthesia, a condition that causes redness, swelling, and pain. palms of hands and / or soles of feet. . However, none of the side effects were reported to be serious.
Based on the benefit of cabozantinib revealed in this study, the NF Clinical Trials Consortium also opened a pediatric cohort, enrolling patients ages 3 to 15. Registration is complete, and the study is ongoing.
It is very interesting that we now have two types of drugs that lead to tumor responses, since we did not have promising agents just a few years ago. However, despite this excitement, the cabozantinib or MEK inhibitors do not reduce all tumors or remove them completely. Therefore, we are building on these results in addition to ongoing laboratory studies and plan a future study of combination therapies, so that we can further improve outcomes for patients. that with those destructive and dangerous tombs. “
Michael J. Fisher, MD, First Study Author, Head of the Department of Neuro-Oncology and Director of the Neurofibromatosis Program, Philadelphia Children’s Hospital
Source:
Philadelphia Children ‘s Hospital
Magazine Reference:
Fisher, MJ, et al. (2021) Cabozantinib for type 1 neurofibromatosis associated with associated plexiform neurofibromas: a phase 2 trial. Nature’s cure. doi.org/10.1038/s41591-020-01193-6.