Testing Olaparib and Temozolomide Versus the Usual Treatment for Uterine Leiomyosarcoma After Chemotherapy Has Stopped Working

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To compare the progression free survival (PFS) of olaparib plus temozolomide (Arm 1) as compared to investigator's choice (trabectedin or pazopanib hydrochloride [pazopanib]) (Arm 2) for the treatment of patients with advanced uterine leiomyosarcoma (uLMS) who have received two or more prior lines of therapy as determined by investigator (local site) assessment. (Phase 2) II. To compare the overall survival (OS) of olaparib plus temozolomide (Arm 1) as compared to investigator's choice (trabectedin or pazopanib) (Arm 2) for the treatment of patients with advanced uLMS who have received two or more prior lines of therapy. (Phase 3) SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of each treatment by determining adverse events using Common Terminology Criteria for Adverse Events (CTCAE) version 5 and patient-reported toxicity using Patient-Reported Outcome (PRO)-CTCAE version 1 in and across each treatment arm. (Phase 2/3) II. To evaluate the objective response rate (ORR), duration of response (DOR) and disease control rate (DCR) in and across each treatment arm as determined by investigator assessment. (Phase 2/3) EXPLORATORY OBJECTIVE: I. To collect results of tumor genomic testing previously conducted as part of clinical care (when available) and (a) to determine the proportion of patients with a genomic alteration in a homologous recombination (HR) pathway gene and (b) to evaluate for any relationship between the presence of such an alteration and clinical benefit from olaparib and temozolomide. (Phase 2/3) OUTLINE: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive temozolomide orally (PO) once daily (QD) on days 1-7 of each cycle and olaparib PO twice daily (BID) on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan and may undergo magnetic resonance imaging (MRI), bone scans, and collection of blood samples throughout the study. ARM 2: Patients receive trabectedin intravenously (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 and may undergo MRI, bone scans, and collection of blood samples throughout the study. After completion of study treatment, patients without disease progression are followed every 6 weeks until disease progression. After disease progression, patients are followed every 3 months for the first 2 years, then every 6 months thereafter until 5 years post-randomization or death, whichever comes first.

Official Title
-----------------
A Randomized Phase 2/3 Study of Olaparib Plus Temozolomide Versus Investigator's Choice for the Treatment of Patients With Advanced Uterine Leiomyosarcoma After Progression on Prior Chemotherapy

Conditions
-----------------
Locally Advanced Uterine Corpus Leiomyosarcoma, Metastatic Uterine Corpus Leiomyosarcoma, Stage III Uterine Corpus Leiomyosarcoma AJCC v8, Stage IV Uterine Corpus Leiomyosarcoma AJCC v8, Unresectable Uterine Corpus Leiomyosarcoma

Intervention / Treatment
-----------------
* Procedure: Biospecimen Collection
* Procedure: Bone Scan
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Drug: Olaparib
* Drug: Pazopanib
* Drug: Temozolomide
* Drug: Trabectedin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed leiomyosarcoma of uterine origin, as established by the site institutional practice for pathology confirmation for research studies when enrolling the patient on study. Central pathology review will not occur. Metastatic or locally advanced and surgically unresectable disease, in the opinion of the treating investigator. Patients must have at least one lesion that is measurable per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria to be eligible for the study. Not pregnant and not nursing, because this study involves agents that have known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required Age >= 18 years. Eastern Cooperative Oncology Group (ECOG) Performance Status =< 2. Patients must have had prior progression on, or intolerance to, at least two prior lines of systemic therapy for advanced uLMS, one of which was an anthracycline (anthracycline monotherapy or combination). Adjuvant chemotherapy will qualify as a prior line of treatment. Endocrine treatment will not qualify as a prior line of treatment. Patients may not have received prior treatment with any PARP inhibitor, temozolomide or dacarbazine (IV analogue of temozolomide). Patients may not have had prior treatment with at least one of the agents included on the investigator's choice arm: trabectedin or pazopanib. If the patient has had prior treatment with one of these agents, they must be assigned to the other agent for investigator's choice. That is, patients who have received prior pazopanib must be assigned to trabectedin, and patients who have received prior trabectedin must be assigned to pazopanib. Patients must have recovered to baseline or =< grade 1 per CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically nonsignificant and/or stable on supportive therapy, with the exception of fatigue (which must be =< grade 2), alopecia and/or endocrinopathies related to prior immunotherapy which are controlled with hormone replacement. Patients must have completed all prior anti-cancer treatment, including radiation, >= 28 days prior to registration. Patients may have undergone major surgery (related or unrelated to their cancer diagnosis) >= 28 days of registration. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. Absolute neutrophil count (ANC) >= 1500/mm^3 (within =< 28 days prior to registration). Platelet count >= 100,000/mm^3 (within =< 28 days prior to registration). Creatinine =< 1.5 * upper limit of normal (ULN) (within =< 28 days prior to registration). If creatinine > 1.5 * ULN, then creatinine clearance (CrCl) must be > 50 mL/min, per Cockcroft-Gault method. Hemoglobin >= 9 g/dL (within =< 28 days prior to registration). No transfusions =< 14 days before cycle 1 day 1 (C1D1). Total bilirubin =< 1.5 x ULN (within =< 28 days prior to registration). If documented Gilbert's: =< 2.0 x ULN. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 3 x ULN (within =< 28 days prior to registration). Patients may not have uncontrolled hypertension defined as a blood pressure (BP) > 150/90 on two consecutive assessments during the screening period. If a patient is found to have a BP > 150/90 on two consecutive assessments during the screening period, the patient may be started on an anti-hypertensive regimen, and will be considered eligible if two subsequent measurements are performed and the BP is =< 150/90. If BP is in range on the first measurement, no further measurements are needed. Patients must demonstrate a QTcF (Fredericia formula) =< 470 msec on an electrocardiography (EKG) performed during screening. This criterion applies only to patients who will receive pazopanib if randomized to Arm 2. Repeat EKG testing during the screening period is allowed. Patients may not have an uncontrolled ventricular arrhythmia or recent (within 3 months) myocardial infarction. In addition to the above, patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible, patients should be class 2B or better. Patients may not have a history of active or unresolved: perforation, abscess or fistula within 28 days prior to registration (either clinically or radiographically). Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or a history of bone marrow biopsy findings at any time consistent with MDS and/or AML. For patients with evidence of chronic hepatitis B (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients with central nervous system (CNS)/leptomeningeal disease must have undergone definitive treatment, have no evidence of CNS progression on follow-up imaging performed at least 4 weeks after the CNS-directed therapy is completed, and be off all steroids, in order to be eligible. Patients must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 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 any other condition that would limit compliance with study requirements. Patients must be able to swallow oral medications. Patients may not require 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 prior to starting study treatment is 2 weeks. Patients may not require concomitant use of known strong (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 prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. In order to complete the mandatory patient-completed measure, participants must be able to speak and/or read English and Spanish. Non-English or non-Spanish readers may still participate in the study but are not required to complete the PRO-CTCAE side effect surveys. For all patients, prior to randomization and as part of eligibility, the investigator must select the agent which the patient would receive if assigned to the investigator's choice arm, prior to randomization. The patient must meet all eligibility criteria for that agent during screening and prior to randomization. Patients without central venous access must be willing to undergo placement of central venous access (i.e. port or peripherally inserted central catheter [PICC] line, per institutional practice) if assigned to the investigator's choice arm and if the investigator intends to treat the patient with trabectedin. The site must be able to place central venous access within 10 days of registration/randomization.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (olaparib, temozolomide)<br>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 and may undergo MRI, bone scans, and collection of blood samples throughout the study. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Scan<br>* Undergo bone scan<br>* Other names: Bone Scintigraphy;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Olaparib<br>* Given PO<br>* Other names: PARP Inhibitor AZD2281;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Active Comparator: Arm 2 (trabectedin, pazopanib)<br>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 and may undergo MRI, bone scans, and collection of blood samples throughout the study. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Scan<br>* Undergo bone scan<br>* Other names: Bone Scintigraphy;Procedure: Computed Tomography<br>* Undergo CT scan<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Drug: Pazopanib<br>* Given PO<br>* Other names: GW786034;Drug: Trabectedin<br>* Given IV<br>* Other names: Yondelis;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) (Phase II) | Will be estimated using the Kaplan-Meier method, where the stratified log-rank test will be used to compare the distributions across the treatment arms. PFS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. Univariable and multivariable Cox models stratified by the stratification factors used in the randomization will be assessed as well. | Time between the date of randomization and the earliest of disease progression or death, assessed up to 5 years | 
| Overall survival (OS) (Phase III) | Will be estimated using the Kaplan-Meier method, where the stratified log-rank test will be used to compare the distributions across the treatment arms. OS rates at 1 year, 2 years, and 5 years will also be reported, along with 95% confidence intervals. Univariable and multivariable Cox models stratified by the stratification factors used in the randomization will be assessed as well. | Time between the date of randomization and the date of death from any cause, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Will be estimated by dividing the number of evaluable patients that achieve a confirmed response (partial response [PR] or better) by the total number of evaluable patients. This estimate will be calculated by arm and will also include a 95% confidence interval using the properties of the binomial distribution, and compared between the arms using a chi-square test. | Up to 5 years | 
| Duration of response (DOR) | This analysis is restricted to those patients that achieved a confirmed response (PR or better). Patients that go off of study treatment prior to progression will have their DOR time censored at that time. | Time from first evidence of response until disease progression (or death), assessed up to 5 years | 
| Disease control rate | Will be estimated using the number of patients that achieve complete response, partial response, or stable disease at the 6 week assessment divided by all evaluable patients. This estimate will be calculated by arm and will also include a 95% confidence interval using the properties of the binomial distribution, and compared between the arms using a chi-square test. | Up to 6 weeks | 
| Incidence of adverse events | Adverse events will be recorded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for each patient. Frequency tables and summary statistics will be used and with the appropriate methods of evaluating categorical and continuous data. In addition, patient reported safety and tolerability will be assessed using Patient-Reported Outcomes (PRO)-CTCAE for a prespecified group of expected toxicities. PRO-CTCAE assessments will occur prior to registration and on day 1 of every cycle during treatment. Collection of PRO-CTCAE will be discontinued after cycle 11. | Up to 4 weeks after the end of study treatment |