A Discussion with Dr Abhijit Guha

Update 2016 – Due to the unfortunate passing of Dr Guha, this trial has been closed. 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 (UHN), 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 Research Institute (HRI) and found thatthey over expressed 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 (VS), 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. They are using a consortium of hospitals throughout Canada to recruit patients, majority of whom will have NF2.

A pediatric Phase 1 dose escalation trial is planned for the near future through Hospital for Sick Children in Toronto, the largest pediatric hospital in Canada.

While Dr. Guha is excited about the potential of this drug, he, like many others believe that NF2 may have to be treated with a combination of current treatment 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’.

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