Reused Drugs to Fight Glioblastoma (part three)

Here we are at the ninth episode of Ben Williams’ guide translation project on treatment options for Glioblastoma Multiforme. This is the last part of chapter 6 of the guide which, as I said, is very long and has been divided into parts. In this second part we talk about Thalidomide, Valcyte, Valporic acid and multi-drug approaches. The advice is still to use this information to discuss it with the medical team that is following you and you can also pass them references to supporting scientific works. As the last topic of the chapter we talk about the CUSP approach, the one for which the fundraising campaign was launched on GoFund.me. Glioblastoma.it for CUSP-ND for Emanuele campaign is continuing and would need a momentum of solidarity. I ask you once again to share the link and to spread the word in order to raise awareness as many people as possible. Enjoy the reading!

Thalidomide

This drug became famous during the 1950s and 1960s because it produced a large number of birth defects that resulted in abnormal or completely missing limbs. It is now believed that this is due to its effects on inhibiting the formation of new blood vessels because the buds of the limbs depend in particular on the growth of new blood vessels for normal development. Thalidomide was initially approved by the FDA for the treatment of leprosy, but is now also approved for multiple myeloma. It also has several common off-label uses, including melanoma, Kaposi’s sarcoma, and prostate cancer. Unfortunately, a significant amount of paperwork is required, both from the pharmacist and the prescribing physician, so getting it for off-label uses isn’t straightforward.
These restrictions have been imposed despite the fact that most potential users of the drug, male and female over the age of menopause, are not affected by the drug’s teratological potential.
The usefulness of thalidomide as a cancer treatment stems from the fact that it is the first anti-angiogenic drug approved by the FDA, although it is now believed that it also has other mechanisms of action. The main side effects are sleepiness (thalidomide was originally introduced for its sedative purposes), constipation and neuropathy with long-term use.
The best results using thalidomide as a single agent come from a small study conducted in Switzerland (91). Nineteen patients with glioblastoma received 200 mg / day of thalidomide immediately after radiotherapy, and increased to 600 mg / day if tolerated. The median effective dose used was 200 mg / day. Median survival time was 63 weeks (14.5 months). Median progression-free survival was 17 weeks (3.9 months). Some patients have undergone surgery for recurrent tumors, so it is difficult to know how much survival time is due to the additional surgery. The same study also reported the results of 25 patients who received the same thalidomide regimen but in combination with temozolomide. Here, the median survival time was 103 weeks (23.7 months) and the median progression-free survival was 36 weeks (8.3 months).
A subsequent study produced a more conservative estimate of the benefits of Temodar combined with thalidomide. In contrast to the median survival time of 103 weeks in the clinical study just described, this second study using the combination of Temodar and thalidomide with newly diagnosed patients produced a median survival time of 73 weeks (16.8 months). , marginally better than 61 weeks after standard treatment with Temodar alone (92). There are two differences in the protocols: the latter study used Temodar and thalidomide during the radiation and was then continued at the end of the radiation; the previous study started treatment with Temodar and thalidomide only after completion of the radiation treatment. Second, the thalidomide dosage was significantly lower in the previous study. This last difference is interesting because it is clinical. Studies using thalidomide as a single agent appear to have better results with lower dosages of the drug. It is possible, but not proven, that the dose-effect curve for thalidomide is not monotonous just as it seems to happen for some other agents that target angiogenesis. However, the most likely difference in the results for the two studies is that the previous study included many patients who had new surgeries for their tumors when they came back, while in the second study, no new surgeries were performed.
A subsequent study failed to find an improvement in results with the addition of thalidomide (92). When the combination of temodar and thalidomide was used with patients with recurrent GBM (93), the PFS-6 was 24%. Although reports on the efficacy of thalidomide have been inconsistent, the weight of evidence suggests that it adds efficacy to the treatment, although probably not in large quantities.
An important exception to the generalization that thalidomide has a limited benefit comes from an Austrian study (317) in which the apparent survival benefits were limited to patients with secondary GBM, that is, those who evolved from initially lower grade tumors.
Twenty-three patients whose tumors had progressed after both radiotherapy and chemotherapy received 100 mg of thalidomide each night, in part to aid sleep. Median survival time after the initiation of thalidomide was essentially 18 months longer than typically achieved with recurrent GBM. It should be noted that the 100 mg dosage is much lower than in studies where thalidomide had limited benefits.

Valganciclovir (Valcyte)

Since 2002, Charles Cobbs et al have demonstrated a role for human cytomegalovirus in promoting the progression of glioblastoma tumors, most of which are positive for CMV proteins. This has led to the conjecture that treating brain tumors with anti-CMV drugs such as valganciclovir (Valcyte) could have therapeutic benefits. A small clinical study using this approach was conducted at the Karolinska Institute in Sweden. Forty-two patients were randomly assigned to the Stupp standard protocol versus the Stupp protocol combined with Valcyte (173). Although there were some differences in tumor volume, these did not reach statistical significance or median survival time (17.9 vs 17.4 months). However, the study design allowed patients to receive Valcyte when their tumors progressed or after six months, thus confusing the determinants of outcome.
As a result, the authors carried out a retrospective analysis of the patients who used the Valcyte for at least six months. For these patients, the median survival was 24 months and the 4-year survival was 27%. A subsequent report analyzed study patients with six-month exposure to Valcyte, along with others who received treatment outside the study (174). For these patients, the 2-year survival was 70% and the median survival was 30 months.
The benefits of Valcyte appear to be partly dependent on the degree of CMV infection (175). For patients with low-grade infection, median survival was 33 months, while those with high-grade infection had a median survival of 14 months.
The retrospective analysis described above has generated a large amount of controversy, mostly centered on the intrinsic bias inherent in this time-dependent analysis (technically defined as “immortal temporal bias”). Properly designed studies will be needed to demonstrate the efficacy of Valcyte for glioblastoma. Meanwhile, many patients impressed with the results of the retrospective analysis have included Valcyte in their treatment regimens, with or without the blessing of their oncologist.

Valproic Acid / Sodium Valproate (Depakote)

A common antiepileptic drug, valproic acid (trade name Depakote), is a histone deacetylase inhibitor (discussed in the section on epigenetics). It also has the advantage of not inducing hepatic enzymes that reduce the concentration of chemotherapy agents in the serum, which occurs when using many other antiepileptic drugs (in fact, valproic acid can increase the concentration of chemotherapy, so standard dosages must be monitored. to evaluate its toxicity).
The fact that its use rather than the use of other antiepileptic drugs can improve the clinical outcome is supported by a retrospective clinical study that compares enzyme-inducing anticonvulsants with valproic acid. The median survival for the former (n = 43) was 11 months, while the median survival for those receiving non-enzyme-inducing antiepileptics (n = 37) was 14 months (203). Valproic acid was the main antiepileptic drug used in the latter group (85%).
Similar results were obtained in a retrospective analysis of the Stupp study which definitively demonstrated the efficacy of temozolomide (204). For patients who received the combination of temozolomide and radiotherapy, median survival was 14 months for those not using anti-seizure drugs, 14.4 months for those using a drug other than valproic acid, and 17, 4 months for those who have used valproic acid. Similar behavior occurred for the 2-year survival rate: 25%, 26%, and 30.6%.
A retrospective study from the Sloan-Kettering dataset produced a similar result. Patients who used valproic acid had a median survival of 16.9 months compared to 13.6 months for those who used other anticonvulsant drugs. When the analysis considered only the patients who received valproic acid during radiotherapy, the corresponding median survival was 23.9 months compared to 15.2 months (318).
Although previous results support the use of valproic acid for its ability to inhibit HDAC, a recent Korean study directly compared 38 patients prospectively enrolled to receive Keppra with 42 patients who took valproic acid as a group. control. The median progression-free interval was 9.3 months for Keppra compared to 6.5 months for valproic acid. Overall survival was 26 months versus 16 months (205). This research does not include full details of dosing or drug scheduling, and it is possible that valproic acid is more effective as an adjuvant during the radiotherapy phase of treatment, while Keppra may be more effective during monthly temozolomide courses, especially for those tumors with unmethylated MGMT methylation status. See the Keppra (levetiracetam) section of this chapter (above), for a discussion of Keppra as a chemosensitizer in glioblastoma therapy.
The most impressive findings on valproic acid were reported by the brain tumor center at the National Cancer Institute at the 2014 SNO meeting. In a prospective study of 37 newly diagnosed patients, valproic acid was used at a dose of 25 mg / kg per day during the six weeks of combined chemoradiotherapy. Median survival was 29.6 and median PFS was 10.5 months. The study was published in full in July 2015 (319).
A very large retrospective analysis (337) based on data from four large randomized clinical trials was conducted in 2016 with the intention of demonstrating the need for a phase 3 trial of valproic acid as an addition to the standard of care for glioblastoma.
This combined dataset was taken from the control arms of studies AVAglio and RTOG0825 and from both arms of the CENTRIC and CORE clinical studies that tested cilengitide in combination with standard of care. This validation group in total consisted of 1582 patients. In the first analysis of this large validation group, no significant difference in progression-free survival (PFS) or overall survival (OS) was found between users (alone or in combination with other antiepileptic drugs) and non-users of valproic acid. In a further analysis, the trend towards improved PFS and OS in users of valproic acid as an antiepileptic monotherapy was then lost when some adjustments were made with respect to the other factors. When the analysis focused on those patients who received valproic acid both at the time of entry into the study before radio-chemotherapy and at the time of the first visit to follow-ups after radio-chemotherapy, there was no significant difference in PFS or OS compared to patients who received no antiepileptic drug at either time. The latter analysis did not include patients from the RTOG 0825 study due to a lack of data.
Similar analyzes found no advantages in terms of PFS or OS for patients who used levetiracetam (Keppra), nor for patients who used levetiracetam at both study entry and the first follow-up visit after radiochemotherapy ( compared to patients who did not use any antiepileptic drug at both time points). However, as one of the proposed primary mechanisms for a survival benefit of levetiracetam is inhibition of MGMT, it could be argued that prolonged use of this drug during adjuvant monthly temozolomide courses is the most critical period to consider compared to temporal moments immediately before or after chemo-radiotherapy.
The lead author of this study is Michael Weller, who was also the first author of the 2011 retrospective analysis that found a survival advantage of valproic acid based on data from the pivotal 2005 EORTC-NCIC study. In contrast to the previous study, the negative results of this study lead the authors to conclude that although a survival advantage of valproic acid could be demonstrated by a prospective randomized phase III study, the advantage is likely to be so small that a sample size of 5,000 patients would be needed to confirm this. The authors also admit that a major limitation of the study is that patients were grouped into antiepileptic drug consumption categories based on use at the single time point of entry into the study (and later after radiochemotherapy for a subgroup of patients).
In response to the criticisms of this study (338), the authors acknowledge once again that the main weakness of the study is the lack of solid data on the dose and duration of exposure to valproic acid. It is conceivable that for a beneficial effect in glioblastoma, early, high-dose treatment with valproic acid would be required, although no categorical data truly supports this hypothesis. Therefore, the analyzes reported here are not suitable for completely excluding an effect of valproic acid on the outcome, especially on tiny subgroups with unique biological characteristics.
However, our data are robust enough to rule out any important effect of valproic acid, especially in significant proportions of patients with glioblastoma.
In this context, it is interesting to recall that the phase II study of valproic acid in addition to the standard radiochemotherapy mentioned above (319) used rather high doses of Depakote (25 mg / kg / day) and that most patients who used this drug may not take the drug at such high doses. Although the EORTC Brain Tumor Group and the authors of this latest large retrospective study (Happold, Weller, et al.) Conclude that valproic acid has little or no survival benefit as an anticancer therapy for glioblastoma, data from studies Phase II suggests that higher doses of valproic acid (25 mg / kg per day) during the six weeks of radiochemotherapy may provide a survival benefit, although prospective randomized studies should be performed. The problem may be that the typical antiepileptic doses of valproic acid may not be sufficient for a constant inhibition of HDAC. As Happold et al. Suggests. One might wonder if valproic acid is really the best inhibitor of histone deacetylase to be studied in this context. New HDAC inhibitors such as panobinostat are being studied in clinical trials for glioblastoma.

A trial with 3 repurposed drugs plus Temodar

The above list of drugs does not exhaust the list of old drugs that have the potential to improve the outcome of treatment if added to standard treatment. The critical question is whether the use of combinations of these drugs actually improves the results in clinical practice.
The most disappointing outcome occurred in a combination of treatment involving Temodar, thalidomide and Celebrex for newly diagnosed patients (134). Fifty GBM patients received standard radiotherapy followed by the standard monthly high-dose Temodar schedule in combination with famousx and thalidomide. The median survival from the time of diagnosis was 16.1 months and the 2-year survival was 21%, apparently without any improvement compared to the current standard of care.
More positive results were obtained in a phase 1 study (135) of different combinations of Temodar, thalidomide, accutane and famousx. Although the objective of the study was a factorial design of different 2- and 3-way combinations, not enough patients were recruited in the various branches of the study to conduct the comparisons planned at the time of the initial report. Forty-two patients were assigned to receive Temodar alone (on an alternating weekly schedule), or Temodar in combination with one or more additional medications. For unclear reasons, 19 of the 42 patients received Temodar alone and 23 patients received a combination. Unfortunately, the results were reported in aggregate with no distinction between patients who received the different combinations, nor was any distinction made between patients who received Temodar alone versus Temodar and adjunct therapy. However, the median survival was 20 months and the two-year survival rate was 40%, despite the inclusion of 12 patients who never received any of the combinations due to early progression. The authors also reported that ten patients were alive for 4.8 to 6.9 years from study initiation.
A Phase 2 follow-up report of this study was presented at the 2012 ASCO meeting (136) and published in full in Neuro-Oncology in September 2014 (307). Patients were randomly placed in one of the following eight arms, with approximately 20 patients in each arm:

• Temodar alone
• Temodar + isotretinoin (Accutane)
• Temodar + celecoxib
• Temodar + thalidomide
• Temodar + isotretinoin + celecoxib
• Temodar + isotretinoin + thalidomide
• Temodar + celecoxib + thalidomide
• Temodar + isotretinoin + celecoxib + thalidomide

Therefore, for each of the three additional drugs, four arms included the drug and four arms that included it. The main objective of the study was to judge the effectiveness of the three additional drugs by comparing the four arms that included a drug against the four arms that did not, in terms of progression-free survival measured from the time of randomization. The four arms that included celecoxib showed a trend towards better progression-free survival than the four arms that did not include celecoxib (hazard ratio = 0.8), although the effect did not reach formal statistical significance. The four arms that included isotretinoin and the four arms that included thalidomide had worse outcomes than the arms that did not include these agents (risk ratios of 1.3 and 1.2 respectively).
When each of the 8 treatment arms was compared individually, Temodar plus isotretinoin resulted in significantly worse results than Temodar alone (hazard ratios of 2 and 2.2 for progression-free survival and overall survival versus to Temodar alone). The combination of Temodar + celecoxib produced a result equivalent to Temodar alone (hazard ratio = 1). All other combinations had lower outcomes than Temodar alone, although since only about 20 patients were included in each arm, only the Temodar + isotretinoin combination achieved statistical significance (worse survival than Temodar alone). Therefore, with the dosages and schedules used in this study, both isotretinoin and thalidomide appeared to be antagonistic when combined with Temodar, with a particularly significant antagonistic effect of isotretinoin on the effectiveness of Temodar.

CUSP9 (Co-ordinated Undermining of Survival Paths) with 9 repurposed drugs

A document published in April 2013 introduced a “conceptually new” approach for recurrent glioblastoma (10). In this paper, various repurposed drugs in addition to metronomic temozolomide have been proposed as part of a broad treatment cocktail, including aprepitant (an anti-nausea drug), artesunate (a malaria drug), disulfiram (discussed above), sertraline (an anti-depressant), captopril (an ACE inhibitor used for hypertension), auranofin (a gold compound used for arthritis), nelfinavir (an HIV drug) and ketoconazole (an antifungal drug) . In the updated version of this combination, called CUSP9 (306), ritonavir was replaced by nelfinavir, and itraconazole replaced ketoconazole, copper gluconate was removed and celecoxib was added. For all these drugs, extensive in vitro evidence is available that demonstrates the effect of inhibiting various biochemical processes underlying the growth of glioblastoma, but none yet has standard evidence from human clinical studies. However, the main argument of the proponents of this approach is that the tests of single treatment agents in isolation are doomed to failure, because there are multiple growth pathways that must be inhibited simultaneously.

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(10) Kast, R.E., Boockvar, J. A., Bruening, A., et al. A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget, 2013, 4(4), 502-530. 
(91) Baumann, F. et al. Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme. J. Neuro-oncology, 2004, 67(1-2), 191-2001. 
(92) Chang, S.M, et al. Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. Int. .J. Radiation Oncology, Biol & Phys., 2004, 60 (2), 353-357. (93) Groves, M.D., et al. A North American brain tumor consortium phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme. Journal of Neuro-oncology, 2007, 81(3). 
(134) Kesari, S., et al. Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro-oncology, 2008, 10 (3) 300-308. 
(135) Gilbert, M.R., Gonzalez,J., Hunter K., et al. A phase I factorial design study of dose-dense temozolomide alone and in combination with thalidomide, Isotretinoin, and/or celecoxib as postchemoradiation adjuvant therapy for newly diagnosed glioblastoma. Neuro-oncology, 2010, 12 (11), 1167-72. 
(136) Gilbert, M.R., Hess, K.R., Lagrone, L., et al. Randomized phase II 8-arm factorial study of adjuvant dose-dense temozolomide with permutations of thalidomide, Isotretinoin, and/or celecoxib for newly diagnosed glioblastoma. Proceedings of the 2012 AACP meeting, Abstract No. 2003. (173) Stragliotto, G., Rahbar, A., Solberg, N. W., et al. Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: A randomized , double-blind hypothesis-generating study. International Journal of Cancer, 2013, 133, 1204-13. 
(174) Söderberg-Nauclér, C., Rahbar, A., & Stragliotto, G., Survival in patients with glioblastoma receiving valganciclovir. New England Journal of Medicine, 2013, 369(10), 985-86. 
(175) Söderberg-Nauclér, C., Rashbar, A., & Stragliotto, G. . High survival in GBM patients receiving oral antiviral therapy against cytomegalovirus. Abstract MR-029. Proceedings of the World Federation of Neuro-oncology, November 2013 
(203) Oberndorfer, S. et al. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J of Neuro-oncology, 2005, 72 (3), 255-260.
(204) Weller, M., Gorlia, T., Cairncross, J. G., et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology, 2011, 77, 1156-64. 
(205) Kim, C-Y, Kim T., Han, J. H., et al. Survival benefit of Levetiracetam in glioblastoma treatment: A prospective single-arm and single-center study. Proceedings of the 2013 meeting of the Society of Neuro-oncology, Abstract #N-070. 
(306) Kast, Richard E, Georg Karpel-Massler, and Marc-Eric Halatsch. “CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide.” Oncotarget 5.18 (2014): 8052. 
(307) Penas-Prado, Marta et al. “Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma.” Neuro-oncology (2014): nou155. 
(317) Hassler, Marco Ronald et al. “Thalidomide as Palliative Treatment in Patients with Advanced Secondary Glioblastoma.” Oncology 88.3 (2015): 173-179. 
(318) Barker, Christopher A et al. “Valproic acid use during radiation therapy for glioblastoma associated with improved survival.” International Journal of Radiation Oncology* Biology* Physics 86.3 (2013): 504-509. 
(319) Krauze, Andra V., Sten D. Myrehaug, Michael G. Chang, Diane J. Holdford, Sharon Smith, Joanna Shih, Philip J. Tofilon, Howard A. Fine, and Kevin Camphausen. “A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.” International Journal of Radiation Oncology*Biology*Physics: 986-92. 
(337) Happold, Caroline et al. “Does Valproic Acid or Levetiracetam Improve Survival inGlioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma.” Journal of Clinical Oncology (2016): JCO636563. 
(338) Fay, Michael F et al. “Valproate in adjuvant glioblastoma treatment.” Journal of Clinical Oncology (2016): JCO672162.

Super! I hope you enjoyed reading, I have been as faithful as possible. Very soon the next chapter!