Atezolizumab in Treating Patients with Non-metastatic Bladder Cancer

Status: Active

Description

This phase II trial studies the best dose of atezolizumab and how well it works in treating patients with bladder cancer that has not spread to other places in the body. 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.

Eligibility Criteria

Inclusion Criteria

  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1
  • Histologically document transitional cell carcinoma with the presence of any of the following stages: carcinoma in situ (CIS), high­grade Ta, any grade T1, or any grade cT2­T4, considered appropriate for radical cystectomy; subjects with mixed histology are required to have a dominant transitional cell carcinoma (TCC) pattern
  • For subjects with NMIBC, BCG-refractory or BCG-resistant disease; BCG-refractory disease is defined as the absence of a complete response by 6 months in patients who have received induction and maintenance OR two induction courses of BCG; BCG-resistant disease is defined as persistent or recurrent disease after 2 induction courses of BCG within 1 year OR cancer recurrence within 1 year of initiation of therapy for patients who have received induction plus maintenance BCG therapy; subjects with NMIBC must be suitable for and willing to undergo a radical cystectomy at the completion of study therapy
  • For subjects with muscle invasive disease: not suitable neoadjuvant cisplatin­based chemotherapy as determined by the following: * Creatinine clearance less than 60 ml/min; glomerular filtration rate (GFR) should be assessed by calculation from serum/plasma creatinine (Cockcroft-Gault formula) * Common Terminology Criteria for Adverse Events (CTCAE) grade (gr) >= 2 hearing loss * CTCAE gr >= 2 neuropathy
  • Subjects with MIBC not meeting the above criteria are still eligible provided the patient declines neoadjuvant cisplatin-based chemotherapy, after specific informed consent describing the known benefits of cisplatin-based chemotherapy
  • White blood cell count (WBC) > 2500 cells/mm^3
  • Absolute neutrophil count (ANC) > 1500 cells/mm^3
  • Hemoglobin > 9 g/dL; patients may be transfused or receive erythropoietic treatment to meet this criterion
  • Platelet count > 100,000 cells/mm^3
  • Serum creatinine < 2 mg/dL OR calculated creatinine clearance (CrCl) > 30 ml/min
  • Serum bilirubin < 1.5 x upper limit of normal (ULN) (except for patients with documented Gilbert’s disease)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN
  • Ability to understand and willingness to sign a written informed consent
  • Have available evaluable archival tumor tissue for PD-L1 biomarker assessment; presence of PD-L1 antigen on tumors is NOT required for study entry
  • The effects of MPDL3280A on the developing human fetus are unknown; for this reason women of child­bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation; 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; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 6 months after completion of study drug administration

Exclusion Criteria

  • Subjects with primary TCC of the ureter, urethra, or renal pelvis without TCC of the bladder are not allowed
  • Known distant metastatic disease (e.g. pulmonary or hepatic metastases) * Subjects with malignant lymphadenopathy in the abdomen or pelvis considered appropriate for radical cystectomy and lymphadnectomy with the goal of complete resection of all malignant disease are allowed
  • Intravesical chemo- or biologic therapy within 6 weeks of first treatment
  • Prior systemic chemotherapy or radiation therapy for transitional cell carcinoma of the bladder * Subjects who have received prior intravesical chemotherapy are allowed
  • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti CTLA-4, anti-PD1 and anti-PD-L1 therapeutic antibodies
  • History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegner’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, vacuities, or glomerulonephritis * Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study * Patients with controlled type I diabetes mellitus on a stable dose of insulin regimen are eligible for this study
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), druginduced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • Chronic liver disease
  • Human immunodeficiency virus (HIV) or active hepatitis B virus (HBV; chronic or acute; defined as having a positive hepatitis B surface antigen [Bag] test at screening) or active hepatitis C * Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of hepatitis B surface antigen [HBsAg]) are eligible; HBV deoxyribonucleic acid (DNA) must be obtained in these patients prior to cycle 1, day 1, but detection of HBV DNA in these patients will not exclude study participation * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
  • Active tuberculosis
  • Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Prior allogeneic stem cell or solid organ transplant
  • Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or anticipation that such a live attenuated vaccine will be required during the study; inactivated vaccines (such as hepatitis A or polio vaccines) are permitted during the study * Influenza vaccination should be given during influenza season only (approximately October to March); patients must no receive live attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to cycle 1, day 1 and for at least 12 weeks after the last dose
  • Clinically significant active infection or uncontrolled medical condition
  • Uncontrolled cystitis, significant bladder pain or spasms, or gross hematuria that in the opinion of the treating investigator, should preclude study entry
  • Significant cardiovascular disease, such as New York Heart Association cardiac disease (class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina * Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
  • Major surgical procedure other than for diagnosis within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure other than cystectomy during the course of the study
  • Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1, or anticipated requirement for systemic immunosuppressive medications during the trial * Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the study chair * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed
  • Pregnant or nursing women are excluded
  • Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the MPDL3280A formulation
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Malignancies other than urothelial cancer (UC) within 5 years prior to cycle 1, day 1, with the exception of those with a low risk of metastasis or death treated with expected curative outcome (such as, but not limited to, adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated with curative intent and absence of PSA relapse, or ductal carcinoma in situ of the breast treated surgically with curative intent) or incidental prostate cancer (T1a, Gleason score =< 6 and PSA < 0.5 ng/mL)

Locations & Contacts

California

San Francisco
UCSF Medical Center-Mission Bay
Status: Active
Contact: Lawrence Fong
Phone: 415-885-7871
Email: lfong@medicine.ucsf.edu
UCSF Medical Center-Mount Zion
Status: Active
Contact: Lawrence Fong
Phone: 415-885-7871
Email: lfong@medicine.ucsf.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the intratumoral immune response associated with increasing numbers of atezolizumab (MPDL3280A) treatments. (Multi-dose cohorts)

II. To assess the anti­tumor activity of MPDL3280A as determined by the pathologic T0 rate (pT0) at the time of cystectomy. (Expansion cohorts)

SECONDARY OBJECTIVES:

I. To evaluate the safety and feasibility of administering up to 3 cycles of MPDL3280A pre­operatively to patients with resectable urothelial bladder cancer. (Multi-dose cohorts)

II. To assess the anti­tumor activity of MPDL3280A as determined by the pathologic T0 rate (pT0) at the time of cystectomy in patients with PD-L1 immunohistochemistry (IHC) 2/3. (Expansion cohorts)

III. To determine the 2-year relapse-free survival (RFS) rate and median RFS in intention-to-treat (ITT) and in patients with PD-L1 IHC 2/3. (Expansion cohorts)

IV. To determine the near complete pathologic response rate (pTa or pTis) at the time of cystectomy in patients with T2 or greater disease at baseline in ITT and in patients with PD-L1 IHC 2/3. (Expansion cohorts)

V. To determine the association of PD-L1/PD-1 expression on bladder tissues and on T cells with clinical response. (Expansion cohorts)

VI. To assess the association between prior Bacillus Calmette-Guerin (BCG) treatment, PD-L1 expression, and correlation with intratumoral immune response. (Expansion cohorts)

VII. To evaluate the safety of MPDL3280A when administered to patients with non-muscle invasive bladder cancer (NMIBC) or MIBC. (Expansion cohorts)

EXPLORAORY OBJECTIVES:

I. To assess intratumoral T cell receptor diversity associated with increasing numbers of MPDL3280A treatments. (Multi-dose cohorts)

II. To assess the treatment-induced effects on circulating immune cells with differing numbers of MPDL3280A treatments. (Multi-dose cohorts)

III. To define the immunologic infiltration within bladder tissue following administration of neoadjuvant MPDL3280A when compared to pre­treatment biopsies, assessing the quantitative change in immune cell subsets and localization. (Expansion cohorts)

IV. To assess for tumor-based biomarkers of response and resistance. (Expansion cohorts)

V. To define the treatment-induced effects on circulating immune cells. (Expansion cohorts)

VI. To assess the presence of antigen-specific immune responses to a broad panel of candidate tumor antigens. (Expansion cohorts)

VII. To explore remodeling of the circulating T cell repertoire associated with adjuvant administration of MPDL3280A. (Expansion cohorts)

OUTLINE: This is a dose-escalation study.

Patients receive atezolizumab intravenously (IV) on day 1. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for up every 4 weeks for 12 weeks and then every 12 weeks for up to 2 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
UCSF Medical Center-Mount Zion

Principal Investigator
Lawrence Fong

Trial IDs

Primary ID 14524
Secondary IDs NCI-2017-01387, 14-15423
Clinicaltrials.gov ID NCT02451423