SBRT Plus Pembrolizumab and Trametinib for Pancreatic Cancer

Phase 2

Completed

Conditions: Pancreatic Cancer

Interventions: Device: Cyberknife plus Gemcitabine
Device: Cyberknife plus Pembrolizumab and Trametinib

Registration Number: NCT02704156

Lead Sponsor: Changhai Hospital

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

Detailed Description: 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:

1. 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%.

2. KRAS mutations were analyzed by PCR amplification and direct sequencing of exon 2. Restriction Length Fragment Polymorphism method was used for further confirmation.

3. In the SBRT plus pembrolizumab and trametinib group, 200mg pembrolizumab was administered intravenously every 3 weeks and 2mg trametinib was given orally once daily.

4. 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.

5. The prescribed dose of SBRT varies from 35-40Gy/5f with a single dose of 7-8Gy.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 170

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SBRT plus Gemcitabine	Cyberknife plus Gemcitabine	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine.
SBRT plus Pembrolizumab and Trametinib	Cyberknife plus Pembrolizumab and Trametinib	Patients with locally recurrent pancreatic cancer were randomly allocated to SBRT plus Pembrolizumab and Trametinib or SBRT plus Gemcitabine.

Primary Outcome Measures

Name	Time	Method
The Median Survival Time Will be Determined.	3 years	The time from the start of treatment to death

Secondary Outcome Measures

Name	Time	Method
One- and Two-year Overall Survival Rate Will be Determined.	2 year	The number of patients alive at 1 year and 2 years.
Treatment-related Adverse Effects Will be Determined.	3 years	Treatment-related adverse effects are determined by National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.
The Quality of Life Will be Analyzed.	3 years	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.
The Median Progression Free Survival Time Will be Determined.	3 years	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.
One- and Two-year Progression Survival Rate Will be Determined. Will be Determined.	2 years	The proportion of patients without disease progressions at 1 year and 2 years.