A Phase II Clinical Trial Evaluating the Combination of Olaparib and Temozolomide for the Treatment of Advanced Uterine Leiomyosarcoma

NCT03880019 | Active Not Recruiting Phase 2 Results FDA Drug

• 5 other identifiers: NCI-2019-01500#AAAS4040WUSM HRPO# 20191010610250UM1CA186686
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 15

Brief Summary

This phase II trial studies olaparib and temozolomide in treating patients with uterine leiomyosarcoma (LMS) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced), that has spread from where it first started to other places in the body (metastatic) or cannot be removed by surgery (unresectable). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving olaparib and temozolomide may work better than giving either drug alone in treating patients with LMS.

Conditions

Stage III Uterine Corpus Leiomyosarcoma AJCC v8; Stage IV Uterine Corpus Leiomyosarcoma AJCC v8; Uterine Corpus Leiomyosarcoma

Outcome Measures

Primary Outcomes (1)

• Confirmed Objective Response Rate (ORR) (Complete Response + Partial Response)

  Will be measured by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria assessed by MRI: Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm (\<1 cm); Partial Response (PR), at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. A response rate of 10% is considered inactive and unworthy of further study. A response rate of 35% would be promising for further study among patients with advanced uterine leiomyosarcoma (LMS) treated with at least one prior systemic regimen. A response rate of 35% for the temozolomide (TMZ) + poly(adenosine diphosphate\[ADP\]-ribose) polymerase inhibitor (PARPi) combination would also be suggestive of superior efficacy over TMZ monotherapy in sarcoma. Will be reported with a 95% confidence interval.

  Within first 6 months of study treatment

Secondary Outcomes (5)

• Number of Patients Experiencing Adverse Events

  Up to 2 years after study treatment

• Progression-free Survival (PFS)

  Time from first treatment with the study drug to the earliest of either disease progression or death from any cause, assessed up to 2 years

• Proportion of Uterine LMS Tumors Exhibit Homologous Recombination (HR) Deficiency

  Up to 2 years

• Schlafen Family Member Number 11(SLFN11) Protein Expression

  Up to 2 years

• Proportion of MGMT Protein Expression in Uterine LMS Tumors

  Up to 2 years

Study Arms (1)

Treatment (olaparib, temozolomide)

EXPERIMENTAL

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.

Procedure: Computed Tomography; Procedure: Core Biopsy; Procedure: Magnetic Resonance Imaging; Drug: Olaparib; Drug: Temozolomide

Interventions

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Treatment (olaparib, temozolomide)

Core Biopsy PROCEDURE

Undergo tumor biopsy

Also known as: BIOPSY, CORE, CNB, Core Needle, Core Needle Biopsy, Needle Biopsy

Treatment (olaparib, temozolomide)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Treatment (olaparib, temozolomide)

Olaparib DRUG

Given PO

Also known as: AZD 2281, AZD-2281, AZD2281, KU 0059436, KU-0059436, KU0059436, Lynparza, Olanib, Olaparix, PARP Inhibitor AZD2281

Treatment (olaparib, temozolomide)

Temozolomide DRUG

Given PO

Also known as: CCRG-81045, Gliotem, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temizole, Temodal, Temodar, Temomedac, TMZ

Treatment (olaparib, temozolomide)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically documented LMS of uterine origin. Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this study.
• Patients must have locally advanced and unresectable or metastatic disease.
• Patients must have disease which is measurable at study entry according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Additionally, patients must have a site of disease deemed accessible for biopsy at no or minimal risk to the patient (including through the use of image-guidance). If there are questions regarding the feasibility of biopsy, the case should be reviewed with interventional radiology or the appropriate department at the study site prior to registration.
• Patients must have had prior progression on, or intolerance to, at least one line of systemic therapy for advanced LMS. Adjuvant therapy administered after curative resection will not qualify as prior treatment. There is no upper limit on the number of prior therapies received.
• Patients must be \>= 18 years of age. Uterine LMS affects older adults and is rarely encountered in children and adolescents.
• Patients must demonstrate an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of =\< 2 (Karnofsky \>= 50%).
• Absolute neutrophil count \>= 1,500/mcL (measured within 14 days prior to administration of study treatment).
• Hemoglobin \>= 9 g/dL (without transfusion of packed red blood cells within the past 28 days) (measured within 14 days prior to administration of study treatment).
• Platelets \>= 100,000/mcL (measured within 14 days prior to administration of study treatment).
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (measured within 14 days prior to administration of study treatment).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional ULN (measured within 14 days prior to administration of study treatment).
• Glomerular filtration rate (GFR) \>= 51 mL/min, based on a 24-hour urine test for creatinine clearance or estimated using the Cockcroft-Gault equation (measured within 14 days prior to administration of study treatment).
• If patients have evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of hepatitis B surface antigen \[HBsAg\]) are eligible.
• If patients have a history of hepatitis C virus (HCV) infection, they must be treated with undetectable HCV viral load (polymerase chain reaction is negative for HCV ribonucleic acid \[RNA\]).
• Patients must be postmenopausal or have evidence of non-childbearing status, OR, for women of childbearing potential, must have a negative urine or serum pregnancy test within 28 days of study treatment and confirmed again on day 1 prior to study treatment.

You may not qualify if:

• Patients must not have had any previous treatment with any poly(adenosine diphosphate\[ADP\]-ribose) polymerase (PARP) inhibitors, including olaparib, or prior treatment with dacarbazine and/or temozolomide.
• Patients must have recovered from adverse events due to prior anti-cancer therapy (i.e., may not have residual toxicities \> grade 1 or above baseline), excluding alopecia. Patients who have endocrinopathies associated with prior immunotherapy treatment but which are controlled with replacement therapy are eligible.
• Prior to initiating study treatment, at least 28 days must have elapsed from the last dose of systemic anti-cancer treatment (cytotoxic, biologic or immunotherapeutic) or radiation therapy (except for palliative radiation, in which case a 14-day washout applies).
• Patients must not have had major surgery within 2 weeks of starting study treatment and must have recovered from any effects of any major surgery that occurred \> 2 weeks before starting study treatment.
• Patients must not be receiving any other investigational agent.
• Patients must not have been diagnosed with another malignancy unless curatively treated with no evidence of disease for \>= 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), or any other malignant condition considered indolent and unlikely to require active therapy.
• Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or bone marrow biopsy findings consistent with MDS and/or AML.
• Patients must not have active central nervous system (CNS) or leptomeningeal disease at the time of enrollment. Patients with a history of such disease previously treated with curative intent (such as with surgery or radiation) that have not progressed on subsequent imaging, have been clinically asymptomatic, and have not received systemic corticosteroids for at least 28 days, are eligible.
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib or TMZ or any of the excipients of any study product.
• Patients must refrain from concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period for strong or moderate CYP3A inhibitors prior to starting olaparib is 2 weeks. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients must refrain from concomitant use of known strong CYP3A inducers (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period for strong or moderate CYP3A inducers prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
• Patients must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan, or psychiatric illness that would limit compliance with study requirements.
• Pregnant women are excluded from this study because olaparib is a PARP inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with olaparib, breastfeeding should be discontinued if the mother is treated with olaparib. These potential risks may also apply to other agents used in this study.
• Patients must not have gastrointestinal disorders likely to interfere with absorption of the study medication.
• Patients must not have had involvement in the planning and/or conduct of the study.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (15)

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, 85054, United States

Location

Stanford Cancer Institute Palo Alto

Palo Alto, California, 94304, United States

Location

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

UF Health Cancer Institute - Gainesville

Gainesville, Florida, 32610, United States

Location

Mayo Clinic in Florida

Jacksonville, Florida, 32224-9980, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Weisberg Cancer Treatment Center

Farmington Hills, Michigan, 48334, United States

Location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, 10032, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

VCU Massey Comprehensive Cancer Center

Richmond, Virginia, 23298, United States

Location

Related Publications (2)

• Ingham M, Allred JB, Chen L, Das B, Kochupurakkal B, Gano K, George S, Attia S, Burgess MA, Seetharam M, Boikos SA, Bui N, Chen JL, Close JL, Cote GM, Thaker PH, Ivy SP, Bose S, D'Andrea A, Marino-Enriquez A, Shapiro GI, Schwartz GK. Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250). J Clin Oncol. 2023 Sep 1;41(25):4154-4163. doi: 10.1200/JCO.23.00402. Epub 2023 Jul 19.

  PMID: 37467452 DERIVED

• Vyse S, Thway K, Huang PH, Jones RL. Next-generation sequencing for the management of sarcomas with no known driver mutations. Curr Opin Oncol. 2021 Jul 1;33(4):315-322. doi: 10.1097/CCO.0000000000000741.

  PMID: 33927108 DERIVED

MeSH Terms

Interventions

Biopsy, Needle; Biopsy, Large-Core Needle; Magnetic Resonance Spectroscopy; olaparib; Temozolomide

Intervention Hierarchy (Ancestors)

Biopsy; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Punctures; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Matthew Ingham, MD
• Organization: Columbia University Medical Center

mi2337@cumc.columbia.edu

646-317-7141

Study Officials

• Mia C Weiss

  Yale University Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 18, 2019
• First Posted: March 19, 2019
• Study Start: August 19, 2019
• Primary Completion: August 1, 2020
• Study Completion (Estimated): November 12, 2026
• Last Updated: December 3, 2025
• Results First Posted: September 21, 2023

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

US (15)