A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma

Chris Twelves, Michael Sabel, Daniel Checketts, Sharon Miller, Bola Tayo, Maria Jove, Lucy Brazil, Susan C Short, GWCA1208 study group, Catherine McBain, Brian Haylock, Paul Mulholland, Christopher Herbert, Allan James, Mohan Hingorani, Joerg Berrouschot, Rainer Fietkau, Jens Panse, Chris Twelves, Michael Sabel, Daniel Checketts, Sharon Miller, Bola Tayo, Maria Jove, Lucy Brazil, Susan C Short, GWCA1208 study group, Catherine McBain, Brian Haylock, Paul Mulholland, Christopher Herbert, Allan James, Mohan Hingorani, Joerg Berrouschot, Rainer Fietkau, Jens Panse

Abstract

Background: Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM.

Methods: Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored.

Results: The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK.

Conclusions: With personalised dosing, nabiximols had acceptable safety and tolerability with no drug-drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial.

Clinical trial registration: ClinicalTrials.gov: Part 1- NCT01812603; Part 2- NCT01812616.

Conflict of interest statement

D.C., S.M. and B.T. are employed by and hold share options in GW. C.T., M.S., M.J., L.B. and S.S. have no conflicts of interest to declare.

Figures

Fig. 1. Proportion of patients in each…
Fig. 1. Proportion of patients in each KPS category at baseline.
KPS Karnofsky Performance Scale.
Fig. 2. Disposition of patients enrolled.
Fig. 2. Disposition of patients enrolled.
a Trial Part 1 (open-label). b Trial Part 2 (randomised). CBD cannabidiol, THC, Δ9-tetrahydrocannabinol.
Fig. 3. Kaplan–Meier survival curves (randomised safety…
Fig. 3. Kaplan–Meier survival curves (randomised safety analysis set).
Patients who did not die during the 1-year analysis period were censored and marked by a +. If a patient was alive at the end of treatment, then the end of treatment visit was the date at which they were censored. Otherwise if a patient withdrew, they were censored at the date of the survival status review. If a patient was lost to follow-up then they were censored at the last known visit date. The number of patients at risk at a given timepoint was the number still alive or who had not been censored.

References

    1. Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013. Neuro Oncol. 2016;18(Suppl 5):v1–v75. doi: 10.1093/neuonc/now207.
    1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330.
    1. Seystahl K, Wick W, Weller M. Therapeutic options in recurrent glioblastoma—an update. Crit. Rev. Oncol. Hematol. 2016;99:389–408. doi: 10.1016/j.critrevonc.2016.01.018.
    1. Carson KA, Grossman SA, Fisher JD, Shaw EG. Prognostic factors for survival in adult patients with recurrent glioma enrolled on new approaches to brain tumour therapy ‘NABTT’ CNS consortium phase I and II clinical trials. J. Clin. Oncol. 2007;25:2601–2606. doi: 10.1200/JCO.2006.08.1661.
    1. Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, et al. Scale to predict survival after surgery for recurrent glioblastoma multiforme. J. Clin. Oncol. 2010;28:3838–3843. doi: 10.1200/JCO.2010.30.0582.
    1. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 2014;15:e395–e403. doi: 10.1016/S1470-2045(14)70011-7.
    1. Mun, E. J., Babiker, H. M., Weinberg, U., Kirson, E. D. & Von Hoff, D.D. Tumor-treating fields: a fourth modality in cancer treatment. Clin. Cancer Res. 24, 266–275 (2018).
    1. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur. J. Cancer. 2012;48:2192–2202. doi: 10.1016/j.ejca.2012.04.011.
    1. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs. temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314:2535–2543. doi: 10.1001/jama.2015.16669.
    1. Tanaka S, Akimoto J, Narita Y, Oka H, Tashiro T. Is the absolute value of O(6)-methylguanine-DNA methyltransferase gene messenger RNA a prognostic factor, and does it predict the results of treatment of glioblastoma with temozolomide? J. Neurosurg. 2014;121:818–826. doi: 10.3171/2014.6.JNS132535.
    1. Hegi ME, Genbrugge E, Gorlia T, Stupp R, Gilbert MR, Chinot OL, et al. MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide. A pooled analysis of four clinical trials. Clin. Cancer Res. 2019;25:1809–1816. doi: 10.1158/1078-0432.CCR-18-3181.
    1. Herrlinger U, Tzaridis T, Mack F, Steinbach JP, Schlegel U, Sabel M, et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet. 2019;393:678–688. doi: 10.1016/S0140-6736(18)31791-4.
    1. Maroon J, Bost J. Review of the neurological benefits of phytocannabinoids. Surg. Neurol. Int. 2018;9:91. doi: 10.4103/sni.sni_45_18.
    1. Pertwee RG. Neuropharmacology and therapeutic potential of cannabinoids. Addict. Biol. 2000;5:37–46. doi: 10.1080/13556210071252.
    1. Pertwee, R. G. In Cannabinoids (ed. Di Marzo V.) pp 32–83 (Kluwer Academic/Plenum Publishers, New York, USA, 2004).
    1. Mechoulam R, Hanus L. Cannabidiol: an overview of some chemical and pharmacological aspects. Part I Chem. Asp. Chem. Phys. Lipids. 2012;121:35–43. doi: 10.1016/S0009-3084(02)00144-5.
    1. Grotenhermen F. Pharmacology of cannabinoids. Neuro Endocrinol. Lett. 2004;25:14–23.
    1. Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802. doi: 10.1111/epi.12631.
    1. Schubart C, Sommer IE, Fusar-Poli P, de Witte L, Kahn RS, Boks MP. Cannabidiol as a potential treatment for psychosis. Eur. Neuropsychopharmacol. 2014;24:51–64. doi: 10.1016/j.euroneuro.2013.11.002.
    1. Espejo-Porras F, Fernández-Ruiz J, Pertwee RG, Mechoulam R, García C. Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors. Neuropharmacology. 2013;75:155–163. doi: 10.1016/j.neuropharm.2013.07.024.
    1. Nabissi M, Morelli MB, Santoni M, Santoni G. Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents. Carcinogenesis. 2013;34:48–57. doi: 10.1093/carcin/bgs328.
    1. Hassan S, Eldeeb K, Millns PJ, Bennett AJ, Alexander SP, Kendall DA. Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation. Br. J. Pharmacol. 2014;171:2426–2439. doi: 10.1111/bph.12615.
    1. Brown KJ, Laun AS, Song ZH. Cannabidiol, a novel inverse agonist for GPR12. Biochem. Biophys. Res. Commun. 2017;493:451–454. doi: 10.1016/j.bbrc.2017.09.001.
    1. Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc. Natl Acad. Sci. USA. 2017;114:11229–11234. doi: 10.1073/pnas.1711351114.
    1. Laun AS, Song ZH. GPR3 and GPR6, novel molecular targets for cannabidiol. Biochem. Biophys. Res. Commun. 2017;490:17–21. doi: 10.1016/j.bbrc.2017.05.165.
    1. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br. J. Pharmacol. 2008;153:199–215. doi: 10.1038/sj.bjp.0707442.
    1. Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol. Psychiatry. 2016;79:516–525. doi: 10.1016/j.biopsych.2015.07.028.
    1. Ellert-Miklaszewska A, Ciechomska I, Kaminsk B. Cannabinoid signaling in glioma cells. Adv. Exp. Med. Biol. 2013;986:209–220. doi: 10.1007/978-94-007-4719-7_11.
    1. Rocha FC, Dos Santos Júnior JG, Stefano SC, da Silveira DX. Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J. Neurooncol. 2014;116:11–24. doi: 10.1007/s11060-013-1277-1.
    1. Dimitru CA, Sandalcioglu IE, Karsak M. Cannabinoids in glioblastoma therapy: new applications for old drugs. Front. Mol. Neurosci. 2018;11:159. doi: 10.3389/fnmol.2018.00159.
    1. Torres S, Lorente M, Rodríguez-Fornés F, Hernández-Tiedra S, Salazar M, García-Taboada E, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol. Cancer Ther. 2011;10:90–103. doi: 10.1158/1535-7163.MCT-10-0688.
    1. Guzmán M, Duarte MJ, Blázquez C, Ravina J, Rosa MC, Galve-Roperh I, et al. A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br. J. Cancer. 2006;95:197–203. doi: 10.1038/sj.bjc.6603236.
    1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109. doi: 10.1007/s00401-007-0243-4.
    1. Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, et al. Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain. J. Pain Symptom Manag. 2018;55:179–188. doi: 10.1016/j.jpainsymman.2017.09.001.
    1. Fallon MT, Lux AE, McQuade R, McQuade R, Rossetti S, Sanchez R, et al. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. Br. J. Pain. 2017;11:119–133. doi: 10.1177/2049463717710042.
    1. Ballman KV, Buckner JC, Brown PD, Giannini C, Flynn PJ, LaPlant BR, et al. The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro Oncol. 2007;9:29–38. doi: 10.1215/15228517-2006-025.
    1. Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G, ESMO Guidelines Working Group. High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2014;25(Suppl 3):iii93–iii101. doi: 10.1093/annonc/mdu050.
    1. Prognostic calculator for survival for patient with recurrent GBM. (2020).
    1. Norden AD, Lesser GL, Drappatz J, Ligon KL, Hammond SN, Lee EQ, et al. Phase 2 study of dose-intense temozolomide in recurrent glioblastoma. Neuro Oncol. 2013;15:930–935. doi: 10.1093/neuonc/not040.
    1. Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318:2306–2316. doi: 10.1001/jama.2017.18718.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe