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Nivolumab, Ipilimumab and Chemoradiation in Treating Patients With Locally Advanced Pancreatic Cancer. (LAPTOP)

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ClinicalTrials.gov Identifier: NCT04247165
Recruitment Status : Recruiting
First Posted : January 29, 2020
Last Update Posted : June 18, 2020
Sponsor:
Information provided by (Responsible Party):
Inna Chen, MD, Herlev Hospital

Brief Summary:

Pancreatic ductal adenocarcinoma (PDAC) remains a dreadful disease due to its often advanced stage at diagnosis and poor sensitivity to chemotherapy. A locally unresectable tumor (locally advanced pancreatic cancer (LAPC)) is present in 30% of the cases and is defined as a surgically unresectable tumor encasing the adjacent arteries [celiac axis, superior mesenteric artery (SMA)]. In these patients, chemotherapy has been the standard treatment for decades, optionally combined with radiotherapy. The results of small randomized trials comparing chemoradiotherapy with chemotherapy of patients with LAPC are divergent. Considering the emerging role of the tumor microenvironment (TME), the combination of checkpoint blocking antibodies with agents that target the inhibitory effects of the TME could lead to better responses in tumor historically resistant to checkpoint blocking antibody approaches. Furthermore, the addition of standard-of-care chemotherapy could further potentiate the anti-tumor effects of immunotherapy approaches by reducing the tumor burden, exposing antigens, and directly affecting the immunosuppressive TME compartment.

To explore the safety and synergy of the proposed combinatorial approach, participants with locally advanced PC will receive nivolumab and ipilimumab administered in combination with gemcitabine and nab-paclitaxel followed by immune-chemoradiation.


Condition or disease Intervention/treatment Phase
Locally Advanced Pancreatic Cancer (LAPC) Drug: Gemcitabine Drug: Nab-paclitaxel Drug: Nivolumab Drug: Ipilimumab Radiation: SBRT Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: LAPTOP: Phase 1/2 Study in Locally Advanced Pancreatic Cancer to Assess Safety and Potential Efficacy of Dual Checkpoint Inhibition in Combination With Gemcitabine and Nab-paclitaxel Followed by Immune-chemoradiation.
Actual Study Start Date : June 2, 2020
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental

Nivolumab 3 mg/kg will be given on day 1 (± 2 days) of each 28-day treatment cycle until the progression of disease, discontinuation due to toxicity, withdrawal of consent. Ipilimumab 1 mg/kg will be given once only on day 1 cycle 1. Nivolumab will be administered as an IV infusion over 30 (± 5) minutes and then, after a 30 minutes rest period, ipilimumab will be administered as an IV infusion over 30 (± 5) minutes. Pre-medication for chemotherapy (based on standard-of-care and local institutional standards) and chemotherapy will then be administered after a further 30 minutes rest period.

The recommended dose of nab-paclitaxel is 100 mg/m2 administered as an IV infusion over 30 to 40 minutes on Days 1, 8, and 15 of each 28-day cycle. Gemcitabine 800 mg/m2 will be administered over 30 to 40 minutes immediately after nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.

Drug: Gemcitabine
800 mg/m2 Day 1, 8, 15: Q4W IV Infusion

Drug: Nab-paclitaxel
100 mg/m2 Day 1, 8, 15: Q4W IV Infusion
Other Name: Abraxane®

Drug: Nivolumab
3 mg/kg Day 1, Q4W IV Infusion
Other Name: Opdivo®

Drug: Ipilimumab
1 mg/kg Day 1 Cycle 1 IV Infusion
Other Name: Yervoy®

Radiation: SBRT

Patients will be planned and treated with SBRT on a MRidian MR guided Linac.

Prescription dose shall be according to the following specifications:

  • Prescription dose shall be according to the following specifications:
  • A total dose of 24 Gy in 3 fractions (3 fractions/week) are prescribed as the mean dose to the PTV.
  • Pauses are accepted but the treatment should be delivered within 10 calendar days.
  • PTV should be covered by 95% isodose (PTV D99% >95%).




Primary Outcome Measures :
  1. Incidence of treatment-related AEs, SAEs, AEs leading to discontinuation, death, and laboratory abnormalities [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Median PFS using RECIST v1.1 [ Time Frame: 12 months ]
  2. Median OS [ Time Frame: 24 months ]
  3. Objective Response Rate (ORR) by RECIST v1.1 [ Time Frame: 12 months ]
  4. Rate of downstaging to surgical resection [ Time Frame: 12 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Signed informed consent

    • Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
    • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
  • Histological or cytological confirmation of locally advanced pancreatic carcinoma prior to entering this study
  • No prior chemotherapy regimens received for PC
  • Age 18 years or older
  • Life expectancy greater than 6 months
  • ECOG/WHO Performance Status (PS) 0-1
  • All participants will be required to undergo mandatory pre- and on-treatment biopsies at acceptable clinical risk as judged by the investigator. An archival pre-treatment sample is acceptable
  • Patients must have normal organ and marrow function as defined below:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
    • Platelet count ≥ 100 x 10⁹/L
    • Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with Gilbert's Syndrome must have a total bilirubin ≤ 50 mmol/L)
    • AST/ALT ≤ 5 x ULN
    • Serum creatinine ≤ 1.5 x ULN or CrCl ≥ 40 mL/min (using the Cockcroft-Gault formula)
  • Women of child bearing potential (WOCBP) must use method(s) of contraception as indicated in Appendix 3. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (Appendix 3). The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half-life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half-lives. The half-life of nivolumab is up to 25 days. Men who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
  • Subjects must have signed and dated a BIOPAC approved written informed consent form in accordance with regulatory and institutional guidelines

Exclusion Criteria:

  • Metastatic disease
  • Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
  • Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
  • Participants with active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
  • Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
  • Allergies and adverse drug reaction

    • History of allergy to study drug components
    • History of severe hypersensitivity reaction to any monoclonal antibody
  • WOCBP who are pregnant or breastfeeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04247165


Contacts
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Contact: Inna M Chen, MD +45 38682898 inna.chen@regionh.dk

Locations
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Denmark
Herlev & Gentofte University Hospital, Denmark Recruiting
Herlev, Denmark, 2730
Contact: Inna Chen, MD    +45 38682898    Inna.Chen@regionh.dk   
Contact: Dorte Nielsen, MD DMSc    +45 38682344    Dorte.Nielsen.01@regionh.dk   
Sponsors and Collaborators
Herlev Hospital
Investigators
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Principal Investigator: Inna M Chen, MD Herlev and Gentofte Hospital
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Responsible Party: Inna Chen, MD, Principal investigator, Herlev Hospital
ClinicalTrials.gov Identifier: NCT04247165    
Other Study ID Numbers: GI 1931
First Posted: January 29, 2020    Key Record Dates
Last Update Posted: June 18, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Inna Chen, MD, Herlev Hospital:
pancreatic cancer
locally advanced pancreatic cancer
LAPC
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Gemcitabine
Paclitaxel
Nivolumab
Ipilimumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological