Olaparib + Temozolomide for Uterine Leiomyosarcoma

Recruiting at 151 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

190 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II/III trial compares the effect of the combination treatment with olaparib and temozolomide to trabectedin or pazopanib (two of the most common chemotherapy drugs used as usual approach) in patients with uterine leiomyosarcoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) after initial chemotherapy has stopped working. The usual approach is defined as care most people get for advanced uterine leiomyosarcoma. Olaparib is a PARP inhibitor. PARP is a protein that helps repair damaged deoxyribonucleic acid (DNA). Blocking PARP may prevent tumor cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Temozolomide is in a class of medications called alkylating agents. It works by slowing or stopping the growth of tumor cells in the body. The combination of olaparib and temozolomide may work better than the usual treatment in shrinking or stabilizing advanced uterine leiomyosarcoma after initial chemotherapy has stopped working.

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.

What data supports the effectiveness of the drug combination Olaparib and Temozolomide for treating uterine leiomyosarcoma?

Research shows that the combination of Olaparib and Temozolomide was highly effective in preclinical studies for inhibiting tumor growth in uterine leiomyosarcoma, a type of aggressive cancer. Additionally, Olaparib has shown promising results in treating ovarian cancer, especially in patients with certain genetic mutations, suggesting its potential effectiveness in other cancers with similar characteristics. ^{1 2 3 4 5}

Is Olaparib safe for use in humans?

Olaparib (Lynparza) has been tested in various clinical trials for ovarian cancer and is approved for use in patients with certain genetic mutations. It has been evaluated for safety in these trials, indicating it is generally safe for human use in the context of ovarian cancer treatment. ^{2 3 4 5 6}

What makes the drug combination of Olaparib and Temozolomide unique for treating uterine leiomyosarcoma?

The combination of Olaparib and Temozolomide is unique because it targets cancer cells in a novel way by combining a PARP inhibitor (Olaparib) with a chemotherapy agent (Temozolomide), potentially enhancing the effectiveness of treatment for uterine leiomyosarcoma, a condition with limited standard treatment options. ^{7 8 9 10 11}

Research Team

Brian Van Tine

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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]

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 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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250). [2023]

2. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. [2015]

3. England 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. [2016]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. [2020]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Vorapaxar and optimal aspirin dose: The FDA outlook. [2016]

8. England 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. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Talimogene Laherparepvec: An Oncolytic Virus Therapy for Melanoma. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Low molecular weight heparins for venous thromboembolism. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Perioperative Recovery and Narcotic Use in Laparoscopic versus Robotic Surgery for Endometrial Cancer. [2021]