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Atezolizumab with or without PEGPH20 before and after Surgery for the Treatment of Stage I-II Resectable Pancreatic Cancer

Trial Status: Active

This phase II trial studies how well atezolizumab with or without PEGPH20 given before and after surgery works in treating patients with stage I-II pancreatic cancer that can be removed by surgery (resectable). 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. PEGPH20 may stop the growth of tumor cells by breaking down hyaluronan, a tissue component needed for cell growth. Giving atezolizumab with PEGPH20 before and after surgery may increase immune response compared to atezolizumab alone.

Inclusion Criteria

  • Cytologic or histologic proof of PDA needs to be verified by the treating institution pathologist either from the initial diagnostic biopsy, or from the required pre-treatment biopsy and prior to initiation of any study-related therapy
  • Stage 1 or 2 PDA and patient deemed a surgical candidate by the principal investigator (PI) in consultation with the designated site radiologist and surgeon at the treating institution
  • No prior surgical, systemic or radiotherapy for PDA
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without granulocyte colony-stimulating factor support (obtained within 14 days prior to initiation of study treatment)
  • White blood cell (WBC) count >= 2.5 x 10^9/L (2500/uL) (obtained within 14 days prior to initiation of study treatment)
  • Lymphocyte count >= 0.5 x 10^9/L (500/uL) (obtained within 14 days prior to initiation of study treatment)
  • Platelet count >= 100 x 10^9/L (100,000/uL) without transfusion within 4 weeks (obtained within 14 days prior to initiation of study treatment)
  • Hemoglobin (Hgb) > 9.0 g/dL without transfusion within 2 weeks (obtained within 14 days prior to initiation of study treatment)
  • Aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy (obtained within 14 days prior to initiation of study treatment). Prior to initiation of therapy, AST =< 2.5 x ULN
  • Alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy (obtained within 14 days prior to initiation of study treatment). Prior to initiation of therapy, ALT =< 2.5 x ULN
  • Alkaline phosphatase (ALP) =< 2.5 x upper limit of normal (ULN) unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy (obtained within 14 days prior to initiation of study treatment). Prior to initiation of therapy, ALP =< 2.5 x ULN
  • Serum total bilirubin =< 1.5 x ULN unless in patients with known Gilbert disease (=< 3 x ULN) or unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to administration of investigational therapy (obtained within 14 days prior to initiation of study treatment). A functioning biliary stent as evidenced by declining total bilirubin and =< 2 x ULN is required prior to initiation of therapy
  • Albumin >= 3.0 g/dL (obtained within 14 days prior to initiation of study treatment)
  • Creatinine within ULN or calculated creatinine clearance (CrCl) > 50 mL/min using the Cockcroft-Gault formula (obtained within 14 days prior to initiation of study treatment)
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained within 14 days prior to initiation of study treatment)
  • Tumor accessible for fresh biopsy
  • Women of child-bearing potential must have a negative serum pregnancy test at screening and must agree to use two forms of effective contraception from the time of the negative pregnancy test and for a minimum of 5 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive (injectable or implantable) in conjunction with a barrier method, or a double barrier method. Women will be considered not of child-bearing potential if amenorrheic at least for one year or have undergone surgical sterilization
  • Fertile men must agree to use an effective method of birth control during the study and for up to 5 months after the last dose of study drug
  • Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements
  • Able to comply with the study protocol, in the investigator’s judgment
  • CRITERIA TO INITIATE CHEMOTHERAPY: Full recovery from surgery and subject able to receive chemotherapy
  • CRITERIA TO INITIATE CHEMOTHERAPY: Subjects who have evidence of recurrent disease prior to initiation of chemotherapy will need to undergo biopsy to prove disease recurrence if deemed safe
  • CRITERIA TO INITIATE CHEMOTHERAPY: ANC >= 1.5 x 10^9/L without granulocyte colony-stimulating factor support
  • CRITERIA TO INITIATE CHEMOTHERAPY: Platelet count >= 100 x 10^9 /L (100,000/uL) without transfusion within 4 weeks
  • CRITERIA TO INITIATE CHEMOTHERAPY: Hemoglobin (Hgb) > 9.0 g/dL
  • CRITERIA TO INITIATE CHEMOTHERAPY: AST =< 2.5 x upper limit of normal (ULN)
  • CRITERIA TO INITIATE CHEMOTHERAPY: ALT =< 2.5 x upper limit of normal (ULN)
  • CRITERIA TO INITIATE CHEMOTHERAPY: Alkaline phosphatase (ALP) =< 2.5 x upper limit of normal (ULN)
  • CRITERIA TO INITIATE CHEMOTHERAPY: Albumin >= 3.0 g/dL
  • CRITERIA TO INITIATE CHEMOTHERAPY: Creatinine within ULN or calculated creatinine clearance (CrCl) > 50 mL/min using the Cockcroft-Gault formula

Exclusion Criteria

  • Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including but not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
  • Patients who are receiving any other investigational agents concurrently
  • Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable)
  • Uncontrolled pleural effusion, pericardial effusion, or ascites
  • Patient receiving therapeutic doses of anticoagulation
  • Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12mg/dL, or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy
  • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study * Patients with controlled type 1 diabetes mellitus who are on a stable insulin regimen are eligible for the study * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
  • History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or 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
  • Patients without a prior positive human immunodeficiency virus (HIV) test result will undergo an HIV test at screening, unless not permitted per local regulations
  • Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening * Note: Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody test at screening, are eligible for the study
  • Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test
  • Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty liver disease, and inherited liver disease
  • Known active tuberculosis
  • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. However, patients who were admitted for biliary tract infection due to bile duct obstruction at time of diagnosis must have a functioning biliary stent (as evidenced by declining total bilirubin and =< 2 x ULN) and resolved infection (defined by normalization of elevated white blood cell count, absence of signs of infection) and completion of an antibiotic course (at least a seven-day course) prior to initiation of therapy
  • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment except for biliary tract infection due to bile duct obstruction from the pancreas mass. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
  • Significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 12 months prior to initiation of study treatment, seizure disorder, uncontrolled hypertension, or unstable arrhythmia or unstable angina within 3 months prior to initiation of study treatment
  • Grade >= 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment
  • Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation
  • History of malignancy other than PDA within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year overall survival of > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer. Patients with history of prior malignancies should have risk of recurrence within 3 years after screening to be less than 90% (to be discussed with the PI for final determination of eligibility)
  • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment with atezolizumab or within 5 months after the last dose of atezolizumab
  • History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
  • Known allergy or hypersensitivity to any of the study drugs or any of their excipients
  • Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment
  • Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions: * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study if receiving equivalent to less than 10 mg of prednisone daily * Patients who received a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after approval from the PI has been obtained
  • Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
  • Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these agents and breastfeeding should be discontinued
  • Major surgical procedure or significant traumatic injury within 14 days of initiating study
  • Previous radiotherapy to 25% or more of the bone marrow
  • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications in the opinion of the treating investigator
  • Considered ineligible to receive full standard dose modified fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX) therapy in the adjuvant setting
  • Peripheral neuropathy > grade 1
  • History of allergy or hypersensitivity to oxaliplatin, irinotecan, leucovorin, fluorouracil, pegfilgrastim, or any excipients
  • History of Gilbert’s disease or known genotype UGT1A1*28/*28.6.2.35
  • Inflammatory disease of the colon or rectum, or severe uncontrolled diarrhea
  • PEGPH20-CONTAINING ARM:
  • Risk of thromboembolic events which are defined as: * History of transient ischemic attack requiring intervention or treatment, carotid artery disease requiring interventions or treatment, of cerebrovascular accident * Evidence of deep vein thrombosis (DVT), pulmonary embolism, or other thromboembolic event at screening, except - ** Superficial vein thrombosis ** Visceral or splanchnic vein thrombosis if the thrombosis is at a location near the site of underlying PDAC which may contribute to the etiology of the thrombus * Treatment with megestrol acetate within 14 days prior to initiation of study treatment
  • Unable to use low-molecular-weight heparin

New York

New York
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Gulam Abbas Manji
Phone: 212-305-0592

PRIMARY OBJECTIVE:

I. To compare the number of CD8+ T cells within the tumor after neoadjuvant atezolizumab alone or in combination with pegylated recombinant human hyaluronidase PH20 (PEGPH20) or other therapies at time of surgery.

SECONDARY OBJECTIVES:

I. To estimate the 18-month survival rate and overall survival in patients treated with atezolizumab versus (vs) atezolizumab + PEGPH20 or other therapies followed by surgery and adjuvant therapy.

II. To determine the R0 resection rates with atezolizumab vs atezolizumab + PEGPH20 or other therapies administered in the neoadjuvant setting.

III. To determine the safety profile with atezolizumab vs atezolizumab + PEGPH20 or other therapies followed by surgery and adjuvant therapy.

IV. To evaluate Ca 19-9 biomarker responses to atezolizumab with or without PEGPH20 or other therapies in the neoadjuvant setting.

V. To evaluate patterns of failure following neoadjuvant atezolizumab with or without PEGPH20 or other therapies and surgery.

VI. Intratumoral CD8+ T cells after neoadjuvant atezolizumab alone or combination with PEGPH20 or other therapies at time of surgery will be compared to intratumoral CD8+ T cells within resected tumors after no neoadjuvant therapy from matched historical controls.

EXPLORATORY OBJECTIVES:

I. To isolate the epithelium and stromal tumor for protein expression profiling using ribonucleic acid sequencing (RNA-seq) for subtype classification of pancreatic ductal adenocarcinoma (PDA).

II. To quantitate the change in CD8+ T cells within paired pre-treatment biopsy and on-treatment resected tumor treated with atezolizumab vs atezolizumab + PEGPH20 or other therapies.

III. To quantitate distinct immune subtypes within on-treatment resected tumor treated with atezolizumab vs atezolizumab + PEGPH20 or other therapies by quantitative multiplex immunofluorescence.

IV. To quantitate the change in immune subtypes within paired pre-treatment biopsy and on-treatment resected tumor treated with atezolizumab vs atezolizumab + PEGPH20 or other therapies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days 4 and 18. Patients then undergo surgical resection. Beginning 4-6 weeks after-surgery, patients receive atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive PEGPH20 IV over 10-12 minutes on days 1 and 4 and atezolizumab IV over 30-60 minutes on days 4 and 18. Treatment with PEGPH20 repeats weekly for 3 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo surgical resection. Beginning 4-6 weeks after-surgery, patients receive PEGPH20 IV over 10-12 minutes on days 1, 8, and 15 and atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 2 cycles and in the absence of disease progression or unacceptable toxicity.

All patients receive standard of care chemotherapy consisting of oxaliplatin IV over 2 hours, leucovorin IV over 2 hours, irinotecan IV over 90 minutes, and fluorouracil via continuous IV infusion over 46 hours on day 1 and pegfilgrastim subcutaneously (SC) on day 3. Treatment repeats every 14 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months during years 1-3, then every 6 months during years 4 and 5.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center

Principal Investigator
Gulam Abbas Manji

  • Primary ID AAAS1908
  • Secondary IDs NCI-2020-02915
  • Clinicaltrials.gov ID NCT03979066