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Patients will receive best physician's choice chemotherapy along with Optune therapy and craniotomy surgery. Optune therapy will be administered in the standard configuration and in accordance with current guidelines with the exception of the surgical intervention.

For further information see www.optune.com

Optune

A small hole is placed in the skull between the tumor and the closest Optune electrode. The position and geometry of the craniotomy is determined by computersimulation of the electric field induced by Optune therapy. Craniotomy is a surgical procedure, which is carried out under general anaesthesia.

Craniectomy

Anders R Korshoej, MD

The present study proposes a new and potentially superior clinical approach to Optune™ therapy of selected glioblastoma patients. The approach is based on combining TTFields with targeted surgical skull remodeling, such as minor craniectomy or a distribution of burr holes, designed for the individual patient. Pre-clinical modeling results suggest that such procedures may enhance the induced electrical field strength by up to \~100% and thereby potentially improve the clinical outcome of treated patients to a significant extent.

The study is an open label phase 1 clinical pilot experiment designed to investigate feasibility, safety and efficacy of the concept. Fifteen patients with first recurrence of glioblastoma will be included in the trial. All patients will receive TTFields therapy with targeted craniotomy and best physician's choice chemotherapy.

Enhancing Optune Therapy With Targeted Craniectomy

Enhancing Optune Therapy of Recurrent Glioblastoma Multiforme Using Targeted Surgical Skull Remodeling

NovoCure Ltd.

Aarhus University Hospital

Patients will apply TTFields (a treatment device referred to as Optune) before surgery and continue using this once the stitches are removed (approximately one to two weeks after surgery). Patients will wear the Optune application for 2 to 3 weeks before their standard-of-care (SoC) surgery and 3 to 4 weeks after the surgery (while awaiting their postoperative radiotherapy). Treatment with TTFields will be delivered through 4 transducer arrays with 9 insulated electrodes each placed on the shaved scalp and connected to a portable device set to generate 200-kHz electric fields within the brain.

Patients will follow the routine care pathway for glioblastoma and timings of the following will be determined by the clinical team.

TTFields will be delivered through 4 transducer arrays with 9 insulated electrodes each placed on the shaved scalp and connected to a portable device set to generate 200-kHz electric fields within the brain.

TTFields

Gerben R Borst, MD PhD

Lauren Hewitt, MSc

PreOperative PreRAdIotherapy Tumour Treating Fields (PORTRAIT) is a Phase I study that will test the safety and feasibility of Optune administered preoperatively and preradiotherapy in patients with a new radiological diagnosis of glioblastoma (GBM). Participants will be required to undergo additional MRI sequencing scans and provide blood, tear fluid and tissue samples over a maximum of 6 months. After the study patients will follow their standard treatment pathway.

Glioblastoma is the most common primary malignant brain tumour in adults. Its outcomes are poor due to local disease progression in most patients. Current treatment includes surgery followed by chemotherapy and radiotherapy 4-6 weeks after surgery. In this time interval, some tumour cells do not receive any treatment. Furthermore, studies show that around half of all glioblastoma patients experience rapid early progression (REP) i.e. growth of the tumour in the time interval between surgery and postoperative chemotherapy/radiotherapy. REP is associated with a shorter survival and there are currently no effective treatments or preventative measures to address it.

Optune is a wearable, portable, FDA-approved glioblastoma (GBM) treatment. It works by creating Tumor Treating Fields (TTFields), which are electric fields that slow down or stop GBM cancer cell division. TTFields is the only treatment modality that contributed to the overall survival in the last decade as shown in one Randomized Controlled Trial. The investigators hypothesize that earlier treatment using Optune before the surgery and between the surgery and postoperative radiotherapy can prevent REP and improve patient outcomes. In this phase 1 trial, PORTRAIT (PreOpeRaTive pRerAdIotherapy Ttfields), the study will test the safety and feasibility of giving Optune before surgery and before post-operative radiotherapy in a maximum of 14 patients. Participants will be required to undergo additional MRI sequencing scans and provide blood, tear fluid and tissue samples over a maximum of 6 months.

To maximise PORTRAIT's translational and clinically relevant components, a non-experimental arm (Non-EA) of 28 patients will allow comparisons of data collected from PORTRAIT patients with comparable Standard of Care (SoC) treated patients from the same time frame.

Participants will be invited to the research study if they are over the age of 35 and have a new radiological diagnosis of glioblastoma. All recruitment and treatment will be conducted at the Christie NHS Foundation Trust and Northern Care Alliance NHS Foundation Trust.

The study is funded by a research grant from Novocure.

PORTRAIT is a cohort study including: 14 prospective patients for the experimental arm which assumes a TRUE toxicity rate of 20% (the study needs 13 patients and we allow 1 patient for replacement). This means that there is less than 10% chance that 4 or more patients will experience a toxicity defined as a complication. For the non-experimental arm, 28 prospective patients will be recruited.

Preoperative Preradiotherapy TTFields

Preoperative Preradiotherapy TTFields (PORTRAIT)

Anonymised IPD relating to specified clinical outcomes may be shared upon request. A Clinical Trials Unit approved Data Management Plan will detail the full sharing criteria and agreements.

This endpoint will be tested by skin toxicity / wound complications.

Toxicity is defined using CTCAE v5.0 and study related complications are defined as;

* Skin toxicity grade 3 or higher
* Wound closure or wound healing problems grade 2 or higher that are possibly related to TTFields treatment

This endpoint will be tested by alterations to the original date of surgery and the start of the postoperative radiotherapy;

Study related complications will be defined as;

* Change of surgery date due to symptoms related to the tumour that are possibly related to the TTFields treatment
* Delay of start of the postoperative RT possibly related to the TTFields treatment (later than 6 weeks postoperative)

Evaluate the use of MRI to select glioblastoma patients for PORTRAIT without pathological confirmation.

Evaluate the effect of TTFields on REP - tumour growth between surgery and postoperative chemoradiotherapy, in patients with a new diagnosis of glioblastoma. A lower value represents a better outcome.

Postoperative surgical complications (e.g. haemorrhage, wound infection, delayed wound healing, seizures). Lower registrations represents a better outcome.

Radiotherapy related complications (e.g. radiation necrosis). Lower registrations represents a better outcome.

Steroid dose recorded after TTFields until the start of the postoperative RT. Lower (or absence of) dose represents a better outcome.

Time period from the date of surgery to the date of the MRI scan demonstrating first progression as determined by the neuro-oncology MDT. A longer time period represents a better outcome.

Time period from the date of surgery to the date of death. A longer time period represents a better outcome.

Collection of blood and tear fluid samples at matched imaging timepoints.

Skin reactions defined by CTCAE V5.0 - a rating scale of 1 to 5. 1 indicates minimal toxicity (skin irritation etc), 5 indicates death - or life threatening complications.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Enhancing Optune Therapy With Targeted Craniectomy	NCT02893137	Glioblastoma	Optune Craniectomy	18 Years -	University of Aarhus
Preoperative Preradiotherapy TTFields	NCT06136611	Glioblastoma	TTFields	35 Years -	The Christie NHS Foundation Trust

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