Olaparib + Temozolomide for Leiomyosarcoma

Recruiting at 15 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

23 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing olaparib and temozolomide in patients with advanced uterine leiomyosarcoma. Olaparib stops cancer cells from repairing themselves, while temozolomide kills or stops the growth of cancer cells. The combination may be more effective than using either drug alone.

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.

What data supports the effectiveness of the drug combination Olaparib and Temozolomide for treating 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 effectiveness in treating ovarian cancer with certain genetic mutations, suggesting its potential benefit in other cancers with similar genetic profiles. ^{1 2 3 4 5}

Is the combination of Olaparib and Temozolomide generally safe for humans?

The combination of Olaparib and Temozolomide has been studied in patients with glioma and glioblastoma, showing common side effects like fatigue, gastrointestinal issues, and blood-related problems. Some patients needed to reduce their dose or stop treatment due to these side effects. ^{2 3 4 6 7}

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

The combination of Olaparib and Temozolomide is unique for treating leiomyosarcoma because it combines a PARP inhibitor (Olaparib) with an alkylating agent (Temozolomide), potentially enhancing the effectiveness of DNA damage in cancer cells, which is different from standard treatments that may not use this dual approach. ^{8 9 10 11 12}

Research Team

Brian Van Tine

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

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

I am 18 years old or older.

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

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

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

Treatment Details

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.

Participant Groups

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+

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, 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 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 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]

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 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]

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]

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

Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety. [2022]

3. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

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

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

Safety and efficacy of ubrogepant for the acute treatment of perimenstrual migraine attacks: A post hoc analysis. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

The FDA review on data quality and conduct in vorapaxar trials: Much better than in PLATO, but still not perfect. [2018]

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

Varespladib. [2021]

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

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