Olaparib + Temozolomide for Leiomyosarcoma

Not currently recruiting at 18 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: PARP inhibitors, Dacarbazine

Disqualifiers: Other malignancy, CNS disease, 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

Compensation: Varies

Number of Visits: 25

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, olaparib and temozolomide, to treat uterine leiomyosarcoma, a cancer that begins in the muscle tissue of the uterus and can spread to other body parts. Olaparib blocks proteins that help cancer cells repair themselves, while temozolomide is a chemotherapy drug that stops cancer cells from growing. The trial aims to determine if using these two drugs together is more effective than using them alone. Suitable participants have advanced uterine leiomyosarcoma that has spread or cannot be surgically removed and have previously tried at least one other treatment without success. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must avoid certain medications that interact with the trial drugs, such as strong or moderate CYP3A inhibitors and inducers, with a washout period (time without taking these medications) of 2 to 5 weeks before starting the trial.

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

Research is exploring the use of a combination of two drugs, olaparib and temozolomide, to treat advanced uterine leiomyosarcoma. In earlier studies, patients have shown varied reactions to this treatment. Some experienced common side effects like nausea and tiredness, which are usually manageable. However, more serious side effects, such as low blood counts, were also reported, increasing the risk of infections or bleeding.

While these side effects might seem concerning, the research aims to determine if the combined use of these drugs offers more benefits than risks. Olaparib is already approved for other conditions, indicating its safety is well understood when used alone. Temozolomide has also been used in other treatments, providing some knowledge about its effects. This ongoing research seeks to ensure that the benefits of using these drugs together outweigh the risks for people with advanced uterine leiomyosarcoma. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about olaparib and temozolomide for leiomyosarcoma because they bring a fresh approach to treatment. Unlike traditional chemotherapy options like doxorubicin, which broadly targets fast-growing cells, olaparib specifically inhibits a protein involved in DNA repair, potentially making cancer cells more susceptible to damage. When combined with temozolomide, a drug that adds additional DNA damage, this duo could enhance the effectiveness of the treatment by hitting the cancer from two angles. This unique mechanism of action offers hope for better outcomes in a condition with limited effective options.

What evidence suggests that this treatment might be an effective treatment for leiomyosarcoma?

Research has shown that using olaparib and temozolomide together may help treat advanced uterine leiomyosarcoma, a cancer affecting the smooth muscle of the uterus. In earlier studies, this drug combination slowed or shrank tumors in 27% of patients, meaning their tumors either got smaller or stopped growing. However, in some cases, this treatment was not more effective than other options like pazopanib or trabectedin. This combination works by making it harder for cancer cells to repair themselves, which helps stop the cancer from growing. Participants in this trial will receive the combination of olaparib and temozolomide to evaluate its effectiveness and safety in treating leiomyosarcoma. ^{1 2 3 4 6}

Who Is on the Research Team?

Mia C Weiss

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

Adults with advanced uterine leiomyosarcoma that's spread or can't be surgically removed, who've had prior treatment failure or intolerance. Must be able to swallow pills, have adequate organ function, use effective contraception if needed, and agree to study procedures.

Inclusion Criteria

AST/ALT =< 2.5 x institutional ULN

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

My cancer is a type of uterine sarcoma confirmed by tissue analysis.

Exclusion Criteria

I am allergic to medications similar to olaparib or TMZ.

Involvement in the planning and/or conduct of the study

You are either pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive olaparib and temozolomide orally on days 1-7 of each 21-day cycle

6 months

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 3 months for 2 years, then every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Temozolomide

Trial Overview

The trial tests a combination of Olaparib (a PARP inhibitor preventing tumor DNA repair) and Temozolomide (chemotherapy), aiming to see if they're more effective together against this cancer than when used separately.

How Is the Trial Designed?

Group I: Treatment (olaparib, temozolomide) Experimental Treatment 5 Interventions

Patients receive olaparib PO BID and temozolomide PO QD on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI throughout the trial and undergo tumor biopsy at screening and on study.

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

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Olaparib is an effective oral treatment for patients with BRCA mutation-positive ovarian cancer, approved for maintenance therapy after platinum-based chemotherapy, showing good tolerability with common side effects like nausea, fatigue, and anemia being mild to moderate.

Long-term monitoring is recommended due to a low risk of serious hematological complications, such as anemia and myelodysplastic syndrome, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. Lheureux, S., Bowering, V., Karakasis, K., et al.[2015]

Olaparib effectively penetrated recurrent glioblastoma tumors in patients, with measurable concentrations found in all tumor core and margin specimens, indicating its potential for therapeutic use.

The combination of olaparib with low-dose temozolomide (TMZ) was associated with increased hematological toxicity, leading to the need for intermittent dosing, but showed promising efficacy with 36% of patients remaining progression-free at 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Hanna, C., Kurian, KM., Williams, K., et al.[2022]

Olaparib, a PARP inhibitor, showed a 36% objective response rate in women with relapsed ovarian cancer and a germline BRCA1/2 mutation, even after they had undergone multiple lines of chemotherapy, indicating its efficacy in this challenging patient population.

The median duration of response to olaparib was 7.4 months, and the safety profile was consistent across patients who had received three or more lines of prior chemotherapy, with similar rates of serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. Matulonis, UA., Penson, RT., Domchek, SM., 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 is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

Vorapaxar, a new medication for preventing blood clots after heart attacks, showed slightly reduced efficacy when used with higher doses of aspirin (≥ 300 mg), while bleeding risks increased significantly at these higher doses.

The study suggests that for safer and more effective use of vorapaxar, the recommended aspirin dosage should be between 75 to 100 mg daily, as higher doses were associated with worse outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorapaxar and optimal aspirin dose: The FDA outlook. Serebruany, VL., Fortmann, SD., Kim, MH.[2016]

Talimogene laherparepvec (T-VEC) is an effective treatment for advanced melanoma, showing an overall response rate of 26% and significantly improving the durable response rate compared to granulocyte-macrophage colony-stimulating factor (16.3% vs 2.1%).

T-VEC is generally well tolerated with mild to moderate adverse effects, and while it does not significantly improve median overall survival compared to other treatments, it is the first approved oncolytic virus for local treatment of melanoma lesions, with ongoing trials exploring its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talimogene Laherparepvec: An Oncolytic Virus Therapy for Melanoma. Corrigan, PA., Beaulieu, C., Patel, RB., et al.[2018]

In a phase II study involving 22 patients with advanced uterine leiomyosarcoma (uLMS), the combination of olaparib and temozolomide showed a promising objective response rate of 27%, indicating potential efficacy in this aggressive cancer type.

Patients with homologous recombination-deficient tumors experienced significantly longer progression-free survival (11.2 months) compared to those with proficient tumors (5.4 months), suggesting that genetic profiling could help tailor treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250). Ingham, M., Allred, JB., Chen, L., et al.[2023]

Citations

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ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.11507

Alliance A092104: A randomized phase 2/3 study of ...

Preclinical studies demonstrated synergistic activity of olaparib and temozolomide (T+O), and a prior single-arm Phase II study of T+O showed ...

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pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/37467452/

Phase II Study of Olaparib and Temozolomide for Advanced ...

In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor ...

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onclive.com

onclive.com/view/olaparib-temozolomide-fails-to-meet-pfs-end-point-in-previously-treated-advanced-uterine-leiomyosarcoma

Olaparib/Temozolomide Fails to Meet PFS End Point in ...

Olaparib plus temozolomide was not superior to pazopanib or trabectedin for the treatment of patients with advanced uterine leiomyosarcoma.

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05633381

Study Details | NCT05633381 | Testing Olaparib and ...

The combination of olaparib and temozolomide may work better than the usual treatment in shrinking or stabilizing advanced uterine leiomyosarcoma after initial ...

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10852403/

Phase II Study of Olaparib and Temozolomide for Advanced ...

Olaparib and temozolomide met the prespecified primary efficacy end point and provided a best ORR rate of 27% among patients with advanced pretreated uLMS.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03880019

Study Details | NCT03880019 | A Phase II ...

This phase II trial studies olaparib and temozolomide in treating patients with uterine leiomyosarcoma (LMS) that may have spread from where it first ...