Ignite Creation Date:
2024-05-06 @ 4:54 PM
Last Modification Date:
2024-10-26 @ 2:18 PM
Study NCT ID:
NCT05128734
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-01-31
First Post:
2021-10-27
Brief Title:
Temozolomide Monotherapy or in Combination With Olaparib in Patients With Triple Negative Breast Cancer TNBC
Sponsor:
AHS Cancer Control Alberta
Organization:
AHS Cancer Control Alberta
Study Overview
Official Title:
A Randomized Phase II Study of Temozolomide Monotherapy or in Combination With Olaparib in Patients With METHYLATED 06-Methylguanine-DNA Methyltransferase MGMT Pre-Treated Triple Negative Breast Cancer TNBC
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is a randomized phase II study to evaluate the disease control rate DCR of patients with metastatic or locally advanced METHYLATED 06-methylguanine-DNA methyltransferase MGMT with triple-negative breast cancer TNBC treated with Temozolomide Olaparib Patients will be randomized 11 to Treatment Arm 1 temozolomide treatment or Arm 2 temozolomide plus olaparib treatment
Detailed Description:
Background and Rationale
Breast cancer BC is the second leading cause of cancer deaths among Canadian women Treatment of BC is based on the expression of estrogen receptor ER progesterone receptor PgR and amplification of human epidermal growth factor receptor 2 HER2 in conjunction with traditional clinical-pathological features such as tumor grade size and lymph node status Patients whose tumours lack ER PgR and show no overexpression of HER2 collectively termed triple negative breast cancer TNBC account for 15-20 of all BC diagnoses These tumours do not respond to hormone therapy or HER2 targeted agents and are treated instead with traditional chemotherapeutic agents which are non-specific and are associated with potentially significant toxicity
The alkylating agent Temozolomide TMZ is an oral chemotherapy drug that damages DNA by adding methyl groups to the O6- and N7- positions of guanine O6-meG and N7-meG respectively and the N3- position of adenine N3-meA 06-methylguanine-DNA methyltransferase MGMT repairs O6- adducts caused by TMZ during DNA replication resulting in cell survival MGMT expression is commonly decreased in cancer due to promoter methylation mMGMT leading to enhanced TMZ-induced cell death MGMT promoter methylation has been noted in many human tumours including BC Intriguingly prevalence of mMGMT has been shown to be higher in TNBC relative to hormone receptor positive BCs TMZ has been explored as a potential treatment option for BC patients
In normal cells the protein poly ADP-ribose polymerase PARP is involved in repairing the N7-meG DNA lesions caused by TMZ to ensure cell survival Although TMZ toxicity is predominantly manifested by non-repair of the O6-meG adducts due to lowdeficiency of MGMT inhibition of PARP using a PARPi such as Olaparib has been shown to enhance TMZs cytotoxicity When PARP is unable to repair DNA damage significant replication stress ensues that ultimately causes formation of double-strand breaks DSBs which can be repaired by homologous recombination HR to promote cell survival Critical to the HR repair process and cell survival in the absence of PARP is a functional BRCA1 and BRCA2 In the absence of these proteins the DSBs caused by replication stress cannot be repaired resulting in cell death Thus individuals with germline mutations in BRCA12 genes BRCA-positive are extremely sensitive to PARPi Approximately 10 of TNBC patients carry a germline BRCA mutation and therefore may be eligible for a PARP inhibitor such as olaparib
Recently early phase trials clinicaltrialsgov NCT01009788 NCT01618136 NCT01506609 have aimed to evaluate TMZ in combination with a PARPi in BC The early trials showed promising results with Veliparib PARPi in combination with Temozolomide with a 25 objective response rate ORR with a 50 clinical benefit rate CBR seen in BRCA-positive patients however recent results from the BROCADE study NCT01506609 found that Veliparib plus TMZ was inferior to the other treatment arms evaluated but still showed a CBR of 73 with 1 complete and 19 partial responses noted 22 of patients in BRCA-positive Importantly this trial did not evaluate mMGMT status in participants tumour samples Although not in BC the recent findings that Veliparib in combination to TMZ in glioblastomas found that Veliparib significantly enhances the efficacy of TMZ in mMGMT tumours in patient-derived xenograft in vivo models have been incorporated into an ongoing phase IIIII clinical trial NCT02152982 with the results still not being reported Overall the preclinical research findings strongly suggest that TMZ and PARPi combination may benefit BC patients with mMGMT tumours Currently there are no known clinical trials evaluating TMZ with the only clinically approved PARPis Olaparib and Talazoparib in BC
Study Design and Duration
This is a randomized phase II study to evaluate DCR of patients with metastatic or locally advanced mMGMT TNBC treated with TMZ Olaparib Patients will be randomized 11 to Treatment Arm 1 or 2
Arm 1 Temozolomide Day 1- 21 of 21-day cycles Arm 2 Temozolomide Day 1-7 of 21-day cycles plus olaparib Day 1-7 of 21 day cycles Duration of treatment Until disease progression unacceptable toxicity withdrawal of consent by patient
Duration of study 5 years the study will end when either all patients die or 3 years have passed since the last patient started study treatment whichever comes first
Breast cancer BC is the second leading cause of cancer deaths among Canadian women Treatment of BC is based on the expression of estrogen receptor ER progesterone receptor PgR and amplification of human epidermal growth factor receptor 2 HER2 in conjunction with traditional clinical-pathological features such as tumor grade size and lymph node status Patients whose tumours lack ER PgR and show no overexpression of HER2 collectively termed triple negative breast cancer TNBC account for 15-20 of all BC diagnoses These tumours do not respond to hormone therapy or HER2 targeted agents and are treated instead with traditional chemotherapeutic agents which are non-specific and are associated with potentially significant toxicity
The alkylating agent Temozolomide TMZ is an oral chemotherapy drug that damages DNA by adding methyl groups to the O6- and N7- positions of guanine O6-meG and N7-meG respectively and the N3- position of adenine N3-meA 06-methylguanine-DNA methyltransferase MGMT repairs O6- adducts caused by TMZ during DNA replication resulting in cell survival MGMT expression is commonly decreased in cancer due to promoter methylation mMGMT leading to enhanced TMZ-induced cell death MGMT promoter methylation has been noted in many human tumours including BC Intriguingly prevalence of mMGMT has been shown to be higher in TNBC relative to hormone receptor positive BCs TMZ has been explored as a potential treatment option for BC patients
In normal cells the protein poly ADP-ribose polymerase PARP is involved in repairing the N7-meG DNA lesions caused by TMZ to ensure cell survival Although TMZ toxicity is predominantly manifested by non-repair of the O6-meG adducts due to lowdeficiency of MGMT inhibition of PARP using a PARPi such as Olaparib has been shown to enhance TMZs cytotoxicity When PARP is unable to repair DNA damage significant replication stress ensues that ultimately causes formation of double-strand breaks DSBs which can be repaired by homologous recombination HR to promote cell survival Critical to the HR repair process and cell survival in the absence of PARP is a functional BRCA1 and BRCA2 In the absence of these proteins the DSBs caused by replication stress cannot be repaired resulting in cell death Thus individuals with germline mutations in BRCA12 genes BRCA-positive are extremely sensitive to PARPi Approximately 10 of TNBC patients carry a germline BRCA mutation and therefore may be eligible for a PARP inhibitor such as olaparib
Recently early phase trials clinicaltrialsgov NCT01009788 NCT01618136 NCT01506609 have aimed to evaluate TMZ in combination with a PARPi in BC The early trials showed promising results with Veliparib PARPi in combination with Temozolomide with a 25 objective response rate ORR with a 50 clinical benefit rate CBR seen in BRCA-positive patients however recent results from the BROCADE study NCT01506609 found that Veliparib plus TMZ was inferior to the other treatment arms evaluated but still showed a CBR of 73 with 1 complete and 19 partial responses noted 22 of patients in BRCA-positive Importantly this trial did not evaluate mMGMT status in participants tumour samples Although not in BC the recent findings that Veliparib in combination to TMZ in glioblastomas found that Veliparib significantly enhances the efficacy of TMZ in mMGMT tumours in patient-derived xenograft in vivo models have been incorporated into an ongoing phase IIIII clinical trial NCT02152982 with the results still not being reported Overall the preclinical research findings strongly suggest that TMZ and PARPi combination may benefit BC patients with mMGMT tumours Currently there are no known clinical trials evaluating TMZ with the only clinically approved PARPis Olaparib and Talazoparib in BC
Study Design and Duration
This is a randomized phase II study to evaluate DCR of patients with metastatic or locally advanced mMGMT TNBC treated with TMZ Olaparib Patients will be randomized 11 to Treatment Arm 1 or 2
Arm 1 Temozolomide Day 1- 21 of 21-day cycles Arm 2 Temozolomide Day 1-7 of 21-day cycles plus olaparib Day 1-7 of 21 day cycles Duration of treatment Until disease progression unacceptable toxicity withdrawal of consent by patient
Duration of study 5 years the study will end when either all patients die or 3 years have passed since the last patient started study treatment whichever comes first
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None