Improving Tumor Treating Fields Treatment for Brain Cancer Patients With Skullremodeling Surgery (Neurosurgery)
Improving Tumor Treating Fields Treatment for Brain Cancer Patients With Skullremodeling Surgery (Neurosurgery)
The aim of this trial is to test a new potential treatment, skullremodeling surgery
 (SR-surgery) combined with tumor treating fields (TTFields), for patients with first
 recurrence of malignant brain tumor (first recurrence of glioblastoma). Glioblastoma is one
 of the most malignant cancers.

 TTFields is a new treatment for brain cancer (glioblastoma), which is used in additional to
 surgery (removal of the tumor), chemotherapy and radiation. TTFields work by sending
 alternating current to the tumor. The current disrupts cell division and thus prevents cancer
 growths. Electrodes are placed on the scalp and the current is delivered via a small portable
 battery (1kg). Treatment duration is 18 hours during the day, where the patient can do normal
 daily activities. The average life expectancy of a newly diagnosed brain cancer patient
 (glioblastoma) is increased from 15 months to 21 months by adding TTFields.

 SR-surgery is a minor and safe procedure, that involves creating small burrholes in the skull
 over the tumor location. The burrholes are approximately 15 mm in diameter. The burrholes
 increase the electric current in the tumor by funneling the electricity trough the path of
 least resistance, since bone hinders the electricity.

 The theory is that combining TTFields with SR-surgery we can increase the effect of TTFields
 and in return increase overall survival for brain cancer patients.

 The investigators have recently finished a phase 1 clinical trial, with 15 trial
 participants, testing the safety and efficacy of our combined treatment. The investigators
 concluded that TTFields and SR-surgery combined is safe and showed promising results by
 increasing overall survival with the trial participants.

 Therefor we wish to proceed with a phase 2 trial.

 Method The investigators aim to include 70 patients with first recurrence of glioblastoma
 (brain cancer). Each patient will be randomized to one of two treatment arms. Both treatment
 arms will receive the best current brain tumor treatment. In addition, one arm receives TTF
 and the other arm TTFields and SR-surgery.

 All patients are expected to receive better treatment than current best practice, since
 TTFields is not standard treatment in Denmark.

 The primary aim of the trial is to assess the 12-month overall survival in both groups. The
 theory is that more trial participants will be alive after 12 months in the group that
 receives both TTF and SR-surgery.

 The trial duration is 36 months with an average expected follow-up of 18 months.
Introduction Tumor treating fields (TTFields) are low-intensity (1-3 v/m) intermediate
 frequency (200 khz for GBM) alternating fields that disrupt cell division. The treatment is
 increasingly used as a supplementary modality for patients with glioblastoma (GBM). Recent
 randomized clinical studies have demonstrated tolerability of TTFields (Optune®, Novocure®)
 for both newly diagnosed and recurrent GBM and a significant and sustained survival benefit
 in the former population. Specifically, the addition of TTFields to maintenance temozolomide
 (TMZ) therapy for newly diagnosed GBM patients, who had completed initial concurrent
 radio-chemotherapy, resulted in significantly prolonged median progression-free survival (PFS
 = 6.7 vs. 4.0 months, p<0.001) and median overall survival (OS = 20.9 vs. 16.0 months,
 p<0.001) compared to maintenance TMZ therapy alone (ef-14 trial) (4). Consequently, TTFields
 were recently approved by the US FDA and included as a category 1 recommendation in the most
 recent guidelines from the National Comprehensive Cancer Network (NCCN) for the treatment of
 newly diagnosed GBM. For recurrent GBM, TTFields monotherapy has been shown to have
 equivalent efficacy and a superior toxicity profile compared to best practice medical
 oncological therapy. This led to US FDA approval for this indication in 2011. In addition, a
 post-hoc analysis of the EF-14 dataset has indicated that the addition of TTFields to 2nd
 line medical oncological treatment at first disease recurrence leads to an overall survival
 benefit. Finally, the pride dataset showed that the addition of TTFields to current practice
 of medical oncological treatment was beneficial.

 Recently, the investigators proposed a novel approach to calculate the electrical field
 distribution induced by TTFields therapy of GBM. The approach utilizes finite element
 analysis and incorporates personalized MRI data to provide a realistic and individualized
 estimate of the field intensity distribution, which is associated with the antimitotic
 efficacy of the treatment. Using this approach, the investigators showed that targeted
 skull-remodeling surgery, e.g. craniectomy or multiple burr-holes, can provide a substantial
 and highly focused enhancement (~100%) of the median field intensity in supratentorial
 tumors, while leaving the field distribution in healthy tissues unaffected.

 These results support the theoretical rationale that small and clinically feasible
 craniectomies may improve the clinical efficacy of TTFields for cerebral hemispheric tumors
 without compromising patient safety. Based on these findings, the investigators recently
 concluded an open-label, single arm, prospective phase 1 trial (NCT02893137) to investigate
 safety and feasibility of SR-surgery with TTFields and best practice neuro-oncological
 therapy for recurrent GBM. The trial was active from December 2016 to May 2019. The planned
 total number of patients was fifteen. Eligibility criteria included age > 18 years, first
 recurrence focal supratentorial GBM (RANO), and KPS ≥ 70. Patients were right-censored for OS
 and PFS at the time of analysis and excluded upon progression, death, SUSARs, or unacceptable
 AEs. The primary endpoint was toxicity (CTCAEv4.0). The secondary endpoints were OS, PFS, PFS
 rate at six months (PFS6), objective response rate (ORR) based on the iRANO criteria (14),
 quality of life (QoL), Karnofsky performance score (KPS), and steroid dose.20 patients were
 screened, 2 declined, and 3 had KPS < 70. Of the 15 enrolled patients, 4 were excluded prior
 to TTFields due to radionecrosis/non-recurrence, post-op infection, neurodeficit and
 withdrawal of consent, respectively. All included patients (11 male and 2 female) had GBM
 IDH-wt tumors (4 MGMT-methylated). Median KPS was 90 (range 70-100) and median age 57 years
 (range 39 to 67). All patients received maximum safe resection at recurrence (4 had no
 residual tumor (RANO), 5 non-measurable disease, and 2 measurable disease). 9 patients
 received adjuvant bevacizumab monotherapy and 2 temozolomide rechallenge. The mean
 skull-defect area was 10.6 cm2 (range 7 to 37 cm2) and the median field enhancement 43 %
 (range 25 to 59%). The median follow-up duration was 10 months and the median TTFields
 compliance 90% (range 48 to 98%). We observed no SUSARs, no grade 4/5 SAEs, 12 grade 3 SAEs
 (6 generalized seizures in patients with known epilepsy, 1 post-op infection, 1 diarrhea,
 1TIA, 1 fatigue, 1 headache and 1 DVT). The most common grade AE 1-2 was headache 60% CI95%=
 [32; 84], fatigue 53%, CI95%= [27; 79], skin rash 47%, CI95%= [21; 73], and nausea 40%,
 CI95%= [16; 68].

 Regarding survival results were PFS6 was 64%, CI95%= [35; 85], PFS= 8.8 months, CI95%= [6.2;
 13.2], OS= 15.0 months, CI95%= [9.6;16.2], and OS12= 64%, CI95%= [35;85]. One patient had
 complete response during TTFields. Based on these results, the investigators concluded that
 skull-remodelling surgery incl. craniectomy is not associated with additional toxicity in
 combination with TTFields and best practice medical oncological treatment and holds promising
 potential for improving TTFields outcome by focally enhancing the field intensity in the
 tumor. The proposed phase 2 trial aims to validate this hypothesis in a randomized
 comparative setting.

 METHODS AND ANALYSIS Trial design The study is designed as an investigator-initiated,
 prospective, multi-center, multi-national, randomized, minimax two-stage, comparative, phase
 2 trial, investigating superior efficacy of the intervention. Patients randomized to the
 control arm will receive TTFields plus best physician's choice medical oncological treatment
 (BPC treatment) and patients in the interventional arm will receive SR-surgery in addition to
 TTFields and BPC treatment. The trial will enroll an expected sample size of 70 patients from
 4-6 scandinavian countries with Aarhus University Hospital, Denmark, as the Sponsor and
 coordinating site. The primary outcome will be overall survival at 12 months (OS12) and the
 trial is designed to detect a 20% increase in OS12 in the interventional arm compared to
 control (from 40% in the control arm to 60% in the interventional arm). Secondary outcomes
 will include progression-free survival (PFS), quality of life (QoL), clinical performance,
 and objective response rate (ORR). Interim futility analysis will be conducted after 12
 months follow-up of the first 52 patients. The trial will be stopped at interim analysis if
 the OS12 months is lower in the control arm compared to the interventional arm. The trial
 design and data reporting is in accordance with the consort 2010 statement, the gnosis
 standards for neuro-oncology trials, recent RANO recommendations for phase 2 trial design in
 neuro-oncology, and general recommendations for phase 2/3 trial design (16-19). The study
 will be performed in the period march 2020 to march 2023. The inclusion period is expected to
 be the first 24 months of the trial.

 Participants Seventy (70) patients with progressive GBM according to RANO criteria will be
 enrolled. Potential trial participants will be identified at an institutional
 multidisciplinary neuro-oncological tumor boards and subsequently referred for eligibility
 screening. All inclusion scans are assessed by a trained neuroradiologist. Patients who are
 immediately ineligible, e.g. due to poor performance status, multifocal disease, significant
 comorbidity, evidence of extracranial primary tumor, or other excluding circumstances, will
 not be referred for screening.

 Experimental intervention Patients will be randomised 1:1 to one of two study arms to receive
 either, 1) SR-surgery, TTFields and best practice medical oncological therapy (interventional
 arm), or 2) TTFields and best practice medical oncological therapy alone (control arm). Best
 practice treatment will typically also include maximum safe resection. Since the intervention
 (SR-surgery) is only effective during TTFields therapy, TTFields will continue until 1)
 patient exclusion from the trial, 2) occurrence of a suspected unexpected serious adverse
 reaction (SUSAR) related to the intervention, or 3) ethical or medical safety
 contraindication for further TTFields therapy determined by the investigators. This means
 that treatment may continue beyond progression, as long as active treatment is indicated, and
 in some cases as compassionate use.

 Sample size and statistical considerations The sample size calculations were based on a
 randomized, comparative, minimax two-stage design and the binomial primary outcome of OS12
 for the patient population treated per protocol, i.e. for whom TTFields therapy was
 initiated. This means that patients excluded prior to TTFields therapy initiation are not
 included in the primary outcome analysis. Therefore, additional patients may be enrolled to
 ensure that the planned sample receives active TTFields treatment. The aim of the trial is to
 determine whether the intervention is superior to control and thus worthy of further phase 3
 investigation. The expected OS12 in the control arm is set to 40% based on the EORTC 26101
 trial, in which patients with first recurrence of GBM were treated with lomustine monotherapy
 or lomustine/bevacizumab combination therapy. The trial showed an OS12 of approximately 30%
 and we therefore set the expected level of OS12 to be slightly above this threshold given the
 fact that TTFields is added to the treatment which otherwise represents recommended practice.
 There are no current studies providing accurate OS12 estimates for a population comparable to
 the study control arm and we therefore based the estimate on an expected benefit of 10% from
 TTFields alone compared to EORTC 26101. Setting the probabilities of false-positive and
 false-negative trial results to α = 0.15 and 1-β = 0.80, respectively, and defining the
 expected target level of OS12 to be OS12 = 0.6, i.e. a 20% absolute increase (and 50%
 relative increase) compared to the control arm, we calculated a maximum sample size of n = 42
 patients in each arm (total n = 84) and an expected total sample size (en = 69.8). The
 expected sample size en is calculated as en = n1 × pet0 + n × (1 - pet0), where n1 = 52 is
 the collective sample size of both groups at interim (stage 1) analysis, pet0 = 0.44 is the
 probability of early futility termination. The numbers are based on the given statistical
 parameters and a two-stage minimax design as given in sh jung 2018. Interim futility analysis
 will be conducted after endpoint assessment of 52 patients and the trial will be terminated
 if the experimental arm performs worse than the control arm. In this case the futility
 criterion will be defined as OS12experimental < OS12control and this conclusion will
 determine futility at marginal power and significance levels of 1-β* = 0.80 and of α* = 0.20,
 respectively. If the trial is not terminated at interim stage 1 analysis, the trial will
 proceed to enroll a total of 84 patients and terminate when the final OS12 endpoint data have
 been obtained for all patients.

 The secondary outcome measures of hazard rate ratios of PFS and OS will be tested using the
 log-rank test at the 0.05 alpha level. Time-to-event endpoints will be estimated from the
 time of randomization. Toxicity and adverse events will be reported using absolute numbers
 and appropriate risk estimates. Final analysis will be conducted when all patients have been
 excluded or censored, e.g. due to end-of-trial, or loss-to-follow-up. Subgroup analysis based
 on prognostic factors will be performed, incl. analysis of patient characteristics in each
 arm and identification of characteristics of potential responders to the intervention. This
 will also include a correlation analysis between the calculated field distribution and
 outcome estimates. Analyses will be based on both the intent-to-treat population and the
 population proceeding to active therapy (per protocol), i.e. At least four weeks of active
 TTFields therapy with ≥75% average compliance.

 Randomisation and blinding Patients will be randomised immediately upon enrollment in the
 trial, i.e. prior to initial surgery. Randomisation will be performed using randomization.com
 and patients will be randomised in a 1:1 ratio to receive TTFields and best practice medical
 oncological treatment w/o skull remodeling surgery. The study endpoint assessment committee
 will be blinded to the intervention. Local principal investigators, co-investigators and
 sub-investigators will not be blinded, as optimal array planning will require knowledge about
 skull-remodeling surgery. The operating surgeon performing the skull-remodeling surgery will
 not be blinded. Patients will not be blinded, as it will be possible for the patient to feel
 the skull configuration and thereby determine whether SR-surgery was performed.

 Risks and safety precautions General safety considerations concerning Optune® therapy are
 outlined in the related technical and safety material provided by Novocure®. In general,
 TTFields therapy is regarded a safe and recognized treatment for GBM. The most common adverse
 effect is local skin rash in the area underlying the transducer arrays. The risk of skin rash
 will be reduced by slightly moving the arrays during regular array changes. Skin rash may be
 treated with topical corticosteroids, more frequent electrode replacement and short pauses in
 TTFields therapy, if needed. The risk of brain injury due to the skull remodeling aspect of
 surgery is minimal, as the entire operation is performed extra-durally. Minor craniectomies
 do not pose a significant risk of mechanical brain injury. For larger craniectomies, external
 protective headgear, such as a cap with mechanical reinforcement over the unprotected brain
 area, may be used to reduce the risk of traumatic brain injury after craniectomy. In the case
 of post-operative infection or impaired wound healing, antibiotic therapy will be
 administered. If needed, surgical revision/debridement of the wound and potentially removal
 of the bone flap may be performed. In such cases, the patient may proceed to receive or
 continue TTFields therapy at an appropriate time, if it is in the patient's best interest.
 TTFields therapy following removal of the infected bone flap may be accepted even if the
 craniectomy size exceeds 30 cm2. In all cases, the decision whether to continue with TTFields
 therapy after surgery will be based on careful consideration of the expected safety and
 benefit for the patient. All participants will be advised of situations and adverse events,
 in which medical attention is required. Investigators or properly trained medical personnel
 will be available for immediate attention or medical advice specific to the treatment or
 protocol. Patients will receive contact information to the device support specialist, whom
 they may contact in case of technical problems or considerations.

 Monitoring and quality control The project will comply with international guidelines good
 clinical practice (ICH-GCP and ds/en iso 14155:2012. Clinical investigation of medical
 devices for human subjects - good clinical practice) and be monitored by the local contract
 research organization (CRO). Source data, verification of consent, and handling of adverse
 events and near-miss incidents will be subject to 20% sampled monitoring. Full access to all
 source data, incl. patient records, will be granted in relation to trial inspection by the
 relevant national competent authorities. Experimental "waivers" from the protocol will be
 registered in the project trial master file and reported to the relevant authorities. Changes
 to the protocol will be submitted for approval by the relevant authorities in accordance with
 GCP guidelines and regulations.

 Dissemination All results will be published in peer-reviewed international scientific
 journals and presented at international scientific conferences, regardless of academic
 conclusions. Positive, negative, and inconclusive results will be publicly available.
Inclusion Criteria:

 1. age 18 years or older

 2. progressive GBM based on the RANO criteria and whole brain MRI according to the
 consensus recommendations for a standardized brain tumor imaging protocol in clinical
 trials , not older than 4 weeks from the assessment

 3. estimated survival≥ 3 months

 4. supratentorial tumor location

 5. focal disease in the vicinity of the previously known tumor or resection cavity,

 6. KPS≥70

 7. ability to comply with TTFields treatment

 8. eligibility for diagnostic or therapeutic neurosurgery and subsequent best practice
 oncological therapy,

 9. tumor characteristics indicating significant expected benefit from feasible
 craniectomy or SR-surgery combined with TTFields i.e. (a) focal tumor and (b) most
 superficial border of tumor or resection cavity closer than 2 cm from brain surface

 10. use of validated anticonception for fertile female participants in concordance with
 guidelines provided by the danish health and medicines authority,

 11. signed written consent form

 Exclusion Criteria:

 1. pregnancy or nursing (fertile female participants will be required to take a validated
 pregnancy test for evaluation of pregnancy)

 2. infra-tentorial tumor

 3. implanted pacemaker, defibrillator, deep brain stimulator, other implanted electronic
 devices in the brain, or documented clinically significant arrhythmia

 4. uncontrollable symptomatic epilepsy refractory to standard medication

 5. contraindications for skullremodeling surgery, e.g.bleeding diathesis or severe
 infection

 6. significant co-morbidities, i.e. (a)significant liver function impairment (alt >210
 u/l for men and > 135 u/l for women or total bilirubin >25umol/l), (b)significant
 renal impairment (serum creatinine > 1.7 mg/dl= 150 umol/l), (c)coagulopathy (inr> 1.8
 or aptt > 57s), (d) thrombocytopenia (platelet count < 100 x 103/μl =100 x 109/l), (e)
 neutropenia (anc< 1.5 x 103/μl =1.5 x 109/l), (f) anemia ( hb < 10 g/l= 6.0 mmol/l)

 7. severe cognitive impairment

 8. active participation in another therapeutic interventional clinical trial