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Radiation Therapy in Combination with Durvalumab for the Treatment of Locally Advanced Pancreatic Cancer

Trial Status: Active

This phase I / II trial studies the effect of durvalumab and stereotactic ablative body radiotherapy in treating patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced). Durvalumab is a PD-L1 inhibitor. It attaches to a protein, programmed death-ligand 1 (PD-L1), which is found on tumor cells and some immune cells. PD-L1 acts as a shield that prevents cancer cells from being attacked by the immune system. When durvalumab attaches to PD-L1, it can break up the protective shield and help the immune system recognize and kill cancer cells. Stereotactic ablative body radiotherapy is a standard radiation treatment (radiotherapy) that uses high-energy x-rays to target tumors while limiting the radiation to the surrounding organs. Stereotactic ablative body radiotherapy may boost the immune system’s ability to fight cancer. Giving durvalumab and stereotactic ablative body radiotherapy may help destroy the tumor cells in patients with pancreatic cancer.

Inclusion Criteria

  • Patients with histopathologic or cytologic diagnosis of adenocarcinoma of the pancreas (PDAC), or suspicious for malignancy per pathology, which is deemed BR or LAPC per National Comprehensive Cancer Network (NCCN) guidelines or following evaluation by a multidisciplinary group of physicians
  • Patients must have received fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) for 3-6 months prior to enrollment with at least stable disease by restaging imaging * Note: Standard of care (SOC) treatment regimen derived from FOLFIRINOX dose modifications are acceptable. ** To maximize potential efficacy no more than a 6-week treatment break is recommended between the completion of SOC chemotherapy (FOLFIRINOX) and initiation of study treatment (durvalumab)
  • Body weight > 30 kg
  • Eastern Cooperative Oncology Group (ECOG) 0-2
  • Absolute neutrophil count (ANC) >= 1.0 K/mcL
  • Platelets >= 75 K/mcL
  • Hemoglobin 9 g/dL
  • Total bilirubin =< 1.5 X upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
  • Creatinine OR creatinine clearance =< 1.5 times the upper limit of normal OR >= 40 mL/min for patients with creatinine levels above normal
  • Note: Patients with biliary stent are eligible provided that all other inclusion criteria are met
  • Negative pregnancy test in women of childbearing potential (WOCBP) within 30 days of durvalumab administration or evidence of post-menopausal status. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Non-sterilized male participants who are sexually active with a female partner of childbearing potential must be willing to use a highly effective method of contraception from day 1 through 90 days after receipt of the final dose of investigational product(s). Not engaging in sexual activity for the total duration of the study and the drug washout period is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male participants must be willing to refrain from sperm donation throughout these periods
  • Ability to understand and the willingness to sign an informed consent document
  • Willingness and ability to comply with the protocol including study treatment, scheduled assessments and follow-up

Exclusion Criteria

  • History of another primary malignancy except for: * Malignancy treated with curative intent with no known active disease for 2 years before the first dose of study drug and low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
  • Patients who have had prior anti-cancer treatment or are currently receiving anti-cancer treatment for their disease other than chemotherapy as stipulated by protocol
  • Women who are breastfeeding
  • Any clinically significant, unresolved toxicity > Common Terminology Criteria for Adverse Events (CTCAE) grade 2 from previous anti-cancer therapy with the exception of alopecia, vitiligo and laboratory values defined in the inclusion criteria
  • Patients with grade >= 2 neuropathy will be included at the investigator’s discretion
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included at the investigator’s discretion
  • Patients who are currently receiving any other investigational agents for therapeutic treatment of their primary cancer
  • Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or other immunotherapy
  • Known metastatic disease
  • Major surgical procedures based on clinical judgement of the investigator within 30 days prior to the first dose of study drug. Patients may undergo staging laparoscopy, percutaneous transhepatic cholangiogram (PTC) placement, endoscopic retrograde cholangiopancreatography (ERCP), etc. at any time which should not interfere with study treatment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, interstitial lung disease, pneumonitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Patients who are receiving radiation treatment outside of the enrolling centers
  • Patients with frank transmural macroscopic invasion of duodenum by tumor as determined by treating investigator
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis, Crohn’s disease], diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel syndrome, or other serious gastrointestinal chronic conditions associated with diarrhea); systemic lupus erythematosus; Wegener syndrome (granulomatosis with polyangiitis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: Patients with vitiligo or alopecia. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement, or psoriasis not requiring systemic treatment
  • Current or prior use of immunosuppressive medication within 28 days before treatment, except with chemotherapy
  • History of organ transplant that requires use of immunosuppressive agents
  • History of active primary immunodeficiency
  • Receipt of live attenuated vaccination within 30 days prior to receiving durvalumab
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings and tuberculosis (TB) testing in line with local practices), active bleeding diatheses, hepatitis B (known positive hepatitis B virus [HBV] surface antigen result), hepatitis C, or human immunodeficiency virus (positive human immunodeficiency virus [HIV] 1/2 antibodies)
  • Patient with known active hepatitis (i.e. hepatitis B or C) * Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg and polymerase chain reaction [PCR] negative) are eligible * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
  • Patients with macroscopic invasion of the bowel or stomach submucosa by primary pancreatic tumor as determined by principal investigator (PI)

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Eileen M. O'Reilly
Phone: 646-888-4182
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Eileen M. O'Reilly
Phone: 646-888-4182
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Eileen M. O'Reilly
Phone: 646-888-4182

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Eileen M. O'Reilly
Phone: 646-888-4182
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Eileen M. O'Reilly
Phone: 646-888-4182
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Eileen M. O'Reilly
Phone: 646-888-4182
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Eileen M. O'Reilly
Phone: 646-888-4182

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of durvalumab in combination with stereotactic ablative body radiotherapy (SABR) in patients with locally advanced (LA) or borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC). (Phase 1)

II. Measure clinical activity of durvalumab with SABR in patients with LA or BR PDAC by assessing 6 month progression free survival using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. (Phase 2)

SECONDARY OBJECTIVE:

I. Measure clinical activity of durvalumab with SABR in patients with LA or BR PDAC by assessing: rates of down staging to resectability, objective response rates using RECIST v1.1, duration of response, CA 19-9 response, and overall survival. (Phase 2)

EXPLORATORY OBJECTIVES:

I. Evaluate pre/post-treatment tumor tissue, blood and stool for pathologic/deoxyribonucleic acid (DNA) damage repair/immunologic markers of response/resistance, including:

Ia. Cytokine analysis from serum examining inflammatory cytokines: GMCSF, IFNgamma, IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, IL-18, TGFbeta, p70, fractaline, FGF2, G-CSF, IFNalpha2, IL12p70, IL1a, IL1RA, IL13 and others. HLA class I alleles.

Ib. Immune cell profiling by flow cytometry from biopsies and blood: CD4+ T cells, CD8+ T cells, regulatory T cells, B cells, natural killer (NK) cells, gamma-delta T Cells, macrophages/macrophage subsets (MDSC, iMC) and dendritic cells with activation markers including MHCII, CD25, CD62L, CD69, CD80.

Ic. Quantitative immunohistochemistry on biopsy samples: PD-L1, cleaved caspase 3, Ki-67, CD31.

Id. Pre/post treatment stool studies for microbiome analysis.

Ie. DNA and ribonucleic acid (RNA) sequencing.

OUTLINE:

Patients receive durvalumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for 4 doses, then every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Beginning day 8, patients also undergo SABR over 45 minutes every other day for 5 treatments in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 4 months during year 3, and then annually thereafter.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Eileen M. O'Reilly

  • Primary ID 20-228
  • Secondary IDs NCI-2020-07146
  • Clinicaltrials.gov ID NCT03245541