Clinical trial NCT04936230: Immunotherapy With or Without Radiation Therapy for Metastatic Urothelial Cancer
Official title: Phase II Randomized Trial of Immunotherapy Versus Immunotherapy and Radiation Therapy for Platinum Ineligible/Refractory Metastatic Urothelial Cancer (IMMORTAL)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Urothelial Carcinoma
Platinum-Resistant Urothelial Carcinoma
Stage IV Bladder Cancer AJCC v8
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2021-06-23
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II trial compares the effect of adding radiation therapy to an immunotherapy drug called pembrolizumab versus pembrolizumab alone in treating patients with urothelial cancer that has spread from where it first started (primary site) to other places in the body (metastatic). The addition of radiation to immunotherapy may shrink the cancer, but it could also cause side effects. Immunotherapy with monoclonal antibodies such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy (SBRT) is a type of radiation therapy that uses high energy x-rays to kill tumor cells and shrink tumors. This method uses special equipment to position a patient and precisely deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and may cause less damage to normal tissue than conventional radiation therapy. The combination of pembrolizumab and radiation therapy may be more efficient in killing tumor cells.

Detailed description: PRIMARY OBJECTIVE:

I. To compare the overall response rates by 6 months in patients with advanced urothelial carcinoma when treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.

SECONDARY OBJECTIVES:

I. To compare the response rates using immune related Response Evaluation Criteria in Solid Tumors (iRECIST) as assessed by central review.

II. To compare progression-free survival (PFS) and overall survival (OS) for patients treated with immunotherapy and immunotherapy plus radiotherapy.

III. To compare the rates of treatment discontinuation at 1 year. IV. To assess adverse events experienced by patients treated with immunotherapy and immunotherapy plus radiotherapy via the Common Terminology Criteria for Adverse Events (CTCAE) and Patient Reported Outcome (PRO)-CTCAE.

IV. To determine whether treatment effects are similar for key subgroups including those defined by the stratification variables.

QUALITY OF LIFE CORRELATIVE STUDY OBJECTIVES:

I. To compare patient-reported fatigue as assessed by the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue 8a from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.

II. To compare health-related quality of life (HRQOL) as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core (C)30 from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.

III. To compare urinary symptoms as assessed by the EORTC QLQ-BLM30 from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.

IV. To compare patient-reported diarrhea, shortness of breath and pain as assessed by the EORTC QLQ-C30 from baseline through 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.

V. To compare health utilities and quality-adjusted survival between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.

VI. To compare other scale scores of the EORTC QLQ-C30 (global health status and quality of life; physical, role, emotional, cognitive, and social function; symptoms) and EORTC QLQ-BLM30 (urostomy problems, catheter problems, future perspectives, abdominal bloating and flatulence, body image, sexual function) at 45 days, and at 6, 12, and 24 months between patients treated with immunotherapy alone and immunotherapy plus radiotherapy to a single site.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 25-40 minutes on day 1 of each cycle. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), bone scan and/or positron emission tomography (PET) scan, as well as optional urine and blood sample collection throughout the study.

ARM B: Patients receive pembrolizumab as in Arm A. Patients also undergo SBRT once daily (QD) every other day for 3 fractions over 2 weeks that must be completed before 12 weeks after the first dose of pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, bone scan, and/or PET scan, as well as optional urine and blood sample collection throughout the study.

After completion of study treatment, patients are followed up within 12 weeks and then every 3 months for 3 years following registration.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed metastatic urothelial carcinoma
* Patients must be either ineligible for platinum treatment or platinum refractory as defined below:

  * Platinum-ineligible: If patients meet any one of the following criteria:

    * Impaired renal function (creatinine clearance \[CrCl\] of \< 30 mL/min)
    * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of \> 2
    * Grade \> 2 peripheral neuropathy
    * New York Heart Association (NYHA) Heart Failure of \> 3
  * Platinum-refractory: If patients meet any one of the following criteria:

    * Prior platinum-based perioperative chemotherapy within 12 months of relapse
    * Prior platinum-based chemotherapy for metastatic disease
* Patients must have at least one measurable site \>= 1 cm in diameter per RECIST 1.1 and a site targetable for radiotherapy. Measurable site must not overlap with radiated site such that measurable site cannot receive \> 2 Gy per fraction
* Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions)
* Men and women, ages \>= 18 years of age
* ECOG performance status =\< 2
* Leukocytes \>= 2,500/mm\^3
* Absolute neutrophil count \>= 1,500/mm\^3
* Platelets \>= 100,000/mm\^3
* Hemoglobin \>= 8 g/dL
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =\< 3 x ULN may be enrolled)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 x upper limit of normal (ULN)

  * AST and/or ALT =\< 5 x ULN for patients with liver involvement
* Alkaline phosphatase =\< 2.5 x ULN

  * =\< 5 x ULN for patients with documented liver involvement or if due to bone metastases primarily in absence of liver disease, no limitation
* No prior allogeneic bone marrow transplantation or prior solid organ transplantation
* No prior radiotherapy to targetable site or measurable site
* No chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier. However, the following therapies are allowed:

  * Hormone-replacement therapy or oral contraceptives
  * Palliative radiotherapy for bone metastases \> 2 weeks prior to registration
* No prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
* No treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
* No prior treatment with any other investigational agent within 4 weeks prior to registration
* No prior treatment with systemic immunostimulatory agents (including, but not limited to, interferon \[IFN\]-alpha or interleukin \[IL\]-2) within 6 weeks prior to registration
* Any prior systemic therapy is permitted except therapy with PD1/PDL1 inhibitor
* Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
* The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
* No active tuberculosis (TB)
* No known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
* Patients with known primary central nervous system (CNS) malignancy or symptomatic CNS metastases are excluded, with the following exceptions:

  * Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met:

    * Evaluable or measurable disease outside the CNS
    * No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm)
    * No history of intracranial hemorrhage or spinal cord hemorrhage
    * No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted
    * No neurosurgical resection or brain biopsy within 28 days prior to registration
* Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following:

  * Radiographic demonstration of improvement upon the completion of CNS directed therapy and no evidence of interim progression between the completion of CNS directed therapy and the screening radiographic study
  * No stereotactic radiation or whole-brain radiation within 28 days prior to registration
  * Screening CNS radiographic study \>= 4 weeks from completion of radiotherapy and \>= 2 weeks from discontinuation of corticosteroids
* No active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
* Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
* No known history of, or any evidence of active, non-infectious pneumonitis or colitis
* No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
* No history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
* No known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; or inherited liver disease causing decompensated cirrhosis
* No history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
* No significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
* No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
* No history of leptomeningeal disease
* No uncontrolled tumor-related pain
* Patients requiring pain medication must be on a stable regimen at study entry
* Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period
* Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
* No uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)

  * Patients with indwelling catheters (e.g., PleurX \[registered trademark\]) are allowed
* Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible
* Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

  * Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
  * Rash must cover less than 10% of body surface area (BSA)
  * Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
* No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation \[PUVA\], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
* No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* No active infections requiring systemic antibiotics within 2 weeks prior to registration. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
* No major surgical procedure within 28 days prior to registration or anticipation of need for a major surgical procedure during the course of the study
* No administration of a live, attenuated vaccine within 30 days before registration or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of immunotherapy
* Patients who have received live attenuated vaccines within 30 days of the first dose of trial treatment are eligible at the discretion of the investigator. All seasonal influenza vaccines and vaccines intended to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) are allowed
* Physicians should consider whether any of the following may render the patient inappropriate for this protocol:

  * Patients with life expectancy of less than 6 months
  * Psychiatric illness which would prevent the patient from giving informed consent
  * Medical conditions such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient

    * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
    * For patients with evidence of chronic hepatitis B virus (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
  * Patients with a "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for \>= 3 years
* Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study and for 4 months (120 days) after the last dose of study agent due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

  * A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

Primary outcomes:
measure: Tumor response
timeFrame: Up to 6 months from randomization
Secondary outcomes:
measure: Tumor response
timeFrame: Up to 3 years from randomization
measure: Progression-free survival
timeFrame: Time from randomization until disease progression as assessed by the treating physician using RECIST 1.1 or death due to any cause, assessed up to 3 years
measure: Overall survival
timeFrame: Time from randomization until death due to any cause. Patients who are not known to be dead at time of analysis will be censored at the time of their last follow-up, assessed up to 3 years
measure: Rate of treatment discontinuation
timeFrame: At 1 year
measure: Incidence of adverse events
timeFrame: Up to 3 years from randomization
Other outcomes:
Locations:
city: Littleton
country: United States
facility: Littleton Adventist Hospital
state: Colorado
city: Bloomington
country: United States
facility: Illinois CancerCare-Bloomington
state: Illinois
city: Canton
country: United States
facility: Illinois CancerCare-Canton
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: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Danville
country: United States
facility: Carle at The Riverfront
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Specialists of Illinois - Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Effingham
country: United States
facility: Carle Physician Group-Effingham
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: Kewanee
country: United States
facility: Illinois CancerCare-Kewanee Clinic
state: Illinois
city: Macomb
country: United States
facility: Illinois CancerCare-Macomb
state: Illinois
city: Mattoon
country: United States
facility: Carle Physician Group-Mattoon/Charleston
state: Illinois
city: O'Fallon
country: United States
facility: Cancer Care Center of O'Fallon
state: Illinois
city: O'Fallon
country: United States
facility: HSHS Saint Elizabeth's Hospital
state: Illinois
city: Ottawa
country: United States
facility: Illinois CancerCare-Ottawa Clinic
state: Illinois
city: Pekin
country: United States
facility: Illinois CancerCare-Pekin
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
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: Princeton
country: United States
facility: Illinois CancerCare-Princeton
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: Springfield Memorial Hospital
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Washington
country: United States
facility: Illinois CancerCare - Washington
state: Illinois
city: Ankeny
country: United States
facility: Mission Cancer and Blood - Ankeny
state: Iowa
city: Clive
country: United States
facility: Mercy Cancer Center-West Lakes
state: Iowa
city: Creston
country: United States
facility: Greater Regional Medical Center
state: Iowa
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: Des Moines
country: United States
facility: Mission Cancer and Blood - Des Moines
state: Iowa
city: Des Moines
country: United States
facility: Broadlawns Medical Center
state: Iowa
city: Des Moines
country: United States
facility: Mercy Medical Center - Des Moines
state: Iowa
city: West Des Moines
country: United States
facility: Mercy Medical Center-West Lakes
state: Iowa
city: Ann Arbor
country: United States
facility: Trinity Health Saint Joseph Mercy Hospital Ann Arbor
state: Michigan
city: Brighton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Brighton
state: Michigan
city: Brighton
country: United States
facility: Trinity Health Medical Center - Brighton
state: Michigan
city: Canton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Canton
state: Michigan
city: Canton
country: United States
facility: Trinity Health Medical Center - Canton
state: Michigan
city: Chelsea
country: United States
facility: Chelsea Hospital
state: Michigan
city: Chelsea
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
state: Michigan
city: Lansing
country: United States
facility: University of Michigan Health - Sparrow Lansing
state: Michigan
city: Livonia
country: United States
facility: Trinity Health Saint Mary Mercy Livonia Hospital
state: Michigan
city: Ypsilanti
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
state: Michigan
city: Duluth
country: United States
facility: Saint Luke's Hospital of Duluth
state: Minnesota
city: Cape Girardeau
country: United States
facility: Saint Francis Medical Center
state: Missouri
city: Columbia
country: United States
facility: MU Health - University Hospital/Ellis Fischel Cancer Center
state: Missouri
city: Farmington
country: United States
facility: Parkland Health Center - Farmington
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
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: BJC Outpatient Center at Sunset Hills
state: Missouri
city: Bozeman
country: United States
facility: Bozeman Health Deaconess Hospital
state: Montana
city: New York
country: United States
facility: NYP/Weill Cornell Medical Center
state: New York
city: Lawton
country: United States
facility: Cancer Centers of Southwest Oklahoma Research
state: Oklahoma
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Lewisburg
country: United States
facility: Geisinger Medical Oncology-Lewisburg
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pottsville
country: United States
facility: Geisinger Cancer Services-Pottsville
state: Pennsylvania
city: Wilkes-Barre
country: United States
facility: Geisinger Wyoming Valley/Henry Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Simmons Cancer Center - RedBird
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Fort Worth
country: United States
facility: UT Southwestern/Simmons Cancer Center-Fort Worth
state: Texas
city: Richardson
country: United States
facility: UT Southwestern Clinical Center at Richardson/Plano
state: Texas
city: Mechanicsville
country: United States
facility: VCU Massey Cancer Center at Hanover Medical Park
state: Virginia
city: Richmond
country: United States
facility: VCU Massey Cancer Center at Stony Point
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Eau Claire
country: United States
facility: Marshfield Medical Center-EC Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center-Marshfield
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Minocqua
country: United States
facility: Marshfield Medical Center - Minocqua
state: Wisconsin
city: Mukwonago
country: United States
facility: ProHealth D N Greenwald Center
state: Wisconsin
city: Oconomowoc
country: United States
facility: ProHealth Oconomowoc Memorial Hospital
state: Wisconsin
city: Rice Lake
country: United States
facility: Marshfield Medical Center-Rice Lake
state: Wisconsin
city: Stevens Point
country: United States
facility: Marshfield Medical Center-River Region at Stevens Point
state: Wisconsin
city: Waukesha
country: United States
facility: UW Cancer Center at ProHealth Care
state: Wisconsin
city: Weston
country: United States
facility: Marshfield Medical Center - Weston
state: Wisconsin
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Himanshu Nagar
role: PRINCIPAL_INVESTIGATOR
References: