SBRT Plus Pembrolizumab and Trametinib for Pancreatic Cancer

February 28, 2022 updated by: Zhang Huo Jun, Changhai Hospital

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

170

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200433
        • Changhai Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Histologically confirmed pancreatic ductal adenocarcinoma with unequivocal first progression after surgery followed by chemotherapy
  2. Without any immunotherapy or targeted therapy
  3. A life expectancy of >3months
  4. ECOG of 0 to1
  5. Age of 18 years or older
  6. Analysis of surgical specimens showed KRAS mutations and positive immunohistochemical staining of PD-L1
  7. 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
  8. 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)
  9. INR < 2 (0.9-1.1)
  10. Ability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Prior immunotherapy or targeted therapy
  2. Evidences of metastatic disease confirmed by chest CT or FDG PET-CT
  3. Contraindication to receiving immunotherapy, targeted therapy or SBRT
  4. ECOG ≥2
  5. Age <18 years
  6. Analysis of surgical specimens showed KRAS wild type or negative immunohistochemical staining of PD-L1
  7. Secondary malignancy
  8. Abnormal results of blood routine examinations and liver and kidney and coagulation tests
  9. Patients with active inflammatory bowel diseases or peptic ulcer
  10. Gastrointestinal bleeding or perforation within 6 months
  11. Heart failure: NYHA III-IV
  12. Respiratory insufficiency
  13. Women who are pregnant
  14. Participation in another clinical treatment trial while on study
  15. Patients in whom fiducial implantation was not possible
  16. Inability of the research subject or authorized legal representative to understand and the willingness to sign a written informed consent document.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The Median Survival Time Will be Determined.
Time Frame: 3 years
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.
Time Frame: 2 year
The number of patients alive at 1 year and 2 years.
2 year
Treatment-related Adverse Effects Will be Determined.
Time Frame: 3 years
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.
Time Frame: 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.
3 years
One- and Two-year Progression Survival Rate Will be Determined. Will be Determined.
Time Frame: 2 years
The proportion of patients without disease progressions at 1 year and 2 years.
2 years
The Quality of Life Will be Analyzed.
Time Frame: 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.
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Changhai Hospital

Investigators

  • Principal Investigator: Huo Jun Zhang, MD., PH.D, Changhai Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2016

Primary Completion (Actual)

December 1, 2020

Study Completion (Actual)

December 1, 2020

Study Registration Dates

First Submitted

March 1, 2016

First Submitted That Met QC Criteria

March 8, 2016

First Posted (Estimate)

March 9, 2016

Study Record Updates

Last Update Posted (Actual)

May 13, 2022

Last Update Submitted That Met QC Criteria

February 28, 2022

Last Verified

February 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ChanghaiHosp

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Pancreatic Cancer

Clinical Trials on Cyberknife plus Pembrolizumab and Trametinib

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Moldova

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe