Title : Comparison of schedule, dose and method of administration of bortezomib in successful and failed studies.
link : Comparison of schedule, dose and method of administration of bortezomib in successful and failed studies.
Comparison of schedule, dose and method of administration of bortezomib in successful and failed studies.
This message is very large, so I decided to publish it in a separate topic.
I analyzed the dose, schedule and mode of administration of bortezomib in successful and failed trials.
As can be seen, only in this successful study (Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy > https://www.ncbi.nlm.nih.gov/pubmed/29722661) bortezemib was used during radiation therapy. As expected, bortezomib is a radiosensitizer. Further, bortrezomib was administered very long - up to 24 cycles (4 times in 28 days) or until progression. Also, perhaps the difference is that in this study from the 10th month bortezomib was administered subcutaneously.
I wrote out some details of each study. The only successful study:
Phase II Study of Bortezomib in Combination with Temozolomide and Regional
Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed
Glioblastoma Multiforme: Safety and Efficacy Assessment
https://www.ncbi.nlm.nih.gov/pubmed/29722661
"Bortezomib is given intravenously/subcutaneously at 1.3 mg/ m² on days 1, 4, 8, 11, 29, 32, 36, and 39 during radiation as early as 14 days after surgery. Temozolomide is given daily (75mg/m2) during radiation, followed by 5 days out of 28 with a dosage of 150-200 mg/m2, for up to 24 cycles. Bortezomib at 1.3 mg/m2 is given on days 1, 4, 8, and 11 of each subsequent 28 day cycle. Both bortezomib and temozolomide will continue until progression or up to 24 cycles.
Bortezomib was initially given via intravenous (IV) infusion, but the protocol was later modified to subcutaneous (SC) injection at ~10 months after the first patient had begun treatment (e.g., August 2012), due to the reported similar efficacy with improved safety profile (11, 12).
Our data were encouraging for newly diagnosed GBM when bortezomib was combined with radiation therapy and temozolomide. In preclinical models, bortezomib has been shown to be a radiosensitizer. That could be one of the reasons for lacking of efficacy in the treatment of recurrent GBM with bortezomib and vorinostat (a histone deacetylase inhibitor) when radiotherapy was not used."
Failed tests or without any outstanding result:
A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/26285768
A minimum of 4 weeks after radiation and full recovery after surgery were required.
Each cycle of therapy consisted of 6 weeks of oral tamoxifen 120 mg twice daily and intravenous bortezomib 1.3 mg/m2 on days 3, 6, 10, 13, 24, 27, 31, and 34 of every 6-week cycle.
A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/27300524
All patients received bortezomib 1.7 mg/m2 intravenously (IV) on day 1, 4 and 8. Patients underwent surgical resection of their tumor on day 8 or 9. Patients started TMZ 75 mg/m2 orally on days 1–7 and 14–21 and bortezomib 1.7 mg/m2 IV on days 7 and 21. Each post surgery cycle was 4 weeks.
Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma
https://www.ncbi.nlm.nih.gov/pubmed/27502784
The three agents were administered in 42 day cycles as shown in Fig. 1. Bortezomib was given at 1.3 mg/m2 on day 1 of weeks 1–4. Bevacizumab was given at a dose of 10 mg/kg on day 1 of weeks 1, 3, and 5. Temozolomide was given at doses of 25 mg/m2 (Group 1), 50 mg/m2 (Group 2), or 75 mg/m2 (Group 3) on days 1–28 of each cycle.
___________________________
I was also interested in this article, where it was concluded that "combination of bortezomib and autophagy inhibitors may shed new light on glioblastoma treatment."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840293/
The open question remains about the use of bortezomib in a cocktail for MGMT-methylated patients only after radiotherapy.
I analyzed the dose, schedule and mode of administration of bortezomib in successful and failed trials.
As can be seen, only in this successful study (Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy > https://www.ncbi.nlm.nih.gov/pubmed/29722661) bortezemib was used during radiation therapy. As expected, bortezomib is a radiosensitizer. Further, bortrezomib was administered very long - up to 24 cycles (4 times in 28 days) or until progression. Also, perhaps the difference is that in this study from the 10th month bortezomib was administered subcutaneously.
I wrote out some details of each study. The only successful study:
Phase II Study of Bortezomib in Combination with Temozolomide and Regional
Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed
Glioblastoma Multiforme: Safety and Efficacy Assessment
https://www.ncbi.nlm.nih.gov/pubmed/29722661
"Bortezomib is given intravenously/subcutaneously at 1.3 mg/ m² on days 1, 4, 8, 11, 29, 32, 36, and 39 during radiation as early as 14 days after surgery. Temozolomide is given daily (75mg/m2) during radiation, followed by 5 days out of 28 with a dosage of 150-200 mg/m2, for up to 24 cycles. Bortezomib at 1.3 mg/m2 is given on days 1, 4, 8, and 11 of each subsequent 28 day cycle. Both bortezomib and temozolomide will continue until progression or up to 24 cycles.
Bortezomib was initially given via intravenous (IV) infusion, but the protocol was later modified to subcutaneous (SC) injection at ~10 months after the first patient had begun treatment (e.g., August 2012), due to the reported similar efficacy with improved safety profile (11, 12).
Our data were encouraging for newly diagnosed GBM when bortezomib was combined with radiation therapy and temozolomide. In preclinical models, bortezomib has been shown to be a radiosensitizer. That could be one of the reasons for lacking of efficacy in the treatment of recurrent GBM with bortezomib and vorinostat (a histone deacetylase inhibitor) when radiotherapy was not used."
Failed tests or without any outstanding result:
A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/26285768
A minimum of 4 weeks after radiation and full recovery after surgery were required.
Each cycle of therapy consisted of 6 weeks of oral tamoxifen 120 mg twice daily and intravenous bortezomib 1.3 mg/m2 on days 3, 6, 10, 13, 24, 27, 31, and 34 of every 6-week cycle.
A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/27300524
All patients received bortezomib 1.7 mg/m2 intravenously (IV) on day 1, 4 and 8. Patients underwent surgical resection of their tumor on day 8 or 9. Patients started TMZ 75 mg/m2 orally on days 1–7 and 14–21 and bortezomib 1.7 mg/m2 IV on days 7 and 21. Each post surgery cycle was 4 weeks.
Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma
https://www.ncbi.nlm.nih.gov/pubmed/27502784
The three agents were administered in 42 day cycles as shown in Fig. 1. Bortezomib was given at 1.3 mg/m2 on day 1 of weeks 1–4. Bevacizumab was given at a dose of 10 mg/kg on day 1 of weeks 1, 3, and 5. Temozolomide was given at doses of 25 mg/m2 (Group 1), 50 mg/m2 (Group 2), or 75 mg/m2 (Group 3) on days 1–28 of each cycle.
___________________________
I was also interested in this article, where it was concluded that "combination of bortezomib and autophagy inhibitors may shed new light on glioblastoma treatment."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840293/
The open question remains about the use of bortezomib in a cocktail for MGMT-methylated patients only after radiotherapy.
Thus Article Comparison of schedule, dose and method of administration of bortezomib in successful and failed studies.
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