Temozolomide + Olaparib for Breast Cancer

Not yet 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two treatments for individuals with a specific type of breast cancer called triple-negative breast cancer (TNBC) that has spread or is advanced. Participants will receive either temozolomide (a chemotherapy drug) alone or a combination of temozolomide and olaparib (a targeted therapy) to evaluate how well these treatments control the cancer. This trial suits those with TNBC who have certain genetic features and have already tried some chemotherapy but seek other options. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that temozolomide is generally well-tolerated by cancer patients. Studies have found it effective for treating brain metastases from breast cancer, with usually manageable side effects. Some reported side effects include nausea and fatigue, but these are typically mild.

For the combination of temozolomide and olaparib, research also indicates a manageable safety profile. One study tested this combination in patients with uterine leiomyosarcoma, a type of cancer. The results were promising, with generally manageable side effects. Common side effects included nausea and low blood cell counts, but these were mostly mild to moderate.

Both treatments have been studied in humans for other types of cancer, providing some confidence in their safety for new trials. However, like any treatment, risks exist, and discussing these with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Temozolomide and Olaparib for breast cancer because it offers a unique approach by pairing a chemotherapy agent with a PARP inhibitor. Unlike traditional treatments that mainly involve surgery, radiation, or hormone therapy, this duo targets cancer cells by damaging their DNA and preventing them from repairing themselves. Temozolomide disrupts the DNA of cancer cells, while Olaparib blocks the PARP enzyme, crucial for repairing DNA damage in these cells. This dual action could potentially enhance the effectiveness of treatment, offering hope for better outcomes in patients with difficult-to-treat breast cancer.

What evidence suggests that this trial's treatments could be effective for triple-negative breast cancer?

Research has shown that temozolomide, one of the treatments in this trial, may extend the lives of breast cancer patients when combined with other therapies. Studies have found it effective for treating breast cancer that has metastasized, although results can vary.

This trial also includes a combination arm of temozolomide and olaparib. Early research suggests this pair could become a new standard treatment, showing promise in other cancer types as well. For instance, in uterine cancer, this combination allowed many patients to go nearly seven months without their cancer worsening.

These findings suggest that this treatment could help manage triple-negative breast cancer, particularly in patients with specific genetic markers that might respond better to these therapies. ^{1 3 4 6 7}

Who Is on the Research Team?

Don Morris, MD, PhD

Principal Investigator

Arthur J.E. Child Comprehensive Cancer Centre

Are You a Good Fit for This Trial?

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.

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.

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/show/NCT01009788

ABT-888 and Temozolomide for Metastatic Breast Cancer ... The purpose of this research study is to find out if the combination of ABT-888 and temozolomide is safe and effective in treating patients with metastatic ...

2. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)38305-X/fulltext

Dose-dense temozolomide regimen for the treatment ... Median progression-free survival was 56, 58, and 66 days for melanoma, BC, and NSCLC, respectively. Median overall survival was 100 days for melanoma, 172 days ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7270957/

Temozolomide in secondary prevention of HER2-positive ... It was demonstrated to prolong survival when used with trastuzumab and docetaxel as first-line treatment for metastatic HER2-positive breast ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10153633/

Phase I Study and Cell-Free DNA Analysis of T-DM1 and ... Preclinical data showed that prophylactic, low dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I ...

5. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)43572-2/fulltext

Temozolomide in metastatic breast cancer (MBC) This phase II trial sought to determine the activity and toxicity of temozolomide in metastatic breast cancer (MBC).

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36705597/

Phase I Study and Cell-Free DNA Analysis of T-DM1 and ... Purpose: Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis.

7. ascopubs.org ascopubs.org/doi/10.1200/OP.23.00794

Breast Cancer Brain Metastasis: A Comprehensive Review In a phase II trial, the combination of temozolomide with cisplatin demonstrated synergistic effects. Over 30% of patients with BMs from breast ...