Phase II trial of ritonavir/lopinavir in patients with progressive or recurrent high-grade gliomas

Abstract

Current therapies for recurrent or progressive high-grade gliomas (HGG, WHO grade 3-4) produce a 6-month progression-free survival of only 10-25%. Migration and invasion by HGG is mediated in part by matrix metalloproteases (MMPs) which promote remodeling of the extracellular matrix. Several HIV protease inhibitors (HIVPI) decrease the expression of MMPs in astrocytes and microglia. Given these mechanisms of antitumor activity of HIVPI, we evaluated the efficacy of ritonavir/lopinavir, a combination HIVPI, in patients with progressive or recurrent HGG in an open label phase II trial. Nineteen patients were treated in this study. Patients received ritonavir/lopinavir (400 mg/100 mg) orally twice daily. All patients were treated until progression of disease or unacceptable toxicity. A complete response was seen in one patient (5%). Three patients (16%) had stable disease as the best response. Fifteen patients (79%) had progressive disease. The 6-month progression free survival (PFS(6)) was 11% (2 of 19 patients). Ritonavir/lopinavir was well tolerated in patients with heavily pretreated refractory HGG, and no grade 3 or 4 toxicity was seen. The activity at the dose and schedule used in this study, however, was modest and the study did not meet its efficacy endpoint.

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

“…Of uncertain significance, there was one complete radiological remission that lasted 11 months before progression [210]. Parenthetically, note that in this report the published doses of ritonavir and lopinavir were reversed from the doses actually given.…”

“…A trial of ritonavir 100mg with lopinavir 400 mg twice daily reporting in 2011 showed little or no benefit in prolonging OS of recurrent glioblastoma [210]. Of uncertain significance, there was one complete radiological remission that lasted 11 months before progression [210].…”

Recent advances in targeted therapy for glioblastoma

“…Proteasome inhibitors induce cell death by downregulating X-linked inhibitors of apoptosis protein and survivin, upregulating death receptors and accumulation of p53, p21 and p27 proteins [69]. Different Phase I and II clinical trials of bortezomib and ritonavir/lopinavir (a 20s proteasome inhibitor) in patients with recurrent GBM have shown modest efficacy and proved unsuitable for use as a single agent [70,71]. TABLE 2 summarizes the above mentioned targeted drugs along with their current clinical trial status.…”

Glioma Cell Biology

“…Despite the wealth of encouraging data in the preclinical studies, protease inhibitors were so far largely ineffective in the majority of the clinical trials in cancer patients (Coussens et al 2002), including patients with gliomas (Groves et al 2002(Groves et al , 2006Larson et al 2002;Ahluwalia et al 2011). There are a number of causes that may have contributed to these failures: 1.…”