Olaparib + Temozolomide for Uterine Leiomyosarcoma

Overseen By Matthew Ingham, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Pregnancy, Hypertension, Cardiac 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: 27

Duration: Varies (until disease progression or unacceptable toxicity)

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a new combination of drugs, olaparib (Lynparza) and temozolomide, can be more effective than the standard treatment for advanced uterine leiomyosarcoma, a cancer that starts in the uterus and spreads after initial treatments. Olaparib may prevent cancer cells from repairing damaged DNA, potentially causing cell death, while temozolomide stops cell growth. Individuals with uterine leiomyosarcoma that has not responded well to at least two rounds of chemotherapy might be suitable for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for strong or moderate CYP3A inhibitors and inducers before starting the study treatment. You may need to stop these medications 2 to 5 weeks prior to the trial, depending on the specific drug. Please consult with the trial team for guidance on your specific medications.

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

Research shows that the combination of olaparib and temozolomide is being tested for safety and effectiveness in treating advanced uterine leiomyosarcoma, a type of cancer. Studies have found that most patients tolerate this treatment well. However, some side effects, such as nausea, tiredness, and low blood cell counts, have been reported, which are common with cancer treatments.

Olaparib is a drug already approved for other cancers, indicating its safety is well-known. Temozolomide is also used in other cancer treatments, so its safety is well-documented. Although this combination did not outperform the usual treatment in some studies, safety was not the issue.

For those considering joining a trial, these findings suggest that the treatment is relatively safe, with side effects similar to many cancer therapies. Discuss potential risks and benefits with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about olaparib and temozolomide for uterine leiomyosarcoma because they offer a novel approach compared to traditional treatments like surgery, radiation, and standard chemotherapy. Olaparib is a PARP inhibitor, which means it works by preventing cancer cells from repairing their DNA, leading to cell death. Temozolomide, an oral chemotherapy drug, is known for its ability to penetrate the blood-brain barrier, offering a unique advantage for widespread cancer. This combination targets cancer cells in a way that potentially reduces tumor growth more effectively than current options.

What evidence suggests that the combination of olaparib and temozolomide could be effective for advanced uterine leiomyosarcoma?

This trial will compare the combination of olaparib and temozolomide with another treatment option for uterine leiomyosarcoma. Research has shown that combining olaparib and temozolomide may benefit patients with advanced cancers, though not specifically for uterine leiomyosarcoma. Olaparib is a targeted therapy that blocks a protein called PARP, which repairs damaged DNA, potentially causing cancer cells to die. Temozolomide slows or stops cancer cell growth. However, earlier studies found that this combination was not more effective than standard treatments for advanced uterine leiomyosarcoma. While promising for other cancers, the effectiveness of this combination for this specific condition remains uncertain. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

This trial is for adults with advanced uterine leiomyosarcoma that has worsened after at least two prior treatments, including an anthracycline. Participants must have no major organ dysfunction, not be pregnant or breastfeeding, and cannot have had certain other cancers or severe illnesses that could interfere with the study.

Inclusion Criteria

I finished my cancer treatment less than 28 days ago.

Specific blood count and chemistry requirements

Ability to speak and/or read English and Spanish

Exclusion Criteria

I do not have any ongoing issues with perforations, abscesses, or fistulas.

I have been diagnosed with MDS or AML.

I have previously taken specific medications for my condition.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either olaparib plus temozolomide or investigator's choice of trabectedin or pazopanib. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Varies (until disease progression or unacceptable toxicity)

Visits every 21 days

Follow-up

Participants without disease progression are followed every 6 weeks until disease progression. After disease progression, follow-up occurs every 3 months for the first 2 years, then every 6 months thereafter until 5 years post-randomization or death.

Up to 5 years

Every 6 weeks initially, then every 3 to 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Temozolomide

Trial Overview The trial compares a new combination of drugs (Olaparib and Temozolomide) against standard treatments (Trabectedin and Pazopanib) to see if they are more effective in shrinking or stabilizing this type of cancer after previous chemotherapy has failed.

How Is the Trial Designed?

Group I: Arm 1 (olaparib, temozolomide) Experimental Treatment 2 Interventions

Patients receive temozolomide is administered at PO QD on days 1-7 of each cycle and olaparib PO BID on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity

Group II: Arm 2 (trabectedin, pazopanib) Active Control 2 Interventions

Patients receive trabectedin IV continuously over 24 hours on day 1 of each cycle and pazopanib PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

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?

Alliance for Clinical Trials in Oncology

Lead Sponsor

Trials

521

Recruited

224,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study involving 48 female rats, heparin and enoxaparin were found to significantly reduce E-cadherin expression in placental and decidual tissues, which may affect trophoblast invasion during pregnancy.

The study suggests that the reduction of E-cadherin by heparin and enoxaparin could be a mechanism that helps improve pregnancy outcomes in women with a history of miscarriage, although laminin expression remained unchanged.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of the effects of heparin and low molecular weight heparin on E-cadherin and laminin expression in rat pregnancy by immunohistochemistry. Erden, O., Imir, A., Guvenal, T., et al.[2023]

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]

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]

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]

In a study of 240 patients undergoing minimally invasive surgery for endometrial cancer, there was no significant difference in narcotic use between robotic and laparoscopic surgery, indicating similar pain management outcomes for both techniques.

Patients who underwent robotic surgery experienced longer recovery room times and were less likely to achieve same-day discharge compared to those who had laparoscopic surgery, suggesting that while robotic surgery may offer certain advantages, it may also lead to longer hospital stays.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative Recovery and Narcotic Use in Laparoscopic versus Robotic Surgery for Endometrial Cancer. Crane, EK., Brown, J., Lehman, A., et al.[2021]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[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]

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]

Low molecular weight heparins (LMWHs) provide better protection against deep vein thrombosis (DVT) compared to conventional unfractionated heparin (UFH) in patients undergoing major orthopedic surgery, with similar bleeding risks.

Several LMWHs, including dalteparin, enoxaparin, and tinzaparin, are now licensed in the UK for both prophylaxis against venous thromboembolism and treatment of DVT and pulmonary embolism, indicating their established efficacy and safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low molecular weight heparins for venous thromboembolism. [2019]

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]

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 oral medication that inhibits poly (ADP-ribose) polymerase and is primarily developed for treating BRCA mutation-positive ovarian cancer, with its capsule formulation already approved in the EU and USA.

The drug is currently undergoing extensive clinical trials for various cancers, including breast, gastric, and pancreatic cancers, indicating its potential broad application in oncology beyond ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. Deeks, ED.[2020]

Citations

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

Phase II Study of Olaparib and Temozolomide for Advanced ... Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, ...

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

Alliance A092104: A randomized phase 2/3 study of ... Background: Advanced uterine leiomyosarcoma (uLMS) is an aggressive malignancy with poor prognosis. Standard-of-care treatments, including ...

3. 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/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 ...

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

Phase II Study of Olaparib and Temozolomide for Advanced ... Advanced disease is incurable and treated with palliative chemotherapy, but outcomes remain poor. Gemcitabine plus docetaxel and doxorubicin-based regimens used ...

6. 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 ...