Pembrolizumab in Treating Patients With Locally Advanced Bladder Cancer (AMBASSADOR)

• ClinicalTrials.gov Identifier: NCT03244384
• Recruitment Status: Recruiting
• First Posted: August 9, 2017
• Last Update Posted: October 23, 2019
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

This randomized phase III trial studies how well pembrolizumab works in treating patients with bladder cancer that has spread from where it started to nearby tissue or lymph nodes. Monoclonal antibodies recognizing and blocking checkpoint molecules can enhance the patient's immune response and therefore help fight cancer. Pembrolizumab is one of the monoclonal antibodies that block the PD-1 axis and can interfere with the ability of tumor cells to grow.

Condition or disease	Intervention/treatment	Phase
Stage II Bladder Urothelial Carcinoma AJCC v6 and v7; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7	Other: Clinical Observation; Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Other: Pharmacological Study; Other: Quality-of-Life Assessment; Other: Questionnaire Administration	Phase 3

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Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 739 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Randomized Adjuvant Study of MK-3475 (Pembrolizumab) in Muscle Invasive and Locally Advanced Urothelial Carcinoma (AMBASSADOR) Versus Observation
• Actual Study Start Date: September 21, 2017
• Estimated Primary Completion Date: June 1, 2025
• Estimated Study Completion Date: June 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Treatment (observation); Patients undergo observation.	Other: Clinical Observation; Undergo observation; Other Name: observation; Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies
Experimental: Treatment (pembrolizumab); Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; Lambrolizumab; MK-3475; SCH 900475; Other: Pharmacological Study; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Name: Quality of Life Assessment; Other: Questionnaire Administration; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. Overall survival [ Time Frame: From randomization to the date of death from any cause, assessed up to 5 years ]
   The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.
2. Disease-free survival [ Time Frame: From randomization to the first metastatic recurrence (presence of any recurrent disease), or death, whichever occurs first, assessed up to 5 years ]
   The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.

Secondary Outcome Measures :

1. Overall survival in PD-L1 positive and negative patients [ Time Frame: From randomization to the date of death from any cause, assessed up to 5 years ]
   The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.
2. Disease-free survival in PD-L1 positive and negative patients [ Time Frame: From randomization to the first metastatic recurrence (presence of any recurrent disease), or death, whichever occurs first, assessed up to 5 years ]
   The stratified proportional hazards model will be the primary analysis. The hazard ratio and its 95% confidence interval from the stratified Cox model with a single treatment covariate will be reported. The unstratified hazard ratio will also be presented.

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:

• PRE-REGISTRATION ELIGIBILITY CRITERIA
• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract; variant histology allowed as long as urothelial carcinoma is predominant (> 50%); pure small-cell carcinoma is excluded
• Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder tumor, upper tract resection, cystectomy/nephrectomy/ureterectomy, or nephroureterectomy must be available; this specimen submission is mandatory prior to registration as results will be used for stratification

• Patient must fit into one of the following three categories:

  • Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is >= pT2 and/or N+ OR
  • Patients who are not cisplatin-eligible (according to >= 1 of the following criteria: Eastern Cooperative Oncology Group [ECOG] performance status of 2, creatinine clearance < 60 mL/min, grade >= 2 hearing loss, grade >= 2 neuropathy, or New York Heart Association class III heart failure and pathologic stage at surgical resection is >= pT3 or pN+) OR
  • Patients that decline adjuvant cisplatin-based or other systemic chemotherapy based on an informed discussion with the physician and pathologic stage at surgical resection is >= pT3 or pN+
• Patient must have had radical surgical resection of their bladder cancer >= 4 weeks but =< 16 weeks prior to pre-registration
• No invasive cancer at the surgical margins
• No evidence of residual cancer or metastasis after surgery
• No metastatic disease on cross-sectional imaging (according to Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 criteria)
• No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease; human immunodeficiency virus (HIV) (+) patients are eligible as long as they have: cd4 > 200, undetectable viral load and on highly active antiretroviral therapy (HAART) therapy
• No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years
• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible
• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• No known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• No postoperative/adjuvant systemic therapy
• No prior treatment with any therapy on the PD-1/PD-L1 axis
• No treatment with any other type of investigational agent =< 4 weeks before pre-registration
• No major surgery =< 4 weeks before pre-registration
• No radiation therapy =< 4 weeks before pre-registration
• No neoadjuvant chemotherapy =< 4 weeks before pre-registration
• Not pregnant and not nursing
• ECOG performance status =< 2
• Absolute neutrophil count (ANC) >= 1,200/mm^3
• Leukocytes >= 3,000/ mm^3
• Platelet count >= 75,000/mm^3
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
• Creatinine =< 2.0 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance >= 30 mL/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN)
• Serum albumin >= 2.8 g/dL
• For women of childbearing potential only: a negative urine or serum pregnancy test done =< 7 days prior to pre-registration is required
• REGISTRATION ELIGIBILITY CRITERIA
• Results of central PD-L1 testing available; Q2 Solutions will forward the PD-L1 results to the statistical center and the statistical center will notify the site that the result is available; the notification from the Alliance registration/randomization office will serve as a confirmation of this eligibility criteria; after sites receive the confirmation e-mail from Alliance they can register the patient

Contacts and Locations

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Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Andrea B Apolo; Alliance for Clinical Trials in Oncology

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT03244384 History of Changes
• Other Study ID Numbers: NCI-2017-01425; NCI-2017-01425 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); A031501; A031501 ( Other Identifier: Alliance for Clinical Trials in Oncology ); A031501 ( Other Identifier: CTEP ); U10CA180821 ( U.S. NIH Grant/Contract )
• First Posted: August 9, 2017
• Last Update Posted: October 23, 2019
• Last Verified: June 2019

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

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Transitional Cell; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents