Immunotherapy With or Without Radiation Therapy for Metastatic Urothelial Cancer

Metastatic Urothelial Carcinoma Clinical Trial

Official title:

Phase II Randomized Trial of Immunotherapy Versus Immunotherapy and Radiation Therapy for Platinum Ineligible/Refractory Metastatic Urothelial Cancer (IMMORTAL)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04936230
• Other study ID #: NCI-2021-06326
• Secondary ID: NCI-2021-06326A0
• Status: Recruiting
• Phase: Phase 2
• Start date: November 22, 2022
• Est. completion date: April 30, 2025

Study information

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

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 144
• Est. completion date: April 30, 2025
• Est. primary completion date: April 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Metastatic Urothelial Carcinoma
• Platinum-Resistant Urothelial Carcinoma
• Stage IV Bladder Cancer AJCC v8

Intervention

Procedure:
• Biospecimen Collection
Undergo urine and blood sample collection
• Bone Scan
Undergo bone scan
• Computed Tomography
Undergo CT scan
• Magnetic Resonance Imaging
Undergo MRI

Biological:
• Pembrolizumab
Given IV

Procedure:
• Positron Emission Tomography
Undergo PET scan

Other:
• Questionnaire Administration
Ancillary studies

Radiation:
• Stereotactic Body Radiation Therapy
Undergo SBRT

Locations

Country	Name	City	State
United States	Mission Cancer and Blood - Ankeny	Ankeny	Iowa
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Illinois CancerCare-Bloomington	Bloomington	Illinois
United States	Bozeman Deaconess Hospital	Bozeman	Montana
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Illinois CancerCare-Canton	Canton	Illinois
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Illinois CancerCare-Carthage	Carthage	Illinois
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Mercy Cancer Center-West Lakes	Clive	Iowa
United States	MU Health - University Hospital/Ellis Fischel Cancer Center	Columbia	Missouri
United States	Greater Regional Medical Center	Creston	Iowa
United States	UT Southwestern Simmons Cancer Center - RedBird	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Carle at The Riverfront	Danville	Illinois
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Broadlawns Medical Center	Des Moines	Iowa
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Saint Luke's Hospital of Duluth	Duluth	Minnesota
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Illinois CancerCare-Eureka	Eureka	Illinois
United States	Parkland Health Center - Farmington	Farmington	Missouri
United States	UT Southwestern/Simmons Cancer Center-Fort Worth	Fort Worth	Texas
United States	Illinois CancerCare-Galesburg	Galesburg	Illinois
United States	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois
United States	University of Michigan Health - Sparrow Lansing	Lansing	Michigan
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Illinois CancerCare-Macomb	Macomb	Illinois
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	VCU Massey Cancer Center at Hanover Medical Park	Mechanicsville	Virginia
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	ProHealth D N Greenwald Center	Mukwonago	Wisconsin
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois
United States	Illinois CancerCare-Pekin	Pekin	Illinois
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	Illinois CancerCare-Peru	Peru	Illinois
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Illinois CancerCare-Princeton	Princeton	Illinois
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	UT Southwestern Clinical Center at Richardson/Plano	Richardson	Texas
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Missouri Baptist Sullivan Hospital	Sullivan	Missouri
United States	BJC Outpatient Center at Sunset Hills	Sunset Hills	Missouri
United States	Carle Cancer Center	Urbana	Illinois
United States	Illinois CancerCare - Washington	Washington	Illinois
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Mercy Medical Center-West Lakes	West Des Moines	Iowa
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Tumor response	Will be defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.	Up to 6 months from randomization
Secondary	Tumor response	Will be determined to have a tumor response if they have a CR or PR as assessed by immune modified RECIST.	Up to 3 years from randomization
Secondary	Progression-free survival	Stratified Cox models will be used to compare the outcomes between the two treatment groups. The results will be summarized with a forest plot displaying the estimate of the hazard ratio and corresponding 95% confidence interval.	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
Secondary	Overall survival	Stratified Cox models will be used to compare the outcomes between the two treatment groups. The results will be summarized with a forest plot displaying the estimate of the hazard ratio and corresponding 95% confidence interval.	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
Secondary	Rate of treatment discontinuation	The proportion of patients who discontinue their protocol directed treatment prior to one year from date of study registration will be determined. Patients who stop their protocol directed treatment for any reason prior to one year from study registration will be considered to have discontinued their treatment. The rates of treatment discontinuation at one year will be summarized with a binomial point estimate and corresponding 95% confidence interval by arm. A comparison between the rates will be performed with a chi-square test or a Fisher's exact test if the assumptions of the chi-square test are violated.	At 1 year
Secondary	Incidence of adverse events	Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized with frequencies and relative frequencies.	Up to 3 years from randomization