A phase I study of irinotecan in combination with metronomic temozolomide in patients with recurrent glioblastoma

Reynés, Gaspar; Balañá, Carmen; Gallego, Óscar; Iglesias, L.; Perez, Pedro; Garcia, Jose Luis Monteserin

doi:10.1097/cad.0000000000000059

Cited by 18 publications

(9 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synergism between DNA cross-linking agents and topoisomerase 1 inhibitors has been suggested in other cancer models, partly due to increased retention of DNA interstrand crosslinks [37–39]. Recent clinical trials that evaluated a combination of irinotecan and alkylating agents such as temozolomide have proven to be safe and effective in pediatric solid tumors [19, 40, 41]. The pharmacokinetics of BO-1055 has been studied in rats using high-performance liquid chromatography with photodiode array (HPLC-PDA) method suggesting an acceptable PK profile with rapid distribution to all organs except brain and a slow elimination of the drug [7].…”

Section: Discussionmentioning

confidence: 99%

BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models

et al. 2016

View full text Add to dashboard Cite

DNA damaging agents cause rapid shrinkage of tumors and form the basis of chemotherapy for sarcomas despite significant toxicities. Drugs having superior efficacy and wider therapeutic windows are needed to improve patient outcomes. We used cell proliferation and apoptosis assays in sarcoma cell lines and benign cells; γ-H2AX expression, comet assay, immunoblot analyses and drug combination studies in vitro and in patient derived xenograft (PDX) models. BO-1055 caused apoptosis and cell death in a concentration and time dependent manner in sarcoma cell lines. BO-1055 had potent activity (submicromolar IC50) against Ewing sarcoma and rhabdomyosarcoma, intermediate activity in DSRCT (IC50 = 2-3μM) and very weak activity in osteosarcoma (IC50 >10μM) cell lines. BO-1055 exhibited a wide therapeutic window compared to other DNA damaging drugs. BO-1055 induced more DNA double strand breaks and γH2AX expression in cancer cells compared to benign cells. BO-1055 showed inhibition of tumor growth in A673 xenografts and caused tumor regression in cyclophosphamide resistant patient-derived Ewing sarcoma xenografts and A204 xenografts. Combination of BO-1055 and irinotecan demonstrated synergism in Ewing sarcoma PDX models. Potent activity on sarcoma cells and its relative lack of toxicity presents a strong rationale for further development of BO-1055 as a therapeutic agent.

show abstract

Section: Discussionmentioning

confidence: 99%

BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In a study of irinotecan in combination with TMZ, 1 of 12 patients developed grade 4 lymphopenia and neutropenia, and grade 3 thrombocytopenia. In particular, 1 patient died of grade 5 pneumonia caused by Legionella [31]. Kreisl et al used BVZ in combination with irinotecan for patients with recurrent GBM, and thromboembolic events occurred in 6 patients (12.5%) [20].…”

Section: Discussionmentioning

confidence: 99%

Concurrent hyperthermia and re-irradiation for recurrent high-grade gliomas

Heo¹,

Kim²,

Oh³

et al. 2017

neo

View full text Add to dashboard Cite

Salvage therapy for recurrent high grade gliomas (HGG) includes surgery, radiotherapy and chemotherapy, however, standard treatment does not exist. We evaluated the tolerability and efficacy of re-irradiation (re-RT) with hyperthermia (HT) for patients with recurrent HGG. From September 2010 to July 2015, 20 patients with recurrent HGG were treated with re-RT and HT. The radiotherapy dose of 30 Gray (Gy) was delivered with 2 Gy per fraction daily, and HT was performed twice weekly. Primary endpoints were treatment compliance and toxicity. Second endpoints were overall survival (OS) and progression free survival (PFS). The median interval between initial RT and re-RT was 11 months. During re-RT with HT, there were no significant acute morbidities over grade 3. Median overall survival (OS) from re-irradiation was 8.4 months and the 6 and 12 months survival rate were 67% and 30%, respectively. The median progression free survival (PFS) from re-irradiation was 4.1 month. Our findings suggested that concurrent re-RT with HT was a safe and well-tolerated. In addition, the combination re-RT and HT could be a valuable salvage treatment option for selected recurrent HGG patients with poor performance status.

show abstract

“…The diagnosis of recurrence was established by an MRI performed within 3 weeks before starting treatment, according to Macdonald's criteria [12]. Additional requirements included adequate bone marrow and renal and hepatic function, as previously described [11].…”

Section: Eligibilitymentioning

confidence: 99%

“…A brain MRI and a Barthel Index were performed on day 8 of odd cycles, as from the third cycle. Dose delays, reductions, and discontinuations were applied according to the protocol, and have been detailed elsewhere [11]. Objective responses were assessed following Macdonald's criteria [12].…”

Section: Surveillance and Follow-upmentioning

confidence: 99%

“…Moreover, the cytotoxic effect of this combination seems to be independent of the methylation status of the MGMT gene promoter [10]. We recently carried out a phase I trial designed to find the maximum tolerated dose of irinotecan given every 2 weeks, combined with a fixed and continuous dose of TMZ, in patients with GB at first relapse [11]. We now report a phase II, multicenter clinical trial conducted by the Spanish Neuro-Oncology Research Group (Grupo Español de Investigación en Neurooncología, GEINO).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma

Reynés¹,

Martínez‐Sales

Vila

et al. 2016

Anti-Cancer Drugs

Self Cite

View full text Add to dashboard Cite

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m/2day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5-15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2-35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.

show abstract

A phase I study of irinotecan in combination with metronomic temozolomide in patients with recurrent glioblastoma

Cited by 18 publications

References 7 publications

BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models

BO-1055, a novel DNA cross-linking agent with remarkable low myelotoxicity shows potent activity in sarcoma models

Concurrent hyperthermia and re-irradiation for recurrent high-grade gliomas

Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma

Contact Info

Product

Resources

About