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Neoadjuvant NALIRIFOX in Combination with Ablative Dose Radiation Therapy and Capecitabine for the Treatment of Borderline Resectable or Locally Advanced Pancreatic Cancer
Trial Status: active
This phase II trial tests how well liposomal irinotecan, oxaliplatin, leucovorin, and fluorouracil (NALIRIFOX) chemotherapy in combination with ablative dose radiation therapy (AD-XRT) and capecitabine given before surgery (neoadjuvant) works in treating patients with pancreatic cancer that could potentially be removed by surgery (borderline resectable) or has spread to nearby tissue or lymph nodes (locally advanced). Patients with pancreatic cancer usually receive the standard chemotherapy regimen FOLFIRINOX, which includes the drugs leucovorin, fluorouracil, irinotecan, and oxaliplatin. The drugs work by damaging the deoxyribonucleic acid (DNA) in tumor cells, which can cause the cells to stop growing and die. NALIRIFOX is similar to FOLFIRINOX because it, too, includes the drugs leucovorin, fluorouracil, and oxaliplatin. However, NALIRIFOX includes liposomal irinotecan instead of irinotecan. Liposomal irinotecan may work better against pancreatic cancer because the drug has a protective shell, called a liposome, surrounding it. The liposome helps liposomal irinotecan stay in the body and continue to attack the cancer. One of the reasons pancreatic cancer is difficult to treat is because of a dense wall of tissue, known as the stroma, that makes it difficult for some anticancer drugs to reach the tumor. Liposomal irinotecan is designed to get through the dense stroma of the pancreatic tumor. AD-XRT is a type of high-dose radiation therapy treatment that delivers extremely precise, intense, and tumor-destroying doses of radiation to tumor cells. This helps target tumors while limiting the radiation to the surrounding organs. Capecitabine is a standard chemotherapy drug that interferes with the growth of tumor cells and slows their ability to spread throughout the body. Neoadjuvant NALIRIFOX in combination with AD-XRT and capecitabine may be a safe and effective way to increase the chance of undergoing surgery to remove the tumor and improve the quality of life in patients with borderline resectable or locally advanced pancreatic cancer.
Inclusion Criteria
Subject has been informed about the nature of the study, has agreed to participate in the study, and has signed the informed consent form before participation in any study-related activities
Individuals with a history of other malignancies are eligible if they have been disease-free for at least 2 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, ductal carcinoma in situ (DCIS), stage I prostate cancer, and basal cell or squamous cell carcinoma of the skin
A multidisciplinary discussion has been undertaken/planned which can include (a) discussion with medical/surgery oncology, (b) Hepatopancreaticobiliary Disease Management Team conference presentation, (c) direct consultation, with confirmation on consensus plan for TNT strategy and potential for future surgery. This plan needs to be documented in the medical record prior to initiation of treatment
Male or nonpregnant and nonlactating female aged >=18 years
* Women of child-bearing potential (i.e., fertile, following menarche, and until becoming postmenopausal unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) must test negative for pregnancy at the time of screening on the basis of a urine or serum pregnancy test. Postmenopausal women are defined as those who have had an absence of menstruation for at least 2 years. If necessary, follicle-stimulating hormone results > 50 IU/L at screening are confirmatory in the absence of a clear postmenopausal history
* Female subjects of reproductive potential must agree to use two effective methods of birth control during the study and for 9 months after the last dose of study medication
* Male subjects must agree to use condoms during the study and for 4 months after the last dose of study medication
Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC) that has not been previously treated
Radiographically borderline resectable (BR) or locally advanced (LA) PDAC in accordance with the National Comprehensive Cancer Network ( NCCN) 2.2021 definition, without evidence of distant metastases by CT
Inoperable status after surgical exploration due to presence of locally advanced, unresectable disease without metastases, in patients who have recovered from surgery, is allowed
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Absolute neutrophil count (ANC) >= 1500/mm^3 without the use of hemopoietic growth factors within 7 days before treatment
Platelet count >= 100,000/mm^3
International normalized ratio (INR) < 1.5 unless the patient is receiving anticoagulation therapy, in which case a therapeutic INR is acceptable. Anticoagulation therapy with low-molecular weight heparin or warfarin, whether medically indicated, is permitted
Serum/plasma creatinine level < 1.6 mg/dL
Exclusion Criteria
Presence of metastatic pancreatic cancer (M1 disease)
Any other medical or social condition deemed by the investigator to be likely to interfere with a subject’s ability to sign informed consent, cooperate, and participate in the study or who is likely to interfere with the interpretation of the results
Unwilling or unable to comply with study procedures and/or study visits
Medical co-morbidities, that preclude major abdominal surgery
Histologic diagnosis other than adenocarcinoma; however, adenosquamous variants are acceptable
Receipt of chemotherapy, prior abdominal radiotherapy, and/or definitive resection for pancreatic cancer
Grade > 2 neuropathy
Pregnant and/or nursing
Uncontrolled active infection, which would preclude with the exception of resolving cholangitis which in the investigator opinion would render the treatment hazardous
Known hypersensitivity to any of the components of the chemotherapeutic agents
Receipt of concurrent investigational therapy or within 30 days of protocol initiation
ADDITIONAL CRITERION FOR THE IMMUNOPET IMAGING SUB-STUDY: Previous anaphylactic reaction to human, humanized or chimeric antibody
ADDITIONAL CRITERION FOR THE IMMUNOPET IMAGING SUB-STUDY: Refusal or inability to tolerate the scanning procedure (e.g. due to claustrophobia)
Additional locations may be listed on ClinicalTrials.gov for NCT05851924.
I. To evaluate event-free survival (EFS), with events defined as: 1) progression (local or systemic progression, per Response Evaluation Criteria in Solid Tumors [RECIST]), 2) recurrence (recurrent disease following resection), or 3) death due to any cause.
SECONDARY OBJECTIVES:
I. To evaluate overall survival (OS) rate.
II. To evaluate time to locoregional recurrence (TLR) and time to distant metastases (TDM) and patterns of recurrence including local progression, distant progression, or both.
III. To evaluate the rate of surgical resection, as defined by the proportion of patients in whom pancreatctomy is performed (R0+R1).
IV. To evaluate R0 resection rates, defined as the proportion of patients in whom an R0 resection is achieved.
V. To evaluate the pathologic response rates.
VI. To determine the Ca 19-9 response, obtained at baseline and at each stage of treatment.
VII. To assess the adverse events (AEs) profile and safety using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and Patient Reported Outcomes-CTCAE (PRO-CTCAE).
VIII. To assess overall quality of life for patients, using the European Organization for Research and Treatment Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).
CORRELATIVE SCIENCE OBJECTIVES:
I. Computed tomography (CT) radiomic analysis to evaluate the value of CT imaging as a noninvasive biomarker for predicting tumor response to total neoadjuvant therapy (TNT) and survival outcomes.
II. Fluorodeoxyglucose-positron emission tomography (FDG-PET) functional imaging to evaluate the value as a noninvasive biomarker for predicting tumor response to TNT and survival outcomes.
III. Immuno-positron emission tomography (immunoPET) advanced imaging to evaluate use of novel imaging modalities as noninvasive biomarkers for predicting tumor response.
IV. Liquid biopsy analysis using Memorial Sloan Kettering Cancer Center (MSK)-Analysis of Circulating Cell-Free DNA (cfDNA) to Evaluate Somatic Status (MSK-ACCESS; cell-free DNA [cfDNA]) will be combined with serum Ca 19-9 analysis (see secondary objectives above) understand the relationship between tumor genomics and survival outcomes.
OUTLINE:
Patients receive liposomal irinotecan intravenously (IV) over 90 minutes, oxaliplatin IV over 2-6 hours, leucovorin IV over 10-20 minutes, and fluorouracil IV over 48 hours or until the infusion is complete on days 1 and 15 of each cycle. Treatment repeats every 4 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. In the absence of distant progression, patients undergo ablative dose radiation therapy (AD-XRT) over 20-40 minutes once daily (QD) for 15 or 25 fractions and concurrent capecitabine orally (PO) twice daily (BID) Monday-Friday over 3-5 weeks within 2-6 weeks of chemotherapy completion. Patients without evidence of metastatic disease undergo a staging laparoscopy or laparotomy and if deemed resectable, undergo pancreatectomy within 8 weeks after AD-XRT completion. Patients undergo a CT scan or magnetic resonance imaging (MRI) within 30 days of treatment, at 8 weeks of chemotherapy, after completion of chemotherapy/before AD-XRT, after completion of AD-XRT/before surgery, every 3 months for 1 year, every 4 months for 1 year, and every 6 months for 3-5 years after study treatment. Patients also undergo blood sample collection within 30 days of treatment, on day 1 of cycles 1-4, after completion of chemotherapy/before AD-XRT, after completion of AD-XRT/before surgery, every 3 months for 1 year, every 4 months for 1 year, and every 6 months for 3-5 years after study treatment. A sub-set of patients undergo an FDG-PET and/or receive zirconium Zr 89-labeled anti-CA19-9 monoclonal antibody 5B1 (89Zr-FO-HuMab-5B1) injection 4-7 days prior to undergoing immunoPET over 25-30 minutes within 30 days of treatment and at restaging for surgical respectability.
After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for year 2, every 6 months for years 3-5, and then annually thereafter.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
