Olaparib + Temozolomide for Uterine Leiomyosarcoma

Not currently recruiting at 157 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Uncontrolled hypertension, Cardiac disease, MDS/AML, 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: Unknown

Duration: Up to 5 years

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 outperform the usual treatments, trabectedin or pazopanib, for advanced uterine leiomyosarcoma. Olaparib hinders a protein that repairs cancer cell DNA, while temozolomide slows the growth of these cells. The goal is to determine if this new combination can better shrink or control the cancer compared to current treatments. This trial may suit individuals with advanced uterine leiomyosarcoma that has worsened despite previous chemotherapy. 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 requires that you stop taking certain medications that are strong or moderate CYP3A inhibitors or inducers. There is a required washout period (time without taking these medications) of 2 weeks for inhibitors and up to 5 weeks for some inducers before starting the study treatment.

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

Research shows that using olaparib and temozolomide together is generally safe. Studies have found that patients with advanced conditions can handle the side effects of this combination without serious problems. Common side effects include nausea and tiredness, but these are usually mild.

Other research indicates that while olaparib, a PARP inhibitor, and temozolomide, a form of chemotherapy, may not be more effective than treatments like pazopanib or trabectedin, they remain safe for most patients, with manageable side effects.

For those considering joining a trial with this combination, current evidence suggests that despite some side effects, the treatment is reasonably safe. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatments for uterine leiomyosarcoma in this trial because they offer new approaches compared to current options. Olaparib, a PARP inhibitor, is unique because it works by blocking DNA repair in cancer cells, potentially leading to cell death. Temozolomide, when used with olaparib, may enhance this effect by further damaging the cancer cells' DNA. On the other hand, trabectedin and pazopanib present another approach; trabectedin disrupts the cancer cell's DNA transcription, while pazopanib inhibits tumor growth by targeting blood vessel development. These combinations aim to provide more effective treatment options with potentially improved outcomes for patients.

What evidence suggests that this trial's treatments could be effective for uterine leiomyosarcoma?

Research has shown that using olaparib with temozolomide has helped some patients with advanced cancers. In this trial, one group of participants will receive this combination. Olaparib is a drug that prevents a protein from repairing damaged DNA in cells. When cancer cells can't repair their DNA, they might die. Temozolomide aids by stopping cancer cells from growing. Another group in this trial will receive standard treatments like trabectedin or pazopanib. Recent studies have found that the olaparib and temozolomide combination is not more effective than these standard treatments for uterine leiomyosarcoma. Despite initial hopes, the combination did not perform better in slowing the disease. ^{1 2 3 5 6}

Who Is on the Research Team?

Brian Van Tine

Principal Investigator

Alliance for Clinical Trials in Oncology

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 measurable disease, be in relatively good health (ECOG <=2), and women must test negative for pregnancy. Those with significant treatment-related side effects or who haven't recovered from previous therapies are excluded.

Inclusion Criteria

I can speak and/or read English and Spanish.

I can take care of myself but might not be able to do heavy physical work.

I don't have uncontrolled heart rhythm problems or recent heart attacks.

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.

Up to 5 years

Regular visits for CT/MRI scans and blood sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up occurs every 6 weeks until disease progression, then every 3 months for the first 2 years, and every 6 months thereafter until 5 years post-randomization or death.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Temozolomide

Trial Overview The study compares a new combination of drugs (Olaparib and Temozolomide) against standard chemotherapy options (Trabectedin or Pazopanib) for advanced uterine leiomyosarcoma post-initial chemo failure. Olaparib may prevent tumor DNA repair, while Temozolomide aims to slow tumor growth.

How Is the Trial Designed?

Group I: Arm 1 (olaparib, temozolomide) Experimental Treatment 8 Interventions

Patients receive temozolomide 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. Patients undergo CT scan or MRI and/or bone scans throughout the trial. Patients also undergo collection of blood samples throughout the trial.

Group II: Arm 2 (trabectedin, pazopanib) Active Control 8 Interventions

Patients receive trabectedin IV continuously over 24 hours on day 1 of each cycle or pazopanib PO QD on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan or MRI and/or bone scans throughout the trial. Patients also undergo TTE or MUGA on study and as clinically indicated, as well as collection of blood samples throughout the trial.

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

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]

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]

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 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 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]

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 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]

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]

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 ...