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 1:1 to Treatment Arm 1 (temozolomide treatment) or Arm 2 (temozolomide plus olaparib treatment).
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 low/deficiency of MGMT, inhibition of PARP using a PARPi, such as Olaparib, has been shown to enhance TMZ's 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 BRCA1/2 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 (clinicaltrials.gov: 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 II/III 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 PARPi's, 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 1:1 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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Temozolomidewill be administered orally for 7 days (D) every 21 days until progression of the disease in both arms.
Olaparib will be administered orally twice daily in treatment arm 2.
Arthur J.E. Child Comprehensive Cancer Centre
Calgary, Alberta, Canada
Disease Control Rate (DCR)
To determine DCR by assessing complete/partial response or stable disease, as per RECIST 1.1 in patients with mMGMT TNBC treated with Temozolomide ± Olaparib.
Time frame: From the date of first study drug dosing to the date of first documented complete response or partial response or stable disease, whichever came first, assessed up to 5 years.
Progression Free Survival (PFS)
To determine progression-free survival (PFS) of patients with mMGMT TNBC treated with Temozolomide ± Olaparib.
Time frame: From the date of first study drug dosing to the date of first documented disease progression, assessed up to 5 years.
Overall Survival (OS)
To determine OS by measuring the time interval from the date of the first dose of the study treatment until death due to any cause. Subjects who are still alive will be censored on the date of last contact.
Time frame: From the date of first study drug dosing to the date of death, assessed up to 5 years.
Number of adverse events in participants treated with Temozolomide ± Olaparib as assessed by CTCAE version 5.0.
To determine the number of adverse events related to Temozolomide ± Olaparib treatment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0, effective November 27, 2017 \[Common Terminology Criteria for Adverse Events (CTCAE).
Time frame: From the date of first study drug dosing until the last date of study drug dosing, assessed up to 5 years.
Duration of Response (DoR)
To determine the time duration between the radiographic documentation of complete response or partial response or stable disease (whichever is recorded first) until the first date that the progressive disease is documented or death.
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Time frame: From the date of radiographic documentation of complete response or partial response or stable disease to the date of documented progression or death, whichever came first, up to 5 years.