Inefficiencies in Phase II to Phase III Transition Impeding Successful Drug Development in Glioblastoma

Overview

Journal Neurooncol Adv

Publisher Oxford University Press

Date 2021 Feb 5

PMID 33543145

Citations 1

Authors

Adithya Balasubramanian

Ashray Gunjur

Umbreen Hafeez

Siddharth Menon

Lawrence M Cher

Sagun Parakh

Hui Kong Gan

Affiliations

Soon will be listed here.

Abstract

Background: Improving outcomes of patients with glioblastoma (GBM) represents a significant challenge in neuro-oncology. We undertook a systematic review of key parameters of phase II and III trials in GBM to identify and quantify the impact of trial design on this phenomenon.

Methods: Studies between 2005 and 2019 inclusive were identified though MEDLINE search and manual bibliography searches. Phase II studies (P2T) were restricted to those referenced by the corresponding phase III trials (P3T). Clinical and statistical characteristics were extracted. For each P3T, corresponding P2T data was "optimally matched," where same drug was used in similar schedule and similar population; "suboptimally matched" if dis-similar schedule and/or treatment setting; or "lacking." Phase II/III transition data were compared by Pearson Correlation, Fisher's exact or chi-square testing.

Results: Of 20 P3Ts identified, 6 (30%) lacked phase II data. Of the remaining 14 P3T, 9 had 1 prior P2T, 4 had 2 P2T, and 1 had 3 P2T, for a total of 20 P3T-P2T pairs (called dyads). The 13 "optimally matched" dyads showed strong concordance for mPFS ( = 0.95, < .01) and mOS ( = 0.84, < .01), while 7 "suboptimally matched" dyads did not ( > .05). Overall, 7 P3Ts underwent an ideal transition from P2T to P3T. "Newly diagnosed" P2Ts with mPFS < 14 months and/or mOS< 22 months had subsequent negative P3Ts. "Recurrent" P2Ts with mPFS < 6 months and mOS< 12 months also had negative P3Ts.

Conclusion: Our findings highlight the critical role of optimally designed phase II trials in informing drug development for GBM.

Citing Articles

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.

Bagley S, Kothari S, Rahman R, Lee E, Dunn G, Galanis E Clin Cancer Res. 2021; 28(4):594-602.

PMID: 34561269 PMC: 9044253. DOI: 10.1158/1078-0432.CCR-21-2750.

References

Friedman H, Prados M, Wen P, Mikkelsen T, Schiff D, Abrey L . Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009; 27(28):4733-40. DOI: 10.1200/JCO.2008.19.8721. View

Schulz K, Altman D, Moher D . CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010; 340:c332. PMC: 2844940. DOI: 10.1136/bmj.c332. View

Batchelor T, Duda D, Tomaso E, Ancukiewicz M, Plotkin S, Gerstner E . Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010; 28(17):2817-23. PMC: 2903316. DOI: 10.1200/JCO.2009.26.3988. View

Brandes A, Franceschi E, Tosoni A, Benevento F, Scopece L, Mazzocchi V . Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer. 2009; 115(15):3512-8. DOI: 10.1002/cncr.24406. View

Immonen A, Vapalahti M, Tyynela K, Hurskainen H, Sandmair A, Vanninen R . AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther. 2004; 10(5):967-72. DOI: 10.1016/j.ymthe.2004.08.002. View

Gilbert M, Dignam J, Armstrong T, Wefel J, Blumenthal D, Vogelbaum M . A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8):699-708. PMC: 4201043. DOI: 10.1056/NEJMoa1308573. View

Crombet Ramos T, Figueredo J, Catala M, Gonzalez S, Selva J, Cruz T . Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3: report from a phase I/II trial. Cancer Biol Ther. 2006; 5(4):375-9. DOI: 10.4161/cbt.5.4.2522. View

Zia M, Siu L, Pond G, Chen E . Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. J Clin Oncol. 2005; 23(28):6982-91. DOI: 10.1200/JCO.2005.06.679. View

Sampson J, Aldape K, Archer G, Coan A, Desjardins A, Friedman A . Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 2010; 13(3):324-33. PMC: 3064599. DOI: 10.1093/neuonc/noq157. View

10.

Monzon J, Hay A, McDonald G, Pater J, Meyer R, Chen E . Correlation of single arm versus randomised phase 2 oncology trial characteristics with phase 3 outcome. Eur J Cancer. 2015; 51(17):2501-7. DOI: 10.1016/j.ejca.2015.08.004. View

11.

Stupp R, Hegi M, Neyns B, Goldbrunner R, Schlegel U, Clement P . Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma. J Clin Oncol. 2010; 28(16):2712-8. DOI: 10.1200/JCO.2009.26.6650. View

12.

Wick W, Puduvalli V, Chamberlain M, van den Bent M, Carpentier A, Cher L . Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010; 28(7):1168-74. PMC: 2834468. DOI: 10.1200/JCO.2009.23.2595. View

13.

Kreisl T, Kotliarova S, Butman J, Albert P, Kim L, Musib L . A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol. 2010; 12(2):181-9. PMC: 2940576. DOI: 10.1093/neuonc/nop042. View

14.

DiMasi J, Grabowski H, Hansen R . Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ. 2016; 47:20-33. DOI: 10.1016/j.jhealeco.2016.01.012. View

15.

Schuster J, Lai R, Recht L, Reardon D, Paleologos N, Groves M . A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 2015; 17(6):854-61. PMC: 4483122. DOI: 10.1093/neuonc/nou348. View

16.

Dresemann G, Weller M, Rosenthal M, Wedding U, Wagner W, Engel E . Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide. J Neurooncol. 2009; 96(3):393-402. DOI: 10.1007/s11060-009-9976-3. View

17.

Taal W, Oosterkamp H, Walenkamp A, Dubbink H, Beerepoot L, Hanse M . Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014; 15(9):943-53. DOI: 10.1016/S1470-2045(14)70314-6. View

18.

Westphal M, Yla-Herttuala S, Martin J, Warnke P, Menei P, Eckland D . Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013; 14(9):823-33. DOI: 10.1016/S1470-2045(13)70274-2. View

19.

Grossman S, Schreck K, Ballman K, Alexander B . Point/counterpoint: randomized versus single-arm phase II clinical trials for patients with newly diagnosed glioblastoma. Neuro Oncol. 2017; 19(4):469-474. PMC: 5464324. DOI: 10.1093/neuonc/nox030. View

20.

Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G . Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol. 2010; 12(8):871-81. PMC: 2940677. DOI: 10.1093/neuonc/nop054. View