Olaparib + Temozolomide for Uterine Leiomyosarcoma

Recruiting in Palo Alto (17 mi)

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: Alliance for Clinical Trials in Oncology

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Pregnancy, Hypertension, Cardiac disease, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This phase II/III trial compares the effect of the combination of olaparib and temozolomide to the usual treatment (trabectedin and pazopanib) for uterine leiomyosarcoma that has spread to other places in the body (advanced) after initial chemotherapy has stopped working. 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 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.

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 stopping the growth of uterine leiomyosarcoma tumors. Additionally, Olaparib has been effective in treating ovarian cancer, especially in patients 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?

Olaparib has been tested in various clinical trials for ovarian cancer and is generally considered safe for use in humans, with approval for certain types of cancer. However, specific safety data for the combination of Olaparib and Temozolomide is not provided in the available research. ^{2 3 4 6 7}

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. ^{8 9 10 11 12}

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 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.

My advanced uLMS has not improved or I couldn't tolerate two previous treatments, including an anthracycline.

Specific blood count and chemistry requirements

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.

Trial 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.

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

Treatment Details

Interventions

• Olaparib (PARP inhibitor)
• Temozolomide (Alkylating agent)

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.

Participant Groups

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Columbia University/Herbert Irving Cancer Center New York, NY

Who Is Running the Clinical Trial?

Alliance for Clinical Trials in Oncology Lead Sponsor

National Cancer Institute (NCI) Collaborator

References

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

Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250). [2023] Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth.

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

Safety evaluation of olaparib for treating ovarian cancer. [2015] Olaparib (Lynparza®) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor that has become the first 'personalized' therapy available for patients with BRCA mutation-positive ovarian cancer (OC). A capsule formulation of the drug has recently received approval for use in this population for platinum-sensitive recurrent disease for maintenance therapy following platinum-based chemotherapy in Europe and as third- or fourth-line platinum-sensitive therapy in the USA.

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

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020] Olaparib (Lynparza™) is a PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumours are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. We report exploratory analyses, including the long-term outcome of candidate biomarkers of sensitivity to olaparib in BRCA wild-type (BRCAwt) tumours.

4. 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] The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy.

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

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. [2016] Olaparib (Lynparza™) is a first-in-class, orally-active, small molecule, poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. In the EU, the capsule formulation of olaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive, relapsed, BRCA-mutated (germline and/or somatic), high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. This approval was based on the results of study 19, a randomized phase II trial in 265 patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer (HGSOC) who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Study 19 met its primary endpoint by demonstrating a significant improvement in progression-free survival in patients receiving olaparib compared with those receiving placebo. Moreover, a preplanned retrospective analysis identified those patients with a BRCA mutation (who comprised one-half of the overall study population) as being the subgroup that derived the greatest clinical benefit from olaparib. Single-agent olaparib was generally well tolerated, with the majority of adverse events being of mild to moderate severity and not requiring interruption of treatment. Fatigue, anaemia and neutropenia were the most frequently reported severe (grade ≥3) adverse events. An as yet unapproved tablet formulation of olaparib that has a lower pill burden than the capsule formulation is currently being investigated in phase III clinical studies.

6. England pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. [2016] Olaparib (Lynparza™; AZD2281) is a potent PARP-1 and PARP-2 inhibitor with biologic activity in ovarian cancer as well as other solid tumors. It has been tested in Phase I and II trials and has single-agent activity in both germline BRCA mutated and sporadic ovarian cancer. Phase III trials assessing the efficacy of olaparib in the maintenance setting following first line and platinum-sensitive recurrence are underway for patients with a germline BRCA mutation, given the inherent molecular compatibility with the drug's mechanism of action.

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

Olaparib: first global approval. [2020] Olaparib (Lynparza™) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by AstraZeneca for the treatment of solid tumours. The primary indication that olaparib is being developed for is BRCA mutation-positive ovarian cancer. A capsule formulation of the drug has received approval for use in this setting in the EU and USA, and a tablet formulation is in global phase III trials (including in the USA, EU, Australia, Brazil, Canada, China, Israel, Japan, Russia and South Korea). In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. This article summarizes the milestones in the development of olaparib leading to this first approval for ovarian cancer.

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

Vorapaxar and optimal aspirin dose: The FDA outlook. [2016] Vorapaxar, a novel thrombin PAR-1 inhibitor, approved for post-myocardial infarction, and peripheral artery disease indications has been tested in 2 major clinical trials. In the successful TRA2P, antecedent aspirin (ASA) has been used in 94% of patients, and in failed TRACER in over 96% of patients. However, both trial publications were silent on the impact of ASA dose on clinical outcomes after voraparax. We determined which ASA dose range should be used in combination with voraparax based on the TRA2P and TRACER secondary FDA review. The data suggest that for both voraparax trials, younger patients, males, and diabetics received higher ASA doses. The interactions between voraparax efficacy and ASA dose ≥ 300 mg was marginally significant by Cox regressions for TRA2P (CI=1.00-1.61; p=0.048) and strongly trended in TRACER (CI=0.98-1.47; p=0.073). Bleeding rates were overall slightly higher with voraparax than with placebo, and were the highest in patients receiving ASA dosages ≥ 300 mg. However, there were no interactions between ASA dose and GUSTO moderate/severe bleeding. In conclusion, the efficacy of voraparax in TRA2P and TRACER, was slightly worse while bleeding was substantially worse with the higher over 300 mg/day of ASA dosages. Voraparax label should recommend ASA daily use in 75 to 100mg range for concomitant use.

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

Talimogene Laherparepvec: An Oncolytic Virus Therapy for Melanoma. [2018] To review the efficacy and safety of talimogene laherparepvec (T-VEC) as well as its pharmacology, pharmacokinetics, drug-drug interactions, handling procedures, cost considerations, and place in therapy.

10. 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] Heparin and low molecular weight heparin (LMWH) are used widely to improve the pregnancy outcome in women with thrombophilia, miscarriage, recurrent miscarriage and fetal death. This study was designed to investigate the effects of heparin and LMWHs, enoxaparin and tinzaparin, on E-cadherin and laminin expression in placental and decidual tissues in rat pregnancy.

11. England pubmed.ncbi.nlm.nih.gov

Low molecular weight heparins for venous thromboembolism. [2019] Five years ago, we concluded that in patients undergoing major orthopaedic surgery, prophylactic use of a low molecular weight heparin (LMWH) gave greater protection against deep vein thrombosis (DVT) than did conventional unfractionated heparin (UFH). The risk of bleeding appeared to be the same. It was unclear whether the clinical advantages of the LMWHs offset their greater cost. In the UK, four LMWHs ([symbol: see text]certoparin, dalteparin, enoxaparin and tinzaparin) are now licensed for prophylaxis against venous thromboembolism during or after surgery; a fifth (nadroparin) is licensed but not yet marketed in the UK. Dalteparin, enoxaparin and tinzaparin are licensed for the treatment of DVT. Additionally, tinzaparin is licensed for the treatment of pulmonary embolism (PE). Here, we review the use of LMWHs for these indications.

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

Perioperative Recovery and Narcotic Use in Laparoscopic versus Robotic Surgery for Endometrial Cancer. [2021] To compare intraoperative and perioperative narcotic use, recovery room time, and total hospital stay for patients treated with robotic vs laparoscopic surgery for endometrial cancer.