Atezolizumab Plus Personalized Neoantigen Vaccination in Patients with Urothelial Cancer: a Phase 1 Trial

This is a phase 1 single center clinical trial evaluating a multi-peptide personalized neoantigen vaccine, PGV001, in combination with atezolizumab for patients with urothelial cancer. Patients were enrolled in either the adjuvant or metastatic setting. Those in the adjuvant setting included patients considered high risk of recurrence (pathological stage ypT2-T4 or ypN+ for those treated with prior neoadjuvant chemotherapy or pT3-T4 or pN+ for those not treated with prior neoadjuvant chemotherapy). Those in the metastatic setting included patients progressing after prior chemotherapy or those with at least stable disease after chemotherapy treated as “switch maintenance” therapy. The primary endpoint was feasibility (including the number of neoantigens identified per patient, vaccine production time, the proportion of patients consenting to the vaccine development phase for whom a vaccine product was prepared, and the proportion of patients eligible for the treatment phase who completed the priming cycle 1 of PGV001 plus atezolizumab) and safety. Secondary endpoints included the objective response rate, progression-free survival or disease-free survival, overall survival, and immunomodulatory effects of treatment. Urothelial tumor tissue and normal tissue or peripheral blood specimens were utilized for DNA sequencing. HLA typing was performed utilizing genomic DNA isolated from whole blood, and RNA sequencing was performed utilizing tumor tissue specimens. Neoantigen prediction and final selection for incorporation into the vaccine was determined by the OpenVax computational pipeline. 12 patients were initially enrolled into the vaccine development phase and 10 patients initiated the treatment phase. PGV001 was administered with poly-ICLC and tetanus peptide on subsequent days for up to 10 doses, including an initial priming cycle 1. Atezolizumab was administered every 3 weeks for up to 1 year in the adjuvant setting or 2 years in the metastatic setting. The vaccine was feasible and safe, the median vaccine production time was 20.3 weeks, and 100% of patients that initiated the treatment phase completed the priming cycle. The most common treatment-related adverse events were local grade 1 injection site reactions, fever, and fatigue. Three of the 4 patients in the adjuvant setting remained disease-free at median follow-up of 39.5 months. There was a 40% objective response rate among patients with measurable disease in the metastatic setting. The single patient treated as “switch maintenance” therapy remained with no evidence of disease at 39.4 month follow-up. All patients demonstrated on-treatment neoantigen-specific T cell reactivity, as measured by ELISPOT and flow cytometry assays. Overall, PGV001 plus atezolizumab was feasible, safe, and warrants further investigation. Whole exome sequencing from tumor tissue and normal tissue or whole blood specimens and RNA sequencing from tumor tissue specimens will be available through dbGaP. ]]>
Eligibility Criteria for Tissue Acquisition, Whole Exome Sequencing, and Vaccine Preparation Inclusion Criteria: Written informed consent and HIPAA authorization for release of personal health information. Age ≥ 18 years at the time of consent. ECOG Performance Status of ≤ 1 within fourteen days of registration for protocol therapy. Histological or cytological evidence of urothelial cancer of the bladder, urethra, ureter, or renal pelvis. Differentiation with variant histologies (e.g., squamous cell differentiated) or pure variant histologies will be permitted. Clinical disease state specific criteria: Subjects with invasive urothelial cancer of the bladder, urethra, 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. Required laboratory values must be obtained within thirty days of consent: ANC ≥ 1500 cells/μL WBC counts > 2500/μL Lymphocyte count ≥ 300/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 8.0 g/dL Total bilirubin ≤ 1.5 × upper limit of normal (ULN) with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled. AST and ALT ≤ 3.0 × ULN with the following exception: Patients with liver involvement: AST and/or ALT ≤ 5 × ULN Alkaline phosphatase ≤ 2.5 × ULN with the following exception: Patients with documented liver involvement or bone metastases: alkaline phosphatase ≤ 5 × ULN Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: [(140 − age) × (weight in kg)] / [72 × (serum creatinine in mg/dL)] × (0.85 if female) INR and 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. Exclusion Criteria: Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease Symptomatic 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 Pregnancy, lactation, or breastfeeding Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies 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, Sjögren's syndrome, Bell's palsy, Guillain-Barré 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) 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. 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. Active tuberculosis A known additional primary malignancy that is progressing or requires active treatment. Exceptions include cancers that have undergone potentially curative therapy. 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 (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 Eligibility Criteria for Atezolizumab plus PGV001 “Treatment Phase” Inclusion Criteria: Available vaccine product. Written informed consent and HIPAA authorization for release of personal health information. Age ≥ 18 years at the time of consent. ECOG Performance Status of ≤ 1 within fourteen days of registration for protocol therapy. 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 who decline and/or are 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 dB at two contiguous frequencies Grade 2 or greater peripheral neuropathy Solitary kidney Subjects who have received adjuvant chemotherapy and ≥ 21 days from last dose of chemotherapy 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. Willing to comply with contraception guidelines (outlined in Section 5.8) Required laboratory values must be obtained within thirty days of consent: ANC ≥ 1500 cells/μL WBC counts > 2500/μL Lymphocyte count ≥ 300/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 8.0 g/dL Total bilirubin ≤ 1.5 × upper limit of normal (ULN) with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled. AST and ALT ≤ 3.0 × ULN with the following exception: Patients with liver involvement: AST and/or ALT ≤ 5 × ULN Alkaline phosphatase ≤ 2.5 × ULN with the following exception: Patients with documented liver involvement or bone metastases: alkaline phosphatase ≤ 5 × ULN Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: [(140 − age) × (weight in kg)] / [72 × (serum creatinine in mg/dL)] × (0.85 if female) INR and 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. Exclusion Criteria: Any approved systemic anticancer therapy (including chemotherapy and 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 AEs from prior anticancer therapy that have not resolved to Grade ≤ 1 except for alopecia Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease Symptomatic CNS metastases. Patients with asymptomatic untreated CNS disease may be enrolled, provided all 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 Pregnancy, lactation, or breastfeeding Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies Inability to comply with study and follow-up procedures 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, Sjögren's syndrome, Bell's palsy, Guillain-Barré 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) 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 o History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 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 drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications 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. 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 Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 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. 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 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 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. A known additional primary malignancy that is progressing or requires active treatment. Exceptions include cancers that have undergone potentially curative therapy. 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]-α 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 halflives 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 ]]>