Temozolomide + Olaparib for Breast Cancer

Recruiting at 1 trial location

Overseen By Michelle Kan

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must not be taking: Investigational agents

Disqualifiers: Other malignancies, Psychiatric illness, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 21

Duration: Up to 5 years

40 Participants Needed

Trial Summary

What is the purpose of this trial?

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).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that patients who have received chemotherapy within 4 weeks or are on other investigational agents within 3 weeks prior to the study are excluded, which might imply a need to pause certain treatments. It's best to discuss your specific medications with the trial coordinators.

What data supports the effectiveness of the drug Olaparib for breast cancer?

Research shows that Olaparib helps patients with certain types of breast cancer live longer without the disease getting worse compared to standard chemotherapy. It is particularly effective for those with specific genetic mutations (BRCA mutations) and has a manageable safety profile. ^{1 2 3 4 5}

Is the combination of Temozolomide and Olaparib safe for humans?

The combination of Temozolomide and Olaparib has been studied in patients with glioma, where common side effects included fatigue, stomach issues, and blood-related problems. Some patients needed to reduce their dose or stop treatment due to these side effects. ^{6 7 8 9 10}

What makes the drug combination of Temozolomide and Olaparib unique for breast cancer treatment?

The combination of Temozolomide and Olaparib for breast cancer is unique because it combines a chemotherapy drug (Temozolomide) with a PARP inhibitor (Olaparib), potentially enhancing the effectiveness of treatment by targeting cancer cells in two different ways. This approach may offer a novel option for patients, especially when standard treatments are limited or ineffective. ^{11 12 13 14 15}

Research Team

Don Morris, MD, PhD

Principal Investigator

Arthur J.E. Child Comprehensive Cancer Centre

Eligibility Criteria

This trial is for adults with a specific type of breast cancer called triple-negative that hasn't spread to the bone. They must have had at least one chemotherapy treatment, be able to use effective birth control, and not be pregnant or breastfeeding. People can't join if they're allergic to the drugs being tested, have certain infections like HIV or Hepatitis B/C, or have been treated with these drugs before.

Inclusion Criteria

I have received chemotherapy for cancer that has spread.

I can sign a form showing I understand and agree to join the trial.

Women of childbearing potential will have a pregnancy test as part of the Pre-Study Evaluation within 7 calendar days prior to first study treatment.

Exclusion Criteria

Patients with psychiatric illness/social situations/substance abuse that would limit compliance with study requirements.

I haven't had chemotherapy in the last 4 weeks or radiotherapy in the last 2 weeks, and I've recovered from previous cancer treatment side effects.

Patients who are receiving any other investigational agents within 3 weeks of signing the main informed consent form.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Temozolomide monotherapy or in combination with Olaparib in 21-day cycles until disease progression or unacceptable toxicity

Up to 5 years

21-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Olaparib
• Temozolomide

Trial Overview The study is testing Temozolomide alone versus Temozolomide combined with Olaparib in patients whose tumors are MGMT-methylated. It's a phase II trial where participants are randomly placed into two groups to compare how well each treatment controls the disease.

Participant Groups

Group I: Temozolomide+Olaparib Arm Experimental Treatment 2 Interventions

Temozolomide 75 mg/m2 day 1 to day 7 with Olaparib 200 mg BID, oral, day 1 to day 7 in cycles of 21 days

Group II: Temozolomide Arm Experimental Treatment 1 Intervention

Temozolomide: 50 mg/m2 daily in cycles of 21 days

Temozolomide is already approved in European Union, United States for the following indications:

Approved in European Union as Temodal for:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
• Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy

Approved in United States as Temodar for:

• Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
• Newly diagnosed or refractory anaplastic astrocytoma

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Findings from Research

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

In the phase III OlympiAD study involving patients with BRCA-mutated metastatic breast cancer, olaparib significantly improved health-related quality of life (HRQoL) compared to standard chemotherapy, with a mean change in global health status score of 3.9 versus -3.6 (P = 0.0035).

Patients receiving olaparib experienced a longer time before deterioration in HRQoL, with a median time not reached compared to 15.3 months for those on chemotherapy, indicating a substantial benefit in maintaining quality of life during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial. Robson, M., Ruddy, KJ., Im, SA., et al.[2020]

In the OlympiAD study, olaparib showed a median overall survival of 19.3 months compared to 17.1 months for standard chemotherapy, although this difference was not statistically significant overall; however, it may benefit patients who had not previously received chemotherapy for metastatic breast cancer.

Olaparib was generally well-tolerated with low-grade adverse events, a low treatment discontinuation rate of 4.9%, and no increased risk of anemia with extended use, indicating its safety profile in patients with germline BRCA mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Robson, ME., Tung, N., Conte, P., et al.[2023]

Olaparib, a PARP inhibitor, has shown significant clinical benefits in improving progression-free survival for patients with BRCA1 or BRCA2 mutated HER2 negative metastatic breast cancer compared to standard chemotherapy.

The drug has a manageable safety profile, making it a promising treatment option, particularly for triple negative breast cancer, although further research is needed to optimize its use with other therapies and identify suitable biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. Griguolo, G., Dieci, MV., Guarneri, V., et al.[2019]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

A review of 5,127 reports on temozolomide (TMZ) revealed 112 cases of major hematologic adverse events (HAEs), with a significant number of these cases leading to death, highlighting the serious risks associated with this medication.

Aplastic anemia (AA) and leukemia were the most common major HAEs linked to TMZ, indicating a unique toxicity profile compared to other alkylating agents, and suggesting that patients should be informed about these risks, especially since AA can develop after a short duration of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. Villano, JL., Letarte, N., Yu, JM., et al.[2018]

In a phase II trial involving 26 patients with advanced mycosis fungoides/Sézary syndrome, temozolomide (TMZ) showed an overall response rate of 27%, with 8% achieving complete remission and 19% partial remission, indicating its potential efficacy in this patient population.

Despite the low levels of MGMT in malignant CD4(+) T cells, which suggested sensitivity to TMZ, the study found that pretreatment levels of MGMT and mismatch repair proteins did not predict treatment response, indicating that other resistance mechanisms may be at play.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. Querfeld, C., Rosen, ST., Guitart, J., et al.[2021]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

In a study of 20 patients with various types of glioma, the combination of olaparib and temozolomide (TMZ) showed a 50% objective radiographic response rate in patients with recurrent IDH-mutant grade 2-3 gliomas, indicating potential efficacy for this specific group.

While the treatment was generally manageable, common side effects included fatigue and gastrointestinal issues, with 30% of patients requiring dose adjustments due to toxicity, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. Schaff, LR., Kushnirsky, M., Lin, AL., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer receiving olaparib versus chemotherapy in the OlympiAD trial. [2020]

4. England pubmed.ncbi.nlm.nih.gov

OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Olaparib for the treatment of breast cancer. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. [2019]

7. Germany pubmed.ncbi.nlm.nih.gov

Hematologic adverse events associated with temozolomide. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of temozolomide in mycosis fungoides/sezary syndrome: correlation with O⁶-methylguanine-DNA methyltransferase and mismatch repair proteins. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]

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[Successful combination therapy of teicoplanin with cefmetazole on postoperative cardiovascular MRSA infections: clinical report on two cases]. [2016]