SBRT Plus Pembrolizumab and Trametinib for Pancreatic Cancer

Study Overview
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Brief Summary
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Hypothesis: Survival benefits could be found in SBRT Plus Pembrolizumab and Trametinib compared with SBRT plus gemcitabine.

Detailed Description
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Background and aim: Pancreatic cancer is one of the most lethal malignancies and fourth leading cause of cancer death in both genders in US, where the mortality and incidence increase over the past decade with a lowest 5-year survival rate of 9% among all cancers. Although surgical resection is deemed to provide long-term disease control, only 20% patients were candidates for upfront surgery and unfortunately, even when adjuvant chemotherapy is prescribed, about 50% of patients will suffer local recurrence. Despite of emergence of immunotherapy as a new treatment paradigm, little improvement of outcomes has been found in pancreatic cancer. This may be ascribed to its inherent genetic mutations and immunosuppressive microenvironment. It has been demonstrated that radiotherapy could enhance the release and uptake of tumor-associated antigens, thus promoting antitumor T cell priming, and enhancing access to tumors due to effects both on the tumor vasculature and the chemokine milieu. Despite of emergence of immune checkpoint inhibitors as a novel treatment paradigm for cancers, the results of investigations about the efficacy of immunotherapy alone for pancreatic cancer was disappointing. Due to enhanced immunogenicity of tumor irradiation, the underlying rationale of combination of radiotherapy and immunotherapy is that radiation can noninvasively prime the immune system against tumor cells, where antigen presentation and co-stimulation are facilitated, thus creating immune responses against previously hidden epitopes that are shared among distant metastases, while immune checkpoint inhibitors can reverse the immunosuppressive effects of the tumor microenvironment, thus facilitating antitumor immunity. Although oncogenic mutations in KRAS are frequent in pancreatic cancer, KRAS proteins are difficult to be targeted due to high affinity for GTP and/or GDP. Therefore, efforts have been made to develop therapies targeting the major downstream effector pathways, which include the RAS-RAF-MEK-ERK and PI3K-PDPK1-AKT signaling pathways. MEK inhibitor trametinib alone or in combinations with chemotherapy or autophagy inhibitor hydroxychloroquine may probably have positive effects on tumor regression. Regarding local recurrence after surgery, it was recommended that chemotherapy with optional radiotherapy may be the first-line treatment without addition of targeted therapy or immunotherapy owing to that no studies have investigated the efficacy of this regimen. Therefore, the aim of our study was to compare the outcomes between stereotactic body radiation therapy (SBRT) with pembrolizumab and trametinib and SBRT with gemcitabine for locally recurrent pancreatic cancer after surgical resection. Study procedure: All surgical specimens underwent immunohistochemical staining of PD-L1, classified as TC3 ≥ 50% or TC2 ≥ 5% but < 50% or TC1 ≥ 1% but <5% and IC3 ≥ 10% or IC2 ≥ 5% but < 10% or IC1 ≥ 1% but <5%. KRAS mutations were analyzed by PCR amplification and direct sequencing of exon 2. Restriction Length Fragment Polymorphism method was used for further confirmation. In the SBRT plus pembrolizumab and trametinib group, 200mg pembrolizumab was administered intravenously every 3 weeks and 2mg trametinib was given orally once daily. In the SBRT plus gemcitabine group, patients received intravenous gemcitabine (1000mg/m2) on day 1 and 8 of each 21-day cycle for eight cycles in the absence of disease progression. The prescribed dose of SBRT varies from 35-40Gy/5f with a single dose of 7-8Gy.

Official Title
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Stereotactic Body Radiation Therapy Plus Pembrolizumab and Trametinib vs. Stereotactic Body Radiation Therapy Plus Gemcitabine for Locally Recurrent Pancreatic Cancer After Surgical Resection: an Open-label, Randomized, Controlled, Phase 2 Trial

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Device: Cyberknife plus Pembrolizumab and Trametinib
* Device: Cyberknife plus Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed pancreatic ductal adenocarcinoma with unequivocal first progression after surgery followed by chemotherapy Without any immunotherapy or targeted therapy A life expectancy of >3months ECOG of 0 to1 Age of 18 years or older Analysis of surgical specimens showed KRAS mutations and positive immunohistochemical staining of PD-L1 Blood routine examination: Absolute neutrophil count (ANC) ≥ 1.5 ×109 cells/L, leukocyte count≥ 3.5 ×109 cells/L, platelets ≥ 70×109 cells/L, hemoglobin ≥ 8.0 g/dl Liver and kidney function tests: Albumin > 2.5 g/dL, total bilirubin < 3 mg/dL, creatinine < 2.0 mg/dL, AST<2.5 × ULN(Upper Limit of Normal)(0-64U/L), ALT<2.5 × ULN(0-64U/L) INR < 2 (0.9-1.1) Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Prior immunotherapy or targeted therapy Evidences of metastatic disease confirmed by chest CT or FDG PET-CT Contraindication to receiving immunotherapy, targeted therapy or SBRT ECOG ≥2 Age <18 years Analysis of surgical specimens showed KRAS wild type or negative immunohistochemical staining of PD-L1 Secondary malignancy Abnormal results of blood routine examinations and liver and kidney and coagulation tests Patients with active inflammatory bowel diseases or peptic ulcer Gastrointestinal bleeding or perforation within 6 months Heart failure: NYHA III-IV Respiratory insufficiency Women who are pregnant Participation in another clinical treatment trial while on study Patients in whom fiducial implantation was not possible Inability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT plus Pembrolizumab and Trametinib<br>Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. | Device: Cyberknife plus Pembrolizumab and Trametinib<br>* Radiation therapy plus drug<br>|
| Active Comparator: SBRT plus Gemcitabine<br>Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine. | Device: Cyberknife plus Gemcitabine<br>* Radiation therapy plus drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Median Survival Time Will be Determined. | The time from the start of treatment to death | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One- and Two-year Overall Survival Rate Will be Determined. | The number of patients alive at 1 year and 2 years. | 2 year | 
| Treatment-related Adverse Effects Will be Determined. | Treatment-related adverse effects are determined by National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. | 3 years | 
| The Median Progression Free Survival Time Will be Determined. | The time from the start of treatment until documentation of any clinical or radiological disease progression or death, whichever occurred first. Progression is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 3 years | 
| One- and Two-year Progression Survival Rate Will be Determined. Will be Determined. | The proportion of patients without disease progressions at 1 year and 2 years. | 2 years | 
| The Quality of Life Will be Analyzed. | The analysis of quality of life is based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30). All scales and subscales range from 0 to 100. Regarding physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning and global health, higher scores may indicate better outcomes. In the case of fatigue, nausea and vomitting, pain, dyspnea, insomina, appetite loss, constipation, diarrhea and financial difficulties, lower scores may indicate better outcomes. Scales of all items are independent and not combined to compute a total score. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stereotactic body radiation therapy, CyberKnife, Initial treatment