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Tremelimumab in Treating Patients with Previously Treated Metastatic Urothelial Cancer

Trial Status: Active

This phase II trial studies how well tremelimumab works in treating patients with previously treated urothelial cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as tremelimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Inclusion Criteria

  • Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior to registration
  • Histologically or cytologically documented urothelial cancer. Locally advanced (T4b, any N; or any T, N 2−3) or metastatic disease (M1, stage IV) (also termed transitional cell carcinoma [TCC] or urothelial cell carcinoma [UCC] of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra). 
Subjects with mixed histologies are eligible provided that the predominant component is urothelial cancer. Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2−N3)
  • Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks preferred) or at least 15 unstained slides. If archival tissue is not available and the subject is undergoing a standard of care biopsy, tissue from the biopsy is required to be submitted for correlative analyses. Subjects without adequate baseline tumor tissue may be considered for enrollment on a case by case basis after discussion with the sponsor-investigator
  • Measurable disease according to RECIST 1.1 within 28 days prior to registration. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as >= 10 mm in the longest diameter (except lymph nodes, which must have short axis >= 15 mm) with computed tomography (CT) (preferred) or magnetic resonance imaging (MRI) scans, preferably with IV contrast, and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines; lesions in a previously irradiated field can be used as a measurable disease provided that there has been demonstrated progression in the lesion
  • A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for >= 2 weeks, and are asymptomatic
  • Subjects must have progressed despite prior treatment with anti-PD-1/PD-L1 antibody therapy. In addition, subjects must meet the following criteria: * Subjects must not have progressed within 2 months of starting prior anti-PD-1/PD-L1 antibody therapy * Subjects must have received at least 1 line of prior systemic therapy * Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy * All adverse events (AEs) while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study with the exception of endocrine related AEs that are stable on replacement therapy (e.g., steroids, thyroid hormone) which may be considered eligible but must be discussed with the sponsor-investigator * Must not have experienced a >= grade 3 immune related AE or an immune related neurologic (neuro-muscular) or ocular AE of any grade while receiving prior immunotherapy. NOTE: Subjects with endocrine AE of =< grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day * Patients with grade (Gr) 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation < 8 fold that resolved with steroids without additional immunosuppression can be included (patients who experienced Hy’s law on PD-1/L1 therapy will be excluded)
  • Prior cancer treatment must be completed at least 28 days or 5 half-lives (whichever is shorter) prior to first dose of study drug. Subjects must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to =< grade 1 or baseline
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained within 14 days prior to registration)
  • Hemoglobin (Hgb) >= 9 g/dL (obtained within 14 days prior to registration)
  • Calculated creatinine clearance >= 30 cc/min or creatinine =< 1.5 (obtained within 14 days prior to registration) * Cockcroft-Gault formula will be used to calculate creatinine clearance or 24 urine collection for creatinine can be utilized
  • Bilirubin =< 1.5 x upper limit of normal (ULN) (obtained within 14 days prior to registration) * This will not apply to subjects with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or hepatic pathology), who may be considered for enrollment after discussion with the sponsor investigator
  • Aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with hepatic metastases) (obtained within 14 days prior to registration)
  • Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN for subjects with hepatic metastases) (obtained within 14 days prior to registration)
  • Evidence of postmenopausal status or negative urinary or serum pregnancy test for female premenopausal subjects. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) * Women >= 50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses > 1 year ago, had chemotherapy-induced menopause with > 1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy)
  • Females of childbearing potential who are sexually active with a non-sterilized male partner must be willing to abstain from heterosexual activity or to use 1 highly of effective method of contraception from the time of informed consent until 90 days after the last dose of tremelimumab. Non-sterilized male partners of a female patient must use male condom plus spermicide throughout this period
  • Non-sterilized males who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 90 days after receipt of the final dose of tremelimumab. Female partners (of childbearing potential) of male subjects must also use a highly effective method of contraception throughout this period
  • Must have life expectancy of >= 12 weeks

Exclusion Criteria

  • Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
  • Known additional malignancy that is active and/or progressive requiring treatment. Patients with incidental histologic findings of prostate cancer (tumor/node/metastasis stage of T1a or T1b or prostate-specific antigen < 10) who have not received hormonal treatment may be included, pending a discussion with the sponsor-investigator
  • Treatment with any investigational drug within 28 days prior to registration
  • Prior treatment with an anti-CTLA-4 antibody, including tremelimumab
  • Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and laboratory values defined in the inclusion criteria * Subjects with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the sponsor investigator * Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with tremelimumab (e.g., hearing loss) may be included after consultation with the sponsor-investigator
  • Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replacement therapy) is acceptable. Note: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable (e.g., local surgery or radiotherapy)
  • Radiation therapy within 14 days of first dose of study drug
  • Major surgical procedure within 28 days prior to first dose of study treatment
  • History of allogeneic organ transplantation that requires use of immunosuppressive agents
  • Active or prior documented autoimmune of inflammatory disorders (including but not limited to inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome [granulomatosis with polyangiitis], Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion: * Subjects with vitiligo * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Subjects without active disease in the last 5 years may be considered for enrollment after discussion with the sponsor-investigator * Subjects with celiac disease controlled by diet alone may be considered for enrollment after discussion with the sponsor-investigator
  • QT interval corrected for heart rate using Fridericia’s formula (QTcF) >= 470 ms calculated. Any clinically significant abnormalities detected require triplicate electrocardiogram (ECG) results and a mean QTcF < 470 ms calculated from 3 ECGs obtained over a brief period (eg, 30 minutes)
  • Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
  • History of active primary immunodeficiency
  • Active infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B, hepatitis C, or human immunodeficiency virus (HIV, positive HIV 1 or 2 antibodies). Active hepatitis B virus (HBV) infection is defined by a positive HBV surface antigen (HBsAg) result. Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core IgG antibody and the absence of HBsAg, deoxyribonucleic acid [DNA] negative) are eligible. Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of tremelimumab. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. NOTE: Subjects, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of tremelimumab
  • Known allergy or hypersensitivity to tremelimumab or any investigation product excipient, or to other humanized monoclonal antibodies (mAbs)
  • Weight =< 35 kg

District of Columbia

MedStar Georgetown University Hospital
Status: ACTIVE
Contact: Suthee Rapisuwon


Emory University Hospital / Winship Cancer Institute
Status: ACTIVE
Contact: Mehmet Asim Bilen


Kansas City
University of Kansas Cancer Center
Status: ACTIVE
Contact: Rahul A. Parikh


Massachusetts General Hospital Cancer Center
Status: ACTIVE
Contact: Xin Gao

New York

New York
Icahn School of Medicine at Mount Sinai
Status: ACTIVE
Contact: Matthew David Galsky
Phone: 212-659-5452

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Tracy L. Rose
Phone: 919-216-0681


Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: ACTIVE
Contact: Benjamin L. Maughan
Phone: 801-585-0255


I. Estimate the objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] 1.11) with tremelimumab in subjects with metastatic urothelial cancer previously treated with PD-1/PD-L1 blockade.


I. Describe the safety of the study treatment.

II. Describe the disease control rate (objective response + stable disease).

III. Describe the duration of response.

IV. Describe the progression-free survival.

V. Describe the overall survival.


I. Explore the relationship between PD-L1 expression and response to treatment.

II. Explore the relationship between gene expression signatures and response to treatment.

III. Explore the relationship between genomic alterations including mutational load and response to treatment.

IV. Explore the impact of treatment on the peripheral blood immune cells and other circulating biomarkers.

V. Explore the relationship between the microbiome and adverse events and outcomes with treatment.


Patients receive tremelimumab intravenously (IV) over 1 hour on day 1. Treatment repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Patients who progress within a year after tremelimumab completion, may be able to receive an additional 7 courses.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Icahn School of Medicine at Mount Sinai

Principal Investigator
Matthew David Galsky

  • Primary ID 18-1027
  • Secondary IDs NCI-2018-02260, HCRN GU17-294
  • ID NCT03557918