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ACTR-54. OPEN-LABEL PHASE 1 CLINICAL TRIAL TESTING PERSONALIZED AND TARGETED INTERVENTION WITH SKULL REMODELLING SURGERY TO MAXIMIZE LEVELS OF TTFIELDS INTENSITY FOR HIGHER TREATMENT BENEFIT - THE OPTIMAL TTF STUDY

ABSTRACT: Abstract We present an ongoing open label phase 1 investigator-sponsored trial (NCT02893137) testing safety/efficacy of a novel therapeutic concept for recurrent glioblastoma (GBM). The intervention combines best choice chemotherapy with tumor treating fields (TTFields) and personalized targeted skull remodeling surgery. The objective of skull remodeling surgery is to create paths, which facilitate electric current flow through into the region of pathology. This may involve formation of strategically placed minor craniectomies or burr holes and thinning of the skull. Finite element (FE) calculations indicate that skull remodeling surgery provides a marked and focal enhancement (~100%) of TTFields intensity without significantly compromising patient safety. Patient accrual began Dec 2016. As of June 2017 seven patients have been screened and six out of fifteen patients enrolled. Major eligibility criteria include age > 18 years, first recurrence supratentorial GBM, Karnofsky performance score (KPS) > 60, focal tumor < 2 cm to cortical surface, lack of uncontrollable epilepsy, and lack of significant co-morbidity. Upon inclusion, personalized FE-calculations are performed to validate TTFields enhancement > 25% due by skull remodeling surgery. The primary endpoint is toxicity assessed by CTCAEv4.0. Secondary endpoints include overall survival, progression free survival (PFS), PFS at six months (PFS6), objective response rate (RANO), quality of life (EORTC QLQ-C30 and BN20), KPS, and steroid dose. Follow-up is 18 months and includes regular toxicity assessment (6 week intervals) as well as quality of life and response assessments (3 month intervals). Patients are censored at the end of scheduled follow-up, occurrence of serious or unacceptable adverse events, withdrawal of consent, or loss to follow-up. Interim analysis will be performed upon censoring of the first five patients. The tested concept holds promising potential for improving TTFields outcome by enhancing field intensity in the tumor. The trial will hopefully lay the foundation for future efficacy investigation.

SUBMITTER: Korshoej A

PROVIDER: S-EPMC5692142 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract Background We present a pre-specified interim analysis of an ongoing open-label, investigator-sponsored phase 1 trial (NCT02893137) testing safety/efficacy of a new rGBM treatment. The intervention combines personalized skull-remodeling (SR) surgery with TTFields and best-choice chemotherapy. SR-surgery involves minor craniectomy, burr-holes, and/or skull thinning personalized to enhance TTFields intensity focally in the tumor. Material and Methods Accrual began Dec 2016 (planned total 15 patients). Eligibility: Age > 18 years, first recurrence focal supratentorial GBM (RANO), and KPS ? 70. Personalized electric field calculations were conducted to validate TTFields enhancement > 25% by SR-surgery. Patients were right-censored for OS and PFS at the time of analysis and excluded upon progression, death, SUSARs, or unacceptable AEs. Primary endpoints: Toxicity (CTCAEv4.0). Secondary endpoints: OS, PFS, PFS6, objective response rate (iRANO), quality of life, KPS, and steroid dose. Results The interim analysis was based on data prior to April 1, 2018. Safety data were analyzed for all enrolled patients and efficacy for all patients treated with TTFields. 16 patients were screened, 1 declined, and 2 had KPS < 70. Of the 13 enrolled patients, 3 were excluded prior to TTFields treatment (1 female due to radionecrosis/non-recurrence, 1 male due to post-op infection, and 1 female due to neurodeficit). All included patients (9 male and 1 female) had GBM IDH-wt tumors (4 MGMT-methylated). Median KPS was 90 (range 70–100) and median age 55 years (range 49 to 67). All patients received maximum safe resection at recurrence (4 had no residual tumor (RANO), 4 had non-measurable disease, and 2 had measurable disease). 8 patients received adjuvant bevacizumab monotherapy (10 mg/kg every 2 weeks, median number of cycles 9.5, range 4 to 23) and 2 received temozolomide rechallenge (200 mg/m2 every 4 weeks, 3 and 4 cycles, respectively). The mean skull-defect area was 10.5 cm2 (range 7 to 24 cm2), the median field enhancement 37 % (range 25 to 61%), and the median TTFields compliance 91% (range 61 to 95%). Within the observation period 5 patients had progression, 3 died, 5 were censored for PFS, and 7 for OS. We observed no SUSARs or grade 4/5 SAEs, but 5 grade 3 SAEs (2 generalized seizures in patients with known epilepsy, 1 post-op infection, 1 diarrhea, and 1 DVT). 2 patients had grade 1–2 skin rash, and 1 had grade 1–2 headaches. Median OS was 15.5 months, 95%-CI: 5.9-NA, median PFS 9.5 months, 95%-CI: 3.7-NA, and PFS6 58%, 95%-CI: 0.27–0.90. 1 patient had complete response during TTFields treatment. Conclusion SR-surgery including craniectomy is not associated with additional toxicity in combination with TTFields and holds promising potential for improving TTFields outcome by focally enhancing the field intensity in the tumor. A future phase 2/3 trial is being planned for efficacy assessment.

Project description:Traditional clinical trial designs strive to definitively establish the superiority of an experimental treatment, which results in risk-adverse criteria and large sample sizes. Increasingly, common cancers are recognized as consisting of small subsets with specific aberrations for targeted therapy, making large trials infeasible.To compare the performance of different trial design strategies over a long-term research horizon.We simulated a series of two-treatment superiority trials over 15 years using different design parameters. Trial parameters examined included the number of positive trials to establish superiority (one-trial vs. two-trial rule), ? level (2.5%-50%), and the number of trials in the 15-year period, K (thus, trial sample size). The design parameters were evaluated for different disease scenarios, accrual rates, and distributions of treatment effect. Metrics used included the overall survival gain at a 15-year horizon measured by the hazard ratio (HR), year 15 versus year 0. We also computed the expected total survival benefit and the risk of selecting as new standard of care at year 15 a treatment inferior to the initial control treatment, P(detrimental effect).Expected survival benefits over the 15-year horizon were maximized when more (smaller) trials were conducted than recommended under traditional criteria, using the criterion of one positive trial (vs. two), and relaxing the ? value from 2.5% to 20%. Reducing the sample size and relaxing the ? value also increased the likelihood of selecting an inferior treatment at the end. The impact of ? and K on the survival benefit depended on the specific disease scenario and accrual rate: greater gains for relaxing ? in diseases with good outcome and/or low accrual rates and greater gains for increasing K for diseases with poor outcomes. Trials with smaller sample size did not perform well when using stringent (standard) level of evidence. For each disease scenario and accrual rate studied, the optimal design, defined as the design that the maximized expected total survival benefit while constraining P(detrimental effect) < 2.5%, specified ? = 20% or 10%, and a sample size considerably smaller than that recommended by the traditional designs. The results were consistent under different assumed distributions for treatment effect.The simulations assumed no toxicity issues and did not consider interim analyses.It is worthwhile to consider a design paradigm that seeks to maximize the expected survival benefit across a series of trials, over a longer research horizon. In today's environment of constrained, biomarker-selected populations, our results indicate that smaller sample sizes and larger ? values lead to greater long-term survival gains compared to traditional large trials designed to meet stringent criteria with a low efficacy bar.

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ACTR-54. OPEN-LABEL PHASE 1 CLINICAL TRIAL TESTING PERSONALIZED AND TARGETED INTERVENTION WITH SKULL REMODELLING SURGERY TO MAXIMIZE LEVELS OF TTFIELDS INTENSITY FOR HIGHER TREATMENT BENEFIT - THE OPTIMAL TTF STUDY

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