A phase I study of nelfinavir concurrent with temozolomide and radiotherapy in patients with glioblastoma multiforme

Abstract

We conducted a phase I trial to examine the maximally tolerated dose (MTD) of the oral protease inhibitor nelfinavir (NFV) in combination with temozolomide and concurrent radiotherapy in patients with glioblastoma and to gather preliminary data for response. The study was conducted in patients with newly diagnosed glioblastoma after surgical resection. Patients were treated with standard radiotherapy (6,000 cGy to the gross tumor volume), temozolomide (75 mg/m2 daily) together with daily oral NFV starting 7–10 days prior to chemoradiotherapy continuing for the duration of chemoradiation for 6 weeks. Temozolomide (150–200 mg/m2) was resumed 4 weeks after completion of chemoradiotherapy. Two dose levels of NFV were investigated: 625 mg twice daily (bid) and 1,250 mg bid in a cohort escalation design. A total of 21 patients were enrolled. At the maximum tolerated dose, 18 subjects were enrolled to further evaluate toxicity and for preliminary estimate of efficacy for further phase II study. No dose-limiting toxicity was noted at 625 mg bid. At 1,250 mg bid, 3 dose-limiting episodes of hepatotoxicity were noted and one dose-limiting episode of diarrhea. The MTD for this study was 1,250 mg bid. NFV (1,250 mg bid) concurrent with temozolomide and radiotherapy is tolerated in most patients with glioblastoma. At the 1,250 mg bid dose level, patients should be monitored for hepatotoxicity and GI side effects.

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

“…Current clinical oncology trials are in different phases of testing the feasibility and applicability of these inhibitors. In general, obtained data from allosteric inhibitors such as perifosine in different advance neoplasms [201,202] and nelfinavir in glioblastoma and locally advanced rectal cancers [203,204] indicate a favorable safety profile. Akt allosteric inhibitor MK2206 in combination with cytotoxic therapies [119,205] or in combination with other molecular targeting agents such as anti-IGF-1R antibody dalotuzumab [206] and EGFR kinase inhibitor erlotinib [119] was shown to be well-tolerated in phase I trials.…”

“…Likewise, nefinavir, administered concurrently with chemoradiotherapy, had acceptable toxicity in patients with NSCLC [213], glioblastoma [203], rectal carcinoma [204] and pancreatic cancer [214]. Importantly, the first tumor response evaluations was promising following combination of nelfinavir and chemoradiotherapy in locally advanced rectal cancer [204] and NSCLC [213].…”

Glioma infiltration and extracellular matrix: key players and modulators

“…A phase I clinical trial was conducted using temozolomide (an alkylating agent resulting in increased apoptosis) together with daily oral NFV and standard radiotherapy in patients with newly diagnosed glioblastoma after surgical resection. The maximally tolerated dose (MTD) of the oral protease inhibitor NFV was stipulated, but it resulted in some side effects, and the overall mean survival rate of patients was only approximately 14 months (Alonso‐Basanta et al, ). The exact mechanism through which NFV promotes glioma inhibition and survival is not well established (Kast & Halatsch, ).…”

“…The maximally tolerated dose (MTD) of the oral protease inhibitor NFV was stipulated, but it resulted in some side effects, and the overall mean survival rate of patients was only approximately 14 months (Alonso-Basanta et al, 2014). The exact mechanism through which NFV promotes glioma inhibition and survival is not well established (Kast & Halatsch, 2012).…”

Impact of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir in patients with pancreatic cancer

“…The radiosensitizing effect of nelfinavir is at least in part owing to the down regulation of hypoxia‐inducible factor 1α and VEGF expression, which results in increased tumor oxygenation . Nelfinavir has been evaluated in patients with solid tumours as a radiosensitizer .…”