Clinical trial information : nct00689221 , 26.3 mo. in both arms
Merck other oncology drug....turfed, deep-sixed, no debate...
Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86)
Background: Cilengitide (CIL) is a selective αvβ3 and αvβ5 integrin inhibitor. In a phase II study in patients with newly diagnosed glioblastoma, CIL added to standard temozolomide (TMZ) and radiotherapy (RT) was well tolerated and appeared to confer improved survival in patients with glioblastoma and methylated MGMT gene promoter (Stupp et al. J Clin Oncol. 2010;28:2712-8). Methods: This multicenter, randomized, controlled, open-label, phase III study randomized (1:1) patients (≥ 18 years) with newly diagnosed, histologically proven supratentorial glioblastoma (WHO Grade IV) and centrally determinedMGMT gene promoter methylation. Treatment consisted of CIL 2000 mg twice weekly i.v. plus standard TMZ/RT→TMZ (concomitant and adjuvant temozolomide and radiotherapy; Stupp et al. N Engl J Med. 2005;352:987-96) or standard TMZ/RT→TMZ alone. CIL was to be administered for ≥ 18 months, or until disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) per investigator read and safety. Results: 272 patients received CIL plus TMZ/RT→TMZ, and 273 were treated with TMZ/RT→TMZ alone (intention-to-treat population). 54% and 52% of patients were male, and 42% and 44% had ECOG-PS ≥ 1, respectively. 75% of patients of both arms were ≥ 50 years old. Overall, baseline characteristics were well balanced across treatment arms. Median OS was 26.3 months in both arms (Hazard Ratio [HR] = 1.02 [95%CI: 0.81-1.29], p = 0.86). Median PFS per investigator read was 13.5 months in the CIL arm and 10.7 months in the control arm (HR = 0.93 [95%CI: 0.76-1.14], p = 0.48). Treatment was generally well tolerated and the known safety profile of CIL was confirmed. Conclusions: CIL failed to prolong PFS or OS in patients with newly diagnosed glioblastoma and methylated MGMT gene promoter. The previously reported safety profile of CIL in addition to standard therapy was confirmed. Clinical trial information:
Interesting...but, it seems the long OS could be directly correlated with the centrally determined MGMT gene promoter methylation requirement of this study. According the the journal of translational Medicine, December 2012:
"Statistical analysis showed a significant correlation between OS and MGMT promoter methylation status (Figure 4A). The median OS among patients with methylated MGMT promoter tumors was 19 months (95% CI, 9.6–28.4 months) compared with 13 months (95% CI, 10.5–15.4 months) in patients with unmethylated MGMT promoter tumors (log-rank, P = 0.031)."
Just having the MGMT promoter methylation status gives the GBM patient a significant OS advantage. I don't believe any of the required indicators for ICT-107 have shown an OS advantage. Hence, our control arm should still fall within a "normal" GBM OS curve. If I am wrong...let me know. Would rather understand then invest poorly.
Yep - just found this:
"Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma
Patients and Methods Patients (age ≥ 18 to ≤ 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months.
Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified.
Conclusion Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation"
so without MGMT - OS was 16.1, with MGMT - OS was 23.2... big difference!
So I'm sophisticated enough to read the 26.3 =) but not to understand why the OS is so high - it is a subset of the GBM population but I would like someone who understands the medical side better to comment...
The actual leaders in methylation with GBM are Henry Friedman of Duke University and Roger Stupp from Switzerland. Rul6t2 is right in his assessment of how methylation works. Temozolomide is an alkylating agent. In short, try to search for this article "Glioblastoma Multiforme: Current ,and Treatment Challenges : Current Approaches to the Treatment of Newly Diagnosed GBM" written in 2010 if you are looking for an article that gives some backdrop into results from past trials, and issues between results seen in treatment arms of protocols vs. those experienced in the clinical setting. Responses can be improved between trials with simple patient selection and that is why it is important to have balanced arms in any comparative protocol. The FDA will be looking at all known, and even assumed, prognostic variables when looking at the efficacy question with ICT-107. For me, there really is no way to tell what the interim results demonstrate without a thorough look at who responded in the trial. One thing you do know, is that the interim results took longer than expected..that could be pro or con pending assumptions (I am leaning pro). All I know is the trial is allowed to continue, which means it was not worse! Remember that although everyone short or long wants to make money in this stock, this drug brings much hope to patients and families...some may be reading these posts, so it is important to be detailed in assumptions.
Methylation usually silences genes. Methylation of MGMT results in downstream AGT being shut off. AGT normally confers (as part of a DNA repair system) resistance to alkylating agents including chemos.
So methylation of MGMT means no AGT means chemos are going to work better. And there's your longer OS.