GENERAL SCIENTIFIC SESSION 4 GENERAL SCIENTIFIC SESSION 4
Brain Tumor Clinical Trials: Perspective 2014 Fred G. Barker II, MD Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts Correspondence: Fred G. Barker II, MD, Yawkey 9E, Brain Tumor Center, Massachusetts General Hospital, Fruit St, Boston, MA 02114. E-mail: [email protected] Copyright © 2015 by the Congress of Neurological Surgeons.
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ecent decades have yielded countless significant advances in the scientific basis of human oncology, and despite their rarity, many types of tumor that affect the brain predominantly or exclusively have shared in this harvest. The goal of this review is to briefly outline the changes in clinical trial design that have accompanied these advances in basic science and drug design, from the era of cytotoxic chemotherapy to the present day. For reasons outlined below, this time period is divided into 2 broad eras: the cytotoxic chemotherapy era, extending from the 1970s to about 2005, and the targeted therapy era, roughly 2005 to the present.
CYTOTOXIC CHEMOTHERAPY ERA
The 2014 CNS Annual Meeting presentation on which this article is based is available at http://bit.ly/1CxlaFg.
CLINICAL NEUROSURGERY
Randomized clinical trials in brain tumors began in the 1970s, with the publication late in that decade of several large randomized clinical trials testing radiation and alkylating agents against malignant glioma.1-4 These trials established both the central role of external beam radiation in postoperative treatment of malignant glioma and a modest benefit for alkylating agents such as lomustine and carmustine in the adjuvant setting. Large randomized trials, however, were only the final step in what came to be recognized as a standard paradigm for cancer drug development (Table 1). In this development sequence, phase I trials offered the initial human exposure to a new drug—safety—and sought to determine its optimal dose. As a rule, the optimal dose of either radiation or chemotherapy in the cytotoxic era was the highest tolerated dose, that is, the dose at which the maximum cytotoxic tumor (and normal tissue) effect could be achieved while maintaining a toxicity burden that patients could be expected to survive with acceptable quality of life. With a typical design of escalating doses administered to cohorts of 3 patients per dose level, about 20 patients would be required to evaluate a new agent, and phase II brain tumor trials typically used the dose defined in phase I trials that were conducted in patients with other types of solid tumors. Phase II trials aim to establish the activity of a new agent. In the cytotoxic era, activity was
typically reflected by response, which in the brain tumor context was defined as shrinkage of the tumor on an appropriate imaging study once cross-sectional imaging became widely available. Because malignant gliomas rarely get smaller as part of their natural history, this design allowed comparison of treated patients with an implied control arm with zero or very few responses, eliminating the need for an actual contemporary control arm of patients not receiving the experimental agent. An efficient 2-stage Simon design5 was usually used with an early stopping rule in case of zero responses, and trial sizes were approximately 10 to 40 patients. Phase III trials establish efficacy. In cancer trials during the cytotoxic era, efficacy was typically understood as increased survival. Randomization between experimental and standard treatment was the invariable phase III design during this era. With realistic assumptions about power and minimal clinically significant benefit, most phase III brain tumor trials in the cytotoxic era enrolled 100 to 500 patients. Even given the short survival of malignant glioma patients, multicenter cooperation was necessary to complete phase III trials in a reasonable time frame. Clinical trials groups such as the glioma-specific Brain Tumor Study Group in North America were formed,1,3,4,6 and larger cancer clinical trials groups formed committees focused on brain tumors, including the UK Medical Research Group,7 the European Organization for Research and Treatment of Cancer,8,9 and several US-led consortia such as the Radiation Therapy Oncology Group.10
CLINICAL TRIAL EVOLUTION DURING THE CYTOTOXIC ERA Clinical trial design was not static during the cytotoxic era, with changes affecting the conduct of all phases of brain tumor clinical trials. In phase I, the early 1990s brought the sudden recognition that the use of phase II doses defined on cohorts of systemic cancer patients might not be appropriate for brain tumor patients. In a phase II trial of paclitaxel conducted by the New Approaches to Brain Tumor Therapy
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TABLE 1. Cancer Drug Development in the Cytotoxic Chemotherapy Era Phase I Phase II Phase III
Safety Activity Efficacy
10-20 patients 10-30 patients 100-500 patients
Consortium, the standard phase II dose of 140 mg/m2 was initially used. After 10 patients were treated, no responses were seen, usually sufficient grounds to stop the trial and to declare paclitaxel inactive. It was realized, however, that the common, expected toxicities of paclitaxel such as cytopenia and nonhematological toxicities had not occurred. With further investigation, blood levels of paclitaxel were found to be about 30% of predicted on the basis of systemic cancer patients treated using the same dose, a difference that was attributed to use of phenytoin or other enzyme-inducing antiepileptics in the brain tumor cohort. The trial was reopened with a phase I dose-escalation design, and a much higher phase II dose was eventually reached and tested.11 This and other examples of the same phenomenon12 caused a shift to brain tumor–specific phase I trials for most cytotoxic agents. In phase II, the main changes in trial design affected the definition and measurement of response. Initially, brain tumor trials defined imaging response using nonquantitative, subjective scales such as the one defined by Levin et al13 in 1977. The complete disappearance of enhancing tumor was a rarity with cytotoxic agents; a major or minor reduction in size (or enlargement) was judged subjectively. In 1990, Macdonald et al14 called for greater precision in defining response and proposed a scale based on the cross-sectional area of enhancing tumor on computed tomography or magnetic resonance scans, which was widely adopted. In phase III studies, the main change in design during these years was one of increasing precision in histological entry criteria. Of the first 4 randomized clinical trials testing radiation, chemotherapy, or both in brain tumors, only 1 trial was glioblastoma specific2; the others enrolled all types of anaplastic gliomas.1,3,4 With increasing standardization of the histological diagnosis of malignant gliomas,15 clinicians recognized the substantial difference in survival between patients with glioblastoma and those with grade III tumors16 and began to investigate possible differences in treatment efficacy between grades. An influential meta-analysis published in 199317 indicated that survival benefits did differ between patients with grade III and grade IV tumor, further prompting individualized trials for grade III glioma.18 (It would be almost a decade before a subsequent meta-analysis based on individual patient data showed this conclusion to be incorrect.19) Even more important, small case series showing striking sensitivity of oligodendroglial tumors to alkylating agents began to appear around 1990,20,21 and clinical trials specific for grade III oligodendroglial and mixed gliomas
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soon followed.22,23 The very different clinical course of grade II gliomas was recognized from the start, and these patients were entered into grade-specific trials starting in the 1980s.8,9 Another development during this era was a shift from intravenous delivery of therapy to more spatially limited methods. This shift incorporated such techniques as brachytherapy, radiosurgery, conformal radiation, and boron neutron capture in radiotherapy; intra-arterial chemotherapy, blood-brain barrier breakdown delivery, and surgically implanted therapy such as wafer-based delivery; direct injection of agents into parenchyma at surgery; or postoperative, catheter-based convection enhanced delivery. Although the improvement in spatial specificity and increased drug delivery to the tumor environment was theoretically attractive, only wafer-based delivery of carmustine achieved any success, and this was a modest one.24
TARGETED THERAPY ERA The last positive randomized trial using a cytotoxic therapy against glioblastoma reported was the Stupp et al25 trial in 2005, which rapidly established adjuvant temozolomide radiochemotherapy as standard glioblastoma treatment in North America and Europe.26-29 The important gains in survival achieved during the cytotoxic era are reflected by comparing the median survival without radiation or chemotherapy in early malignant glioma trials, about 4 to 6 months, with the median survival in temozolomide-treated patients with glioblastoma in the Stupp trial, 14.6 months.25 Although some of this gain was undoubtedly due to improvements in general care of glioma patients, the majority can probably be attributed to radiation and temozolomide. In the last 15 years, targeted agents have become the focus for much of investigational oncology. Although the term lacks a precise definition, I use it here to include a wide spectrum of agents including antiangiogenic drugs, immunotherapy, and pharmaceutic agents that act against molecules or pathways that are truly specific for cancer cell growth or survival. All of these classes of agents have now demonstrated clear success in treating systemic cancer. For example, ipilimumab (an immune checkpoint inhibitor) in metastatic melanoma,30 bevacizumab (an antiangiogenic agent) in metastatic colon cancer,31 and imatinib (a selective inhibitor of a tumor-specific BCR-ABL fusion kinase) in chronic myelogenic leukemia32 all demonstrated significant survival benefits in phase III trials in the early 2000s and rapidly gained regulatory approval as standard therapy in these diseases. In some cases, the advance in both safety and efficacy over standard cytotoxic treatment was startling. In a phase III trial reported in 2003, imatinib achieved a 76% complete cytogenetic response rate against patients compared with 15% for standard treatment.32 Toxicity with the targeted agent was much less frequent than with standard therapy; for example, 1% of imatinib patients reported fatigue compared with 24% with standard therapy. The imaging response seen after some targeted agents is so rapid and profound that it has been called a “Lazarus
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BRAIN TUMOR CLINICAL TRIALS
response.” An example was the 81% imaging response rate seen in an early phase I trial of vemurafenib, a V600E-specific BRAF inhibitor, in metastatic melanoma, a tumor previously notoriously resistant to drug treatment.33 Not surprisingly, the many differences in mechanism and results seen with these novel therapies have required changes in clinical trial design. Some themes to keep in mind when considering these specific changes are extensions of the trends described above as beginning during the cytotoxic era: increasing precision in patient selection, care in defining response and selecting end points and success criteria in early-phase trials, and an ever-increasing need for broad-based multicenter cooperation.
TRIAL DESIGN IN THE TARGETED THERAPY ERA In the cytotoxic era, the earliest-phase trial was typically phase I, defining the optimal safe dose for a new agent, typically the highest dose that patients could tolerate because of the tacit assumption that this would maximize antitumor effect. For several reasons, the optimal dose of noncytotoxic agents may not be the maximum tolerated dose. For example, an agent may have sufficiently low toxicity on normal tissues that other considerations actually govern dosing, for example, the maximum “feasible” dose, determined by manufacturing processes, delivery methods, or cost. For some agents, the biological effect no longer increases with higher delivered doses. These issues can be explored with a so-called phase 0 component to an early-phase study.34-36 In phase 0 studies, low doses of the experimental agent are administered, and $1 tumor-specific end points are assessed. Often, this requires sampling of tissue from the tumor, which is then assayed to determine drug penetration into tumor tissue (of obvious importance in brain tumors) and/or a biological effect on tumor metabolism such as inhibition of a target pathway. Phase 0 trials with an imaging end point such as magnetic resonance spectroscopy for an oncometabolite or a positron emission tomography measure of tumor metabolism are also possible although used less often in practice. A phase 0 cohort is an important component of many modern phase I and phase II trials. In addition, the high response rate characteristic of many targeted agents means that significant tumor responses should be anticipated in phase I trials. A desire to maximize efficiency when a drug is targeted at a molecular subpopulation that may be rare can prompt “bucket” phase I trials in which patients with many histological diagnoses are eligible for treatment as long as they have the defining molecular characteristic such as a specific mutation. When such trials include brain tumors, phase 0 arms can help define brain tumor–appropriate dosing and potentially explain failures to achieve responses in brain tumors, thus guiding the decision of whether to proceed to phase II testing.37 In phase II trials, the definition of treatment success has become much more complex with targeted agents.38,39 Through most of the cytotoxic era, reduction of enhancing volume was equated
CLINICAL NEUROSURGERY
directly with a therapeutic tumor effect. Although it was recognized that collateral damage to brain surrounding the tumor from radiation, chemotherapy, or both could produce imaging changes that were indistinguishable from tumor, especially in high-dose radiation context such as brachytherapy, only with the introduction of temozolomide therapy during radiation treatment did these changes become so frequent that imaging progression began to be questioned as a valid end point for phase II studies.40,41 The broader class of mechanisms of noncytotoxic agents also means that tumor stability, rather than tumor shrinkage, might be a plausible form of benefit in many trials. In addition, the observed extremely rapid reduction in contrast-enhancing volume seen with some agents such as vascular endothelial growth factor inhibitors42 can reflect the reconstitution of an intact blood-brain barrier rather than an actual tumor response.43 For all of these reasons, an end point such as progression-free survival44 or overall survival may reflect clinical benefit more accurately than response rate. Use of these end points usually mandates a randomized phase II design,45,46 increasing the size of the trial47 from #30 patients in the cytotoxic era to a typical size of 120 patients in current practice, many of whom will not receive the experimental agent (making accrual and patient retention more difficult). The increasing trend toward conducting phase II trials on enriched populations often compounds accrual problems because multiple patients may need to be screened for each patient who eventually enters the trial. Initial attempts to enrich phase II (and phase III) cohorts were based on biomarkers such as MGMT methylation status or epidermal growth factor receptor vIII amplification in glioblastoma, and future medulloblastoma trials are almost certain to limit cohorts by similar molecular markers. The rarity of many types of brain tumor implies that drugs developed for more common cancers may need to be repurposed for brain tumor subpopulations that may form tiny minorities in already-uncommon tumors.48 As an example, drugs developed against SMO or AKT1 mutations might offer benefit to patients whose meningiomas harbor these mutations, but they each account for only about 5% of all tumors.49,50 In trials enriched for specific biomarkers or molecular characteristics, even obtaining adequate historical control information to choose the sample size for a randomized phase II trial may become problematic. Finally, the possibility that a benefit other than extended survival may be testable in a phase II trial is now more plausible. Regulatory agencies may offer approval based on improvement of symptoms or quality of life in tumor patients, although a minority of drugs are actually approved on this basis.51,52 A possible example is the unexpected improvement of hearing seen in patients with neurofibromatosis type II with acoustic neuromas after treatment with bevacizumab.53 To date, the impact of targeted treatments on brain tumor phase III trial design has been more modest. Aside from the accrual problems mentioned above when trials are limited to enriched subpopulations, certain difficulties can be expected to arise if targeted agents succeed in achieving profound responses in
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Disclosure TABLE 2. Central Nervous System (and Skull Base) Tumor Histologies (Excluding Malignant Glioma) Pilocytic astrocytoma Subependymal giant-cell astrocytoma Pleomorphic xanthoastrocytoma Pilomyxoid tumor Ependymoma Subependymoma Choroid plexus papilloma and carcinoma Medulloblastoma Pineal parenchymal tumors Neurocytoma Acoustic neuroma Meningioma Hemangioblastoma Endolymphatic sac tumor Craniopharyngioma Chordoma Chondrosarcoma Esthesioneuroblastoma Sinonasal undifferentiated carcinoma
enriched populations. Among these is the question of whether a randomized trial against standard treatment can be considered ethical in this situation. To date, full regulatory approval for new cancer drugs has typically required the performance of confirmatory phase III trials even in the face of highly promising phase II trial results. Another problem that would be almost completely novel to neuro-oncology, with the exception of central nervous system lymphoma, is what to do after a complete imaging response has been achieved.
TARGETED THERAPY AND THE UNIVERSE OF CENTRAL NERVOUS SYSTEM TUMORS This review, like neuro-oncology in general, has been heavily weighted toward malignant glioma treatment. The shift toward targeted therapy, however, almost certainly implies that the broad range of nonglioma tumors that occur in the central nervous system will need to be carefully re-evaluated and continually re-examined. Successful examples of targeted therapy use in nonmalignant glioma histologies already exist. Everolimus was first shown to cause a clinically meaningful reduction in tumor volume in tuberous sclerosis–associated subependymal giant-cell astrocytomas in a 2010 phase II trial,54 subsequently confirmed in phase III testing.55 The hearing benefit of bevacizumab in neurofibromatosis-associated acoustic neuromas53 was already mentioned. In fact, many such rare brain tumors (Table 2) are likely to have much simpler tumor genomes than glioblastoma, offering the hope that some rare tumor types may frequently contain driver mutations for which effective drugs have already been developed for other cancers. It is tempting to suggest that these cases will offer the first successes for the targeted therapy era in neuro-oncology.
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Dr Barker receives consulting fees from National Cancer Institute-Cancer Treatment Evaluation Program.
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20. Macdonald DR, Gaspar LE, Cairncross JG. Successful chemotherapy for newly diagnosed aggressive oligodendroglioma. Ann Neurol. 1990;27(5):573-574. 21. Cairncross G, Macdonald D, Ludwin S, et al. Chemotherapy for anaplastic oligodendroglioma: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1994;12(10):2013-2021. 22. Cairncross G, Berkey B, Shaw E, et al. Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. J Clin Oncol. 2006;24(18):2707-2714. 23. van den Bent MJ, Carpentier AF, Brandes AA, et al. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24(18):2715-2722. 24. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas: the Polymer-Brain Tumor Treatment Group. Lancet. 1995;345(8956):1008-1012. 25. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. 26. Johnson DR, O’Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol. 2012;107(2):359-364. 27. Ronning PA, Helseth E, Meling TR, Johannesen TB. A population-based study on the effect of temozolomide in the treatment of glioblastoma multiforme. Neuro Oncol. 2012;14(9):1178-1184. 28. Yabroff KR, Harlan L, Zeruto C, Abrams J, Mann B. Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006. Neuro Oncol. 2012;14(3):351-359. 29. Graus F, Bruna J, Pardo J, et al. Patterns of care and outcome for patients with glioblastoma diagnosed during 2008-2010 in Spain. Neuro Oncol. 2013;15(6): 797-805. 30. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. 31. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350(23):2335-2342. 32. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. 33. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596-599. 34. Kummar S, Doroshow JH, Tomaszewski JE, Calvert AH, Lobbezoo M, Giaccone G. Phase 0 clinical trials: recommendations from the Task Force on Methodology for the Development of Innovative Cancer Therapies. Eur J Cancer. 2009;45(5):741-746. 35. Murgo AJ, Kummar S, Rubinstein L, et al. Designing phase 0 cancer clinical trials. Clin Cancer Res. 2008;14(12):3675-3682. 36. Calvert AH, Plummer R. The development of phase I cancer trial methodologies: the use of pharmacokinetic and pharmacodynamic end points sets the scene for phase 0 cancer clinical trials. Clin Cancer Res. 2008;14(12):3664-3669. 37. Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from
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38. 39.
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the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee. Clin Cancer Res. 2010;16(6): 1726-1736. Galanis E, Wu W, Cloughesy T, et al. Phase 2 trial design in neuro-oncology revisited: a report from the RANO group. Lancet Oncol. 2012;13(5):e196-e204. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in Neuro-Oncology Working Group. J Clin Oncol. 2010;28(11):1963-1972. Brandes AA, Franceschi E, Tosoni A, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 2008; 26(13):2192-2197. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9(5):453-461. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11(1):83-95. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699-708. Lamborn KR, Yung WK, Chang SM, et al. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008;10(2):162-170. Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep. 1985;69(12):1375-1381. Lee JJ, Feng L. Randomized phase II designs in cancer clinical trials: current status and future directions. J Clin Oncol. 2005;23(19):4450-4457. Tang H, Foster NR, Grothey A, Ansell SM, Goldberg RM, Sargent DJ. Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. J Clin Oncol. 2010;28(11):1936-1941. Dirix L. Discovery and exploitation of novel targets by approved drugs. J Clin Oncol. 2014;32(8):720-721. Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet. 2013;45(3):285-289. Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339(6123):1077-1080. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol. 2003;21(7):1404-1411. Rock EP, Kennedy DL, Furness MH, Pierce WF, Pazdur R, Burke LB. Patientreported outcomes supporting anticancer product approvals. J Clin Oncol. 2007;25 (32):5094-5099. Plotkin SR, Stemmer-Rachamimov AO, Barker FG II, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009; 361(4):358-367. Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363(19):1801-1811. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381(9861):125-132.
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Brain Tumor Clinical Trials: Perspective 2014 Fred G. Barker II, MD Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts Correspondence: Fred G. Barker II, MD, Yawkey 9E, Brain Tumor Center, Massachusetts General Hospital, Fruit St, Boston, MA 02114. E-mail: [email protected] Copyright © 2015 by the Congress of Neurological Surgeons.
R
ecent decades have yielded countless significant advances in the scientific basis of human oncology, and despite their rarity, many types of tumor that affect the brain predominantly or exclusively have shared in this harvest. The goal of this review is to briefly outline the changes in clinical trial design that have accompanied these advances in basic science and drug design, from the era of cytotoxic chemotherapy to the present day. For reasons outlined below, this time period is divided into 2 broad eras: the cytotoxic chemotherapy era, extending from the 1970s to about 2005, and the targeted therapy era, roughly 2005 to the present.
CYTOTOXIC CHEMOTHERAPY ERA
The 2014 CNS Annual Meeting presentation on which this article is based is available at http://bit.ly/1CxlaFg.
CLINICAL NEUROSURGERY
Randomized clinical trials in brain tumors began in the 1970s, with the publication late in that decade of several large randomized clinical trials testing radiation and alkylating agents against malignant glioma.1-4 These trials established both the central role of external beam radiation in postoperative treatment of malignant glioma and a modest benefit for alkylating agents such as lomustine and carmustine in the adjuvant setting. Large randomized trials, however, were only the final step in what came to be recognized as a standard paradigm for cancer drug development (Table 1). In this development sequence, phase I trials offered the initial human exposure to a new drug—safety—and sought to determine its optimal dose. As a rule, the optimal dose of either radiation or chemotherapy in the cytotoxic era was the highest tolerated dose, that is, the dose at which the maximum cytotoxic tumor (and normal tissue) effect could be achieved while maintaining a toxicity burden that patients could be expected to survive with acceptable quality of life. With a typical design of escalating doses administered to cohorts of 3 patients per dose level, about 20 patients would be required to evaluate a new agent, and phase II brain tumor trials typically used the dose defined in phase I trials that were conducted in patients with other types of solid tumors. Phase II trials aim to establish the activity of a new agent. In the cytotoxic era, activity was
typically reflected by response, which in the brain tumor context was defined as shrinkage of the tumor on an appropriate imaging study once cross-sectional imaging became widely available. Because malignant gliomas rarely get smaller as part of their natural history, this design allowed comparison of treated patients with an implied control arm with zero or very few responses, eliminating the need for an actual contemporary control arm of patients not receiving the experimental agent. An efficient 2-stage Simon design5 was usually used with an early stopping rule in case of zero responses, and trial sizes were approximately 10 to 40 patients. Phase III trials establish efficacy. In cancer trials during the cytotoxic era, efficacy was typically understood as increased survival. Randomization between experimental and standard treatment was the invariable phase III design during this era. With realistic assumptions about power and minimal clinically significant benefit, most phase III brain tumor trials in the cytotoxic era enrolled 100 to 500 patients. Even given the short survival of malignant glioma patients, multicenter cooperation was necessary to complete phase III trials in a reasonable time frame. Clinical trials groups such as the glioma-specific Brain Tumor Study Group in North America were formed,1,3,4,6 and larger cancer clinical trials groups formed committees focused on brain tumors, including the UK Medical Research Group,7 the European Organization for Research and Treatment of Cancer,8,9 and several US-led consortia such as the Radiation Therapy Oncology Group.10
CLINICAL TRIAL EVOLUTION DURING THE CYTOTOXIC ERA Clinical trial design was not static during the cytotoxic era, with changes affecting the conduct of all phases of brain tumor clinical trials. In phase I, the early 1990s brought the sudden recognition that the use of phase II doses defined on cohorts of systemic cancer patients might not be appropriate for brain tumor patients. In a phase II trial of paclitaxel conducted by the New Approaches to Brain Tumor Therapy
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TABLE 1. Cancer Drug Development in the Cytotoxic Chemotherapy Era Phase I Phase II Phase III
Safety Activity Efficacy
10-20 patients 10-30 patients 100-500 patients
Consortium, the standard phase II dose of 140 mg/m2 was initially used. After 10 patients were treated, no responses were seen, usually sufficient grounds to stop the trial and to declare paclitaxel inactive. It was realized, however, that the common, expected toxicities of paclitaxel such as cytopenia and nonhematological toxicities had not occurred. With further investigation, blood levels of paclitaxel were found to be about 30% of predicted on the basis of systemic cancer patients treated using the same dose, a difference that was attributed to use of phenytoin or other enzyme-inducing antiepileptics in the brain tumor cohort. The trial was reopened with a phase I dose-escalation design, and a much higher phase II dose was eventually reached and tested.11 This and other examples of the same phenomenon12 caused a shift to brain tumor–specific phase I trials for most cytotoxic agents. In phase II, the main changes in trial design affected the definition and measurement of response. Initially, brain tumor trials defined imaging response using nonquantitative, subjective scales such as the one defined by Levin et al13 in 1977. The complete disappearance of enhancing tumor was a rarity with cytotoxic agents; a major or minor reduction in size (or enlargement) was judged subjectively. In 1990, Macdonald et al14 called for greater precision in defining response and proposed a scale based on the cross-sectional area of enhancing tumor on computed tomography or magnetic resonance scans, which was widely adopted. In phase III studies, the main change in design during these years was one of increasing precision in histological entry criteria. Of the first 4 randomized clinical trials testing radiation, chemotherapy, or both in brain tumors, only 1 trial was glioblastoma specific2; the others enrolled all types of anaplastic gliomas.1,3,4 With increasing standardization of the histological diagnosis of malignant gliomas,15 clinicians recognized the substantial difference in survival between patients with glioblastoma and those with grade III tumors16 and began to investigate possible differences in treatment efficacy between grades. An influential meta-analysis published in 199317 indicated that survival benefits did differ between patients with grade III and grade IV tumor, further prompting individualized trials for grade III glioma.18 (It would be almost a decade before a subsequent meta-analysis based on individual patient data showed this conclusion to be incorrect.19) Even more important, small case series showing striking sensitivity of oligodendroglial tumors to alkylating agents began to appear around 1990,20,21 and clinical trials specific for grade III oligodendroglial and mixed gliomas
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soon followed.22,23 The very different clinical course of grade II gliomas was recognized from the start, and these patients were entered into grade-specific trials starting in the 1980s.8,9 Another development during this era was a shift from intravenous delivery of therapy to more spatially limited methods. This shift incorporated such techniques as brachytherapy, radiosurgery, conformal radiation, and boron neutron capture in radiotherapy; intra-arterial chemotherapy, blood-brain barrier breakdown delivery, and surgically implanted therapy such as wafer-based delivery; direct injection of agents into parenchyma at surgery; or postoperative, catheter-based convection enhanced delivery. Although the improvement in spatial specificity and increased drug delivery to the tumor environment was theoretically attractive, only wafer-based delivery of carmustine achieved any success, and this was a modest one.24
TARGETED THERAPY ERA The last positive randomized trial using a cytotoxic therapy against glioblastoma reported was the Stupp et al25 trial in 2005, which rapidly established adjuvant temozolomide radiochemotherapy as standard glioblastoma treatment in North America and Europe.26-29 The important gains in survival achieved during the cytotoxic era are reflected by comparing the median survival without radiation or chemotherapy in early malignant glioma trials, about 4 to 6 months, with the median survival in temozolomide-treated patients with glioblastoma in the Stupp trial, 14.6 months.25 Although some of this gain was undoubtedly due to improvements in general care of glioma patients, the majority can probably be attributed to radiation and temozolomide. In the last 15 years, targeted agents have become the focus for much of investigational oncology. Although the term lacks a precise definition, I use it here to include a wide spectrum of agents including antiangiogenic drugs, immunotherapy, and pharmaceutic agents that act against molecules or pathways that are truly specific for cancer cell growth or survival. All of these classes of agents have now demonstrated clear success in treating systemic cancer. For example, ipilimumab (an immune checkpoint inhibitor) in metastatic melanoma,30 bevacizumab (an antiangiogenic agent) in metastatic colon cancer,31 and imatinib (a selective inhibitor of a tumor-specific BCR-ABL fusion kinase) in chronic myelogenic leukemia32 all demonstrated significant survival benefits in phase III trials in the early 2000s and rapidly gained regulatory approval as standard therapy in these diseases. In some cases, the advance in both safety and efficacy over standard cytotoxic treatment was startling. In a phase III trial reported in 2003, imatinib achieved a 76% complete cytogenetic response rate against patients compared with 15% for standard treatment.32 Toxicity with the targeted agent was much less frequent than with standard therapy; for example, 1% of imatinib patients reported fatigue compared with 24% with standard therapy. The imaging response seen after some targeted agents is so rapid and profound that it has been called a “Lazarus
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response.” An example was the 81% imaging response rate seen in an early phase I trial of vemurafenib, a V600E-specific BRAF inhibitor, in metastatic melanoma, a tumor previously notoriously resistant to drug treatment.33 Not surprisingly, the many differences in mechanism and results seen with these novel therapies have required changes in clinical trial design. Some themes to keep in mind when considering these specific changes are extensions of the trends described above as beginning during the cytotoxic era: increasing precision in patient selection, care in defining response and selecting end points and success criteria in early-phase trials, and an ever-increasing need for broad-based multicenter cooperation.
TRIAL DESIGN IN THE TARGETED THERAPY ERA In the cytotoxic era, the earliest-phase trial was typically phase I, defining the optimal safe dose for a new agent, typically the highest dose that patients could tolerate because of the tacit assumption that this would maximize antitumor effect. For several reasons, the optimal dose of noncytotoxic agents may not be the maximum tolerated dose. For example, an agent may have sufficiently low toxicity on normal tissues that other considerations actually govern dosing, for example, the maximum “feasible” dose, determined by manufacturing processes, delivery methods, or cost. For some agents, the biological effect no longer increases with higher delivered doses. These issues can be explored with a so-called phase 0 component to an early-phase study.34-36 In phase 0 studies, low doses of the experimental agent are administered, and $1 tumor-specific end points are assessed. Often, this requires sampling of tissue from the tumor, which is then assayed to determine drug penetration into tumor tissue (of obvious importance in brain tumors) and/or a biological effect on tumor metabolism such as inhibition of a target pathway. Phase 0 trials with an imaging end point such as magnetic resonance spectroscopy for an oncometabolite or a positron emission tomography measure of tumor metabolism are also possible although used less often in practice. A phase 0 cohort is an important component of many modern phase I and phase II trials. In addition, the high response rate characteristic of many targeted agents means that significant tumor responses should be anticipated in phase I trials. A desire to maximize efficiency when a drug is targeted at a molecular subpopulation that may be rare can prompt “bucket” phase I trials in which patients with many histological diagnoses are eligible for treatment as long as they have the defining molecular characteristic such as a specific mutation. When such trials include brain tumors, phase 0 arms can help define brain tumor–appropriate dosing and potentially explain failures to achieve responses in brain tumors, thus guiding the decision of whether to proceed to phase II testing.37 In phase II trials, the definition of treatment success has become much more complex with targeted agents.38,39 Through most of the cytotoxic era, reduction of enhancing volume was equated
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directly with a therapeutic tumor effect. Although it was recognized that collateral damage to brain surrounding the tumor from radiation, chemotherapy, or both could produce imaging changes that were indistinguishable from tumor, especially in high-dose radiation context such as brachytherapy, only with the introduction of temozolomide therapy during radiation treatment did these changes become so frequent that imaging progression began to be questioned as a valid end point for phase II studies.40,41 The broader class of mechanisms of noncytotoxic agents also means that tumor stability, rather than tumor shrinkage, might be a plausible form of benefit in many trials. In addition, the observed extremely rapid reduction in contrast-enhancing volume seen with some agents such as vascular endothelial growth factor inhibitors42 can reflect the reconstitution of an intact blood-brain barrier rather than an actual tumor response.43 For all of these reasons, an end point such as progression-free survival44 or overall survival may reflect clinical benefit more accurately than response rate. Use of these end points usually mandates a randomized phase II design,45,46 increasing the size of the trial47 from #30 patients in the cytotoxic era to a typical size of 120 patients in current practice, many of whom will not receive the experimental agent (making accrual and patient retention more difficult). The increasing trend toward conducting phase II trials on enriched populations often compounds accrual problems because multiple patients may need to be screened for each patient who eventually enters the trial. Initial attempts to enrich phase II (and phase III) cohorts were based on biomarkers such as MGMT methylation status or epidermal growth factor receptor vIII amplification in glioblastoma, and future medulloblastoma trials are almost certain to limit cohorts by similar molecular markers. The rarity of many types of brain tumor implies that drugs developed for more common cancers may need to be repurposed for brain tumor subpopulations that may form tiny minorities in already-uncommon tumors.48 As an example, drugs developed against SMO or AKT1 mutations might offer benefit to patients whose meningiomas harbor these mutations, but they each account for only about 5% of all tumors.49,50 In trials enriched for specific biomarkers or molecular characteristics, even obtaining adequate historical control information to choose the sample size for a randomized phase II trial may become problematic. Finally, the possibility that a benefit other than extended survival may be testable in a phase II trial is now more plausible. Regulatory agencies may offer approval based on improvement of symptoms or quality of life in tumor patients, although a minority of drugs are actually approved on this basis.51,52 A possible example is the unexpected improvement of hearing seen in patients with neurofibromatosis type II with acoustic neuromas after treatment with bevacizumab.53 To date, the impact of targeted treatments on brain tumor phase III trial design has been more modest. Aside from the accrual problems mentioned above when trials are limited to enriched subpopulations, certain difficulties can be expected to arise if targeted agents succeed in achieving profound responses in
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Disclosure TABLE 2. Central Nervous System (and Skull Base) Tumor Histologies (Excluding Malignant Glioma) Pilocytic astrocytoma Subependymal giant-cell astrocytoma Pleomorphic xanthoastrocytoma Pilomyxoid tumor Ependymoma Subependymoma Choroid plexus papilloma and carcinoma Medulloblastoma Pineal parenchymal tumors Neurocytoma Acoustic neuroma Meningioma Hemangioblastoma Endolymphatic sac tumor Craniopharyngioma Chordoma Chondrosarcoma Esthesioneuroblastoma Sinonasal undifferentiated carcinoma
enriched populations. Among these is the question of whether a randomized trial against standard treatment can be considered ethical in this situation. To date, full regulatory approval for new cancer drugs has typically required the performance of confirmatory phase III trials even in the face of highly promising phase II trial results. Another problem that would be almost completely novel to neuro-oncology, with the exception of central nervous system lymphoma, is what to do after a complete imaging response has been achieved.
TARGETED THERAPY AND THE UNIVERSE OF CENTRAL NERVOUS SYSTEM TUMORS This review, like neuro-oncology in general, has been heavily weighted toward malignant glioma treatment. The shift toward targeted therapy, however, almost certainly implies that the broad range of nonglioma tumors that occur in the central nervous system will need to be carefully re-evaluated and continually re-examined. Successful examples of targeted therapy use in nonmalignant glioma histologies already exist. Everolimus was first shown to cause a clinically meaningful reduction in tumor volume in tuberous sclerosis–associated subependymal giant-cell astrocytomas in a 2010 phase II trial,54 subsequently confirmed in phase III testing.55 The hearing benefit of bevacizumab in neurofibromatosis-associated acoustic neuromas53 was already mentioned. In fact, many such rare brain tumors (Table 2) are likely to have much simpler tumor genomes than glioblastoma, offering the hope that some rare tumor types may frequently contain driver mutations for which effective drugs have already been developed for other cancers. It is tempting to suggest that these cases will offer the first successes for the targeted therapy era in neuro-oncology.
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Dr Barker receives consulting fees from National Cancer Institute-Cancer Treatment Evaluation Program.
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