Phase I/II Study of Temozolomide Plus Nimustine Chemotherapy for Recurrent Malignant Gliomas: Kyoto Neuro-oncology Group

Abstract

The objective of this phase I/II study was to examine the efficacy and toxicity profile of temozolomide (TMZ) plus nimustine (ACNU). Patients who had received a standard radiotherapy with one or two previous chemo-regimens were enrolled. In phase I, the maximum-tolerated dose (MTD) by TMZ (150 mg/m2/day) (Day 1–5) plus various doses of ACNU (30, 35, 40, 45 mg/m2/day) (Day 15) per 4 weeks was defined on a standard 3 + 3 design. In phase II, these therapeutic activity and safety of this regimen were evaluated. Forty-nine eligible patients were enrolled. The median age was 50 years-old. Eighty percent had a KPS of 70–100. Histologies were glioblastoma (73%), anaplastic astrocytoma (22%), anaplastic oligodendroglioma (4%). In phase I, 15 patients were treated at four cohorts by TMZ plus ACNU. MTD was TMZ (150 mg/m2) plus ACNU (40 mg/m2). In phase II, 40 patients were treated at the dose of cohort 3 (MTD). Thirty-five percent of patients experienced grade 3 or 4 toxicities, mainly hematologic. The overall response rate was 11% (4/37). Sixty-eight percent (25/37) had stable disease. Twenty-two percent (8/37) showed progression. Progression-free survival (PFS) rates at 6 and 12 months were 24% (95% CI, 12–35%) and 8% (95% CI, 4–15%). Median PFS was 13 months (95% CI, 9.2–17.2 months). Overall survival (OS) at 6 and 12 were 78% (95% CI, 67–89%) and 49% (95% CI, 33–57%). Median OS was 11.8 months (95% CI, 8.2–14.5 months). This phase I/II study showed a moderate toxicity in hematology and may has a promising efficacy in OS, without inferiority in PFS.

Lomustine and nimustine exert efficient antitumor effects against glioblastoma models with acquired temozolomide resistance

“…As well as TMZ, nitrosoureas are also alkylating agents and have been used for the treatment of GBM before the appearance of TMZ. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 Representative nitrosoureas used in GBM treatment are carmustine (BCNU), lomustine (CCNU), and nimustine (ACNU). 16 In the last 10 years or so, CCNU has been used for salvage therapy against TMZ‐R‐GBM 4 , 5 , 6 , 8 , 9 , 11 , 14 , 15 ; however, the efficacy of CCNU against TMZ‐R‐GBM has not yet been thoroughly investigated.…”

“… 10 , 12 ACNU has also been used as a salvage therapy for TMZ‐R‐GBM. 3 , 7 However, as is the case with CCNU, there is no clear evidence for ACNU to be utilized for the treatment of TMZ‐R‐GBM.…”

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of cytotoxic chemotherapy and other cytotoxic therapies in the management of progressive glioblastoma in adults

“…Table 1A summarizes the 6 studies [6][7][8][9][10][11] that examined the use of TMZ at doses different than what published by Stupp et al [4]. Table 1B summarizes 6 studies [12][13][14][15][16][17] reporting on the use of TMZ in combination with other cytotoxic agents. All of these studies provided Class III evidence.…”

“…Aoki et al [13] reported a phase I/II trial of 49 patients with malignant glioma treated with combination of TMZ and ACNU (nimustine). There were 40 patients unrolled in the phase II trial including one cohort from the phase I trial.…”

Recurrent Glioblastoma Treatment: State of the Art and Future Perspectives in the Precision Medicine Era

“…A broad analysis of the literature specifically focused on cytotoxic therapies yielded a total of forty-three publications adhering to all inclusion criteria. Among the collected citations, six studies focused on the role of TMZ administered at doses different from Stupp’s protocol [ 2 ], and an additional six publications evaluated TMZ in combination with other cytotoxic agents [ 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 ]. With regard to the metronomic administration of TMZ (25–50 mg/m 2 daily), the authors concluded that such protocols also show discrete efficacy in terms of OS and PFS in the case of patients previously treated with bevacizumab.…”