by Barbara Franklin
Advocure NF2, Inc.
A new NF2 Phase 2 clinical trial has been announced using Nilotinib, the second generation of Gleevec (which has been used for decades in a variety of other human tumors). This trial will be through the University Health Network, Toronto Western Hospital (UHN TWH), in Toronto Canada. Dr. Abhijit Guha, Professor of Neurosurgery will conduct and is the Primary Investigator of this trial. Dr. Guha studied sporadic and NF2 schwannomas cell lines provided by House Ear Institute (HEI) and found they overexpressed PDGF and c-Kit Receptors, which are inhibited by Gleevec. He then tested Gleevec on these cell lines. It inhibited schwannoma viability, proliferation and growth, as well as induced apoptosis or cell death. He reported these findings in Cancer Research, in 2009.
Novartis has developed Nilotinib, by slightly modifying the structure of Gleevec, to address the problem of tumors which become resistance to Gleevec after a period of treatment. This targeted biologic also offers lower toxicity and increased tissue penetration - thus potentially having even better results with less side effects. To date, Nilotinib only has been given to adults who have developed a resistance to Gleevec with very satisfactory results. There have been no similar studies in children and its potential use in schwannomas has not been tested. This trial will consist of 45 adult patients with growing vestibular schwannomas, i.e., as seen in serial MRIs showing volumetric growth greater than 15%. Nilotinib is an oral drug, and in the trial will be taken twice a day. The cohort will include both sporadic and NF2 patients. The drug will be administered for 12 months, with follow up for another two years.
The key exclusions will be vestibular schwannomas which due to compression of the brainstem or hydrocephalus is already causing symptoms such as ataxia and headache. The objectives are to determine if the drug can stabilize the growth of the vestibular schwannomas or cause shrinkage of the tumors as defined by 20% or more reduction by MRI volumetric measurement. In addition to tumor growth, other parameters related to hearing, quality of life will also be measured and compared to historical and concurrent patient groups who are managed with current standard treatment strategies which include observation, surgery or radiosurgery.
It is Dr. Guha’s intention to also track other NF2 associated tumors, such as meningiomas and other schwannomas during the trial. A pediatric Phase 1 dose escalation trial is planned for the near future through Hospital for Sick Children, the largest pediatric hospital in Canada. They are using a consortium of hospitals throughout Canada to recruit patients, the majority of whom will have NF2. While Dr. Guha is excited about the potential of this drug, he, like many others, believes NF2 may have to be treated with a combination of current reatment strategies (surgery, radiosurgery) and likely multiple biological therapies aimed at different biological properties of the tumor cells such as increased proliferation, vascularization etc. The treatment strategies will likely not be the same for all patients, but must be individualized and altered as the tumor and patient characteristics change with time. He pointed out that schwannomas are not driven by just one genetic alteration, but rather multiple pathways and thus, monotherapy will not be the holy grail.
“With Novartis we will evaluate Nilotinib in a single arm Phase2 study on growing vestibular schwannomas (VS) based on serial MRIs (>15% in 3mths). Rationale is based on our published pre-clinical work. 30 patients will be enrolled (per statistical advice), with both sporadic and NF2 associated VS eligible. Patients will receive 400mg Nilotinib bid PO. Tumor response will be monitored with serial MRI using volumetric analysis at 1,3mths and q3mths for 2yrs. Treatment duration will be 1yr.” - Dr. Guha
Abhijit Guha, FACS, FRCSC, MD, MSc, is co-director of the Arthur & Sonia Labbatt Brain Tumour Research Centre at the Hospital for Sick Children’s Research Institute and holds the Alan & Susan Hudson Chair in Neuro-oncology at the University of Toronto. Dr. Guha also undertakes clinical trials in surgical neuro-oncology as a neurosurgeon-scientist based at UHN’s Toronto Western.