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

Stage III Uterine Corpus Leiomyosarcoma AJCC v8 Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05432791
• Other study ID #: NCI-2022-05065
• Secondary ID: NCI-2022-05065A0
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 30, 2023
• Est. completion date: March 9, 2030

Study information

• Verified date: February 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 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.

Other known NCT identifiers

• NCT05633381

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: March 9, 2030
• Est. primary completion date: March 9, 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 BOTH of the agents included on the investigator's choice arm: trabectedin AND pazopanib. If the patient has had prior treatment with one of these agents, they are eligible; however, 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.

Related Conditions & MeSH terms

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

Intervention

Procedure:
• Biospecimen Collection
Undergo collection of blood samples
• Bone Scan
Undergo bone scan
• Computed Tomography
Undergo CT scan
• Magnetic Resonance Imaging
Undergo MRI
• Multigated Acquisition Scan
Undergo MUGA

Drug:
• Olaparib
Given PO
• Pazopanib
Given PO
• Temozolomide
Given PO
• Trabectedin
Given IV

Procedure:
• Transthoracic Echocardiography
Undergo TTE

Locations

Country	Name	City	State
Puerto Rico	Centro Comprensivo de Cancer de UPR	San Juan
United States	Mary Greeley Medical Center	Ames	Iowa
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Alaska Women's Cancer Care	Anchorage	Alaska
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	UH Seidman Cancer Center at UH Avon Health Center	Avon	Ohio
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Our Lady of the Lake Medical Oncology	Baton Rouge	Louisiana
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Saint Joseph's/Candler - Bluffton Campus	Bluffton	South Carolina
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	McFarland Clinic - Boone	Boone	Iowa
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	Northwestern University	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Memorial Hospital North	Colorado Springs	Colorado
United States	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Heartland Oncology and Hematology LLP	Council Bluffs	Iowa
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Carle at The Riverfront	Danville	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Epic Care-Dublin	Dublin	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Epic Care Partners in Cancer Care	Emeryville	California
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Smilow Cancer Hospital Care Center-Fairfield	Fairfield	Connecticut
United States	Cancer Care and Hematology-Fort Collins	Fort Collins	Colorado
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	McFarland Clinic - Trinity Cancer Center	Fort Dodge	Iowa
United States	Saint Luke's Cancer Institute - Fruitland	Fruitland	Idaho
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Smilow Cancer Hospital Care Center at Glastonbury	Glastonbury	Connecticut
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	UCHealth Greeley Hospital	Greeley	Colorado
United States	ECU Health Medical Center	Greenville	North Carolina
United States	Smilow Cancer Hospital Care Center at Greenwich	Greenwich	Connecticut
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Smilow Cancer Hospital Care Center - Guilford	Guilford	Connecticut
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	City of Hope at Irvine Lennar	Irvine	California
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	McFarland Clinic - Jefferson	Jefferson	Iowa
United States	Ascension Borgess Cancer Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	Baptist Health Lexington	Lexington	Kentucky
United States	Medical Center of the Rockies	Loveland	Colorado
United States	McFarland Clinic - Marshalltown	Marshalltown	Iowa
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Contra Costa Regional Medical Center	Martinez	California
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Providence Newberg Medical Center	Newberg	Oregon
United States	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut
United States	Cancer and Hematology Centers of Western Michigan - Norton Shores	Norton Shores	Michigan
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Cancer Specialists/Oncology Hematology West PC - MECC	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Oncology Associates PC	Omaha	Nebraska
United States	Providence Willamette Falls Medical Center	Oregon City	Oregon
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Women and Infants Hospital	Providence	Rhode Island
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	FHCC South Lake Union	Seattle	Washington
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Smilow Cancer Hospital Care Center at Long Ridge	Stamford	Connecticut
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut
United States	Munson Medical Center	Traverse City	Michigan
United States	Smilow Cancer Hospital Care Center-Trumbull	Trumbull	Connecticut
United States	Legacy Meridian Park Hospital	Tualatin	Oregon
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	Legacy Cancer Institute Medical Oncology and Day Treatment	Vancouver	Washington
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Epic Care Cyberknife Center	Walnut Creek	California
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut
United States	Smilow Cancer Hospital Care Center - Waterford	Waterford	Connecticut
United States	Smilow Cancer Hospital Care Center - Westerly	Westerly	Rhode Island
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Asplundh Cancer Pavilion	Willow Grove	Pennsylvania
United States	University of Michigan Health - West	Wyoming	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Proportion of patients with a genomic alteration in a homologous recombination (HR) pathway gene	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.	Within 60 days of registration
Other	Relationship between the presence of an alteration in HR pathway genes and clinical benefit from olaparib and temozolomide	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.	Assessed up to 5 years
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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