Olaparib + Navitoclax for Breast Cancer

Not currently recruiting at 2 trial locations

Overseen By Helen Mackay

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Sunnybrook Health Sciences Centre

Must not be taking: Anticoagulants, Ibuprofen

Disqualifiers: Active bleeding, Thrombocytopenia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 42 days (14 days + 28 days)

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether two drugs, olaparib (also known as Lynparza, a type of targeted therapy) and navitoclax, can effectively treat breast cancer together. Researchers are focusing on women with triple-negative breast cancer (TNBC) or high-grade serous carcinoma (HGSC) who have specific genetic mutations and whose cancer has progressed after chemotherapy. The goal is to identify a safe and effective dose combination for future studies. This trial may suit women whose breast cancer has specific gene mutations (such as BRCA1 or BRCA2) and has worsened after previous treatments, but who can still take the medications orally. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you cannot take certain blood thinners or medications that affect platelet function within 14 days before starting the trial drugs. It's best to discuss your current medications with the trial team to see if any changes are needed.

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

Research shows that olaparib is generally well-tolerated by patients with BRCA-mutated breast cancer. Studies have found that it does not cause increasing side effects over time, even with long-term use. Patients in these studies lived longer, and most side effects were manageable.

Safety studies indicate that navitoclax can be safely used with other cancer treatments. Some patients experienced reduced bone marrow activity, which limited the dose. Overall, navitoclax showed promising effects against tumors.

In summary, both olaparib and navitoclax have been studied separately and found to be generally safe, with some manageable side effects. This trial aims to find a safe way to use them together, making close monitoring of safety important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of olaparib and navitoclax for breast cancer because it offers a novel approach compared to traditional treatments like chemotherapy and hormone therapy. Olaparib is a PARP inhibitor, which works by blocking a protein that cancer cells need to repair their DNA, causing them to die. Navitoclax enhances this effect by inhibiting proteins that prevent cancer cell death, potentially leading to more effective treatment outcomes. This combination targets cancer cells in two unique ways, offering hope for improved results over existing therapies.

What evidence suggests that the combination of olaparib and navitoclax could be effective for breast cancer?

Research has shown that olaparib helps patients with certain breast cancer genes, such as BRCA1 and BRCA2, live longer without their cancer worsening. In studies, olaparib reduced the risk of cancer progression or death by 32% compared to standard treatments.

Navitoclax aids in killing cancer cells and has slowed tumor growth, especially when combined with other drugs. While navitoclax alone may not always destroy cancer cells, it becomes more effective when used with other treatments.

In this trial, participants will receive a combination of olaparib and navitoclax. This combination could be more powerful because olaparib makes cancer cells more dependent on navitoclax, enhancing the overall treatment effect. ^{5 6 7 8 9}

Who Is on the Research Team?

Helen MacKay, MD

Principal Investigator

Sunnybrook Cancer Centre

Are You a Good Fit for This Trial?

This trial is for women over 18 with certain types of advanced ovarian or breast cancer (HGSC, TNBC) who have specific genetic mutations (BRCA1/2, PALB2). They should not have had more than two treatments for TNBC and must be able to take oral medications. Women must not be pregnant and should have a life expectancy of at least 16 weeks.

Inclusion Criteria

Patients must have a life expectancy ≥16 weeks

I have had no more than two treatments for triple-negative breast cancer.

My triple-negative breast cancer has harmful mutations in BRCA1, BRCA2, or PALB2.

Exclusion Criteria

I haven't taken blood thinners or certain pain relievers in the last 14 days.

I haven't had major bleeding, stomach ulcers, severe esophagitis or gastritis, or blood disorders in the past year.

I haven't had cancer treatment or experimental drugs in the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Olaparib is administered alone for 14 days, followed by continuous administration with escalating doses of navitoclax in 28-day cycles

42 days (14 days + 28 days)

Dose Escalation

Navitoclax dose is escalated with a fixed dose of olaparib to determine the recommended Phase II dose (RP2D)

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Navitoclax
• Olaparib

Trial Overview The study tests combining Olaparib, a PARP inhibitor, with Navitoclax, which blocks proteins that prevent cell death in cancers like HGSC and TNBC. It aims to find the safest dose combination for future Phase II trials by observing side effects and determining the maximum tolerated dose.

How Is the Trial Designed?

Group I: Single Experimental Treatment 2 Interventions

Olaparib tablet will be administered alone for 14 days at a starting dose of 200 mg twice daily (bid). Subsequently olaparib will be administered continuously over 28 days at a fixed dose and the dose of navitoclax will be escalated. Navitoclax will be administered daily. The initial dose of olaparib 200 mg has been selected after considering the single agent Phase I/II dose based and on ongoing combination studies on expected toxicity and evidence for reduced PARP inhibition

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Princess Margaret Hospital, Canada

Collaborator

Trials

121

Recruited

40,000+

Centre hospitalier de l'Université de Montréal (CHUM)

Collaborator

Trials

389

Recruited

143,000+

Exactis Innovation

Collaborator

Trials

9

Recruited

10,700+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7708921/

Navitoclax enhances the effectiveness of EGFR-targeted ... Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7563413/

Multi-Omics Investigation of Innate Navitoclax Resistance in ... The breast cancer subtype with the least therapeutic options and therefore the poorest outcome is triple-negative breast cancer (TNBC) [20].

3. sciencedirect.com sciencedirect.com/science/article/pii/S1043661822005746

Combination of palbociclib with navitoclax based-therapies ... In the case of breast cancer, navitoclax is not sufficient to induce tumour death in some breast cancer cell lines [60], as we have also observed in MDA-MB-231 ...

4. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.564108/full

Clinical Review: Navitoclax as a Pro-Apoptotic and Anti ... Navitoclax has been demonstrated as a single agent or in combination with other drugs to successfully ameliorate tumor progression and fibrosis development.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0887233317302758?via%3Dihub

Human breast cancer cells display different sensitivities to ... These data indicate that navitoclax induces cell death in MDA-MB-231 cells ... The sensitivity of both cell lines to navitoclax demonstrates breast cancer ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4534314/

Phase 1 Study of the Safety, Pharmacokinetics, and ... Responses were assessed while patients continued treatment with navitoclax. Statistical Analysis. Safety data were summarized by navitoclax dose level.

7. tandfonline.com tandfonline.com/doi/full/10.2217/fon-2021-0140

Full article: A Phase I Study of the Safety, Pharmacokinetics ... Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01989585

NCT01989585 | Testing the Addition of Navitoclax to ... Because no dosing or adverse event data are currently available on the use of navitoclax in combination with dabrafenib and trametinib in ...

9. breast-cancer-research.biomedcentral.com breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-020-01374-8

Navitoclax enhances the effectiveness of EGFR-targeted ... Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer.