Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study

Abstract

The planned study primary endpoint was not met. However, its tolerability makes TEMIRI a suitable candidate chemotherapy backbone for molecularly targeted agents in future trials in this setting.

Phase II study of temozolomide and topotecan (TOTEM) in children with relapsed or refractory extracranial and central nervous system tumors including medulloblastoma with post hoc Bayesian analysis: A European ITCC study

“…As expected, the CNS tumor cohort detected signals in high‐grade glioma, medulloblastoma, and PNET, diseases that have been reported to be associated with responses to temozolomide alone or in combination with the topoisomerase I inhibitor irinotecan . In our study, all the best responses were achieved at cycle 2.…”

“…The median PFS was 2.8 months (95% CI, 1.6‐5.9), and the median OS 12.2 months (95% CI, 3.3‐17.6). These results appear similar to the data reported for the temozolomide‐irinotecan combination in a comparable study population of 66 patients (i.e., ORR during the first four cycles of 33%; 95% CI, 19.5%‐48.0%; median duration of response 27.0 weeks (95% CI, 7.7‐44.1), 46% PFS at six months, median time to progression of 4.3 months, 6‐month survival of 80% and median survival of 16.7 months) . Importantly, response to the temozolomide combination in our patients was associated with longer delay from diagnosis to first relapse, which had not been reported in the other trials and which will have to be explored prospectively.…”

“…In addition, their distinct mode of action may increase the sensitivity of tumors with DNA mismatch‐repair deficiency, which are usually resistant to alkylating agents, through their sensitivity to topoisomerase I inhibitors . Pediatric phase I and II studies have been performed combining temozolomide with irinotecan . Our pediatric phase I study combining the semisynthetic camptothecin derivative topotecan and temozolomide (TOTEM) had shown absence of pharmacokinetic interaction between both drugs, mainly hematological toxicity, and preliminary responses in neuroblastoma and glioma …”

Effect of O6‑methylguanine‑DNA methyltransferase methylation in medulloblastoma

“…Chemotherapy may also affect the MGMT status of the tumors; thus, relapsed tumors may exhibit different methylation profiles. Temozolomide is an alkylating agent that is increasingly used for relapsed medulloblastoma (20)(21)(22). Although a significant correlation between MGMT methylation status and temozolomide sensitivity has been confirmed in glioblastoma (7,8), sensitivity to temozolomide in relapsed medulloblastoma may not be predicted from the MGMT status of primarily resected tumor samples.…”

Feasibility of Administering A Modified Outpatient Regimen of Vincristine, Doxorubicin, Cyclophosphamide Alternating with Ifosfamide, and Etoposide (VAC/IE) For High-Risk Desmoplastic Small Round Blue Cell Tumor and the Role of Tumor Profiling in Selecting Treatments

“…Our options for failure in the future are Irinotecan (TEMIRI) [18] however IHC for TOPO1 was negative suggested limited benefit from Irinotecan [19,20] and MGMT IHC was positive (60%) suggest a potential lack of benefit [21,22], therefore Gemcitabine docetaxel was used [23][24][25] given that his tumor was RRM1 negative [26] and TUBB3 negative IHC [27][28][29] suggesting a potential benefit. The restaging scan however showed progression and the patient received Pazopanib as third line treatment progressing after 2 months.…”