Clinical trial NCT01959139: S1313, PEGPH20 in Treating Patients With Newly Diagnosed Metastatic Pancreatic Cancer
Official title: S1313, A Phase IB/II Randomized Study of Modified FOLFIRINOX + Pegylated Recombinant Human Hyaluronidase (PEGPH20) Versus Modified FOLFIRINOX Alone in Patients With Good Performance Status Metastatic Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Pancreatic Adenocarcinoma
Lead sponsor: SWOG Cancer Research Network
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: Halozyme Therapeutics
First posted: 2013-10-09
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This partially randomized phase I/II trial studies the side effects and best dose of pegylated recombinant human hyaluronidase (PEGPH20) when given together with combination chemotherapy and to see how well they work compared with combination chemotherapy alone in treating patients with newly diagnosed pancreatic cancer that has spread to other places in the body. Pegylated recombinant human hyaluronidase may help chemotherapy drugs work better by making tumor cells more sensitive to the drugs. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, 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. It is not yet known whether combination chemotherapy is more effective with or without pegylated recombinant human hyaluronidase in treating pancreatic cancer.

Detailed description: PRIMARY OBJECTIVES:

I. To assess the safety of modified leucovorin calcium, fluorouracil, irinotecan hydrochloride and oxaliplatin (mFOLFIRINOX) in combination with PEGPH20 and select the optimal dose of PEGPH20 for the phase II portion in patients with metastatic pancreatic adenocarcinoma. (Phase I) II. To assess the overall survival of patients with metastatic pancreatic adenocarcinoma treated with mFOLFIRINOX + PEGPH20 compared to those treated with mFOLFIRINOX alone. (Phase II)

SECONDARY OBJECTIVES:

I. To assess progression free survival (PFS) in patients receiving mFOLFIRINOX with PEGPH20 and patients receiving mFOLFIRINOX alone in this patient population.

II. To assess objective tumor response (confirmed and unconfirmed, complete and partial) in patients with measurable disease treated with mFOLFIRINOX with PEGPH20 and patients receiving mFOLFIRINOX alone in this patient population.

III. To determine the frequency, severity, and tolerability of adverse events of mFOLFIRINOX with PEGPH20.

TERTIARY OBJECTIVES:

I. To explore the correlation of maximum decrease in cancer antigen (CA) 19-9 levels and time to maximum decrease in CA 19-9 levels with overall survival, progression-free survival and response.

II. To explore the correlation of plasma hyaluronan (HA) and tumor expression of HA with overall survival, progression-free survival and response.

OUTLINE: This is a phase I, dose de-escalation study of pegylated recombinant human hyaluronidase followed by a randomized phase II study.

PHASE I: Patients receive pegylated recombinant human hyaluronidase intravenously (IV) over 10 minutes on day 1\*; oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 1.5 hours on day 2; and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

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

ARM I: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 1.5 hours on day 2, and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pegylated recombinant human hyaluronidase IV over 10 minutes on day 1\* and oxaliplatin, leucovorin calcium, irinotecan hydrochloride, and fluorouracil as in Arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

\*NOTE: Some patients also receive pegylated recombinant human hyaluronidase on day 3 or 4 of courses 1 and 2.

After completion of study treatment, patients are followed up for 3 years.

Eligibility criteria: * Patients must have newly diagnosed, untreated metastatic histologically or cytologically documented pancreatic adenocarcinoma; patients must not have known history of brain metastases
* Patients must have measurable metastatic disease; computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1)
* Patients must not have had any prior treatment with oxaliplatin or irinotecan within 3 years prior to registration; patients must not have had prior chemotherapy in metastatic setting; prior abdominal radiation therapy is not allowed
* Patients must have a Zubrod performance status of 0-1
* Absolute neutrophil count (ANC) \>= 1,500/mcL
* Platelets \>= 100,000/mcL
* Hemoglobin \>= 9 g/dL
* Total bilirubin =\< institutional upper limit of normal (IULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =\< 2.5 X IULN in the absence of liver metastases or =\< 5.0 x IULN with liver metastasis
* Serum albumin \>= 3 g/dL
* Serum creatinine =\< ULN within 14 days prior to registration OR calculated creatinine clearance \> 50 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to registration
* Patients must have international normalized ratio (INR) =\< 1.2 within 14 days prior to registration; patients must not be receiving warfarin for therapeutic use, have history of cerebrovascular accident (CVA), history of transient ischemic attack (TIA) requiring intervention or treatment, pre-existing carotid artery disease requiring intervention or treatment, or current use of megestrol acetate (use within 10 days of registration)
* Patients must not be receiving chronic treatment (equivalent of prednisone \> 10 mg/day) with systemic steroids or other immuno-suppressive agent
* Patients must not have liver disease such a cirrhosis, chronic active hepatitis or chronic persistent hepatitis
* Patients must not have active bleeding or a pathological condition that is associated with a high risk of bleeding
* Patients with a known history of human immunodeficiency virus (HIV) must not be on active treatment for HIV
* Patients must have no non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with protocol therapy
* No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
* Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
* Patients must have tumor (paraffin block or slides) available for submission and be willing to submit tumor and blood samples
* Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
* As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system
* Patients planning to enroll in the phase I portion of this study must first have a slot reserved in advance of the registration; all site staff will use OPEN to create a slot reservation

Primary outcomes:
measure: Phase I: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With mFOLFIRINOX
timeFrame: 2 cycles of 14 days
measure: Phase II: Overall Survival
timeFrame: From date of registration to date of death due to any cause, assessed up to 3 years
Secondary outcomes:
measure: Progression Free Survival (PFS) (Phase II)
timeFrame: From date of registration to date of death due to any cause, assessed up to 3 years
measure: Objective Tumor Response Rate (Confirmed and Unconfirmed, Complete and Partial)
timeFrame: Up to 3 years
measure: Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
timeFrame: Duration of treatment and follow up until death or 3 years post registration
Other outcomes:
measure: Cancer Antigen (CA) 19-9 Levels
timeFrame: Within 2 years of the end of the study
measure: Plasma Expression of Hyaluronan (HA)
timeFrame: Within 2 years of end of study
measure: Tumor Expression of HA
timeFrame: Within 2 years of end of study
Locations:
city: Anchorage
country: United States
facility: Anchorage Associates in Radiation Medicine
state: Alaska
city: Anchorage
country: United States
facility: Alaska Breast Care and Surgery LLC
state: Alaska
city: Anchorage
country: United States
facility: Alaska Women's Cancer Care
state: Alaska
city: Anchorage
country: United States
facility: Katmai Oncology Group
state: Alaska
city: Anchorage
country: United States
facility: Providence Alaska Medical Center
state: Alaska
city: Tucson
country: United States
facility: University of Arizona Cancer Center-North Campus
state: Arizona
city: Tucson
country: United States
facility: The University of Arizona Medical Center-University Campus
state: Arizona
city: Auburn
country: United States
facility: Sutter Auburn Faith Hospital
state: California
city: Auburn
country: United States
facility: Sutter Cancer Centers Radiation Oncology Services-Auburn
state: California
city: Berkeley
country: United States
facility: Alta Bates Summit Medical Center-Herrick Campus
state: California
city: Burbank
country: United States
facility: Providence Saint Joseph Medical Center/Disney Family Cancer Center
state: California
city: Burlingame
country: United States
facility: Mills - Peninsula Hospitals
state: California
city: Cameron Park
country: United States
facility: Sutter Cancer Centers Radiation Oncology Services-Cameron Park
state: California
city: Castro Valley
country: United States
facility: Eden Hospital Medical Center
state: California
city: Corona
country: United States
facility: City of Hope Corona
state: California
city: Costa Mesa
country: United States
facility: UC Irvine Health Cancer Center-Newport
state: California
city: Davis
country: United States
facility: Sutter Davis Hospital
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Los Angeles County-USC Medical Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Marysville
country: United States
facility: Fremont - Rideout Cancer Center
state: California
city: Modesto
country: United States
facility: Memorial Medical Center
state: California
city: Mountain View
country: United States
facility: Palo Alto Medical Foundation-Camino Division
state: California
city: Mountain View
country: United States
facility: Palo Alto Medical Foundation-Gynecologic Oncology
state: California
city: Novato
country: United States
facility: Sutter Cancer Research Consortium
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Palo Alto
country: United States
facility: Palo Alto Medical Foundation Health Care
state: California
city: Roseville
country: United States
facility: Sutter Cancer Centers Radiation Oncology Services-Roseville
state: California
city: Roseville
country: United States
facility: Sutter Roseville Medical Center
state: California
city: Sacramento
country: United States
facility: Sutter General Hospital
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center-Pacific Campus
state: California
city: Santa Cruz
country: United States
facility: Palo Alto Medical Foundation-Santa Cruz
state: California
city: Santa Rosa
country: United States
facility: Sutter Pacific Medical Foundation
state: California
city: Sunnyvale
country: United States
facility: Palo Alto Medical Foundation-Sunnyvale
state: California
city: Truckee
country: United States
facility: Gene Upshaw Memorial Tahoe Forest Cancer Center
state: California
city: Vacaville
country: United States
facility: Sutter Cancer Centers Radiation Oncology Services-Vacaville
state: California
city: Vallejo
country: United States
facility: Sutter Solano Medical Center/Cancer Center
state: California
city: West Covina
country: United States
facility: City of Hope West Covina
state: California
city: Derby
country: United States
facility: Smilow Cancer Hospital-Derby Care Center
state: Connecticut
city: Fairfield
country: United States
facility: Smilow Cancer Hospital Care Center-Fairfield
state: Connecticut
city: Guilford
country: United States
facility: Medical Oncology and Hematology Group PC-Guilford
state: Connecticut
city: Hartford
country: United States
facility: Smilow Cancer Hospital Care Center at Saint Francis
state: Connecticut
city: New Haven
country: United States
facility: Smilow Cancer Center/Yale-New Haven Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: North Haven
country: United States
facility: Yale-New Haven Hospital North Haven Medical Center
state: Connecticut
city: Orange
country: United States
facility: Smilow Cancer Hospital-Orange Care Center
state: Connecticut
city: Torrington
country: United States
facility: Charlotte Hungerford Hospital Center for Cancer Care
state: Connecticut
city: Trumbull
country: United States
facility: Smilow Cancer Hospital Care Center-Trumbull
state: Connecticut
city: Waterbury
country: United States
facility: Smilow Cancer Hospital-Waterbury Care Center
state: Connecticut
city: Boise
country: United States
facility: Saint Luke's Mountain States Tumor Institute
state: Idaho
city: Fruitland
country: United States
facility: Saint Luke's Mountain States Tumor Institute - Fruitland
state: Idaho
city: Meridian
country: United States
facility: Saint Luke's Mountain States Tumor Institute - Meridian
state: Idaho
city: Nampa
country: United States
facility: Saint Luke's Mountain States Tumor Institute - Nampa
state: Idaho
city: Twin Falls
country: United States
facility: Saint Luke's Mountain States Tumor Institute-Twin Falls
state: Idaho
city: Bloomington
country: United States
facility: Saint Joseph Medical Center
state: Illinois
city: Bloomington
country: United States
facility: Illinois CancerCare-Bloomington
state: Illinois
city: Canton
country: United States
facility: Illinois CancerCare-Canton
state: Illinois
city: Carbondale
country: United States
facility: Memorial Hospital of Carbondale
state: Illinois
city: Carthage
country: United States
facility: Illinois CancerCare-Carthage
state: Illinois
city: Centralia
country: United States
facility: Centralia Oncology Clinic
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Center of Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Effingham
country: United States
facility: Crossroads Cancer Center
state: Illinois
city: Eureka
country: United States
facility: Illinois CancerCare-Eureka
state: Illinois
city: Galesburg
country: United States
facility: Illinois CancerCare-Galesburg
state: Illinois
city: Galesburg
country: United States
facility: Western Illinois Cancer Treatment Center
state: Illinois
city: Kewanee
country: United States
facility: Illinois CancerCare-Kewanee Clinic
state: Illinois
city: Macomb
country: United States
facility: Illinois CancerCare-Macomb
state: Illinois
city: Ottawa
country: United States
facility: Illinois CancerCare-Ottawa Clinic
state: Illinois
city: Ottawa
country: United States
facility: Radiation Oncology of Northern Illinois
state: Illinois
city: Pekin
country: United States
facility: Illinois CancerCare-Pekin
state: Illinois
city: Pekin
country: United States
facility: OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Radiation Oncology at Peoria Cancer Center
state: Illinois
city: Peoria
country: United States
facility: OSF Saint Francis Medical Center
state: Illinois
city: Peru
country: United States
facility: Illinois CancerCare-Peru
state: Illinois
city: Peru
country: United States
facility: Valley Radiation Oncology
state: Illinois
city: Princeton
country: United States
facility: Illinois CancerCare-Princeton
state: Illinois
city: Springfield
country: United States
facility: Central Illinois Hematology Oncology Center
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Springfield
country: United States
facility: Memorial Medical Center
state: Illinois
city: Swansea
country: United States
facility: Cancer Care Specialists of Illinois-Swansea
state: Illinois
city: Lenexa
country: United States
facility: Kansas Institute of Medicine Cancer and Blood Center
state: Kansas
city: Lenexa
country: United States
facility: Minimally Invasive Surgery Hospital
state: Kansas
city: Overland Park
country: United States
facility: Menorah Medical Center
state: Kansas
city: Overland Park
country: United States
facility: Saint Luke's South Hospital
state: Kansas
city: Prairie Village
country: United States
facility: Kansas City NCI Community Oncology Research Program
state: Kansas
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Farmington Hills
country: United States
facility: Weisberg Cancer Treatment Center
state: Michigan
city: Bonne Terre
country: United States
facility: Parkland Health Center-Bonne Terre
state: Missouri
city: Cape Girardeau
country: United States
facility: Saint Francis Medical Center
state: Missouri
city: Cape Girardeau
country: United States
facility: Southeast Cancer Center
state: Missouri
city: Independence
country: United States
facility: Centerpoint Medical Center LLC
state: Missouri
city: Jefferson City
country: United States
facility: Capital Region Medical Center-Goldschmidt Cancer Center
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Kansas City
country: United States
facility: Heartland Hematology and Oncology Associates Incorporated
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Lee's Summit
country: United States
facility: Saint Luke's East - Lee's Summit
state: Missouri
city: Liberty
country: United States
facility: Liberty Radiation Oncology Center
state: Missouri
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Sainte Genevieve
country: United States
facility: Sainte Genevieve County Memorial Hospital
state: Missouri
city: Sullivan
country: United States
facility: Missouri Baptist Sullivan Hospital
state: Missouri
city: Sunset Hills
country: United States
facility: Missouri Baptist Outpatient Center-Sunset Hills
state: Missouri
city: Asheboro
country: United States
facility: Randolph Hospital
state: North Carolina
city: Burlington
country: United States
facility: Cone Health Cancer Center at Alamance Regional
state: North Carolina
city: Clinton
country: United States
facility: Southeastern Medical Oncology Center-Clinton
state: North Carolina
city: Goldsboro
country: United States
facility: Southeastern Medical Oncology Center-Goldsboro
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Hendersonville
country: United States
facility: Hendersonville Hematology and Oncology at Pardee
state: North Carolina
city: Hendersonville
country: United States
facility: Margaret R Pardee Memorial Hospital
state: North Carolina
city: Jacksonville
country: United States
facility: Southeastern Medical Oncology Center-Jacksonville
state: North Carolina
city: Mebane
country: United States
facility: Cone Heath Cancer Center at Mebane
state: North Carolina
city: Reidsville
country: United States
facility: Annie Penn Memorial Hospital
state: North Carolina
city: Wilson
country: United States
facility: Southeastern Medical Oncology Center-Wilson
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Bend
country: United States
facility: Saint Charles Health System
state: Oregon
city: Clackamas
country: United States
facility: Clackamas Radiation Oncology Center
state: Oregon
city: Clackamas
country: United States
facility: Providence Oncology and Hematology Care Southeast
state: Oregon
city: Coos Bay
country: United States
facility: Bay Area Hospital
state: Oregon
city: Newberg
country: United States
facility: Providence Newberg Medical Center
state: Oregon
city: Oregon City
country: United States
facility: Providence Willamette Falls Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent Medical Center
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Aberdeen
country: United States
facility: Providence Regional Cancer System-Aberdeen
state: Washington
city: Anacortes
country: United States
facility: Cancer Care Center at Island Hospital
state: Washington
city: Bellingham
country: United States
facility: PeaceHealth Saint Joseph Medical Center
state: Washington
city: Centralia
country: United States
facility: Providence Regional Cancer System-Centralia
state: Washington
city: Edmonds
country: United States
facility: Swedish Medical Center-Edmonds
state: Washington
city: Everett
country: United States
facility: Providence Regional Cancer Partnership
state: Washington
city: Issaquah
country: United States
facility: Swedish Cancer Institute-Issaquah
state: Washington
city: Kennewick
country: United States
facility: Kadlec Clinic Hematology and Oncology
state: Washington
city: Kirkland
country: United States
facility: Seattle Cancer Care Alliance at EvergreenHealth
state: Washington
city: Lacey
country: United States
facility: Providence Regional Cancer System-Lacey
state: Washington
city: Longview
country: United States
facility: PeaceHealth Saint John Medical Center
state: Washington
city: Seattle
country: United States
facility: Minor and James Medical PLLC
state: Washington
city: Seattle
country: United States
facility: Pacific Gynecology Specialists
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-Ballard Campus
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: Group Health Cooperative-Seattle
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Shelton
country: United States
facility: Providence Regional Cancer System-Shelton
state: Washington
city: Spokane Valley
country: United States
facility: Rockwood Clinic Cancer Treatment Center-Valley
state: Washington
city: Spokane
country: United States
facility: Rockwood Cancer Treatment Center-DHEC-Downtown
state: Washington
city: Vancouver
country: United States
facility: PeaceHealth Southwest Medical Center
state: Washington
city: Walla Walla
country: United States
facility: Providence Saint Mary Regional Cancer Center
state: Washington
city: Yelm
country: United States
facility: Providence Regional Cancer System-Yelm
state: Washington
Study officials:
affiliation: Virginia G. Piper Cancer Center
name: Ramesh K Ramanathan, M.D.
role: STUDY_CHAIR
References:
citation: Ramanathan RK, McDonough SL, Philip PA, Hingorani SR, Lacy J, Kortmansky JS, Thumar J, Chiorean EG, Shields AF, Behl D, Mehan PT, Gaur R, Seery T, Guthrie KA, Hochster HS. Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313. J Clin Oncol. 2019 May 1;37(13):1062-1069. doi: 10.1200/JCO.18.01295. Epub 2019 Feb 28.