Preoperative Preradiotherapy TTFields

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Preoperative Preradiotherapy TTFields (PORTRAIT)

Conditions
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Glioblastoma

Intervention / Treatment
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* Device: TTFields


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 35 years (age range of likely to suffer from an IDHwt WHO grade 4 astrocytoma)* Male or female. New radiological diagnosis of glioblastoma. Performance status judged by World Health Organisation, Eastern Cooperative Oncology Group [ECOG] score = 0-1. The patient has been reviewed by Neuro-oncology multidisciplinary team (MDT - neurosurgeon, clinical oncologist, radiologist and pathologist); MDT consensus that offering study entry is clinically appropriate and safe i.e. patient unlikely to come to harm (e.g. hydrocephalus) from delayed surgery and pre-operative TTFields based on available clinical information and imaging. Confirmation at the first clinic visit that study entry is clinically appropriate and safe (e.g. lack of severe and debilitating symptoms of raised intracranial pressure). Intention to treat with surgical resection and postoperative adjuvant therapy as per current standard of care (40Gy/15 fr or 60Gy/30fr). Adequate hematological and biochemical parameters for surgery and contrast agent administration (full blood count and coagulation profile deemed acceptable by clinical team, eGFR >30ml/min). Mental capacity to consent for treatment. Able and willing to give informed consent Able and willing to comply with study protocol requirements to shave head and wear TTFields equipment. Exclusion Criteria: Planned biopsy procedure only. Suspicion of other tumour on CT body scan or known malignancy except non-melanoma skin cancer, completely resected cerCTcCT or prostate cancer (with Prostate Specific Antigen of less than or equal to 0.1 ng/ml) within the past three years. Contraindications to contrast-enhanced MRI scanning (e.g. claustrophobia, gadolinium allergy).

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Optune<br>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. | Device: TTFields<br>* 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.<br>|
| No Intervention: Non-Experimental Arm<br>Patients will follow the routine care pathway for glioblastoma and timings of the following will be determined by the clinical team. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of Pre-Operative and Pre-Radiotherapy TTFields additional to the standard treatment of care (SoC) including adjuvant TTFields. | 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 | 18 months | 
| To determine the incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] of Pre-Operative and Pre-Radiotherapy TTFields additional to the standard treatment of care (SoC) including adjuvant TTFields. | 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) | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concordance between MRI based diagnosis of glioblastoma and definitive histological diagnosis | Evaluate the use of MRI to select glioblastoma patients for PORTRAIT without pathological confirmation. | 18 months | 
| REP: tumour volume difference between the post-operative MRI and pre-radiotherapy MRI. | 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. | 18 months | 
| Registration of postoperative surgical complications | Postoperative surgical complications (e.g. haemorrhage, wound infection, delayed wound healing, seizures). Lower registrations represents a better outcome. | 18 months | 
| Registration of radiotherapy related complications | Radiotherapy related complications (e.g. radiation necrosis). Lower registrations represents a better outcome. | 18 months | 
| Steroid dose after TTFields | Steroid dose recorded after TTFields until the start of the postoperative RT. Lower (or absence of) dose represents a better outcome. | 18 months | 
| Progression free survival | 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. | 18 months | 
| Overall survival | Time period from the date of surgery to the date of death. A longer time period represents a better outcome. | 18 months | 
| Collection of liquid biopsies | Collection of blood and tear fluid samples at matched imaging timepoints. | 18 months | 
| Skin reactions | 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. | 18 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant, Preoperative, Tumour Treating Fields