Atezolizumab and PGV001 in Treating Patients with Locally Advanced or Metastatic Urothelial Cancer

Status: Active

Description

This phase I trial studies the side effects and how well atezolizumab and PGV001 work in treating patients with urothelial cancer that has spread to nearby tissues or lymph nodes or 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. PGV001 is a type of vaccine that is created based on analyzing an individual's tumor tissue. Giving atezolizumab and PGV001 may work better in treating patients with urothelial cancer.

Eligibility Criteria

Inclusion Criteria

  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Eastern Cooperative Oncology Group (ECOG) Performance Status of =< 1 within fourteen days of registration for protocol therapy
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Histological or cytological evidence of urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell differentiated) will be permitted
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Clinical disease state specific criteria: * Subjects with invasive urothelial cancer of the bladder or upper urinary tract may consent either before or after transurethral resection of tumor, radical cystectomy or nephroureterectomy. * Subjects with metastatic and/or unresectable disease must have a metastatic site amenable to biopsy. In situations where a metastatic biopsy does not yield sufficient genetic material for sequencing, or a biopsy cannot be feasibly performed, the use of archival tumor tissue may be considered on a case by case basis. The archival tissue must be derived from a muscle-invasive urothelial cancer specimen or metastatic urothelial cancer specimen
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Absolute neutrophil count (ANC) >= 1500 cells/uL (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: White blood cell (WBC) counts > 2500/uL (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Lymphocyte count >= 300/uL (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Platelet count >= 100,000/uL (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Hemoglobin >= 8.0 g/dL (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception: * Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN with the following exception: * Patients with liver involvement: AST and/or ALT =< 5 x ULN (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Alkaline phosphatase =< 2.5 x ULN with the following exception: * Patients with documented liver involvement or bone metastases: alkaline phosphatase =< 5 x ULN (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Serum creatinine =< 1.5 x ULN or creatinine clearance >= 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (within thirty days of consent)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: 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 (within 30 days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Available vaccine product
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Written informed consent and HIPAA authorization for release of personal health information
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": ECOG Performance Status of =< 1 within fourteen days of registration for protocol therapy
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Clinical disease state specific criteria: * Adjuvant setting: ** >= 28 days from the time of radical cystectomy or nephroureterectomy ** For subjects treated with prior neoadjuvant chemotherapy: tumor stage of ypT2−T4 or ypN+ ** For subjects who have not received prior neoadjuvant chemotherapy: tumor stage of pT3−T4 or pN+ ** Subjects who have not received neoadjuvant chemotherapy must decline or be ineligible for adjuvant chemotherapy; cisplatin ineligibility is defined by any one of the following criteria: *** Impaired renal function (glomerular filtration rate [GFR] >= 30 but < 60 mL/min); GFR should be assessed by direct measurement (i.e., creatinine clearance) or by calculation from serum/plasma creatinine (Cockcroft-Gault formula) *** A hearing loss (measured by audiometry) of 25 decibels (dB) at two contiguous frequencies *** Grade 2 or greater peripheral neuropathy *** Solitary kidney * Metastatic and/or unresectable disease ** At least stable disease after at least 4 cycles of chemotherapy OR disease progression despite prior chemotherapy OR as first-line treatment for metastatic disease for patients initially consenting for treatment in the adjuvant setting but with metastatic recurrence prior to vaccine availability ** There is no limit on the number of prior chemotherapy regimens
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Willing to comply with contraception guidelines
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": ANC >= 1500 cells/uL (within thirty days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": WBC counts > 2500/uL (within thirty days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Lymphocyte count >= 300/uL (within thirty days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Platelet count >= 100,000/uL (within thirty days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Hemoglobin >= 8.0 g/dL (within thirty days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception: * Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled (within 30 days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": AST and ALT =< 3.0 x ULN with the following exception: * Patients with liver involvement: AST and/or ALT =< 5 x ULN (within 30 days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Alkaline phosphatase =< 2.5 x ULN with the following exception: * Patients with documented liver involvement or bone metastases: alkaline phosphatase =< 5 x ULN (within 30 days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Serum creatinine =< 1.5 x ULN or creatinine clearance >= 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (within 30 days of consent)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": INR and 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 (within 30 days of consent)

Exclusion Criteria

  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Symptomatic central nervous system (CNS) metastases and/or metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm) and/or history of intracranial hemorrhage or spinal cord hemorrhage
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Pregnancy, lactation, or breastfeeding
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: 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%, flucinolone 0.01%, desonide 0.05%, aclometasone 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)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic or acute) or hepatitis C infection * 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 (PCR) is negative for HCV ribonucleic acid (RNA)
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Active tuberculosis
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: A known additional primary malignancy that is progressing or requires active treatment. Exceptions include cancers that have undergone potentially curative therapy
  • TISSUE ACQUISITION, WHOLE EXOME SEQUENCING, AND VACCINE PREPARATION: Medication-Related Exclusion Criteria: * Prior treatment with anti−PD-1, or anti−PD-L1 therapeutic antibody or pathway-targeting agents * No history of severe immune-related adverse effects from anti−CTLA-4 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Grade 3 and 4) * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Any approved anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are allowed: * Hormone-replacement therapy or oral contraceptives * Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to cycle 1, day 1) * Palliative radiotherapy for bone metastases > 2 weeks prior to cycle 1, day 1
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": AEs from prior anticancer therapy that have not resolved to Grade =< 1 except for alopecia
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Symptomatic CNS metastases * 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 prior to cycle 1, day 1 * Subjects 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 prior to cycle 1, day 1 ** Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Pregnancy, lactation, or breastfeeding
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Inability to comply with study and follow-up procedures
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": 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%, flucinolone 0.01%, desonide 0.05%, aclometasone 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)
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection * 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 (PCR) is negative for HCV RNA
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Active tuberculosis
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": 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
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Received oral or IV antibiotics within 2 weeks prior to cycle 1, day 1 * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Major surgical procedure within 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": 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
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to cycle 1, day 1 or at any time during the study
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": A known additional primary malignancy that is progressing or requires active treatment. Exceptions include cancers that have undergone potentially curative therapy
  • ATEZOLIZUMAB PLUS PGV001 "TREATMENT PHASE": Medication-Related Exclusion Criteria: * 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 (NCI CTCAE Grade 3 and 4) * Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]-alpha or interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1 * Treatment with investigational agent within 4 weeks prior to cycle 1, day 1 (or within five half-lives of the investigational product, whichever is longer) * 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 prior to cycle 1, day 1 ** 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 * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation

Locations & Contacts

New York

New York
Icahn School of Medicine at Mount Sinai
Status: Active
Contact: Matthew David Galsky
Phone: 212-824-8583
Email: matthew.galsky@mssm.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the feasibility and safety of administration of a personalized genomic vaccine 001 (personalized neoantigen-based vaccine [PGV001]) plus atezolizumab in subjects with locally advanced or metastatic urothelial cancer.

SECONDARY OBJECTIVES:

I. To determine the success rate, and feasibility, of peptide manufacturing for vaccination.

II. To determine the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with measurable disease.

III. To determine the duration of response and progression-free survival by RECIST 1.1 and immune-related RECIST criteria in patients with metastatic disease or time-to-progression in adjuvant patients.

IV. To determine the overall survival of subjects treated with the combination therapy.

V. To determine the qualitative and quantitative changes in the population of vaccine-induced, neoantigen-specific T lymphocytes in the peripheral circulation and/or tumor microenvironment.

VI. To characterize vaccine-induced quantitative and qualitative changes in immune cells in the peripheral circulation and/or tumor microenvironment.

VII. To profile circulating anti-tumor associated antigen immunoglobulins found in the peripheral blood of subjects after vaccination relative to baseline values determined prior to the start of vaccination.

VIII. To correlate changes in the tumor microenvironment with neoantigens and clinical outcomes.

OUTLINE:

Patients then receive PGV001 intracuteanously on days 1, 4, 8, 15, and 22 of cycle 1 and on day 1 of cycles 2-5 and 9 and poly-ICLC intracuteanously on days 2, 5, 9, 16, and 23 of cycle 1 and on day 2 of cycles 2-5 and 9. Patients also receive atezolizumab intravenously (IV) over 30-60 minutes on day 8 of cycle 1 and on day 1 of subsequent cycles. Treatment repeats every 21-28 days for up to 12 months in the adjuvant setting and up to 24 months in the metastatic setting.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Icahn School of Medicine at Mount Sinai

Principal Investigator
Matthew David Galsky

Trial IDs

Primary ID 16-1387
Secondary IDs NCI-2018-03596
Clinicaltrials.gov ID NCT03359239