CTNI-11. CC-115 IN NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA IN THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT): A PHASE II RANDOMIZED BAYESIAN ADAPTIVE PLATFORM TRIAL
Authors: Rahman Rifaquat , Trippa Lorenzo , Fell Geoffrey , Lee Eudocia , Arrillaga-Romany Isabel , Touat Mehdi , McCluskey Christine , Brunno Jennifer , Gaffey Sarah , Drappatz Jan , Lassman Andrew , Galanis Evanthia , Ahluwalia Manmeet , Colman Howard , Nabors Louis , Hepel Jaroslaw , Elinzano Heinrich , Schiff David , Chukwueke Ugonma , Beroukhim Rameen , Nayak Lakshmi , Mcfaline-Figueroa Jose , Batchelor Tracy , Rinne Mikael , Kaley Thomas , Lu-Emerson Christine , Bi Wenya Linda , Arnaout Omar , Haas-Kogan Daphne , Tanguturi Shyam , Cagney Daniel , Aizer Ayal A , Welch Mary , Doherty Lisa , Lavallee Maria , Fisher-Longden Brittany , Dowling Shanna , Geduldig Jack , Watkinson Fiona , Santagata Sandro , Meredith David , Chiocca E Antonio , Reardon David , Ligon Keith , Alexander Brian , Wen Patrick 
Published: December 2020

Abstract

BACKGROUND
CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents.

METHODS
Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used.

RESULTS
Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade &gt; 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to &lt; 10% at time of the trial arm closure.

CONCLUSION
Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.