Advanced Bladder Urothelial CarcinomaPhase 2NCT03513952
Atezolizumab and CYT107 in Treating Participants With Locally Advanced, Inoperable, or Metastatic Urothelial Carcinoma
A Phase 2 study testing Atezolizumab, Biopsy and Biospecimen Collection in people with Advanced Bladder Urothelial Carcinoma and Advanced Ureter Urothelial Carcinoma, run by National Cancer Institute (NCI) at 9 sites in United States.
Trial summary
This phase II trial studies how well atezolizumab when given with glycosylated recombinant human interleukin-7 (CYT107) works in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes (locally advanced), cannot be removed by surgery (inoperable), or has spread to other places in… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Bladder Urothelial Carcinoma, Advanced Ureter Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma
- What is being tested?
- Atezolizumab, Biopsy and Biospecimen Collection
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 47 participants
- Where
- 9 sitesUnited States
- Study dates
- 5 Jun 2019to 1 Apr 2024
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have histologically or cytologically documented locally advanced/inoperable or metastatic urothelial bladder carcinoma (UBC), including renal pelvis, ureters, urinary bladder, and urethra
- Note: Mixed histology tumors allowed if predominant histology is urothelial carcinoma
- Note: Small cell or neuroendocrine carcinoma is not allowed if predominant
- Patients must have recurrent disease after any prior platinum-based chemotherapy regimen
- Patients must have measurable disease per RECIST 1.1 assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI)
- ECOG performance status =< 2 (Karnofsky >= 60%)
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- Patients must have a life expectancy of greater or equal to 12 weeks
- Leukocytes >= 2,500/mcL
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 8 g/dL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert's disease who have serum bilirubin level =< 3 x ULN may be enrolled)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x 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 bone metastases)
- Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault
- At the discretion of the treating physician, a 24-hour urine creatinine clearance could be obtained and utilized as the gold standard if creatinine clearance by Cockcroft-Gault is < 30, and prevents patient enrollment on the trial
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
- Patients must provide tissue from an archival tumor sample (obtained within 2 years from screening visit) or newly obtained core, punch, or excisional biopsy of a tumor lesion if deemed relatively safe and technically feasible
- Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours before receiving the first dose of study agent(s); if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required;
- Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality; CYT107 has not been tested for reproductive toxicity yet and may expose to the same risk; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) before study entry, for the duration of study participation, and for 5 months (150 days) after the last dose of study agent; 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
- Patients must have the ability to understand and the willingness to sign a written informed consent document
- Patients positive for human immunodeficiency virus (HIV) are allowed on study, but HIV-positive patients must have:
- A stable regimen of highly active antiretroviral therapy (HAART)
- No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
- A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests
Who cannot join
- Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks for nitrosoureas or systemic mitomycin C) before the initiation of study treatment
- Patients who have received more than 2 systemic cytotoxic chemotherapy regimens for metastatic urothelial carcinoma
- Note: Prior perioperative chemotherapy is allowed and is not counted as a line of therapy if patient relapsed >= 12 months later and received additional platinum-based chemotherapy for metastatic disease
- Patients who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier (i.e., have residual toxicities > grade 1); however, the following therapies are allowed:
- Hormone-replacement therapy or oral contraceptives
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- Herbal therapy >= 1 week before initiation of study treatment (herbal therapy intended as anticancer therapy must be discontinued at least 1 week before initiation of study treatment)
- Palliative radiotherapy for bone metastases > 2 weeks before initiation of study treatment
- Patients who have received prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody, or pathway -targeting agents
- Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met:
- Minimum of 12 weeks from the first dose of anti-CTLA-4 and > 6 weeks from the last dose
- No history of severe immune-related adverse effects from anti-CTLA-4 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4)
- Patients who have received treatment with any other investigational agent within 4 weeks before initiation of study treatment
- Patients who have received treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks before initiation of study treatment
- Patients who have received treatment with systemic immunosuppressive medications (including, but not limited to, oral prednisone ( > 10 mg/day or equivalent), cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti TNF] agents) within 2 weeks before initiation of study treatment
- 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
- Patients taking bisphosphonate therapy for symptomatic hypercalcemia
- Note: Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
- 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 before initiation of study treatment
- 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 before initiation of study treatment
- Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
- Note: Patients with CNS metastases enrolled on trial must also have a brain MRI imaging at all standard radiologic evaluation timepoints
- Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
- Patients who have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Patients with known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver/nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH); and inherited liver disease
- Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Patients with active underlying autoimmune disease requiring systemic immunosuppressive medication (oral prednisone > 10 mg/day or equivalent). Topical, inhaled, or intra-articular steroids or physiologic endocrine replacement (insulin, levothyroxine, etc.) are permitted. Patients with a history of autoimmune disease that is not currently active require consultation with the protocol principal investigator (PI) and/or Cancer Immunotherapy Trials Network (CITN) Coordinating Center
- Patients who have a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Patients who have known additional malignancies other than UBC within 2 years before initiation of study treatment; exceptions include malignancies with a negligible risk of metastasis or death and treated with expected curative outcome (e.g., non-melanomatous skin cancers), or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer
- Patients with active tuberculosis (TB)
- Patients who have leptomeningeal disease
- Patients who have severe infections within 4 weeks before initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia;
- Exception: Uncomplicated urinary tract infection will not be considered as a severe infection in these patients
- Patients who have signs or symptoms of infection within 2 weeks before initiation of study treatment
- Patients who have received oral or IV antibiotics within 2 weeks before initiation of study treatment; patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
- Patients who have major surgical procedure, other than for diagnosis, within 28 days before initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
- Patients who have had a live, attenuated vaccine within 4 weeks before initiation of study treatment or anticipation that such a live, attenuated vaccine will be required during the study and up to 5 months after the last dose of atezolizumab.
- Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine within 4 weeks before initiation of study treatment or at any time during the study
- Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association class III or IV), unstable angina pectoris, cardiac arrhythmia, recent myocardial infarction (within the last 6 months), or psychiatric illness/social situations that would limit compliance with study requirements
- Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or medical (e.g., infectious) illness
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
Roswell Park Cancer Institute
Buffalo, New York, 14263
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637
Straub Clinic and Hospital
Honolulu, Hawaii, 96813
University of Hawaii Cancer Center
Honolulu, Hawaii, 96813
East Jefferson General Hospital
Metairie, Louisiana, 70006
Kaiser Permanente-Riverside
Riverside, California, 92505
FHCC South Lake Union
Seattle, Washington, 98109
Washington University School of Medicine
St Louis, Missouri, 63110
Moffitt Cancer Center
Tampa, Florida, 33612
About this study
Official title: A Randomized Phase II Study of Atezolizumab (MPDL3280A) Plus Recombinant Human IL7 (CYT107) in Patients With Locally Advanced or Metastatic Urothelial Carcinoma
This phase II trial studies how well atezolizumab when given with glycosylated recombinant human interleukin-7 (CYT107) works in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes (locally advanced), cannot be removed by surgery (inoperable), or has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. CYT107 is a biological product naturally made by the body that may stimulate the immune system to destroy tumor cells. Giving atezolizumab and CYT107 may work better in treating patients with locally advanced, inoperable, or metastatic urothelial carcinoma compared to atezolizumab alone.
Read the detailed description
PRIMARY OBJECTIVE:
- To determine the clinical efficacy of the investigational treatment combination.
SECONDARY OBJECTIVES:
- To determine the clinical activity and toxicity of the investigational treatment combination.
II. The clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related response criteria (irRC), and overall survival (OS).
III. The CBR, PFS, DOR, and OS in all patients and patients stratified by PD-L1 expression levels in the tumor microenvironment.
IV. The safety and toxicity of addition of CYT107 to atezolizumab.
EXPLORATORY OBJECTIVES:
- To determine the immune correlates of the clinical activity of the investigational treatment combination.
II. Explore the effect of the investigational treatment combination on the number and phenotype of tumor-specific T cells in the peripheral blood.
III. Investigate for evidence that the investigational treatment combination increases the exposure of bladder cancer-specific antigens (e.g., cancer/testis antigens or neoantigens).
IV. Investigate changes in tumor microenvironment that correlate with response or provide information on potential actionable causes for lack of clinical benefit.
- Investigate the potential that administration of atezolizumab with CYT107 may perturb the pharmacokinetics and immunogenicity of CYT107.
OUTLINE:
SAFETY RUN-IN PHASE: Patients assigned to the experimental arm (atezolizumab + CYT107). If the treatment combination of the experimental arm demonstrates an acceptable safety profile in the Safety Run-In (one or fewer patient experiences a protocol-defined Dose Limiting-Toxicity), randomized enrollment into the trial will begin. The Run-in phase patients will be analyzed and reported separately both for safety and for efficacy.
Patients are randomized to 1 of 2 groups.
GROUP 1 (experimental arm): Patients receive CYT107 intramuscularly (IM) on days 1, 8, 15, and 22, and atezolizumab intravenously (IV) over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.
GROUP 2 (control arm): Patients receive atezolizumab IV over 60 minutes on cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.
After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 2 years.
- Conditions
- Advanced Bladder Urothelial Carcinoma, Advanced Ureter Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma
- Being tested
- Atezolizumab, Biopsy, Biospecimen Collection, Computed Tomography, Glycosylated Recombinant Human Interleukin-7
- Medical subject headings
- Carcinoma, Transitional Cell, Urinary Bladder Neoplasms, Ureteral Neoplasms, Urethral Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AtezolizumabDrug
Also called MPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A
Given IV
BiopsyProcedure or surgery
Also called BIOPSY_TYPE, Bx
Undergo biopsy of tumor
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection
Undergo collection of blood and stool samples
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
Glycosylated Recombinant Human Interleukin-7Biological
Also called CYT-107, CYT107, Glycosylated rhIL-7, INTERLEUKIN-7 HUMAN RECOMBINANT
Given IM
Laboratory Biomarker AnalysisOther
Correlative studies
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
Positron Emission Tomography and Computed Tomography ScanProcedure or surgery
Also called PET-CT Scan, PET/CT SCAN, Positron Emission Tomography/Computed Tomography
Undergo PET/CT
| Study group | Role | What they receive |
|---|---|---|
| Group 1 (CYT107, atezolizumab) | Experimental | Patients receive CYT107 IM on days 1, 8, 15, and 22, and atezolizumab IV over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study. Receives: Drug: Atezolizumab; Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Glycosylated Recombinant Human Interleukin-7; Other: Laboratory Biomarker Analysis; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography and Computed Tomography Scan |
| Group 2 (atezolizumab) | Active comparator | Patients receive atezolizumab IV over 60 minutes on cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study. Receives: Drug: Atezolizumab; Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Other: Laboratory Biomarker Analysis; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography and Computed Tomography Scan |
| Safety run in phase | Experimental | Patients assigned to the experimental arm (atezolizumab + CYT107). If the treatment combination of the experimental arm demonstrates an acceptable safety profile in the Safety Run-In (one or fewer patient experiences a protocol-defined Dose Limiting-Toxicity), randomized enrollment into the trial will begin. The Run-in phase patients will be analyzed and reported separately both for safety and for efficacy. Receives: Drug: Atezolizumab; Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Biological: Glycosylated Recombinant Human Interleukin-7; Other: Laboratory Biomarker Analysis; Procedure: Magnetic Resonance Imaging; Procedure: Positron Emission Tomography and Computed Tomography Scan |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate (ORR)
ORR is defined as the proportion of patients who have achieved Complete Response (CR) - disappearance of all target lesions or Partial Response (PR) - >=30% decrease in the sum of the longest diameter of target lesions according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; Overall Response (OR) = CR + PR.
Measured: Up to 2 years
Secondary outcomes (4)
Clinical Benefit Rate (CBR) Measured by RECIST v1.1
CBR is defined as the percentage of patients with advanced or metastatic cancer who have achieved CR (disappearance of all target lesions), PR (>=30% decrease in the sum of the longest diameter of target lesions), and stable disease (SD) (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum diameters of target lesions) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; CBR = CR + PR + SD.
Will also assess CBR in patients stratified by PD-L1 expression levels in the tumor microenvironment.
Measured: Up to 2 years
Progression-free Survival (PFS)
Progression is defined, per RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions (the sum must demonstrate an absolute increase of at least 5 mm), or the appearance of new lesions and/or unequivocal progression of non-target lesions.
PFS will be summarized using Kaplan-Meier estimates. Will also assess PFS in patients stratified by PD-L1 expression levels in the tumor microenvironment.
Measured: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years.
Duration of Response (DOR)
DOR is measured by RECIST v1.1. DOR will be summarized using Kaplan-Meier estimates. Will also assess DOR in patients stratified by PD-L1 expression levels in the tumor microenvironment.
Measured: Time interval between the date of first response (CR/PR) and the date of progression, assessed up to 2 years.
Overall Survival (OS)
OS will be summarized using Kaplan-Meier estimates. Will also assess OS in patients stratified by PD-L1 expression levels in the tumor microenvironment.
Measured: Time interval between start of treatment to death due to any cause, assessed up to 48 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 May 2018
- Study start5 Jun 2019
- Primary completion30 Sep 2023
- Study completion1 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Advanced Bladder Urothelial CarcinomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Evan Y Yu, Principal investigator, Cancer Immunotherapy Trials Network
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03513952
- Sponsor's protocol ID
- NCI-2018-00684
- Other IDs
- NCI-2018-00684, CITN-14, CITN-14, P30CA015704, U01CA154967
- Status last verified
- May 2024
- First submitted
- 1 May 2018
- Last updated
- 26 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No