Atezolizumab and CYT107 in Treating Participants With Locally Advanced, Inoperable, or Metastatic Urothelial Carcinoma

• ClinicalTrials.gov Identifier: NCT03513952
• Recruitment Status: Recruiting
• First Posted: May 2, 2018
• Last Update Posted: September 5, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This phase II trial studies how well atezolizumab when given with glycosylated recombinant human interleukin-7 (CYT107) works in treating participants with urothelial carcinoma that has spread to nearby tissue or lymph nodes, cannot be removed by surgery, or has spread to other places in the body. Monoclonal antibodies, such as atezolizumab, 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 participants with locally advanced, inoperable, or metastatic urothelial carcinoma.

Condition or disease	Intervention/treatment	Phase
Metastatic Bladder Urothelial Carcinoma; Metastatic Renal Pelvis Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Metastatic Urethral Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Recurrent Bladder Urothelial Carcinoma; Recurrent Renal Pelvis Urothelial Carcinoma; Recurrent Ureter Urothelial Carcinoma; Recurrent Urethral Urothelial Carcinoma; Stage III Bladder Cancer AJCC v8; Stage III Renal Pelvis Cancer AJCC v8; Stage III Ureter Cancer AJCC v8; Stage III Urethral Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8; Stage IV Renal Pelvis Cancer AJCC v8; Stage IV Ureter Cancer AJCC v8; Stage IV Urethral Cancer AJCC v8; Stage IVA Bladder Cancer AJCC v8; Stage IVB Bladder Cancer AJCC v8	Drug: Atezolizumab; Biological: Glycosylated Recombinant Human Interleukin-7; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the clinical efficacy of the investigational treatment combination.

SECONDARY OBJECTIVES:

I. To determine the clinical activity 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 (ir) RECIST, 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.

EXPLORATORY OBJECTIVES:

I. 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.

OUTLINE: Participants are randomized to 1 of 2 groups.

GROUP 1: Participants 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, participants receive atezolizumab IV over 30-60 minutes on day 1. Courses with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

GROUP 2: Participants receive atezolizumab IV over 30-60 minutes on day 1. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days and then every 12 weeks for up to 2 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Atezolizumab (MPDL3280A) Plus Recombinant Human IL-7 (CYT107) in Patients With Locally Advanced or Metastatic Urothelial Carcinoma
• Actual Study Start Date: September 28, 2018
• Estimated Primary Completion Date: December 31, 2020
• Estimated Study Completion Date: December 31, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1 (CYT107, atezolizumab); Participants 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, participants receive atezolizumab IV over 30-60 minutes on day 1. Courses with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.	Drug: Atezolizumab; Given IV; Other Names: MPDL 3280A; MPDL 328OA; MPDL-3280A; MPDL3280A; MPDL328OA; RG7446; RO5541267; Tecentriq; Biological: Glycosylated Recombinant Human Interleukin-7; Given IM; Other Names: CYT107; Glycosylated rhIL-7; Other: Laboratory Biomarker Analysis; Correlative studies
Experimental: Group 2 (atezolizumab); Participants receive atezolizumab IV over 30-60 minutes on day 1. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.	Drug: Atezolizumab; Given IV; Other Names: MPDL 3280A; MPDL 328OA; MPDL-3280A; MPDL3280A; MPDL328OA; RG7446; RO5541267; Tecentriq; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. Objective response rate (ORR) [ Time Frame: Up to 2 years ]
   ORR to be defined by complete response (CR) or partial response (PR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.) 1.1. The Cochran Mantel Haenszel test will be conducted to compare ORR in the experimental arm (atezolizumab + CYT107) to the ORR in the control arm (atezolizumab monotherapy). A one-sided significance level of 0.10 will be considered for the test.

Secondary Outcome Measures :

1. Clinical benefit rate (CBR) measured by RECIST version (v.) 1.1 and immune-related (ir) RECIST [ Time Frame: Up to 2 years ]
   CBR is defined as the percentage of patients with advanced or metastatic cancer who have achieved CR, PR, and stable disease (SD) to a therapeutic intervention in clinical trials of anticancer agents. A two-sided test for a difference in proportions will be conducted to compare the CBR in the experimental arm to the CBR in the control arm. A two-sided significance level of 0.05 will be considered for the test. Will also assess CBR in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.
2. Progression-free survival (PFS) [ Time Frame: Up to 2 years ]
   PFS to be measured by RECIST v1.1 and irRECIST. PFS will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for overall survival (OS) and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess PFS in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.
3. Duration of response (DOR) [ Time Frame: Up to 2 years ]
   DOR is measured by RECIST v1.1 and irRECIST. DOR will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for OS and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess DOR in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.
4. Overall survival [ Time Frame: Up to 2 years ]
   OS will be summarized using Kaplan-Meier estimates. Long-rank tests will be conducted for OS and PFS to compare between the 2 arms. A one-sided significance level of 0.10 will be considered. Will also assess OS in patients stratified by PD-L1 expression levels in the tumor microenvironment, as assayed by Genentech.

Other Outcome Measures:

1. Assessment of investigation treatment combination on the immune-bias of the tumor microenvironment [ Time Frame: Up to 2 years ]
   The evaluation of the effect of the investigation treatment combination on the immune-bias of the tumor microenvironment, based upon baseline and post-baseline tumor biopsy comparisons of number, distribution, and phenotype of tumor-infiltrating cells; PD-L1 expression, and expression of Interferon gamma (IFN-gamma) and associated proinflammatory gene expression in the tumor microenvironment.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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 either may be treatment-naive and considered ineligible for cisplatin-based chemotherapy or have recurrent disease after any prior platinum-based chemotherapy regimen and meet at least one of the following criteria:

  • Glomerular filtration rate ≥ 30 mL/min and < 60 mL/min (by Cockcroft-Gault)
  • Grade 2 or higher hearing loss
  • Grade 2 or higher peripheral neuropathy
  • Eastern Cooperative Oncology Group (ECOG) performance status 2
  • OR 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%)
• 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 × institutional upper limit of normal (ULN) (however, patients with known Gilbert's disease who have serum bilirubin level ≤ 3 × ULN may be enrolled)
• Aspartate aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 × ULN (AST and/or ALT ≤ 5 × ULN for patients with liver involvement)
• Alkaline phosphatase ≤ 2.5 × ULN (≤ 5 ± 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 × 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;

  • 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

• 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

Exclusion Criteria:

• 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 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
  • 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, prednisone, 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 requiring treatment with a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor (e.g., denosumab) who cannot discontinue it before initiation of study treatment

• 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
• 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)

• Patient who have a history or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis

  • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible
  • Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 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%, fluocinolone 0.01%, desonide 0.05%, alclometasone 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)
• 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

Contacts and Locations

Locations

United States, California

Kaiser Permanente-Riverside; Recruiting

Riverside, California, United States, 92505

Contact: Site Public Contact 800-398-3996 clinical.trials@kp.org

Principal Investigator: Helen H. Moon

United States, Florida

Moffitt Cancer Center; Recruiting

Tampa, Florida, United States, 33612

Contact: Site Public Contact 800-679-0775 canceranswers@moffitt.org

Principal Investigator: Rohit Jain

United States, Illinois

University of Chicago Comprehensive Cancer Center; Recruiting

Chicago, Illinois, United States, 60637

Contact: Site Public Contact 773-702-8222 cancerclinicaltrials@bsd.uchicago.edu

Principal Investigator: Randy F. Sweis

United States, Louisiana

East Jefferson General Hospital; Recruiting

Metairie, Louisiana, United States, 70006

Contact: Site Public Contact 504-210-3539 emede1@lsuhsc.edu

Principal Investigator: Scott E. Delacroix

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Site Public Contact 800-600-3606 info@siteman.wustl.edu

Principal Investigator: Russell K. Pachynski

United States, New York

Roswell Park Cancer Institute; Recruiting

Buffalo, New York, United States, 14263

Contact: Site Public Contact 800-767-9355 askroswell@roswellpark.org

Principal Investigator: Gurkamal S. Chatta

United States, Washington

Seattle Cancer Care Alliance; Recruiting

Seattle, Washington, United States, 98109

Contact: Site Public Contact 800-804-8824

Principal Investigator: Evan Y. Yu

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Evan Y Yu; Cancer Immunotherapy Trials Network

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03513952 History of Changes
• Other Study ID Numbers: NCI-2018-00684; NCI-2018-00684 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CITN-14 ( Other Identifier: Cancer Immunotherapy Trials Network ); CITN-14 ( Other Identifier: CTEP ); P30CA015704 ( U.S. NIH Grant/Contract ); U01CA154967 ( U.S. NIH Grant/Contract )
• First Posted: May 2, 2018
• Last Update Posted: September 5, 2019
• Last Verified: April 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Urethral Neoplasms; Ureteral Neoplasms; Kidney Neoplasms; Pelvic Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urinary Bladder Diseases; Urologic Diseases; Urethral Diseases; Ureteral Diseases; Kidney Diseases; Atezolizumab; Antibodies, Monoclonal; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs