Neoplasms

All Conditions

Rare Diseases

Leiomyosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Sarcoma

Soft Tissue Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Olaparib

Poly(ADP-ribose) Polymerase Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Enzyme Inhibitors

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.

Computed Tomography

Core Biopsy

Magnetic Resonance Imaging

Brian Van Tine

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.

PRIMARY OBJECTIVE:

I. To evaluate whether combination treatment with temozolomide (TMZ) + olaparib shows preliminary evidence of clinical activity among patients with advanced uterine leiomyosarcoma (LMS) as measured by the confirmed objective response rate (ORR).

SECONDARY OBJECTIVES:

I. To evaluate the toxicity profile associated with the combination treatment. II. To evaluate the progression free survival (PFS) associated with the combination treatment.

III. To evaluate what proportion of uterine LMS tumors exhibit homologous recombination (HR) deficiency as measured by (1) genomic alterations in HR components at baseline and (2) deoxyribonucleic acid (DNA) repair protein RAD51 homolog (RAD51) foci formation at baseline and while on study treatment.

IV. To evaluate the feasibility of these assays in human tissue, and to preliminarily evaluate for any association between presence of HR deficiency as measured by each assay and increased clinical benefit from the study treatment.

EXPLORATORY OBJECTIVES:

I. To evaluate what proportion of uterine LMS tumors exhibit HR deficiency as measured by Schlafen family member number 11(SLFN11) protein expression at baseline.

II. To evaluate the feasibility of this assay in human tissue, and to preliminarily evaluate for any association between presence of HR deficiency as measured by this assay and increased clinical benefit from the study treatment.

III. To evaluate MGMT protein expression in uterine LMS tumors, and to preliminarily evaluate for any association between MGMT expression and increased clinical benefit from the study treatment.

IV. To perform an optional third tissue biopsy in patients who initially benefit from study treatment but later show early evidence of disease progression to evaluate for changes in the status of the RAD51 foci, MGMT, and SLFN11 assays at that time.

OUTLINE:

Patients receive olaparib orally (PO) twice per day (BID) and temozolomide PO once daily (QD) 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) or magnetic resonance imaging (MRI) throughout the trial and undergo tumor biopsy at screening and on study.

After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months until death or withdrawal of consent.

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

A Phase II Study of the PARP Inhibitor Olaparib in Combination With the DNA Damaging Agent Temozolomide for the Treatment of Advanced Uterine Leiomyosarcoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

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.

Recorded at each clinical visit and will be categorized according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Number of patients experiencing a grade 3 or greater adverse event will be reported.

The Kaplan-Meier method will be used to evaluate time to event endpoints. Median PFS will be reported with a 95% confidence interval.

Will be measured by genomic alterations in HR components at baseline and deoxyribonucleic acid (DNA) repair protein RAD51 homolog (RAD51) foci formation. The two integrated assays are genomics for alterations in HR genes and RAD51 foci formation. Both of these assays report binary results. The rate of response will be compared between binary variables using the Fisher's exact test. The log-rank test will be used to compare PFS between binary variables. Additional results from whole exome sequencing and ribonucleic acid sequencing (RNAseq) analysis on study samples will be reported in a descriptive fashion.

Will be assessed by immunohistochemistry (ICH). Macro ribonucleic acid (mRNA) expression may also be performed. Expression are reported as a continuous variable. Logistic regression will be used to estimate the odds of response for every unit increase in protein expression. Cox-regression will be used to evaluate the association between PFS and protein expression. Graphical displays such as box plots and Kaplan-Meier plots will be used to visualize the data. Evaluate for any association between presence of HR deficiency and increased clinical benefit from study treatment.

Will be assessed by ICH. mRNA expression may also be performed. Expression are reported as a continuous variable. Logistic regression will be used to estimate the odds of response for every unit increase in protein expression. Cox-regression will be used to evaluate the association between PFS and protein expression. Graphical displays such as box plots and Kaplan-Meier plots will be used to visualize the data. Evaluate for any association between MGMT expression and increased clinical benefit from the study treatment.

National Cancer Institute (NCI)

Treatment (Olaparib, Temozolomide)

Patients receive olaparib PO BID and temozolomide PO QD on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI once every 2 cycles. For patients who continue beyond 12 cycles, MRI or CT imaging may be changed to once every 4 cycles. Patients undergo tumor biopsy cycle 2 days 3-5.\>

\> Computed Tomography: Undergo CT\>

\> Core Biopsy: Undergo tumor biopsy\>

\> Magnetic Resonance Imaging: Undergo MRI\>

\> Olaparib: Given orally (PO)\>

\> Temozolomide: Given PO

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Stage at Study Entry

Prior Lines of Treatment

0 Fully active, able to carry on all pre-disease performance without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3. Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4. Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5. Dead

ECOG Performance Status

Matthew Ingham, MD

Patients receive olaparib PO BID and temozolomide PO QD on days 1-7. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI once every 2 cycles. For patients who continue beyond 12 cycles, MRI or CT imaging may be changed to once every 4 cycles. Patients undergo tumor biopsy cycle 2 days 3-5.

\>

\> Computed Tomography: Undergo CT

\>

\> Core Biopsy: Undergo tumor biopsy

\>

\> Magnetic Resonance Imaging: Undergo MRI

\>

\> Olaparib: Given orally (PO)

\>

\> Temozolomide: Given PO

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

Number of Patients Experiencing Adverse Events

Progression-free Survival (PFS)

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

Schlafen Family Member Number 11(SLFN11) Protein Expression

Proportion of MGMT Protein Expression in Uterine LMS Tumors

Overall Study

Symptoms and General Pathology

Nervous System Diseases

Skin and Connective Tissue Diseases

Diseases and Abnormalities at or Before Birth

Recurrence

Histiocytoma, Malignant Fibrous

Sarcoma, Synovial

Nerve Sheath Neoplasms

Neurofibrosarcoma

Histiocytoma

Disease Attributes

Neoplasms, Connective Tissue

Neoplasms, Nerve Tissue

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Fibrosarcoma

Neoplasms, Fibrous Tissue

Neurofibromatoses

Neurofibroma

Undifferentiated Pleomorphic Sarcoma

Synovial Sarcoma

Malignant Peripheral Nerve Sheath Tumor

Neurofibromatosis

Patients receive sapanisertib as in Phase I. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients receive pazopanib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm I.

Pazopanib

Pazopanib Hydrochloride

Sapanisertib

William D Tap

This phase I/II trial studies the side effects and best dose of sapanisertib and to see how well it works compared to pazopanib hydrochloride in treating patients with sarcoma that is too large to be removed (locally advanced) or has spread to other areas of the body (metastatic). Sapanisertib and pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the safety and maximum tolerable dose of sapanisertib (MLN0128 \[TAK-228\]) within this patient population. (Phase I) II. To determine the differences in progression-free survival (PFS) in patients with sarcoma who receive MLN0128 (TAK-228) as compared to pazopanib (pazopanib hydrochloride). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate adverse events. (Phase I/II) II. To evaluate overall response rate (ORR), clinical benefit rate (CBR), and duration of response (DOR). (Phase I/II) III. To evaluate time to progression (TTP) and overall survival (OS). (Phase I/II)

EXPLORATORY OBJECTIVES:

I. To evaluate PFS and secondary endpoints within patients crossing over to MLN0128 (TAK-228), upon disease progression during treatment with pazopanib. (Phase II) II. To evaluate the 4 month CBR observed within patients treated with MLN0128 (TAK-228) and grouped by histologically defined cohorts. (Phase II)

OUTLINE: This is a phase I, dose-escalation study, followed by a randomized phase II study.

PHASE I: Patients receive sapanisertib orally (PO) on days 1, 8, 15, and 22 in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sapanisertib as in Phase I. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pazopanib hydrochloride PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover to Arm I.

After completion of study treatment, patients are followed up at 4 weeks and then every 6 months for 2 years.

Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma

A Phase I/Randomized Phase II Study of MLN0128 (TAK-228) VS. Pazopanib in Patients With Locally Advanced/Unresectable and/or Metastatic Sarcoma

Defined as either disease progression or death (in cases where patients have died without evidence of disease progression) in crossover patients.

Will be analyzed using Kaplan-Meier methodology.

Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> TTP.

Kaplan-Meier methodology will be used to estimate the distribution of\>\>\> OS.

The Maximum Tolerated Dose (MTD) of sapanisertib (MLN0128) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients graded according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose-limiting toxicities include non-hematologic events graded 3 or higher and deemed at least possibly related to treatment. The number of patients reporting a dose-limiting event is reported.

Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and an upper confidence boundary from a 1-sided, 85% confidence interval are estimated using the Kaplan-Meier methods.

The number of patients who experienced grade 3+ adverse events for Phase II Analysis Group 2 for the initial treatment period is reported below.

The frequencies (and percentages) of tumor response categories (CR, PR, SD, PD) will be summarized for Phase II Analysis Group 2. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion, b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.

Duration of response is defined as the time between each patient's best tumor response and progression (or date of last disease assessment for patients who die without progression or are lost to follow-up). Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD.

Will be defined as the number of patients having either complete response (CR), partial response (PR), or stable disease for at least 6 months after starting treatment. The frequencies and rates of tumor response categories (CR, PR, SD, PD, and too early/not evaluated) will be summarized by dose cohort and treatment arm. Complete Response (CR): All of the following must be true: a. Disappearance of all target lesions. b. Each target lymph node must have reduction in short axis to \< 1.0 cm. Partial Response (PR): At least a 30% decrease in PBSD taking as reference the BSD. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. symptomatic deterioration. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD taking as reference the MSD.

Time to progression is defined as the time between randomization and disease progression. Kaplan-Meier methodology will be used to estimate the distribution of TTP. Progression (PD): At least one of the following must be true: a. At least one new malignant lesion,b. At least a 20% increase in PBSD. c. PD via FDG-PET imaging. d. unequivocal progression of existing non-target lesions and non-target lymph nodes. e. Symptomatic deterioration.

Overall survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period). Kaplan-Meier methodology will be used to estimate the distribution of OS.

Adverse events from all registered Phase I and randomized Phase II patients who initiated treatment (Initial treatment period) and had adverse events assessed are summarized below.

Protocol therapy will consist of 20 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle.

Phase I - Dose Level 0

Protocol therapy will consist of 25 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle.

Phase I - Dose Level 1

Protocol therapy will consist of 30 mg MLN0128 (TAK-228) administered weekly on days 1, 8, 15, and 22 over a 28-day cycle.

Phase I - Dose Level 2

Protocol therapy will consist of 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle.

Phase II - Analysis Group 1 MLN0128

Patients receive 800mg Pazopanib orally once daily over a 4-week cycle in the first intervention period/initial treatment period.

Phase II - Analysis Group 1 Pazopanib

Phase II - Analysis Group 2 MLN0128

Patients receive 400mg Pazopanib orally once daily over a 4-week cycle and titrated to tolerance (maximum 800mg) by the treating physician in the first intervention period/initial treatment period.

Phase II - Analysis Group 2 Pazopanib

Total

Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

Registered Phase I patients and Randomized Phase II patients

William D. Tap, MD

Number of Phase I Participants With Dose-Limiting Toxicity Events (Phase I)

Phase II Analysis Group 2 - Initial Treatment Period

Progression-free Survival (PFS) (Phase II Analysis Group 2 - Initial Treatment Period)

Phase II Analysis Group 2 - Initial Treatment Period; This analysis excludes cancel patients (who never received treatment i.e. Withdrew before initiation of regimen )

The Number of Patients Who Experienced Grade 3+ Adverse Events (Phase II Analysis Group 2 - Initial Treatment Period)

Complete Response

Partial Response

Stable Disease

Progressive Disease

Phase II Analysis Group 2 - Initial Treatment Period; Patients with tumor response data available are included in this analysis.

Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD], and Progressive Disease [PD])(Phase II Analysis Group 2 - Initial Treatment Period)

Phase II Analysis Group 2 - Initial Treatment Period; Only patients that had a complete response or partial response are included in this analysis.

Duration of Response (Phase II Analysis Group 2 - Initial Treatment Period)

Number of Patients Having CR, PR, or SD at 6 Months (Phase II Analysis Group 2 - Initial Treatment Period)

Time to Progression (TTP) (Phase II Analysis Group 2 - Initial Treatment Period)

Overall Survival (OS) (Phase II Analysis Group 2 - Initial Treatment Period)

Progression-free Survival (PFS) (Phase II)

Duration of Response in Crossover Patients (Phase II)

Time to Progression (TTP) in Crossover Patients (Phase II)

Overall Survival (OS) in Crossover Patients (Phase II)

Cohort-specific Evaluation of 4-month Clinical Benefit Rate (CBR) (Phase II, Analysis Group II)

Patients receive 800mg Pazopanib orally once daily over a 4-week cycle in the first intervention period/initial treatment period. Patients who chose to crossover (crossover to MLN0128 is optional) receive 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle in the second intervention period/optional crossover period.

Phase II - Analysis Group 1 Pazopanib Crossover

Patients receive 400mg Pazopanib orally once daily over a 4-week cycle and titrated to tolerance (maximum 800mg) by the treating physician in the first intervention period/initial treatment period. Patients who chose to crossover (crossover to MLN0128 is optional) receive 30 mg MLN0128 (TAK-228) administered weekly over a 4-week cycle in the second intervention period/optional crossover period.

Phase II - Analysis Group 2 Pazopanib Crossover

Initial Treatment (Up to 4 Months)

Optional Crossover (Up to 2 Months)

Patients receive cabozantinib PO QD on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cabozantinib

Quality-of-Life Assessment

Questionnaire Administration

Mark Agulnik, MD

This phase II trial studies how well cabozantinib and temozolomide work in treating patients with leiomyosarcoma or other soft tissue sarcoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, 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 cabozantinib and temozolomide may work better than either one alone in treating patients with leiomyosarcoma or other soft tissue sarcoma. Cabozantinib is an investigational drug, which means that it has not been approved by the United States (US) Food and Drug Administration (FDA) or any other regulatory agencies for sale or use by the public for the indication under investigation in this study.

PRIMARY OBJECTIVE:

I. To determine the progression-free survival (defined as complete response \[CR\]+partial response \[PR\]+stable disease \[SD\]) assessed at 12 weeks for subjects in Cohort 1 (Leiomyosarcoma Arm) treated with cabozantinib and temozolomide as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

SECONDARY OBJECTIVES:

I. To determine the overall response rate (defined as CR+PR) for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.

II. To determine the clinical benefit rate (CR+PR+SD) for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.

III. To evaluate the median progression free rate for subjects with combination of cabozantinib and temozolomide.

IV. To evaluate overall survival for subjects in Cohort 1 treated with a combination of cabozantinib and temozolomide.

V. To assess safety and tolerability for subjects treated with a combination of cabozantinib and temozolomide.

VI. To determine the overall response rate (defined as CR+PR) in Cohort 2 (other soft tissue sarcomas).

VII. To assess Quality of Life (QoL) and subject-reported outcomes as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the EuroQoL-Group Health Questionnaire (EQ-5D-5L).

EXPLORATORY OBJECTIVE:

I. To estimate the correlation of progression free rate (PFR) and overall survival (OS) to levels of sVEGFR2, PIGF, VEGF, HGF, sMET, VEGF-C, VEGF-D, and soluble AXL.

OUTLINE:

Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients with progressive disease (PD) are followed up every 6 months for up to 2 years and patients without PD are followed up every 6 months for up to 5 years.

Cabozantinib and Temozolomide for the Treatment of Unresectable or Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma

A Phase II Study of Cabozantinib and Temozolomide in Patients With Unresectable or Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas

PFS will be the time from the start of treatment to the time of progression, with progression defined as changes in Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined imaging, progression in non-target lesions as defined by RECIST 1.1, unequivocal clinical deterioration, or death from any cause.

Will be defined as complete response (CR) + partial response (PR).

Will be defined as CR + PR + stable disease (SD).

Will assess the time from the first dose of study treatment until progression based upon changes in RECIST 1.1, unequivocal clinical deterioration, or death from any cause.

Will assess the time from the first dose of the study treatment until death from any cause, up to a maximum follow-up of two years.

Will assess the presence of all toxicities outlined in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Will be assessed by the EuroQoL-Group Health Questionnaire (EQ-5D-5L).

City of Hope Medical Center

Disease Progression

Trabectedin

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.

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.

Biospecimen Collection

Bone Scan

Multigated Acquisition Scan

Transthoracic Echocardiography

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.

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 or magnetic resonance imaging (MRI) and/or bone scans throughout the trial. Patients also undergo collection of blood samples throughout the trial.

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 or MRI and/or bone scans throughout the trial. Patients also undergo transthoracic echocardiography (TTE) or multi-gated acquisition scan (MUGA) on study and as clinically indicated, as well as collection of blood samples throughout the trial.

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.

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

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

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will collect results of next generation sequencing that is known to the treating investigator and was previously performed as part of the patient's clinical care, for all patients registered to the study. Will evaluate for genomic alterations in HR pathway genes. A genomic alteration is defined as a homozygous deletion or deleterious (loss-of-function) mutation in any of the pre-defined HR pathway genes.

Will evaluate whether patients with an HR pathway alteration experience increased clinical benefit from olaparib and temozolomide as compared patients who lack such an alteration, as determined by objective response rate, progression-free survival and overall survival. Response rates will be compared using the Fisher's exact test, and time to event endpoints summarized using the Kaplan-Meier curves and the log-rank test.

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.

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.

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.

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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase II Clinical Trial Evaluating the Combination of Olaparib and Temozolomide for the Treatment of Advanced Uterine Leiomyosarcoma	NCT03880019	Stage III Uteri... Stage IV Uterin... Uterine Corpus ...	Computed Tomogr... Core Biopsy Magnetic Resona... Olaparib Temozolomide	18 Years -	National Cancer Institute (NCI)
Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma	NCT02601209	High Grade Sarc... Metastatic Leio... Metastatic Mali... Metastatic Syno... Metastatic Undi... Metastatic Unre... Myxofibrosarcom... Recurrent Leiom... Recurrent Malig... Recurrent Synov... Recurrent Undif... Stage III Uteri... Stage IIIA Uter... Stage IIIB Uter... Stage IIIC Uter... Stage IV Uterin... Stage IVA Uteri... Stage IVB Uteri... Unresectable Le...	Pazopanib Pazopanib Hydro... Sapanisertib	18 Years -	National Cancer Institute (NCI)
Cabozantinib and Temozolomide for the Treatment of Unresectable or Metastatic Leiomyosarcoma or Other Soft Tissue Sarcoma	NCT04200443	Metastatic Leio... Metastatic Soft... Stage III Uteri... Stage IIIA Uter... Stage IIIB Uter... Stage IIIC Uter... Stage IV Uterin... Stage IVA Uteri... Stage IVB Uteri... Unresectable Le... Unresectable So...	Cabozantinib Quality-of-Life... Questionnaire A... Temozolomide	18 Years -	City of Hope Medical Center
Testing Olaparib and Temozolomide Versus the Usual Treatment for Uterine Leiomyosarcoma After Chemotherapy Has Stopped Working	NCT05432791	Locally Advance... Metastatic Uter... Stage III Uteri... Stage IV Uterin... Unresectable Ut...	Biospecimen Col... Bone Scan Computed Tomogr... Magnetic Resona... Multigated Acqu... Olaparib Pazopanib Temozolomide Trabectedin Transthoracic E...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for stage iii uterine corpus leiomyosarcoma ajcc v8