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A Vaccine (Personalized Cancer Vaccine RO7198457), Atezolizumab, and Combination Chemotherapy for the Treatment of Resectable Stage I-III Pancreatic Cancer

Trial Status: Active

This phase I trial studies how well a personalized cancer vaccine RO7198457 works in combination with atezolizumab and fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin in treating patients with stage I-III pancreatic cancer that has been removed by surgery (resected). The personalized cancer vaccine RO7198457 is a vaccine that is customized according to changes (mutations) in a patient's tumor cells so that it can be recognized by the immune system and target the tumor. 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. Drugs used in chemotherapy, such as fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving personalized cancer vaccine RO7198457, atezolizumab, fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin may work better compared to chemotherapy alone in treating patients with pancreatic cancer.

Inclusion Criteria

  • Able to comply with the study protocol, in the investigator’s judgment
  • Subjects with radiographically resectable primary pancreatic tumors with radiographic features consistent with adenocarcinoma will be evaluated for surgical resection
  • Tumors must be radiographically resectable, defined as: * A clear fat plane around the celiac and superior mesenteric arteries * Patent superior mesenteric and portal veins without primary tumor involvement * No encasement of the superior mesenteric vein or portal veins * No encasement of the superior mesenteric or hepatic arteries * No metastatic disease * No extra-regional nodal disease
  • Subjects with histologically confirmed resected ductal pancreatic adenocarcinoma with macroscopic complete resection (R0 and R1) will be selected for neoantigen vaccine creation. Subjects with neuroendocrine (and mixed type) tumors are excluded
  • Pancreatic cancer surgical staging: T 1-3, N0-2, M0 * Per American Joint Committee on Cancer (AJCC) 8th edition staging
  • Performance status of 0 or 1 on Eastern Cooperative Oncology Group (ECOG) scale of performance status
  • Subjects must not have had prior chemotherapy, radiation therapy, or immunotherapy for pancreatic ductal adenocarcinoma (PDAC)
  • Subjects must be able to read, understand, and sign informed consent
  • Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to study initiation
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures that result in a failure rate of less than (<) 1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab and for at least 90 days after the last dose of RO7198457. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus)
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom during the entire study period and up to 90 days after last administration of RO7198457. Male participants should not donate sperm for 90 days after the last dose of RO7198457
  • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
  • Hormonal contraceptive methods must be supplemented by a barrier method plus spermicide
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception

Exclusion Criteria

  • Prior neoadjuvant treatment or radiation therapy for PDAC
  • Prior therapy with alpha PD-L1 antibody or any other immune therapy
  • Borderline resectable, locally unresectable or metastatic PDAC
  • Pancreas tumor histology other than PDAC
  • Pregnancy, breastfeeding, or intending to become pregnant during the study or within 90 days after the last dose of study treatment
  • Life expectancy less than 12 weeks
  • Inability to comply with study and/or follow-up procedures
  • Any other malignancy within 5 years of study enrollment, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, or non-melanomatous skin cancer
  • Patients with unresolved Clavien-Dindo >= grade 3 postoperative complications
  • Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment
  • Active tuberculosis
  • Known infection with hepatitis B or C, or history of human immunodeficiency virus (HIV) infection, or subjects receiving immunosuppressive or myelosuppressive medications that would, in the opinion of the investigator, increase the risk of serious neutropenic complications
  • Known hypersensitivity or allergy to the active substance or to any of the excipients in RO7198457, atezolizumab, oxaliplatin, leucovorin, irinotecan, or fluorouracil
  • Serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the subject's safety or the study data integrity. These include, but are not limited to: * History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa) * History of interstitial lung disease, slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or multiple allergies * History of the following within 6 months prior to RO7198457 administration: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia, or electrocardiogram (ECG) abnormality (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), cerebrovascular accident, transient ischemic attack, or seizure disorder
  • History 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, vasculitis, or glomerulonephritis with the following caveats: * 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 type 2 diabetes mellitus may be eligible * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) may be eligible provided that they meet the following conditions: ** Rash must cover less than 10% of the body surface area (BSA) ** Disease is well controlled at baseline and only requires low potency topical steroids ** No acute exacerbations of underlying condition within the last 12 months (e.g., not requiring psoralen and ultraviolet A [PUVA] radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency, or oral steroids)
  • Treatment with systemic immunosuppressive medications (including but not limited to prednisone > 10 mg/day, cyclophosphamide, azathioprine, methotrexate, thalidomide, and TNF-alpha antagonists) within 2 weeks prior to RO7198457 administration. 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 principal investigator (PI) and co-PI. The use of inhaled corticosteroids (e.g., fluticasone for chronic obstructive pulmonary disease) is allowed. The use of oral mineralocorticoids (e.g., fludrocortisone for patients with orthostatic hypotension) is allowed. Physiologic doses of corticosteroids for adrenal insufficiency are allowed
  • Subjects with allergies to IV contrast agents requiring pretreatment with corticosteroids will be excluded. Corticosteroids are immunosuppressive and may interfere with RO7198457 tolerability and efficacy. Given that there are serial contrast agent-dependent follow-up imaging studies built into the study which will overlap with vaccination, subjects who require pretreatment with corticosteroids prior to IV contrast administration will be excluded
  • 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
  • Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T-negative severe combined immunodeficiency [SCID]) or combined T- and B-cell immunodeficiencies (e.g., T- and B-negative SCID, Wiskott-Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency)
  • Prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease or current alcohol abuse
  • Previous splenectomy
  • Administration of a live, attenuated vaccine within 4 weeks before RO7198457 administration or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to RO7198457 administration or at any time during the study, and for 90 days following the last study treatment

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Vinod P. Balachandran
Phone: 212-639-5785
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Vinod P. Balachandran
Phone: 212-639-5785
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Vinod P. Balachandran
Phone: 212-639-5785

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Vinod P. Balachandran
Phone: 212-639-5785
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Vinod P. Balachandran
Phone: 212-639-5785
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Vinod P. Balachandran
Phone: 212-639-5785
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Vinod P. Balachandran
Phone: 212-639-5785

PRIMARY OBJECTIVE:

I. To determine the safety of sequential administration of atezolizumab and personalized cancer vaccine RO7198457 (RO7198457) (an ribonucleic acid [RNA]-based individualized neoantigen specific therapy, iNeST), followed by standard of care modified fluorouracil, irinotecan hydrochloride (irinotecan), leucovorin calcium (leucovorin) and oxaliplatin (mFOLFIRINOX).

SECONDARY OBJECTIVES:

I. To assess 18-month recurrence-free survival (RFS).

II. To assess 18-month overall survival (OS).

EXPLORATORY SCIENTIFIC CORRELATIVE OBJECTIVES:

I. To assess induction of vaccine-specific immune responses.

II. To evaluate cancer antigen (CA) 19-9 biomarker changes over time.

IIa. To identify the most immunogenic neoantigens for clinical vaccination.

IIb. To evaluate patterns of failure/disease recurrence.

III. To evaluate cell free deoxyribonucleic acid (DNA) (cfDNA) at specified time points during patient's treatment and follow up.

IIIa. To track KRAS for recurrence.

OUTLINE:

Patients undergo standard of care surgical resection of their pancreatic tumor. Approximately 6 weeks post-surgery, patients receive atezolizumab intravenously (IV) over 60 minutes. Approximately 9 weeks post-surgery, patients receive RO7198457 IV push once weekly (QW) for 7 doses, followed by an 8th dose 2 weeks later, and a final dose 46 weeks post-surgery. Approximately 21 weeks post-surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 30-90 minutes on day 1, and fluorouracil via continuous IV infusion over 46 hours on days 1-2. Treatment repeats every 14 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 weeks following completion of chemotherapy with mFOLFIRINOX, every 3 months after surgical resection for 2 years, every 6 months for 3 years, then annually thereafter.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Vinod P. Balachandran

  • Primary ID 19-039
  • Secondary IDs NCI-2019-08153
  • Clinicaltrials.gov ID NCT04161755